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Much has changed in our understanding of psoriasis over the past decade, which is having a major effect on its treatment.
Although topical corticosteroids and phototherapy remain mainstays of treatment, a variety of biologic agents have given new hope to those with the most severe forms of the disease. We are also beginning to understand that patients with psoriasis are at greater risk of cardiovascular disease, though the exact nature of that risk and how we should respond remains unclear. Finally, genome-wide association studies are just beginning to unravel the genetic basis of psoriasis.
In this paper, we review the epidemiology and impact of psoriasis, current views of its pathogenesis, its varied clinical forms, and its treatment.
PSORIASIS IMPOSES A GREAT BURDEN
Psoriasis is common, with a reported prevalence ranging from approximately 2%1 to 4.7%.2 It can manifest at any age, but it is most common in two age groups, ie, 20 to 30 years and 50 to 60 years.
For the patient, the burden is great, affecting physical, psychological, and occupational well-being. In fact, patients with psoriasis report quality-of-life impairment equal to or worse than that in patients with cancer or heart disease.3,4 Notably, functional disability secondary to psoriatic arthritis has been reported in up to 19% of psoriatic arthritis patients, and this negatively affects quality of life.5
In 2004, the annual direct medical costs of psoriasis in the United States were estimated to exceed $1 billion. Its indirect costs, measured as missed days and loss of productivity at work, are estimated to exceed the direct costs by $15 billion annually.6,7
Linked to cardiovascular and other diseases
Studies in the past 10 years have uncovered a link between psoriasis, metabolic syndrome, and cardiovascular disease.8–13 Specifically, patients with severe psoriasis are at higher risk of myocardial infarction and cardiovascular death than control patients. Interestingly, the risk decreases with age; patients at greatest risk are young men with severe psoriasis.8–10
In a large cohort study in the United Kingdom7 comparing patients with and without psoriasis, the hazard ratio for cardiovascular death in patients with severe psoriasis was 1.57 (95% confidence interval 1.26–1.96). This translated to 3.5 excess deaths per 1,000 patient-years. These patients were also at higher risk of death from malignancies, chronic lower respiratory disease, diabetes, dementia, infection, kidney disease, and unknown causes.
How much of the risk is due to psoriasis itself, its treatments, associated behaviors, or other factors requires more study. However, some evidence points to the dysregulation of the immune system, notably chronic elevation of pro-inflammatory cytokines.
Psoriasis and its comorbid conditions are thought to arise from chronically elevated levels of cytokines such as tumor necrosis factor alpha (TNF-alpha), interleukin 1 beta (IL-1 beta), and IL-17. These cytokines impair insulin signaling, deregulate lipid metabolism, and increase atherosclerotic changes in the coronary, cerebral, and peripheral arteries. In addition, several other diseases that involve the immune system occur more frequently with psoriasis, including Crohn disease, ulcerative colitis, lymphoma, obesity, and type 2 diabetes.1,8,14–18
In view of the prevalence of these comorbid conditions and the risks they pose, primary care physicians should consider screening patients with severe psoriasis for metabolic disorders and cardiovascular risk factors and promptly begin preventive therapies.19 Unfortunately, to date, there are no consensus guidelines as to the appropriate screening tests or secondary cardiovascular preventive measures for patients with severe psoriasis.
A VICIOUS CIRCLE OF INFLAMMATION AND KERATINOCYTE PROLIFERATION
The hallmark of plaque psoriasis is chronic inflammation in the skin, leading to keratinocyte proliferation.
External and internal triggers that have been identified include cutaneous injury (eg, sunburn, drug rash, viral exanthems), infections (eg, streptococcal), hypocalcemia, pregnancy, psychogenic stress, drugs (eg, lithium, interferon, beta-blockers, and antimalarials), alcohol, smoking, and obesity.20–23
As reviewed by Nestle et al,24 the initiation of lesion formation is still poorly understood but is thought to occur when a trigger (physical trauma, bacterial product, cellular stress) causes DNA to be released from keratinocytes. DNA forms a complex with the antimicrobial protein LL-37 and activates plasmacytoid dendritic cells (PDCs) via toll-like receptor 9. Activated PDCs release type I interferons, which in turn activate myeloid dendritic cells. Myeloid dendritic cells release IL-20 locally, which speeds keratinocyte proliferation.
A subset of myeloid dendritic cells leaves the dermis and migrates to local lymph nodes, where they release IL-23 and activate naive T cells. T helper 1 (Th1) and Th17 cells are recruited to the lesions and begin producing numerous cytokines, including interferon gamma, IL-17, and IL-22. This cytokine milieu increases keratinocyte proliferation and causes the keratinocytes to secrete antimicrobial proteins (LL-37, beta defensins), chemokines, and S100 proteins. These soluble factors have three main functions: stimulation of dendritic cells to release more IL-23, recruitment of neutrophils to the epidermis, and activation of dermal fibroblasts.
This cycle of keratinocytes activating dendritic cells, dendritic cells activating T cells, and T cells activating keratinocytes appears to be the main force maintaining the disease.24 It is unclear, however, whether this applies to all forms of psoriasis or only to plaque psoriasis.
Genetic factors discovered
In recent years, genome-wide association studies have identified at least 10 psoriasis-susceptibility loci that involve functioning of the immune system.25 These genes include those of the major histocompatibility complex, cytokines, receptors, and beta-defensins.
Of specific interest, polymorphisms in the IL-12/IL-13 receptor, the p40 subunit of IL-12 and IL-23, and the p19 subunit of IL-23 strongly associate with psoriasis, supporting their critical role in the disease process and providing targets for medical therapy.26
PSORIASIS HAS SEVERAL CLINICAL PHENOTYPES
Psoriasis has several clinical variants, each with a distinct clinical course and response to treatment.27 Moreover, many patients present with more than one variant.
Plaque psoriasis
Figure 1. Well-demarcated erythematous, scaly plaques characteristic of plaque psoriasis on the elbow.Plaque psoriasis(Figure 1)accounts for more than 80% of cases. It is characterized by well-demarcated, scaly, pink-to-red plaques of various sizes with a relatively symmetric distribution. Involvement of the extensor surfaces such as the elbows and knees and of the scalp, trunk, and intergluteal cleft is common.
Plaques can persist for several months to years, even in the same location, and only about 5% of patients report complete remission for up to 5 years.
Inverse psoriasis
Photo courtesy of Joseph C. English III, MD.
Figure 2. Patient with inverse psoriasis of the axilla.Involvement of the skin folds, including the axillary, genital, perineal, intergluteal, and inframammary regions with pink-to-red plaques with minimal scale is the main clinical feature of inverse psoriasis (Figure 2). Absence of satellite pustules clinically distinguishes it from candidiasis.
Guttate psoriasis
Photo courtesy of Laura K. Ferris, MD, PhD.
Figure 3. Guttate psoriasis with characteristic erythematous, scaly papules and small plaques on the back.Guttate psoriasis (named for its droplet-shaped lesions) presents abruptly with 1-mm to 10-mm pink papules with associated fine scale over the trunk and extremities (Figure 3). This variant occurs in fewer than 2% of patients with psoriasis, who are usually younger than 30 years. It is often preceded 2 to 3 weeks earlier by an upper respiratory tract infection with group A beta-hemolytic streptococci.
Erythrodermic psoriasis
Approximately 1% to 2.25% of all patients with psoriasis develop this severe form, affecting more than 75% of the body surface area. It presents as generalized erythema, which is the most prominent feature, and it is often associated with superficial desquamation, hair loss, nail dystrophy, and systemic symptoms such as fever, chills, malaise, or high-output cardiac failure. There may be a history of preceding characteristic psoriatic plaques, recent withdrawal of treatment (usually corticosteroids), phototoxicity, or infection.
Conversely, approximately 25% of all patients with erythroderma have underlying psoriasis.28
Pustular psoriasis
Photo courtesy of Joseph C. English III, MD.
Figure 4. Erythematous plaques studded with pustules and red-brown macules on the acral surface of the foot in palmoplantar pustulosis.Pustular psoriasis (Figure 4)is uncommon. The predominant lesions are large collections of neutrophils in the stratum corneum that clinically present as sterile pustules. The pustules may be localized within or at the edge of existing psoriatic plaques or may present as a generalized eruption.
There are several forms of pustular psoriasis, including generalized pustular psoriasis, annular pustular psoriasis, impetigo herpetiformis (pustular psoriasis of pregnancy), and palmoplantar pustulosis. However, there is some evidence to suggest that palmoplantar pustulosis may be distinct from psoriasis.29
Several triggers have been identified, including pregnancy, rapid tapering of medications, hypocalcemia, infection, or topical irritants.
Generalized pustular psoriasis, annular pustular psoriasis, and impetigo herpetiformis often present in association with fever and other systemic symptoms and, if left untreated, can result in life-threatening complications including bacterial superinfection, sepsis, dehydration, and, in rare cases, acute respiratory distress secondary to aseptic pneumonitis.30
Placental insufficiency resulting in stillbirth or neonatal death and other fetal abnormalities can occur in severe pustular psoriasis of pregnancy.31
Psoriatic arthritis
Psoriatic arthritis is a seronegative inflammatory spondyloarthropathy that can result in erosive arthritis in up to 57% of cases and functional disability in up to 19%.32 Although rare in the general population, it affects approximately 6% to 10% of psoriasis patients and up to 40% of patients with severe psoriasis.33 In 70% of cases, psoriasis precedes the onset of arthritis by about 10 years, and approximately 10% to 15% of patients simultaneously present with psoriasis and arthritis or develop arthritis before skin involvement.5,34
Patients complain of joint discomfort that is most prominent after periods of prolonged rest. Patterns of involvement are extremely variable but have been reported as an asymmetric oligoarthritis (involving four or fewer joints) or polyarthritis (involving more than four joints) in most patients. A rheumatoid arthritis-like presentation with a symmetric polyarthropathy involving the small and medium-sized joints has also been reported, making it difficult to clinically distinguish this from rheumatoid arthritis.
A distal interphalangeal-predominant pattern is reported in 5% to 10% of patients. Axial disease resembling ankylosing spondylitis occurs only in 5% of patients. Arthritis mutilans, characterized by severe, rapidly progressive joint inflammation, joint destruction, and deformity, occurs rarely. Enthesitis, ie, inflammation at the point of attachment of tendons or ligaments to bone, is present in up to 42% of patients.5,35
Nail disease
Photo courtesy of Joseph C. English III, MD.
Figure 5. Nail pitting and onycholysis with surrounding psoriatic plaques along the perionychium and proximal nail fold.Nail psoriasis occurs in 35% to 50% of patients and can be seen with all forms of psoriasis.1 Involvement of the nail matrix can result in nail pitting and leukonychia. Oil spots, subungual hyperkeratosis, and distal onycholysis are the result of disease involvement of the nail bed (Figure 5). Up to 90% of patients with psoriatic arthritis have nail changes, especially patients with enthesitis.36
Disease severity also varies
Disease severity also differs among patients. An estimated 80% of patients have mild to moderate disease and 20% have moderate to severe disease, which includes disease involving more than 5% of the body surface or involvement of the face, hands, feet, or genitalia.1
The Psoriasis Area and Severity Index (PASI) is an objective measure used in clinical trials. It incorporates the amount of redness, scaling, and induration of each psoriatic lesion over the body surface involved. A 75% improvement in the PASI score (PASI-75) is regarded as clinically significant.37
PSORIASIS IS DIAGNOSED CLINICALLY
In most cases, the diagnosis of psoriasis is made clinically and is straightforward. However, in more difficult cases, biopsy may be needed. In particular:
The plaques of psoriasis may be confused with squamous cell carcinoma in situ, dermatophyte infection, or cutaneous T-cell lymphoma, especially if they are treatment-resistant.
Guttate psoriasis may be difficult to distinguish from pityriasis rosea.
Erythrodermic psoriasis must be distinguished from other causes of erythroderma, including Sézary syndrome, pityriasis rubra pilaris, and drug reactions.
Intertrigo, candidiasis, extramammary Paget disease, squamous cell carcinoma, and contact dermatitis all may mimic inverse psoriasis.
Palmoplantar pustulosis may be difficult to differentiate from dyshidrotic eczema.
Generalized pustular psoriasis should be distinguished from a pustular drug eruption (acute generalized exanthematous pustular drug eruption or acute generalized exanthematous pustulosis), impetigo, candidiasis, or an autoimmune blistering disorder such as pemphigus.
TREATMENT OF LIMITED DISEASE
Topical corticosteroids
A topical corticosteroid, either by itself or combined with a steroid-sparing agent, is the first-line therapy for patients with limited disease. The potency required for treatment should be based on the extent of disease and on the location, the choice of vehicle, and the patient’s preference and age.
Several double-blind studies have assessed the efficacy of various topical corticosteroids in treating psoriasis. In general, super-potent (class I) and potent (class II) topical corticosteroids are more efficacious than mild or moderate corticosteroids.38 Class I and class II steroids include agents such as clobetasol propionate 0.05% (Temovate), betamethasone dipropionate 0.05% (Diprolene), fluocinonide 0.05% (Lidex), and desoximetasone 0.25% (Topicort).
Use of class I steroids should be limited to an initial treatment course of twice-daily application for 2 to 4 weeks in an effort to avoid some of the local toxicities such as skin atrophy, telangiectasia, and striae. Decreasing class I topical steroid use to 1 to 2 times per week with the gradual introduction of a steroid-sparing agent following the initial 2 to 4 weeks of treatment is advised.
Steroid-sparing agents
Steroid-sparing agents include vitamin D analogues, retinoids, and tacrolimus ointment (Protopic).
Vitamin D analogues and retinoids are thought to decrease keratinocyte proliferation and enhance keratinocyte differentiation.39 The vitamin D analogues are also considered first-line topical agents and include calcipotriol (Dovonex), calcipotriene (Dovonex), and calcitriol (Vectical). To prevent hypercalcemia, use of more than 100 g of vitamin D analogues per week should be avoided.39
Treatment of inverse psoriasis and scalp psoriasis may be challenging
The areas affected in inverse psoriasis, such as the genitalia and axillae, are more prone to side effects when potent topical steroids are used because of increased absorption and occlusion in these areas. Agents that minimize irritation and toxicity in sensitive areas, such as topical tacrolimus, less-potent topical steroids, or calcitriol, can be used.39
For scalp psoriasis, alternative vehicles such as shampoos, gels, solutions, oils, sprays, and foams have improved patient compliance and efficacy of treatment.40
PHOTOTHERAPY FOR SEVERE DISEASE
Narrow-band ultraviolet B
Narrow-band ultraviolet B, ie, light confined to wavelengths of 311 to 313 nm, is a first-line treatment for moderate to severe psoriasis, either as monotherapy or in combination with other treatments. It is an especially attractive option in patients who are on medications or who have comorbidities that may preclude treatment with other systemic agents.
The mechanism of action may be via immunosuppressive effects on Langerhans cells, alteration of cytokines and adhesion molecules that lead to an increase in Th2 cells, and induction of apoptosis of T lymphocytes. Additionally, ultraviolet light affects the proliferation and differentiation of keratinocytes.41
Dosing is based on skin type, and treatment usually involves two or three visits per week for a total of 15 to 20 treatments, with additional therapy for maintenance. Adding acitretin (Soriatane), with close monitoring of aspartate aminotransferase and alanine aminotransferase levels and the patient’s lipid panel, can be considered in treatment-resistant cases.42
Psoralen combined with ultraviolet A
Psoralen combined with ultraviolet A is another option. It can be considered if narrow-band ultraviolet B treatment fails. It is also useful for dark-skinned patients and those with thicker plaques because ultraviolet A penetrates deeper than ultraviolet B. Oral or topical treatment with psoralen is followed by ultraviolet A treatment.
The duration of remission is much longer with psoralen plus ultraviolet A than with narrow-band ultraviolet B. However, this treatment caries a significant risk of cutaneous squamous cell carcinoma and melanoma, especially in light-skinned people and those who receive high doses of ultraviolet A (200 or more treatments) or cyclosporine.40,41,43–46 Long-term effects include photoaging, lentigines, and telangiectasias. As a consequence of these well-established side effects, this treatment is used less frequently.
Cautions with phototherapy
Careful screening and caution should be used in patients who have:
Fair skin that tends to burn easily
A history of arsenic intake or treatment with ionizing radiation
A history of use of photosensitizing medications (fluoroquinolone antibiotics, doxycycline, hydrochlorothiazide)
A history of melanoma or atypical nevi
Multiple risk factors for melanoma
A history of nonmelanoma skin cancer
Immunosuppression due to organ transplantation.
ORAL THERAPIES FOR SEVERE PSORIASIS
Patients who have severe psoriasis—ie, affecting more than 5% of the body surface or debilitating disease affecting the palms, soles, or genitalia—are best managed with systemic medications, especially if they do not have access to phototherapy.20
Methotrexate
In 1972, the US Food and Drug Administration (FDA) approved methotrexate for treating severe psoriasis.42 In studies of methotrexate at doses of 15 to 20 mg weekly, 36% to 68% of patients with severe plaque psoriasis achieved a PASI-75 score.40,42,47
Dosages of methotrexate for treating severe psoriasis range from 7.5 to 25 mg once a week. Patients should also receive a folate supplement of 1 to 5 mg every day except the day they take methotrexate. The folate is to protect against gastrointestinal side effects, bone marrow suppression, and hepatic toxicity associated with methotrexate.
Other side effects of methotrexate include pulmonary fibrosis and stomatitis. Pregnancy, nursing, alcoholism, chronic liver disease, immunodeficiency syndromes, bone-marrow hypoplasia, leukopenia, thrombocytopenia, anemia, and hypersensitivity to methotrexate are all contraindications to methotrexate use.
The National Psoriasis Foundation, in its 2009 guidelines for the use of methotrexate in treating psoriasis,48 recommends obtaining a complete blood cell count with platelets, blood urea nitrogen, creatinine, and liver function tests at baseline and at 1- to 3-month intervals thereafter.
Liver biopsies were previously recommended for patients receiving methotrexate long-term when the cumulative dose of therapy reached 1.5 g. However, given the invasive nature of the liver biopsy procedure and the low incidence of methotrexate-induced hepatotoxicity, this recommendation has been revised.
For patients with no significant risk factors for hepatic toxicity (eg, obesity, diabetes, hyperlipidemia, hepatitis, or history of or current alcohol consumption) and normal liver function tests, liver biopsy should be considered when a cumulative methotrexate dose of 3.5 to 4.0 g is reached. Alternatively, one may choose to continue to monitor the patient without liver biopsy or to switch to another medication, if possible.42,48
Patients at high risk should be monitored more carefully, and liver biopsy should be considered soon after starting methotrexate and repeated after every 1.0 to 1.5 g.48
No reliable noninvasive measures to evaluate for liver fibrosis are routinely available in the United States. Serial measurements of serum type III procollagen aminopeptide have been reported to correlate with the risk of developing liver fibrosis; however, this test is readily available only in Europe.49
Cyclosporine
Cyclosporine (Gengraf, Neoral, Sandimmune) is very effective for treating psoriasis, especially erythrodermic psoriasis. It is often used only short-term or as a bridge to other maintenance therapies because it has a rapid onset and because long-term therapy (3 to 5 years) is associated with a risk of glomerulosclerosis.50
Cyclosporine works by decreasing T-cell activation by binding cyclophilin, which leads to inhibition of transcription of calcineurin and nuclear factor of activated T cells.51 Given at doses of 2.5 to 5 mg/kg/day, cyclosporine has been shown to result in rapid improvement in up to 80% to 90% of psoriatic patients.52,53
The initial recommended dose of cyclosporine is usually 2.5 to 3 mg/kg/day in two divided doses, which is maintained for 4 weeks and then increased by 0.5 mg/kg/day until the disease is stable.42
Nephrotoxicity and hypertension are cyclosporine’s most serious side effects. Blood urea nitrogen, creatinine, and blood pressure should be monitored at baseline and then twice a month for the first 3 months and once monthly thereafter. Liver function tests, complete blood cell count, lipid profile, magnesium, uric acid, and potassium should also be checked every month.
Cyclosporine also increases the risk of cutaneous squamous cell carcinoma, especially in patients who have received psoralen plus ultraviolet A treatment.42
Patients with hypersensitivity to cyclosporine, a history of chronic infection (eg, tuberculosis, hepatitis B, hepatitis C), renal insufficiency, or a history of systemic malignancy should not receive cyclosporine.
Acitretin
Acitretin, an oral retinoid, has been used for several years to treat psoriasis. Its onset is slow, typically ranging from 3 to 6 months, and its effects are dose-dependent. It is most effective as a maintenance therapy, usually after the disease has been stabilized by agents such as cyclosporine, or in combination with other treatments such as phototherapy.42 Acitretin has been shown to be effective in patients with pustular psoriasis.54
Acitretin does not alter the immune system and has not been shown to have significant cumulative toxicities. Serum triglycerides are monitored closely, since acitretin can lead to hypertriglyceridemia.
All retinoids, including acitretin, are in pregnancy category X and should therefore be avoided during pregnancy. Although its half-life is only 49 hours, acitretin may be transformed to etretinate either spontaneously or as a result of alcohol ingestion. Etretinate has a half-life of 168 days and can take up to 3 years to be eliminated from the body. Therefore, acitretin is contraindicated in women who plan to become pregnant or who do not agree to use adequate contraception for 3 years after the drug is discontinued.42
Biologic agents
Advances in our understanding of the pathogenesis of psoriasis have resulted in more specific, targeted therapy.
Alefacept (Amevive) is a human Fc IgG1 receptor fused to the alpha subunit of LFA3. It binds to CD2, blocks costimulatory signaling, and induces apoptosis in activated memory T cells.
Alefacept was the first biologic agent approved by the FDA for the treatment of psoriasis and one of the few biologic agents to induce long-term remission.55 However, its use has declined because few patients achieved significant clearance of their psoriasis and its onset of action was much slower than that of other medications.56
The currently approved biologic therapies commonly used for moderate to severe psoriasis include the TNF-alpha inhibitors and ustekinumab (Stelara).
The TNF-alpha inhibitors include infliximab (Remicade), etanercept (Enbrel), and adalimumab (Humira). They are generally well tolerated and highly effective. However, TNF-alpha inhibitors and other biologic agents are contraindicated in patients with serious infection, a personal history or a family history in a first-degree relative of demyelinating disease, or class III or IV congestive heart failure. Patients should be screened for active infection, including tuberculosis and hepatitis B, since reactivation has been reported following initiation of TNF-alpha inhibitors.1
Adalimumab is a human monoclonal antibody against TNF-alpha. It binds to soluble and membrane-bound TNF-alpha and prevents it from binding to p55 and p75 cell-surface TNF receptors.
The dosing schedule for adalimumab is 80 mg subcutaneously for the first week, followed by 40 mg subcutaneously the next week, and then 40 mg subcutaneously every 2 weeks thereafter.1
Etanercept is a recombinant human TNF-alpha receptor (p75) protein fused with the Fc portion of IgG1, which binds to soluble TNF-alpha.57 Dosing for etanercept is 50 mg subcutaneously twice weekly for the first 12 weeks, followed by 50 mg weekly thereafter.
Infliximab is a chimeric antibody composed of a human IgG1 constant region fused to a mouse variable region that binds to both soluble and membrane-bound TNF-alpha.58 Infliximab is given as an infusion at a dose of 5 mg/kg over 2 to 3 hours at weeks 0, 2, and 6, and then every 8 weeks thereafter.
Efficacy of TNF inhibitors. There are no specific guidelines for the sequence of initiation of TNF inhibitors because no studies have directly compared the efficacy of these medications. However, response to infliximab is relatively rapid compared with adalimumab and etanercept.
In a phase III clinical trial,59 as many as 80% of patients achieved PASI-75 clearance of their psoriasis after three doses of infliximab. Interestingly, only 61% of patients maintained PASI-75 clearance by week 50. This loss of efficacy of infliximab is also reported with other TNF-alpha inhibitors and is thought to be secondary to the development of antibodies to the drugs. For infliximab, this loss of efficacy is less when infliximab is given continuously rather than on an as-needed basis. Simultaneous treatment with methotrexate is also thought to decrease the development of antibodies to infliximab.60
Ustekinumab is an monoclonal antibody directed against the common p40 subunit of IL-12 and IL-23, which have been shown to be at increased levels in psoriatic lesions and important for the pathogenesis of psoriasis.
Between 66% and 76% of patients treated with ustekinumab achieved significant clearance of their disease after 12 weeks of treatment in two large phase III multicenter, randomized, double-blind, placebo-controlled trials.61,62
Dosing of ustekinumab is weight-based. For those weighing less than 100 kg, ustekinumab is given at 45 mg subcutaneously at baseline, at 4 weeks, and every 12 weeks thereafter. The same dosing schedule is used for those weighing more than 100 kg, but the dose is increased to 90 mg.
Guidelines for monitoring patients while on ustekinumab are similar to those for other biologic agents. Information on long-term toxicities is still being collected. However, injection-site reactions, serious infections, malignancies, and a single case of reversible posterior leukoencephalopathy have been reported.20
While biologic agents are significantly more expensive than the conventional therapies discussed above and insurance coverage for these agents varies, they have demonstrated superior efficacy and may be indicated for patients with recalcitrant moderate to severe psoriasis for whom multiple types of treatment have failed.
FOR PSORIATIC ARTHRITIS: SYSTEMIC MEDICATIONS
For patients with known or questionable psoriatic arthritis, evaluation by a rheumatologist is highly recommended.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are usually first-line in the treatment of mild psoriatic arthritis. If after 2 to 3 months of therapy with NSAIDs no benefit is achieved, treatment with methotrexate as monotherapy is a practical consideration because of its low cost. However, methotrexate as a monotherapy has not been shown to prevent radiologic progression of disease.5,32
The TNF-alpha inhibitors have been shown to have similar efficacy when compared among each other in the treatment of psoriatic arthritis.32,63 Based on radiologic evidence, ustekinumab has not shown to be as efficacious as the TNF-alpha inhibitors for treating psoriatic arthritis. Therefore, TNF inhibitors should be considered first-line in the treatment of psoriatic arthritis.21,64
Few studies have been done on the efficacy or sequence of therapies that should be used in the treatment of psoriatic arthritis. The American Academy of Dermatology’s Psoriasis Guidelines of Care recommend adding a TNF-alpha inhibitor or switching to a TNF-alpha inhibitor if no significant improvement is achieved after 12 to 16 weeks of treatment with oral methotrexate.20
FOR ERYTHRODERMIC PSORIASIS: MEDICATIONS THAT ACT PROMPTLY
The care of erythrodermic psoriatic patients is distinct from that of other psoriatic patients because of their associated systemic symptoms. Care should be taken to rule out sepsis, as this is a reported trigger of erythrodermic psoriasis.28
Systemic medications with a quick onset, such as oral cyclosporine, are recommended. Infliximab has also been reported to be beneficial because of its rapid onset.28
TREATMENT BASED ON THE TYPE AND THE SEVERITY OF PSORIASIS
The treatment of psoriasis can be as complex as the disease it itself and should be based on the type and the severity of psoriasis. Recognition of the various manifestations of psoriasis is important for effective treatment. However, in patients with moderate to severe psoriasis, atypical presentations, or recalcitrant disease, referral to a specialist is recommended.
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Nair RP, Duffin KC, Helms C, et al; Collaborative Association Study of Psoriasis. Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways. Nat Genet2009; 41:199–204.
Griffiths CE, Christophers E, Barker JN, et al. A classification of psoriasis vulgaris according to phenotype. Br J Dermatol2007; 156:258–262.
Rosenbach M, Hsu S, Korman NJ, et al; National Psoriasis Foundation Medical Board. Treatment of erythrodermic psoriasis: from the medical board of the National Psoriasis Foundation. J Am Acad Dermatol2010; 62:655–662.
Mrowietz U, van de Kerkhof PC. Management of palmoplantar pustulosis: do we need to change?Br J Dermatol2011; 164:942–946.
Kluger N, Bessis D, Guillot B, Girard C. Acute respiratory distress syndrome complicating generalized pustular psoriasis (psoriasis-associated aseptic pneumonitis). J Am Acad Dermatol2011; 64:1154–1158.
Roth MM. Pregnancy dermatoses: diagnosis, management, and controversies. Am J Clin Dermatol2011; 12:25–41.
Gottlieb A, Korman NJ, Gordon KB, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: section 2. Psoriatic arthritis: overview and guidelines of care for treatment with an emphasis on the biologics. J Am Acad Dermatol2008; 58:851–864.
Ogdie A, Gelfand JM. Identification of risk factors for psoriatic arthritis: scientific opportunity meets clinical need. Arch Dermatol2010; 146:785–788.
Gelfand JM, Gladman DD, Mease PJ, et al. Epidemiology of psoriatic arthritis in the population of the United States. J Am Acad Dermatol2005; 53:573.
Moll JM, Wright V. Psoriatic arthritis. Semin Arthritis Rheum1973; 3:55–78.
McGonagle D. Enthesitis: an autoinflammatory lesion linking nail and joint involvement in psoriatic disease. J Eur Acad Dermatol Venereol2009; 23(suppl 1):9–13.
Feldman SR, Krueger GG. Psoriasis assessment tools in clinical trials. Ann Rheum Dis2005; 64(suppl 2):ii65–ii68.
Mason J, Mason AR, Cork MJ. Topical preparations for the treatment of psoriasis: a systematic review. Br J Dermatol2002; 146:351–364.
Menter A, Korman NJ, Elmets CA, et al; American Academy of Dermatology. Guidelines of care for the management of psoriasis and psoriatic arthritis. Section 3. Guidelines of care for the management and treatment of psoriasis with topical therapies. J Am Acad Dermatol2009; 60:643–659.
Zivkovich AH, Feldman SR. Are ointments better than other vehicles for corticosteroid treatment of psoriasis?J Drugs Dermatol2009; 8:570–572.
Menter A, Korman NJ, Elmets CA, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: section 5. Guidelines of care for the treatment of psoriasis with phototherapy and photochemotherapy. J Am Acad Dermatol2010; 62:114–135.
Menter A, Korman NJ, Elmets CA, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: section 4. Guidelines of care for the management and treatment of psoriasis with traditional systemic agents. J Am Acad Dermatol2009; 61:451–485.
Murase JE, Lee EE, Koo J. Effect of ethnicity on the risk of developing nonmelanoma skin cancer following long-term PUVA therapy. Int J Dermatol2005; 44:1016–1021.
Stern RS, Lunder EJ. Risk of squamous cell carcinoma and methoxsalen (psoralen) and UV-A radiation (PUVA). A meta-analysis. Arch Dermatol1998; 134:1582–1585.
Stern RS, Väkevä LH. Noncutaneous malignant tumors in the PUVA follow-up study: 1975–1996. J Invest Dermatol1997; 108:897–900.
Patel RV, Clark LN, Lebwohl M, Weinberg JM. Treatments for psoriasis and the risk of malignancy. J Am Acad Dermatol2009; 60:1001–1017.
Flytström I, Stenberg B, Svensson A, Bergbrant IM. Methotrexate vs. ciclosporin in psoriasis: effectiveness, quality of life and safety. A randomized controlled trial. Br J Dermatol2008; 158:116–121.
Kalb RE, Strober B, Weinstein G, Lebwohl M. Methotrexate and psoriasis: 2009 National Psoriasis Foundation Consensus Conference. J Am Acad Dermatol2009; 60:824–837.
Zachariae H, Heickendorff L, Søgaard H. The value of aminoterminal propeptide of type III procollagen in routine screening for methotrexate-induced liver fibrosis: a 10-year follow-up. Br J Dermatol2001; 144:100–103.
Lowe NJ, Wieder JM, Rosenbach A, et al. Long-term low-dose cyclosporine therapy for severe psoriasis: effects on renal function and structure. J Am Acad Dermatol1996; 35:710–719.
Gottlieb AB, Grossman RM, Khandke L, et al. Studies of the effect of cyclosporine in psoriasis in vivo: combined effects on activated T lymphocytes and epidermal regenerative maturation. J Invest Dermatol1992; 98:302–309.
Ellis CN, Fradin MS, Messana JM, et al. Cyclosporine for plaque-type psoriasis. Results of a multidose, double-blind trial. N Engl J Med1991; 324:277–284.
Faerber L, Braeutigam M, Weidinger G, et al. Cyclosporine in severe psoriasis. Results of a meta-analysis in 579 patients. Am J Clin Dermatol2001; 2:41–47.
Ozawa A, Ohkido M, Haruki Y, et al. Treatments of generalized pustular psoriasis: a multicenter study in Japan. J Dermatol1999; 26:141–149.
Krueger GG, Ellis CN. Alefacept therapy produces remission for patients with chronic plaque psoriasis. Br J Dermatol2003; 148:784–788.
Lebwohl M, Christophers E, Langley R, Ortonne JP, Roberts J, Griffiths CE; Alefacept Clinical Study Group. An international, randomized, double-blind, placebo-controlled phase 3 trial of intramuscular alefacept in patients with chronic plaque psoriasis. Arch Dermatol2003; 139:719–727.
Gottlieb AB, Matheson RT, Lowe N, et al. A randomized trial of etanercept as monotherapy for psoriasis. Arch Dermatol2003; 139:1627–1632.
Gottlieb AB, Masud S, Ramamurthi R, et al. Pharmacodynamic and pharmacokinetic response to anti-tumor necrosis factor-alpha monoclonal antibody (infliximab) treatment of moderate to severe psoriasis vulgaris. J Am Acad Dermatol2003; 48:68–75.
Reich K, Nestle FO, Papp K, et al; EXPRESS study investigators. Infliximab induction and maintenance therapy for moderate-to-severe psoriasis: a phase III, multicentre, double-blind trial. Lancet2005; 366:1367–1374.
Menter A, Feldman SR, Weinstein GD, et al. A randomized comparison of continuous vs. intermittent infliximab maintenance regimens over 1 year in the treatment of moderate-to-severe plaque psoriasis. J Am Acad Dermatol2007; 56:31.e1–31.e15.
Papp KA, Langley RG, Lebwohl M, et al; PHOENIX 2 study investigators. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2). Lancet2008; 371:1675–1684.
Leonardi CL, Kimball AB, Papp KA, et al; PHOENIX 1 study investigators. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1). Lancet2008; 371:1665–1674.
Griffiths CE, Strober BE, van de Kerkhof P, et al; ACCEPT Study Group. Comparison of ustekinumab and etanercept for moderate-to-severe psoriasis. N Engl J Med2010; 362:118–128.
Gottlieb A, Menter A, Mendelsohn A, et al. Ustekinumab, a human interleukin 12/23 monoclonal antibody, for psoriatic arthritis: randomised, double-blind, placebo-controlled, crossover trial. Lancet. 2009; 373:633–640.
Jennifer Villaseñor-Park, MD, PhD University of Pittsburgh, Department of Dermatology, Pittsburgh, PA
David Wheeler, BS University of Pittsburgh School of Medicine, Pittsburgh, PA
Lisa Grandinetti, MD, FAAD University of Pittsburgh, Department of Dermatology, Pittsburgh, PA
Address: Lisa M. Grandinetti, MD, FAAD, Department of Dermatology, University of Pittsburgh, Presby South Tower Suite 3880, 200 Lothrop Street, Pittsburgh, PA 15213; e-mail grandinettilm@upmc.edu
Jennifer Villaseñor-Park, MD, PhD University of Pittsburgh, Department of Dermatology, Pittsburgh, PA
David Wheeler, BS University of Pittsburgh School of Medicine, Pittsburgh, PA
Lisa Grandinetti, MD, FAAD University of Pittsburgh, Department of Dermatology, Pittsburgh, PA
Address: Lisa M. Grandinetti, MD, FAAD, Department of Dermatology, University of Pittsburgh, Presby South Tower Suite 3880, 200 Lothrop Street, Pittsburgh, PA 15213; e-mail grandinettilm@upmc.edu
Author and Disclosure Information
Jennifer Villaseñor-Park, MD, PhD University of Pittsburgh, Department of Dermatology, Pittsburgh, PA
David Wheeler, BS University of Pittsburgh School of Medicine, Pittsburgh, PA
Lisa Grandinetti, MD, FAAD University of Pittsburgh, Department of Dermatology, Pittsburgh, PA
Address: Lisa M. Grandinetti, MD, FAAD, Department of Dermatology, University of Pittsburgh, Presby South Tower Suite 3880, 200 Lothrop Street, Pittsburgh, PA 15213; e-mail grandinettilm@upmc.edu
Much has changed in our understanding of psoriasis over the past decade, which is having a major effect on its treatment.
Although topical corticosteroids and phototherapy remain mainstays of treatment, a variety of biologic agents have given new hope to those with the most severe forms of the disease. We are also beginning to understand that patients with psoriasis are at greater risk of cardiovascular disease, though the exact nature of that risk and how we should respond remains unclear. Finally, genome-wide association studies are just beginning to unravel the genetic basis of psoriasis.
In this paper, we review the epidemiology and impact of psoriasis, current views of its pathogenesis, its varied clinical forms, and its treatment.
PSORIASIS IMPOSES A GREAT BURDEN
Psoriasis is common, with a reported prevalence ranging from approximately 2%1 to 4.7%.2 It can manifest at any age, but it is most common in two age groups, ie, 20 to 30 years and 50 to 60 years.
For the patient, the burden is great, affecting physical, psychological, and occupational well-being. In fact, patients with psoriasis report quality-of-life impairment equal to or worse than that in patients with cancer or heart disease.3,4 Notably, functional disability secondary to psoriatic arthritis has been reported in up to 19% of psoriatic arthritis patients, and this negatively affects quality of life.5
In 2004, the annual direct medical costs of psoriasis in the United States were estimated to exceed $1 billion. Its indirect costs, measured as missed days and loss of productivity at work, are estimated to exceed the direct costs by $15 billion annually.6,7
Linked to cardiovascular and other diseases
Studies in the past 10 years have uncovered a link between psoriasis, metabolic syndrome, and cardiovascular disease.8–13 Specifically, patients with severe psoriasis are at higher risk of myocardial infarction and cardiovascular death than control patients. Interestingly, the risk decreases with age; patients at greatest risk are young men with severe psoriasis.8–10
In a large cohort study in the United Kingdom7 comparing patients with and without psoriasis, the hazard ratio for cardiovascular death in patients with severe psoriasis was 1.57 (95% confidence interval 1.26–1.96). This translated to 3.5 excess deaths per 1,000 patient-years. These patients were also at higher risk of death from malignancies, chronic lower respiratory disease, diabetes, dementia, infection, kidney disease, and unknown causes.
How much of the risk is due to psoriasis itself, its treatments, associated behaviors, or other factors requires more study. However, some evidence points to the dysregulation of the immune system, notably chronic elevation of pro-inflammatory cytokines.
Psoriasis and its comorbid conditions are thought to arise from chronically elevated levels of cytokines such as tumor necrosis factor alpha (TNF-alpha), interleukin 1 beta (IL-1 beta), and IL-17. These cytokines impair insulin signaling, deregulate lipid metabolism, and increase atherosclerotic changes in the coronary, cerebral, and peripheral arteries. In addition, several other diseases that involve the immune system occur more frequently with psoriasis, including Crohn disease, ulcerative colitis, lymphoma, obesity, and type 2 diabetes.1,8,14–18
In view of the prevalence of these comorbid conditions and the risks they pose, primary care physicians should consider screening patients with severe psoriasis for metabolic disorders and cardiovascular risk factors and promptly begin preventive therapies.19 Unfortunately, to date, there are no consensus guidelines as to the appropriate screening tests or secondary cardiovascular preventive measures for patients with severe psoriasis.
A VICIOUS CIRCLE OF INFLAMMATION AND KERATINOCYTE PROLIFERATION
The hallmark of plaque psoriasis is chronic inflammation in the skin, leading to keratinocyte proliferation.
External and internal triggers that have been identified include cutaneous injury (eg, sunburn, drug rash, viral exanthems), infections (eg, streptococcal), hypocalcemia, pregnancy, psychogenic stress, drugs (eg, lithium, interferon, beta-blockers, and antimalarials), alcohol, smoking, and obesity.20–23
As reviewed by Nestle et al,24 the initiation of lesion formation is still poorly understood but is thought to occur when a trigger (physical trauma, bacterial product, cellular stress) causes DNA to be released from keratinocytes. DNA forms a complex with the antimicrobial protein LL-37 and activates plasmacytoid dendritic cells (PDCs) via toll-like receptor 9. Activated PDCs release type I interferons, which in turn activate myeloid dendritic cells. Myeloid dendritic cells release IL-20 locally, which speeds keratinocyte proliferation.
A subset of myeloid dendritic cells leaves the dermis and migrates to local lymph nodes, where they release IL-23 and activate naive T cells. T helper 1 (Th1) and Th17 cells are recruited to the lesions and begin producing numerous cytokines, including interferon gamma, IL-17, and IL-22. This cytokine milieu increases keratinocyte proliferation and causes the keratinocytes to secrete antimicrobial proteins (LL-37, beta defensins), chemokines, and S100 proteins. These soluble factors have three main functions: stimulation of dendritic cells to release more IL-23, recruitment of neutrophils to the epidermis, and activation of dermal fibroblasts.
This cycle of keratinocytes activating dendritic cells, dendritic cells activating T cells, and T cells activating keratinocytes appears to be the main force maintaining the disease.24 It is unclear, however, whether this applies to all forms of psoriasis or only to plaque psoriasis.
Genetic factors discovered
In recent years, genome-wide association studies have identified at least 10 psoriasis-susceptibility loci that involve functioning of the immune system.25 These genes include those of the major histocompatibility complex, cytokines, receptors, and beta-defensins.
Of specific interest, polymorphisms in the IL-12/IL-13 receptor, the p40 subunit of IL-12 and IL-23, and the p19 subunit of IL-23 strongly associate with psoriasis, supporting their critical role in the disease process and providing targets for medical therapy.26
PSORIASIS HAS SEVERAL CLINICAL PHENOTYPES
Psoriasis has several clinical variants, each with a distinct clinical course and response to treatment.27 Moreover, many patients present with more than one variant.
Plaque psoriasis
Figure 1. Well-demarcated erythematous, scaly plaques characteristic of plaque psoriasis on the elbow.Plaque psoriasis(Figure 1)accounts for more than 80% of cases. It is characterized by well-demarcated, scaly, pink-to-red plaques of various sizes with a relatively symmetric distribution. Involvement of the extensor surfaces such as the elbows and knees and of the scalp, trunk, and intergluteal cleft is common.
Plaques can persist for several months to years, even in the same location, and only about 5% of patients report complete remission for up to 5 years.
Inverse psoriasis
Photo courtesy of Joseph C. English III, MD.
Figure 2. Patient with inverse psoriasis of the axilla.Involvement of the skin folds, including the axillary, genital, perineal, intergluteal, and inframammary regions with pink-to-red plaques with minimal scale is the main clinical feature of inverse psoriasis (Figure 2). Absence of satellite pustules clinically distinguishes it from candidiasis.
Guttate psoriasis
Photo courtesy of Laura K. Ferris, MD, PhD.
Figure 3. Guttate psoriasis with characteristic erythematous, scaly papules and small plaques on the back.Guttate psoriasis (named for its droplet-shaped lesions) presents abruptly with 1-mm to 10-mm pink papules with associated fine scale over the trunk and extremities (Figure 3). This variant occurs in fewer than 2% of patients with psoriasis, who are usually younger than 30 years. It is often preceded 2 to 3 weeks earlier by an upper respiratory tract infection with group A beta-hemolytic streptococci.
Erythrodermic psoriasis
Approximately 1% to 2.25% of all patients with psoriasis develop this severe form, affecting more than 75% of the body surface area. It presents as generalized erythema, which is the most prominent feature, and it is often associated with superficial desquamation, hair loss, nail dystrophy, and systemic symptoms such as fever, chills, malaise, or high-output cardiac failure. There may be a history of preceding characteristic psoriatic plaques, recent withdrawal of treatment (usually corticosteroids), phototoxicity, or infection.
Conversely, approximately 25% of all patients with erythroderma have underlying psoriasis.28
Pustular psoriasis
Photo courtesy of Joseph C. English III, MD.
Figure 4. Erythematous plaques studded with pustules and red-brown macules on the acral surface of the foot in palmoplantar pustulosis.Pustular psoriasis (Figure 4)is uncommon. The predominant lesions are large collections of neutrophils in the stratum corneum that clinically present as sterile pustules. The pustules may be localized within or at the edge of existing psoriatic plaques or may present as a generalized eruption.
There are several forms of pustular psoriasis, including generalized pustular psoriasis, annular pustular psoriasis, impetigo herpetiformis (pustular psoriasis of pregnancy), and palmoplantar pustulosis. However, there is some evidence to suggest that palmoplantar pustulosis may be distinct from psoriasis.29
Several triggers have been identified, including pregnancy, rapid tapering of medications, hypocalcemia, infection, or topical irritants.
Generalized pustular psoriasis, annular pustular psoriasis, and impetigo herpetiformis often present in association with fever and other systemic symptoms and, if left untreated, can result in life-threatening complications including bacterial superinfection, sepsis, dehydration, and, in rare cases, acute respiratory distress secondary to aseptic pneumonitis.30
Placental insufficiency resulting in stillbirth or neonatal death and other fetal abnormalities can occur in severe pustular psoriasis of pregnancy.31
Psoriatic arthritis
Psoriatic arthritis is a seronegative inflammatory spondyloarthropathy that can result in erosive arthritis in up to 57% of cases and functional disability in up to 19%.32 Although rare in the general population, it affects approximately 6% to 10% of psoriasis patients and up to 40% of patients with severe psoriasis.33 In 70% of cases, psoriasis precedes the onset of arthritis by about 10 years, and approximately 10% to 15% of patients simultaneously present with psoriasis and arthritis or develop arthritis before skin involvement.5,34
Patients complain of joint discomfort that is most prominent after periods of prolonged rest. Patterns of involvement are extremely variable but have been reported as an asymmetric oligoarthritis (involving four or fewer joints) or polyarthritis (involving more than four joints) in most patients. A rheumatoid arthritis-like presentation with a symmetric polyarthropathy involving the small and medium-sized joints has also been reported, making it difficult to clinically distinguish this from rheumatoid arthritis.
A distal interphalangeal-predominant pattern is reported in 5% to 10% of patients. Axial disease resembling ankylosing spondylitis occurs only in 5% of patients. Arthritis mutilans, characterized by severe, rapidly progressive joint inflammation, joint destruction, and deformity, occurs rarely. Enthesitis, ie, inflammation at the point of attachment of tendons or ligaments to bone, is present in up to 42% of patients.5,35
Nail disease
Photo courtesy of Joseph C. English III, MD.
Figure 5. Nail pitting and onycholysis with surrounding psoriatic plaques along the perionychium and proximal nail fold.Nail psoriasis occurs in 35% to 50% of patients and can be seen with all forms of psoriasis.1 Involvement of the nail matrix can result in nail pitting and leukonychia. Oil spots, subungual hyperkeratosis, and distal onycholysis are the result of disease involvement of the nail bed (Figure 5). Up to 90% of patients with psoriatic arthritis have nail changes, especially patients with enthesitis.36
Disease severity also varies
Disease severity also differs among patients. An estimated 80% of patients have mild to moderate disease and 20% have moderate to severe disease, which includes disease involving more than 5% of the body surface or involvement of the face, hands, feet, or genitalia.1
The Psoriasis Area and Severity Index (PASI) is an objective measure used in clinical trials. It incorporates the amount of redness, scaling, and induration of each psoriatic lesion over the body surface involved. A 75% improvement in the PASI score (PASI-75) is regarded as clinically significant.37
PSORIASIS IS DIAGNOSED CLINICALLY
In most cases, the diagnosis of psoriasis is made clinically and is straightforward. However, in more difficult cases, biopsy may be needed. In particular:
The plaques of psoriasis may be confused with squamous cell carcinoma in situ, dermatophyte infection, or cutaneous T-cell lymphoma, especially if they are treatment-resistant.
Guttate psoriasis may be difficult to distinguish from pityriasis rosea.
Erythrodermic psoriasis must be distinguished from other causes of erythroderma, including Sézary syndrome, pityriasis rubra pilaris, and drug reactions.
Intertrigo, candidiasis, extramammary Paget disease, squamous cell carcinoma, and contact dermatitis all may mimic inverse psoriasis.
Palmoplantar pustulosis may be difficult to differentiate from dyshidrotic eczema.
Generalized pustular psoriasis should be distinguished from a pustular drug eruption (acute generalized exanthematous pustular drug eruption or acute generalized exanthematous pustulosis), impetigo, candidiasis, or an autoimmune blistering disorder such as pemphigus.
TREATMENT OF LIMITED DISEASE
Topical corticosteroids
A topical corticosteroid, either by itself or combined with a steroid-sparing agent, is the first-line therapy for patients with limited disease. The potency required for treatment should be based on the extent of disease and on the location, the choice of vehicle, and the patient’s preference and age.
Several double-blind studies have assessed the efficacy of various topical corticosteroids in treating psoriasis. In general, super-potent (class I) and potent (class II) topical corticosteroids are more efficacious than mild or moderate corticosteroids.38 Class I and class II steroids include agents such as clobetasol propionate 0.05% (Temovate), betamethasone dipropionate 0.05% (Diprolene), fluocinonide 0.05% (Lidex), and desoximetasone 0.25% (Topicort).
Use of class I steroids should be limited to an initial treatment course of twice-daily application for 2 to 4 weeks in an effort to avoid some of the local toxicities such as skin atrophy, telangiectasia, and striae. Decreasing class I topical steroid use to 1 to 2 times per week with the gradual introduction of a steroid-sparing agent following the initial 2 to 4 weeks of treatment is advised.
Steroid-sparing agents
Steroid-sparing agents include vitamin D analogues, retinoids, and tacrolimus ointment (Protopic).
Vitamin D analogues and retinoids are thought to decrease keratinocyte proliferation and enhance keratinocyte differentiation.39 The vitamin D analogues are also considered first-line topical agents and include calcipotriol (Dovonex), calcipotriene (Dovonex), and calcitriol (Vectical). To prevent hypercalcemia, use of more than 100 g of vitamin D analogues per week should be avoided.39
Treatment of inverse psoriasis and scalp psoriasis may be challenging
The areas affected in inverse psoriasis, such as the genitalia and axillae, are more prone to side effects when potent topical steroids are used because of increased absorption and occlusion in these areas. Agents that minimize irritation and toxicity in sensitive areas, such as topical tacrolimus, less-potent topical steroids, or calcitriol, can be used.39
For scalp psoriasis, alternative vehicles such as shampoos, gels, solutions, oils, sprays, and foams have improved patient compliance and efficacy of treatment.40
PHOTOTHERAPY FOR SEVERE DISEASE
Narrow-band ultraviolet B
Narrow-band ultraviolet B, ie, light confined to wavelengths of 311 to 313 nm, is a first-line treatment for moderate to severe psoriasis, either as monotherapy or in combination with other treatments. It is an especially attractive option in patients who are on medications or who have comorbidities that may preclude treatment with other systemic agents.
The mechanism of action may be via immunosuppressive effects on Langerhans cells, alteration of cytokines and adhesion molecules that lead to an increase in Th2 cells, and induction of apoptosis of T lymphocytes. Additionally, ultraviolet light affects the proliferation and differentiation of keratinocytes.41
Dosing is based on skin type, and treatment usually involves two or three visits per week for a total of 15 to 20 treatments, with additional therapy for maintenance. Adding acitretin (Soriatane), with close monitoring of aspartate aminotransferase and alanine aminotransferase levels and the patient’s lipid panel, can be considered in treatment-resistant cases.42
Psoralen combined with ultraviolet A
Psoralen combined with ultraviolet A is another option. It can be considered if narrow-band ultraviolet B treatment fails. It is also useful for dark-skinned patients and those with thicker plaques because ultraviolet A penetrates deeper than ultraviolet B. Oral or topical treatment with psoralen is followed by ultraviolet A treatment.
The duration of remission is much longer with psoralen plus ultraviolet A than with narrow-band ultraviolet B. However, this treatment caries a significant risk of cutaneous squamous cell carcinoma and melanoma, especially in light-skinned people and those who receive high doses of ultraviolet A (200 or more treatments) or cyclosporine.40,41,43–46 Long-term effects include photoaging, lentigines, and telangiectasias. As a consequence of these well-established side effects, this treatment is used less frequently.
Cautions with phototherapy
Careful screening and caution should be used in patients who have:
Fair skin that tends to burn easily
A history of arsenic intake or treatment with ionizing radiation
A history of use of photosensitizing medications (fluoroquinolone antibiotics, doxycycline, hydrochlorothiazide)
A history of melanoma or atypical nevi
Multiple risk factors for melanoma
A history of nonmelanoma skin cancer
Immunosuppression due to organ transplantation.
ORAL THERAPIES FOR SEVERE PSORIASIS
Patients who have severe psoriasis—ie, affecting more than 5% of the body surface or debilitating disease affecting the palms, soles, or genitalia—are best managed with systemic medications, especially if they do not have access to phototherapy.20
Methotrexate
In 1972, the US Food and Drug Administration (FDA) approved methotrexate for treating severe psoriasis.42 In studies of methotrexate at doses of 15 to 20 mg weekly, 36% to 68% of patients with severe plaque psoriasis achieved a PASI-75 score.40,42,47
Dosages of methotrexate for treating severe psoriasis range from 7.5 to 25 mg once a week. Patients should also receive a folate supplement of 1 to 5 mg every day except the day they take methotrexate. The folate is to protect against gastrointestinal side effects, bone marrow suppression, and hepatic toxicity associated with methotrexate.
Other side effects of methotrexate include pulmonary fibrosis and stomatitis. Pregnancy, nursing, alcoholism, chronic liver disease, immunodeficiency syndromes, bone-marrow hypoplasia, leukopenia, thrombocytopenia, anemia, and hypersensitivity to methotrexate are all contraindications to methotrexate use.
The National Psoriasis Foundation, in its 2009 guidelines for the use of methotrexate in treating psoriasis,48 recommends obtaining a complete blood cell count with platelets, blood urea nitrogen, creatinine, and liver function tests at baseline and at 1- to 3-month intervals thereafter.
Liver biopsies were previously recommended for patients receiving methotrexate long-term when the cumulative dose of therapy reached 1.5 g. However, given the invasive nature of the liver biopsy procedure and the low incidence of methotrexate-induced hepatotoxicity, this recommendation has been revised.
For patients with no significant risk factors for hepatic toxicity (eg, obesity, diabetes, hyperlipidemia, hepatitis, or history of or current alcohol consumption) and normal liver function tests, liver biopsy should be considered when a cumulative methotrexate dose of 3.5 to 4.0 g is reached. Alternatively, one may choose to continue to monitor the patient without liver biopsy or to switch to another medication, if possible.42,48
Patients at high risk should be monitored more carefully, and liver biopsy should be considered soon after starting methotrexate and repeated after every 1.0 to 1.5 g.48
No reliable noninvasive measures to evaluate for liver fibrosis are routinely available in the United States. Serial measurements of serum type III procollagen aminopeptide have been reported to correlate with the risk of developing liver fibrosis; however, this test is readily available only in Europe.49
Cyclosporine
Cyclosporine (Gengraf, Neoral, Sandimmune) is very effective for treating psoriasis, especially erythrodermic psoriasis. It is often used only short-term or as a bridge to other maintenance therapies because it has a rapid onset and because long-term therapy (3 to 5 years) is associated with a risk of glomerulosclerosis.50
Cyclosporine works by decreasing T-cell activation by binding cyclophilin, which leads to inhibition of transcription of calcineurin and nuclear factor of activated T cells.51 Given at doses of 2.5 to 5 mg/kg/day, cyclosporine has been shown to result in rapid improvement in up to 80% to 90% of psoriatic patients.52,53
The initial recommended dose of cyclosporine is usually 2.5 to 3 mg/kg/day in two divided doses, which is maintained for 4 weeks and then increased by 0.5 mg/kg/day until the disease is stable.42
Nephrotoxicity and hypertension are cyclosporine’s most serious side effects. Blood urea nitrogen, creatinine, and blood pressure should be monitored at baseline and then twice a month for the first 3 months and once monthly thereafter. Liver function tests, complete blood cell count, lipid profile, magnesium, uric acid, and potassium should also be checked every month.
Cyclosporine also increases the risk of cutaneous squamous cell carcinoma, especially in patients who have received psoralen plus ultraviolet A treatment.42
Patients with hypersensitivity to cyclosporine, a history of chronic infection (eg, tuberculosis, hepatitis B, hepatitis C), renal insufficiency, or a history of systemic malignancy should not receive cyclosporine.
Acitretin
Acitretin, an oral retinoid, has been used for several years to treat psoriasis. Its onset is slow, typically ranging from 3 to 6 months, and its effects are dose-dependent. It is most effective as a maintenance therapy, usually after the disease has been stabilized by agents such as cyclosporine, or in combination with other treatments such as phototherapy.42 Acitretin has been shown to be effective in patients with pustular psoriasis.54
Acitretin does not alter the immune system and has not been shown to have significant cumulative toxicities. Serum triglycerides are monitored closely, since acitretin can lead to hypertriglyceridemia.
All retinoids, including acitretin, are in pregnancy category X and should therefore be avoided during pregnancy. Although its half-life is only 49 hours, acitretin may be transformed to etretinate either spontaneously or as a result of alcohol ingestion. Etretinate has a half-life of 168 days and can take up to 3 years to be eliminated from the body. Therefore, acitretin is contraindicated in women who plan to become pregnant or who do not agree to use adequate contraception for 3 years after the drug is discontinued.42
Biologic agents
Advances in our understanding of the pathogenesis of psoriasis have resulted in more specific, targeted therapy.
Alefacept (Amevive) is a human Fc IgG1 receptor fused to the alpha subunit of LFA3. It binds to CD2, blocks costimulatory signaling, and induces apoptosis in activated memory T cells.
Alefacept was the first biologic agent approved by the FDA for the treatment of psoriasis and one of the few biologic agents to induce long-term remission.55 However, its use has declined because few patients achieved significant clearance of their psoriasis and its onset of action was much slower than that of other medications.56
The currently approved biologic therapies commonly used for moderate to severe psoriasis include the TNF-alpha inhibitors and ustekinumab (Stelara).
The TNF-alpha inhibitors include infliximab (Remicade), etanercept (Enbrel), and adalimumab (Humira). They are generally well tolerated and highly effective. However, TNF-alpha inhibitors and other biologic agents are contraindicated in patients with serious infection, a personal history or a family history in a first-degree relative of demyelinating disease, or class III or IV congestive heart failure. Patients should be screened for active infection, including tuberculosis and hepatitis B, since reactivation has been reported following initiation of TNF-alpha inhibitors.1
Adalimumab is a human monoclonal antibody against TNF-alpha. It binds to soluble and membrane-bound TNF-alpha and prevents it from binding to p55 and p75 cell-surface TNF receptors.
The dosing schedule for adalimumab is 80 mg subcutaneously for the first week, followed by 40 mg subcutaneously the next week, and then 40 mg subcutaneously every 2 weeks thereafter.1
Etanercept is a recombinant human TNF-alpha receptor (p75) protein fused with the Fc portion of IgG1, which binds to soluble TNF-alpha.57 Dosing for etanercept is 50 mg subcutaneously twice weekly for the first 12 weeks, followed by 50 mg weekly thereafter.
Infliximab is a chimeric antibody composed of a human IgG1 constant region fused to a mouse variable region that binds to both soluble and membrane-bound TNF-alpha.58 Infliximab is given as an infusion at a dose of 5 mg/kg over 2 to 3 hours at weeks 0, 2, and 6, and then every 8 weeks thereafter.
Efficacy of TNF inhibitors. There are no specific guidelines for the sequence of initiation of TNF inhibitors because no studies have directly compared the efficacy of these medications. However, response to infliximab is relatively rapid compared with adalimumab and etanercept.
In a phase III clinical trial,59 as many as 80% of patients achieved PASI-75 clearance of their psoriasis after three doses of infliximab. Interestingly, only 61% of patients maintained PASI-75 clearance by week 50. This loss of efficacy of infliximab is also reported with other TNF-alpha inhibitors and is thought to be secondary to the development of antibodies to the drugs. For infliximab, this loss of efficacy is less when infliximab is given continuously rather than on an as-needed basis. Simultaneous treatment with methotrexate is also thought to decrease the development of antibodies to infliximab.60
Ustekinumab is an monoclonal antibody directed against the common p40 subunit of IL-12 and IL-23, which have been shown to be at increased levels in psoriatic lesions and important for the pathogenesis of psoriasis.
Between 66% and 76% of patients treated with ustekinumab achieved significant clearance of their disease after 12 weeks of treatment in two large phase III multicenter, randomized, double-blind, placebo-controlled trials.61,62
Dosing of ustekinumab is weight-based. For those weighing less than 100 kg, ustekinumab is given at 45 mg subcutaneously at baseline, at 4 weeks, and every 12 weeks thereafter. The same dosing schedule is used for those weighing more than 100 kg, but the dose is increased to 90 mg.
Guidelines for monitoring patients while on ustekinumab are similar to those for other biologic agents. Information on long-term toxicities is still being collected. However, injection-site reactions, serious infections, malignancies, and a single case of reversible posterior leukoencephalopathy have been reported.20
While biologic agents are significantly more expensive than the conventional therapies discussed above and insurance coverage for these agents varies, they have demonstrated superior efficacy and may be indicated for patients with recalcitrant moderate to severe psoriasis for whom multiple types of treatment have failed.
FOR PSORIATIC ARTHRITIS: SYSTEMIC MEDICATIONS
For patients with known or questionable psoriatic arthritis, evaluation by a rheumatologist is highly recommended.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are usually first-line in the treatment of mild psoriatic arthritis. If after 2 to 3 months of therapy with NSAIDs no benefit is achieved, treatment with methotrexate as monotherapy is a practical consideration because of its low cost. However, methotrexate as a monotherapy has not been shown to prevent radiologic progression of disease.5,32
The TNF-alpha inhibitors have been shown to have similar efficacy when compared among each other in the treatment of psoriatic arthritis.32,63 Based on radiologic evidence, ustekinumab has not shown to be as efficacious as the TNF-alpha inhibitors for treating psoriatic arthritis. Therefore, TNF inhibitors should be considered first-line in the treatment of psoriatic arthritis.21,64
Few studies have been done on the efficacy or sequence of therapies that should be used in the treatment of psoriatic arthritis. The American Academy of Dermatology’s Psoriasis Guidelines of Care recommend adding a TNF-alpha inhibitor or switching to a TNF-alpha inhibitor if no significant improvement is achieved after 12 to 16 weeks of treatment with oral methotrexate.20
FOR ERYTHRODERMIC PSORIASIS: MEDICATIONS THAT ACT PROMPTLY
The care of erythrodermic psoriatic patients is distinct from that of other psoriatic patients because of their associated systemic symptoms. Care should be taken to rule out sepsis, as this is a reported trigger of erythrodermic psoriasis.28
Systemic medications with a quick onset, such as oral cyclosporine, are recommended. Infliximab has also been reported to be beneficial because of its rapid onset.28
TREATMENT BASED ON THE TYPE AND THE SEVERITY OF PSORIASIS
The treatment of psoriasis can be as complex as the disease it itself and should be based on the type and the severity of psoriasis. Recognition of the various manifestations of psoriasis is important for effective treatment. However, in patients with moderate to severe psoriasis, atypical presentations, or recalcitrant disease, referral to a specialist is recommended.
Much has changed in our understanding of psoriasis over the past decade, which is having a major effect on its treatment.
Although topical corticosteroids and phototherapy remain mainstays of treatment, a variety of biologic agents have given new hope to those with the most severe forms of the disease. We are also beginning to understand that patients with psoriasis are at greater risk of cardiovascular disease, though the exact nature of that risk and how we should respond remains unclear. Finally, genome-wide association studies are just beginning to unravel the genetic basis of psoriasis.
In this paper, we review the epidemiology and impact of psoriasis, current views of its pathogenesis, its varied clinical forms, and its treatment.
PSORIASIS IMPOSES A GREAT BURDEN
Psoriasis is common, with a reported prevalence ranging from approximately 2%1 to 4.7%.2 It can manifest at any age, but it is most common in two age groups, ie, 20 to 30 years and 50 to 60 years.
For the patient, the burden is great, affecting physical, psychological, and occupational well-being. In fact, patients with psoriasis report quality-of-life impairment equal to or worse than that in patients with cancer or heart disease.3,4 Notably, functional disability secondary to psoriatic arthritis has been reported in up to 19% of psoriatic arthritis patients, and this negatively affects quality of life.5
In 2004, the annual direct medical costs of psoriasis in the United States were estimated to exceed $1 billion. Its indirect costs, measured as missed days and loss of productivity at work, are estimated to exceed the direct costs by $15 billion annually.6,7
Linked to cardiovascular and other diseases
Studies in the past 10 years have uncovered a link between psoriasis, metabolic syndrome, and cardiovascular disease.8–13 Specifically, patients with severe psoriasis are at higher risk of myocardial infarction and cardiovascular death than control patients. Interestingly, the risk decreases with age; patients at greatest risk are young men with severe psoriasis.8–10
In a large cohort study in the United Kingdom7 comparing patients with and without psoriasis, the hazard ratio for cardiovascular death in patients with severe psoriasis was 1.57 (95% confidence interval 1.26–1.96). This translated to 3.5 excess deaths per 1,000 patient-years. These patients were also at higher risk of death from malignancies, chronic lower respiratory disease, diabetes, dementia, infection, kidney disease, and unknown causes.
How much of the risk is due to psoriasis itself, its treatments, associated behaviors, or other factors requires more study. However, some evidence points to the dysregulation of the immune system, notably chronic elevation of pro-inflammatory cytokines.
Psoriasis and its comorbid conditions are thought to arise from chronically elevated levels of cytokines such as tumor necrosis factor alpha (TNF-alpha), interleukin 1 beta (IL-1 beta), and IL-17. These cytokines impair insulin signaling, deregulate lipid metabolism, and increase atherosclerotic changes in the coronary, cerebral, and peripheral arteries. In addition, several other diseases that involve the immune system occur more frequently with psoriasis, including Crohn disease, ulcerative colitis, lymphoma, obesity, and type 2 diabetes.1,8,14–18
In view of the prevalence of these comorbid conditions and the risks they pose, primary care physicians should consider screening patients with severe psoriasis for metabolic disorders and cardiovascular risk factors and promptly begin preventive therapies.19 Unfortunately, to date, there are no consensus guidelines as to the appropriate screening tests or secondary cardiovascular preventive measures for patients with severe psoriasis.
A VICIOUS CIRCLE OF INFLAMMATION AND KERATINOCYTE PROLIFERATION
The hallmark of plaque psoriasis is chronic inflammation in the skin, leading to keratinocyte proliferation.
External and internal triggers that have been identified include cutaneous injury (eg, sunburn, drug rash, viral exanthems), infections (eg, streptococcal), hypocalcemia, pregnancy, psychogenic stress, drugs (eg, lithium, interferon, beta-blockers, and antimalarials), alcohol, smoking, and obesity.20–23
As reviewed by Nestle et al,24 the initiation of lesion formation is still poorly understood but is thought to occur when a trigger (physical trauma, bacterial product, cellular stress) causes DNA to be released from keratinocytes. DNA forms a complex with the antimicrobial protein LL-37 and activates plasmacytoid dendritic cells (PDCs) via toll-like receptor 9. Activated PDCs release type I interferons, which in turn activate myeloid dendritic cells. Myeloid dendritic cells release IL-20 locally, which speeds keratinocyte proliferation.
A subset of myeloid dendritic cells leaves the dermis and migrates to local lymph nodes, where they release IL-23 and activate naive T cells. T helper 1 (Th1) and Th17 cells are recruited to the lesions and begin producing numerous cytokines, including interferon gamma, IL-17, and IL-22. This cytokine milieu increases keratinocyte proliferation and causes the keratinocytes to secrete antimicrobial proteins (LL-37, beta defensins), chemokines, and S100 proteins. These soluble factors have three main functions: stimulation of dendritic cells to release more IL-23, recruitment of neutrophils to the epidermis, and activation of dermal fibroblasts.
This cycle of keratinocytes activating dendritic cells, dendritic cells activating T cells, and T cells activating keratinocytes appears to be the main force maintaining the disease.24 It is unclear, however, whether this applies to all forms of psoriasis or only to plaque psoriasis.
Genetic factors discovered
In recent years, genome-wide association studies have identified at least 10 psoriasis-susceptibility loci that involve functioning of the immune system.25 These genes include those of the major histocompatibility complex, cytokines, receptors, and beta-defensins.
Of specific interest, polymorphisms in the IL-12/IL-13 receptor, the p40 subunit of IL-12 and IL-23, and the p19 subunit of IL-23 strongly associate with psoriasis, supporting their critical role in the disease process and providing targets for medical therapy.26
PSORIASIS HAS SEVERAL CLINICAL PHENOTYPES
Psoriasis has several clinical variants, each with a distinct clinical course and response to treatment.27 Moreover, many patients present with more than one variant.
Plaque psoriasis
Figure 1. Well-demarcated erythematous, scaly plaques characteristic of plaque psoriasis on the elbow.Plaque psoriasis(Figure 1)accounts for more than 80% of cases. It is characterized by well-demarcated, scaly, pink-to-red plaques of various sizes with a relatively symmetric distribution. Involvement of the extensor surfaces such as the elbows and knees and of the scalp, trunk, and intergluteal cleft is common.
Plaques can persist for several months to years, even in the same location, and only about 5% of patients report complete remission for up to 5 years.
Inverse psoriasis
Photo courtesy of Joseph C. English III, MD.
Figure 2. Patient with inverse psoriasis of the axilla.Involvement of the skin folds, including the axillary, genital, perineal, intergluteal, and inframammary regions with pink-to-red plaques with minimal scale is the main clinical feature of inverse psoriasis (Figure 2). Absence of satellite pustules clinically distinguishes it from candidiasis.
Guttate psoriasis
Photo courtesy of Laura K. Ferris, MD, PhD.
Figure 3. Guttate psoriasis with characteristic erythematous, scaly papules and small plaques on the back.Guttate psoriasis (named for its droplet-shaped lesions) presents abruptly with 1-mm to 10-mm pink papules with associated fine scale over the trunk and extremities (Figure 3). This variant occurs in fewer than 2% of patients with psoriasis, who are usually younger than 30 years. It is often preceded 2 to 3 weeks earlier by an upper respiratory tract infection with group A beta-hemolytic streptococci.
Erythrodermic psoriasis
Approximately 1% to 2.25% of all patients with psoriasis develop this severe form, affecting more than 75% of the body surface area. It presents as generalized erythema, which is the most prominent feature, and it is often associated with superficial desquamation, hair loss, nail dystrophy, and systemic symptoms such as fever, chills, malaise, or high-output cardiac failure. There may be a history of preceding characteristic psoriatic plaques, recent withdrawal of treatment (usually corticosteroids), phototoxicity, or infection.
Conversely, approximately 25% of all patients with erythroderma have underlying psoriasis.28
Pustular psoriasis
Photo courtesy of Joseph C. English III, MD.
Figure 4. Erythematous plaques studded with pustules and red-brown macules on the acral surface of the foot in palmoplantar pustulosis.Pustular psoriasis (Figure 4)is uncommon. The predominant lesions are large collections of neutrophils in the stratum corneum that clinically present as sterile pustules. The pustules may be localized within or at the edge of existing psoriatic plaques or may present as a generalized eruption.
There are several forms of pustular psoriasis, including generalized pustular psoriasis, annular pustular psoriasis, impetigo herpetiformis (pustular psoriasis of pregnancy), and palmoplantar pustulosis. However, there is some evidence to suggest that palmoplantar pustulosis may be distinct from psoriasis.29
Several triggers have been identified, including pregnancy, rapid tapering of medications, hypocalcemia, infection, or topical irritants.
Generalized pustular psoriasis, annular pustular psoriasis, and impetigo herpetiformis often present in association with fever and other systemic symptoms and, if left untreated, can result in life-threatening complications including bacterial superinfection, sepsis, dehydration, and, in rare cases, acute respiratory distress secondary to aseptic pneumonitis.30
Placental insufficiency resulting in stillbirth or neonatal death and other fetal abnormalities can occur in severe pustular psoriasis of pregnancy.31
Psoriatic arthritis
Psoriatic arthritis is a seronegative inflammatory spondyloarthropathy that can result in erosive arthritis in up to 57% of cases and functional disability in up to 19%.32 Although rare in the general population, it affects approximately 6% to 10% of psoriasis patients and up to 40% of patients with severe psoriasis.33 In 70% of cases, psoriasis precedes the onset of arthritis by about 10 years, and approximately 10% to 15% of patients simultaneously present with psoriasis and arthritis or develop arthritis before skin involvement.5,34
Patients complain of joint discomfort that is most prominent after periods of prolonged rest. Patterns of involvement are extremely variable but have been reported as an asymmetric oligoarthritis (involving four or fewer joints) or polyarthritis (involving more than four joints) in most patients. A rheumatoid arthritis-like presentation with a symmetric polyarthropathy involving the small and medium-sized joints has also been reported, making it difficult to clinically distinguish this from rheumatoid arthritis.
A distal interphalangeal-predominant pattern is reported in 5% to 10% of patients. Axial disease resembling ankylosing spondylitis occurs only in 5% of patients. Arthritis mutilans, characterized by severe, rapidly progressive joint inflammation, joint destruction, and deformity, occurs rarely. Enthesitis, ie, inflammation at the point of attachment of tendons or ligaments to bone, is present in up to 42% of patients.5,35
Nail disease
Photo courtesy of Joseph C. English III, MD.
Figure 5. Nail pitting and onycholysis with surrounding psoriatic plaques along the perionychium and proximal nail fold.Nail psoriasis occurs in 35% to 50% of patients and can be seen with all forms of psoriasis.1 Involvement of the nail matrix can result in nail pitting and leukonychia. Oil spots, subungual hyperkeratosis, and distal onycholysis are the result of disease involvement of the nail bed (Figure 5). Up to 90% of patients with psoriatic arthritis have nail changes, especially patients with enthesitis.36
Disease severity also varies
Disease severity also differs among patients. An estimated 80% of patients have mild to moderate disease and 20% have moderate to severe disease, which includes disease involving more than 5% of the body surface or involvement of the face, hands, feet, or genitalia.1
The Psoriasis Area and Severity Index (PASI) is an objective measure used in clinical trials. It incorporates the amount of redness, scaling, and induration of each psoriatic lesion over the body surface involved. A 75% improvement in the PASI score (PASI-75) is regarded as clinically significant.37
PSORIASIS IS DIAGNOSED CLINICALLY
In most cases, the diagnosis of psoriasis is made clinically and is straightforward. However, in more difficult cases, biopsy may be needed. In particular:
The plaques of psoriasis may be confused with squamous cell carcinoma in situ, dermatophyte infection, or cutaneous T-cell lymphoma, especially if they are treatment-resistant.
Guttate psoriasis may be difficult to distinguish from pityriasis rosea.
Erythrodermic psoriasis must be distinguished from other causes of erythroderma, including Sézary syndrome, pityriasis rubra pilaris, and drug reactions.
Intertrigo, candidiasis, extramammary Paget disease, squamous cell carcinoma, and contact dermatitis all may mimic inverse psoriasis.
Palmoplantar pustulosis may be difficult to differentiate from dyshidrotic eczema.
Generalized pustular psoriasis should be distinguished from a pustular drug eruption (acute generalized exanthematous pustular drug eruption or acute generalized exanthematous pustulosis), impetigo, candidiasis, or an autoimmune blistering disorder such as pemphigus.
TREATMENT OF LIMITED DISEASE
Topical corticosteroids
A topical corticosteroid, either by itself or combined with a steroid-sparing agent, is the first-line therapy for patients with limited disease. The potency required for treatment should be based on the extent of disease and on the location, the choice of vehicle, and the patient’s preference and age.
Several double-blind studies have assessed the efficacy of various topical corticosteroids in treating psoriasis. In general, super-potent (class I) and potent (class II) topical corticosteroids are more efficacious than mild or moderate corticosteroids.38 Class I and class II steroids include agents such as clobetasol propionate 0.05% (Temovate), betamethasone dipropionate 0.05% (Diprolene), fluocinonide 0.05% (Lidex), and desoximetasone 0.25% (Topicort).
Use of class I steroids should be limited to an initial treatment course of twice-daily application for 2 to 4 weeks in an effort to avoid some of the local toxicities such as skin atrophy, telangiectasia, and striae. Decreasing class I topical steroid use to 1 to 2 times per week with the gradual introduction of a steroid-sparing agent following the initial 2 to 4 weeks of treatment is advised.
Steroid-sparing agents
Steroid-sparing agents include vitamin D analogues, retinoids, and tacrolimus ointment (Protopic).
Vitamin D analogues and retinoids are thought to decrease keratinocyte proliferation and enhance keratinocyte differentiation.39 The vitamin D analogues are also considered first-line topical agents and include calcipotriol (Dovonex), calcipotriene (Dovonex), and calcitriol (Vectical). To prevent hypercalcemia, use of more than 100 g of vitamin D analogues per week should be avoided.39
Treatment of inverse psoriasis and scalp psoriasis may be challenging
The areas affected in inverse psoriasis, such as the genitalia and axillae, are more prone to side effects when potent topical steroids are used because of increased absorption and occlusion in these areas. Agents that minimize irritation and toxicity in sensitive areas, such as topical tacrolimus, less-potent topical steroids, or calcitriol, can be used.39
For scalp psoriasis, alternative vehicles such as shampoos, gels, solutions, oils, sprays, and foams have improved patient compliance and efficacy of treatment.40
PHOTOTHERAPY FOR SEVERE DISEASE
Narrow-band ultraviolet B
Narrow-band ultraviolet B, ie, light confined to wavelengths of 311 to 313 nm, is a first-line treatment for moderate to severe psoriasis, either as monotherapy or in combination with other treatments. It is an especially attractive option in patients who are on medications or who have comorbidities that may preclude treatment with other systemic agents.
The mechanism of action may be via immunosuppressive effects on Langerhans cells, alteration of cytokines and adhesion molecules that lead to an increase in Th2 cells, and induction of apoptosis of T lymphocytes. Additionally, ultraviolet light affects the proliferation and differentiation of keratinocytes.41
Dosing is based on skin type, and treatment usually involves two or three visits per week for a total of 15 to 20 treatments, with additional therapy for maintenance. Adding acitretin (Soriatane), with close monitoring of aspartate aminotransferase and alanine aminotransferase levels and the patient’s lipid panel, can be considered in treatment-resistant cases.42
Psoralen combined with ultraviolet A
Psoralen combined with ultraviolet A is another option. It can be considered if narrow-band ultraviolet B treatment fails. It is also useful for dark-skinned patients and those with thicker plaques because ultraviolet A penetrates deeper than ultraviolet B. Oral or topical treatment with psoralen is followed by ultraviolet A treatment.
The duration of remission is much longer with psoralen plus ultraviolet A than with narrow-band ultraviolet B. However, this treatment caries a significant risk of cutaneous squamous cell carcinoma and melanoma, especially in light-skinned people and those who receive high doses of ultraviolet A (200 or more treatments) or cyclosporine.40,41,43–46 Long-term effects include photoaging, lentigines, and telangiectasias. As a consequence of these well-established side effects, this treatment is used less frequently.
Cautions with phototherapy
Careful screening and caution should be used in patients who have:
Fair skin that tends to burn easily
A history of arsenic intake or treatment with ionizing radiation
A history of use of photosensitizing medications (fluoroquinolone antibiotics, doxycycline, hydrochlorothiazide)
A history of melanoma or atypical nevi
Multiple risk factors for melanoma
A history of nonmelanoma skin cancer
Immunosuppression due to organ transplantation.
ORAL THERAPIES FOR SEVERE PSORIASIS
Patients who have severe psoriasis—ie, affecting more than 5% of the body surface or debilitating disease affecting the palms, soles, or genitalia—are best managed with systemic medications, especially if they do not have access to phototherapy.20
Methotrexate
In 1972, the US Food and Drug Administration (FDA) approved methotrexate for treating severe psoriasis.42 In studies of methotrexate at doses of 15 to 20 mg weekly, 36% to 68% of patients with severe plaque psoriasis achieved a PASI-75 score.40,42,47
Dosages of methotrexate for treating severe psoriasis range from 7.5 to 25 mg once a week. Patients should also receive a folate supplement of 1 to 5 mg every day except the day they take methotrexate. The folate is to protect against gastrointestinal side effects, bone marrow suppression, and hepatic toxicity associated with methotrexate.
Other side effects of methotrexate include pulmonary fibrosis and stomatitis. Pregnancy, nursing, alcoholism, chronic liver disease, immunodeficiency syndromes, bone-marrow hypoplasia, leukopenia, thrombocytopenia, anemia, and hypersensitivity to methotrexate are all contraindications to methotrexate use.
The National Psoriasis Foundation, in its 2009 guidelines for the use of methotrexate in treating psoriasis,48 recommends obtaining a complete blood cell count with platelets, blood urea nitrogen, creatinine, and liver function tests at baseline and at 1- to 3-month intervals thereafter.
Liver biopsies were previously recommended for patients receiving methotrexate long-term when the cumulative dose of therapy reached 1.5 g. However, given the invasive nature of the liver biopsy procedure and the low incidence of methotrexate-induced hepatotoxicity, this recommendation has been revised.
For patients with no significant risk factors for hepatic toxicity (eg, obesity, diabetes, hyperlipidemia, hepatitis, or history of or current alcohol consumption) and normal liver function tests, liver biopsy should be considered when a cumulative methotrexate dose of 3.5 to 4.0 g is reached. Alternatively, one may choose to continue to monitor the patient without liver biopsy or to switch to another medication, if possible.42,48
Patients at high risk should be monitored more carefully, and liver biopsy should be considered soon after starting methotrexate and repeated after every 1.0 to 1.5 g.48
No reliable noninvasive measures to evaluate for liver fibrosis are routinely available in the United States. Serial measurements of serum type III procollagen aminopeptide have been reported to correlate with the risk of developing liver fibrosis; however, this test is readily available only in Europe.49
Cyclosporine
Cyclosporine (Gengraf, Neoral, Sandimmune) is very effective for treating psoriasis, especially erythrodermic psoriasis. It is often used only short-term or as a bridge to other maintenance therapies because it has a rapid onset and because long-term therapy (3 to 5 years) is associated with a risk of glomerulosclerosis.50
Cyclosporine works by decreasing T-cell activation by binding cyclophilin, which leads to inhibition of transcription of calcineurin and nuclear factor of activated T cells.51 Given at doses of 2.5 to 5 mg/kg/day, cyclosporine has been shown to result in rapid improvement in up to 80% to 90% of psoriatic patients.52,53
The initial recommended dose of cyclosporine is usually 2.5 to 3 mg/kg/day in two divided doses, which is maintained for 4 weeks and then increased by 0.5 mg/kg/day until the disease is stable.42
Nephrotoxicity and hypertension are cyclosporine’s most serious side effects. Blood urea nitrogen, creatinine, and blood pressure should be monitored at baseline and then twice a month for the first 3 months and once monthly thereafter. Liver function tests, complete blood cell count, lipid profile, magnesium, uric acid, and potassium should also be checked every month.
Cyclosporine also increases the risk of cutaneous squamous cell carcinoma, especially in patients who have received psoralen plus ultraviolet A treatment.42
Patients with hypersensitivity to cyclosporine, a history of chronic infection (eg, tuberculosis, hepatitis B, hepatitis C), renal insufficiency, or a history of systemic malignancy should not receive cyclosporine.
Acitretin
Acitretin, an oral retinoid, has been used for several years to treat psoriasis. Its onset is slow, typically ranging from 3 to 6 months, and its effects are dose-dependent. It is most effective as a maintenance therapy, usually after the disease has been stabilized by agents such as cyclosporine, or in combination with other treatments such as phototherapy.42 Acitretin has been shown to be effective in patients with pustular psoriasis.54
Acitretin does not alter the immune system and has not been shown to have significant cumulative toxicities. Serum triglycerides are monitored closely, since acitretin can lead to hypertriglyceridemia.
All retinoids, including acitretin, are in pregnancy category X and should therefore be avoided during pregnancy. Although its half-life is only 49 hours, acitretin may be transformed to etretinate either spontaneously or as a result of alcohol ingestion. Etretinate has a half-life of 168 days and can take up to 3 years to be eliminated from the body. Therefore, acitretin is contraindicated in women who plan to become pregnant or who do not agree to use adequate contraception for 3 years after the drug is discontinued.42
Biologic agents
Advances in our understanding of the pathogenesis of psoriasis have resulted in more specific, targeted therapy.
Alefacept (Amevive) is a human Fc IgG1 receptor fused to the alpha subunit of LFA3. It binds to CD2, blocks costimulatory signaling, and induces apoptosis in activated memory T cells.
Alefacept was the first biologic agent approved by the FDA for the treatment of psoriasis and one of the few biologic agents to induce long-term remission.55 However, its use has declined because few patients achieved significant clearance of their psoriasis and its onset of action was much slower than that of other medications.56
The currently approved biologic therapies commonly used for moderate to severe psoriasis include the TNF-alpha inhibitors and ustekinumab (Stelara).
The TNF-alpha inhibitors include infliximab (Remicade), etanercept (Enbrel), and adalimumab (Humira). They are generally well tolerated and highly effective. However, TNF-alpha inhibitors and other biologic agents are contraindicated in patients with serious infection, a personal history or a family history in a first-degree relative of demyelinating disease, or class III or IV congestive heart failure. Patients should be screened for active infection, including tuberculosis and hepatitis B, since reactivation has been reported following initiation of TNF-alpha inhibitors.1
Adalimumab is a human monoclonal antibody against TNF-alpha. It binds to soluble and membrane-bound TNF-alpha and prevents it from binding to p55 and p75 cell-surface TNF receptors.
The dosing schedule for adalimumab is 80 mg subcutaneously for the first week, followed by 40 mg subcutaneously the next week, and then 40 mg subcutaneously every 2 weeks thereafter.1
Etanercept is a recombinant human TNF-alpha receptor (p75) protein fused with the Fc portion of IgG1, which binds to soluble TNF-alpha.57 Dosing for etanercept is 50 mg subcutaneously twice weekly for the first 12 weeks, followed by 50 mg weekly thereafter.
Infliximab is a chimeric antibody composed of a human IgG1 constant region fused to a mouse variable region that binds to both soluble and membrane-bound TNF-alpha.58 Infliximab is given as an infusion at a dose of 5 mg/kg over 2 to 3 hours at weeks 0, 2, and 6, and then every 8 weeks thereafter.
Efficacy of TNF inhibitors. There are no specific guidelines for the sequence of initiation of TNF inhibitors because no studies have directly compared the efficacy of these medications. However, response to infliximab is relatively rapid compared with adalimumab and etanercept.
In a phase III clinical trial,59 as many as 80% of patients achieved PASI-75 clearance of their psoriasis after three doses of infliximab. Interestingly, only 61% of patients maintained PASI-75 clearance by week 50. This loss of efficacy of infliximab is also reported with other TNF-alpha inhibitors and is thought to be secondary to the development of antibodies to the drugs. For infliximab, this loss of efficacy is less when infliximab is given continuously rather than on an as-needed basis. Simultaneous treatment with methotrexate is also thought to decrease the development of antibodies to infliximab.60
Ustekinumab is an monoclonal antibody directed against the common p40 subunit of IL-12 and IL-23, which have been shown to be at increased levels in psoriatic lesions and important for the pathogenesis of psoriasis.
Between 66% and 76% of patients treated with ustekinumab achieved significant clearance of their disease after 12 weeks of treatment in two large phase III multicenter, randomized, double-blind, placebo-controlled trials.61,62
Dosing of ustekinumab is weight-based. For those weighing less than 100 kg, ustekinumab is given at 45 mg subcutaneously at baseline, at 4 weeks, and every 12 weeks thereafter. The same dosing schedule is used for those weighing more than 100 kg, but the dose is increased to 90 mg.
Guidelines for monitoring patients while on ustekinumab are similar to those for other biologic agents. Information on long-term toxicities is still being collected. However, injection-site reactions, serious infections, malignancies, and a single case of reversible posterior leukoencephalopathy have been reported.20
While biologic agents are significantly more expensive than the conventional therapies discussed above and insurance coverage for these agents varies, they have demonstrated superior efficacy and may be indicated for patients with recalcitrant moderate to severe psoriasis for whom multiple types of treatment have failed.
FOR PSORIATIC ARTHRITIS: SYSTEMIC MEDICATIONS
For patients with known or questionable psoriatic arthritis, evaluation by a rheumatologist is highly recommended.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are usually first-line in the treatment of mild psoriatic arthritis. If after 2 to 3 months of therapy with NSAIDs no benefit is achieved, treatment with methotrexate as monotherapy is a practical consideration because of its low cost. However, methotrexate as a monotherapy has not been shown to prevent radiologic progression of disease.5,32
The TNF-alpha inhibitors have been shown to have similar efficacy when compared among each other in the treatment of psoriatic arthritis.32,63 Based on radiologic evidence, ustekinumab has not shown to be as efficacious as the TNF-alpha inhibitors for treating psoriatic arthritis. Therefore, TNF inhibitors should be considered first-line in the treatment of psoriatic arthritis.21,64
Few studies have been done on the efficacy or sequence of therapies that should be used in the treatment of psoriatic arthritis. The American Academy of Dermatology’s Psoriasis Guidelines of Care recommend adding a TNF-alpha inhibitor or switching to a TNF-alpha inhibitor if no significant improvement is achieved after 12 to 16 weeks of treatment with oral methotrexate.20
FOR ERYTHRODERMIC PSORIASIS: MEDICATIONS THAT ACT PROMPTLY
The care of erythrodermic psoriatic patients is distinct from that of other psoriatic patients because of their associated systemic symptoms. Care should be taken to rule out sepsis, as this is a reported trigger of erythrodermic psoriasis.28
Systemic medications with a quick onset, such as oral cyclosporine, are recommended. Infliximab has also been reported to be beneficial because of its rapid onset.28
TREATMENT BASED ON THE TYPE AND THE SEVERITY OF PSORIASIS
The treatment of psoriasis can be as complex as the disease it itself and should be based on the type and the severity of psoriasis. Recognition of the various manifestations of psoriasis is important for effective treatment. However, in patients with moderate to severe psoriasis, atypical presentations, or recalcitrant disease, referral to a specialist is recommended.
References
Menter A, Gottlieb A, Feldman SR, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: section 1. Overview of psoriasis and guidelines of care for the treatment of psoriasis with biologics. J Am Acad Dermatol2008; 58:826–850.
Christophers E. Psoriasis—epidemiology and clinical spectrum. Clin Exp Dermatol2001; 26:314–320.
Rapp SR, Feldman SR, Exum ML, Fleischer AB, Reboussin DM. Psoriasis causes as much disability as other major medical diseases. J Am Acad Dermatol1999; 41:401–407.
Weiss SC, Kimball AB, Liewehr DJ, Blauvelt A, Turner ML, Emanuel EJ. Quantifying the harmful effect of psoriasis on health-related quality of life. J Am Acad Dermatol2002; 47:512–518.
Garg A, Gladman D. Recognizing psoriatic arthritis in the dermatology clinic. J Am Acad Dermatol2010; 63:733–748.
Kimball AB, Yu AP, Signorovitch J, et al. The effects of adalimumab treatment and psoriasis severity on self-reported work productivity and activity impairment for patients with moderate to severe psoriasis. J Am Acad Dermatol2012; 66:e67–e76.
Schmitt JM, Ford DE. Work limitations and productivity loss are associated with health-related quality of life but not with clinical severity in patients with psoriasis. Dermatology2006; 213:102–110.
Gelfand JM, Neimann AL, Shin DB, Wang X, Margolis DJ, Troxel AB. Risk of myocardial infarction in patients with psoriasis. JAMA2006; 296:1735–1741.
Abuabara K, Azfar RS, Shin DB, Neimann AL, Troxel AB, Gelfand JM. Cause-specific mortality in patients with severe psoriasis: a population-based cohort study in the U.K. Br J Dermatol2010; 163:586–592.
Ahlehoff O, Gislason GH, Charlot M, et al. Psoriasis is associated with clinically significant cardiovascular risk: a Danish nationwide cohort study. J Intern Med2011; 270:147–157.
Lin HW, Wang KH, Lin HC, Lin HC. Increased risk of acute myocardial infarction in patients with psoriasis: a 5-year population-based study in Taiwan. J Am Acad Dermatol2011; 64:495–501.
Bremmer S, Van Voorhees AS, Hsu S, et al; National Psoriasis Foundation. Obesity and psoriasis: from the Medical Board of the National Psoriasis Foundation. J Am Acad Dermatol2010; 63:1058–1069.
Tobin AM, Veale DJ, Fitzgerald O, et al. Cardiovascular disease and risk factors in patients with psoriasis and psoriatic arthritis. J Rheumatol2010; 37:1386–1394.
Najarian DJ, Gottlieb AB. Connections between psoriasis and Crohn’s disease. J Am Acad Dermatol2003; 48:805–821.
Neimann AL, Shin DB, Wang X, Margolis DJ, Troxel AB, Gelfand JM. Prevalence of cardiovascular risk factors in patients with psoriasis. J Am Acad Dermatol2006; 55:829–835.
Shapiro J, Cohen AD, Weitzman D, Tal R, David M. Psoriasis and cardiovascular risk factors: a case-control study on inpatients comparing psoriasis to dermatitis. J Am Acad Dermatol2012; 66:252–258.
Gelfand JM, Shin DB, Neimann AL, Wang X, Margolis DJ, Troxel AB. The risk of lymphoma in patients with psoriasis. J Invest Dermatol2006; 126:2194–2201.
Chen YJ, Wu CY, Chen TJ, et al. The risk of cancer in patients with psoriasis: a population-based cohort study in Taiwan. J Am Acad Dermatol2011; 65:84–91.
Friedewald VE, Cather JC, Gelfand JM, et al. AJC editor’s consensus: psoriasis and coronary artery disease. Am J Cardiol2008; 102:1631–1643.
American Academy of Dermatology Work Group; Menter A, Korman NJ, Elmets CA, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: section 6. Guidelines of care for the treatment of psoriasis and psoriatic arthritis: case-based presentations and evidence-based conclusions. J Am Acad Dermatol2011; 65:137–174.
Mallbris L, Larsson P, Bergqvist S, Vingård E, Granath F, Ståhle M. Psoriasis phenotype at disease onset: clinical characterization of 400 adult cases. J Invest Dermatol2005; 124:499–504.
Armstrong AW, Armstrong EJ, Fuller EN, Sockolov ME, Voyles SV. Smoking and pathogenesis of psoriasis: a review of oxidative, inflammatory and genetic mechanisms. Br J Dermatol2011; 165:1162–1168.
Qureshi AA, Dominguez PL, Choi HK, Han J, Curhan G. Alcohol intake and risk of incident psoriasis in US women: a prospective study. Arch Dermatol2010; 146:1364–1369.
Nestle FO, Kaplan DH, Barker J. Psoriasis. N Engl J Med2009; 361:496–509.
Genetic Analysis of Psoriasis Consortium & the Wellcome Trust Case Control Consortium 2; Strange A, Capon F, Spencer CC, et al. A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1. Nat Genet2010; 42:985–990.
Nair RP, Duffin KC, Helms C, et al; Collaborative Association Study of Psoriasis. Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways. Nat Genet2009; 41:199–204.
Griffiths CE, Christophers E, Barker JN, et al. A classification of psoriasis vulgaris according to phenotype. Br J Dermatol2007; 156:258–262.
Rosenbach M, Hsu S, Korman NJ, et al; National Psoriasis Foundation Medical Board. Treatment of erythrodermic psoriasis: from the medical board of the National Psoriasis Foundation. J Am Acad Dermatol2010; 62:655–662.
Mrowietz U, van de Kerkhof PC. Management of palmoplantar pustulosis: do we need to change?Br J Dermatol2011; 164:942–946.
Kluger N, Bessis D, Guillot B, Girard C. Acute respiratory distress syndrome complicating generalized pustular psoriasis (psoriasis-associated aseptic pneumonitis). J Am Acad Dermatol2011; 64:1154–1158.
Roth MM. Pregnancy dermatoses: diagnosis, management, and controversies. Am J Clin Dermatol2011; 12:25–41.
Gottlieb A, Korman NJ, Gordon KB, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: section 2. Psoriatic arthritis: overview and guidelines of care for treatment with an emphasis on the biologics. J Am Acad Dermatol2008; 58:851–864.
Ogdie A, Gelfand JM. Identification of risk factors for psoriatic arthritis: scientific opportunity meets clinical need. Arch Dermatol2010; 146:785–788.
Gelfand JM, Gladman DD, Mease PJ, et al. Epidemiology of psoriatic arthritis in the population of the United States. J Am Acad Dermatol2005; 53:573.
Moll JM, Wright V. Psoriatic arthritis. Semin Arthritis Rheum1973; 3:55–78.
McGonagle D. Enthesitis: an autoinflammatory lesion linking nail and joint involvement in psoriatic disease. J Eur Acad Dermatol Venereol2009; 23(suppl 1):9–13.
Feldman SR, Krueger GG. Psoriasis assessment tools in clinical trials. Ann Rheum Dis2005; 64(suppl 2):ii65–ii68.
Mason J, Mason AR, Cork MJ. Topical preparations for the treatment of psoriasis: a systematic review. Br J Dermatol2002; 146:351–364.
Menter A, Korman NJ, Elmets CA, et al; American Academy of Dermatology. Guidelines of care for the management of psoriasis and psoriatic arthritis. Section 3. Guidelines of care for the management and treatment of psoriasis with topical therapies. J Am Acad Dermatol2009; 60:643–659.
Zivkovich AH, Feldman SR. Are ointments better than other vehicles for corticosteroid treatment of psoriasis?J Drugs Dermatol2009; 8:570–572.
Menter A, Korman NJ, Elmets CA, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: section 5. Guidelines of care for the treatment of psoriasis with phototherapy and photochemotherapy. J Am Acad Dermatol2010; 62:114–135.
Menter A, Korman NJ, Elmets CA, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: section 4. Guidelines of care for the management and treatment of psoriasis with traditional systemic agents. J Am Acad Dermatol2009; 61:451–485.
Murase JE, Lee EE, Koo J. Effect of ethnicity on the risk of developing nonmelanoma skin cancer following long-term PUVA therapy. Int J Dermatol2005; 44:1016–1021.
Stern RS, Lunder EJ. Risk of squamous cell carcinoma and methoxsalen (psoralen) and UV-A radiation (PUVA). A meta-analysis. Arch Dermatol1998; 134:1582–1585.
Stern RS, Väkevä LH. Noncutaneous malignant tumors in the PUVA follow-up study: 1975–1996. J Invest Dermatol1997; 108:897–900.
Patel RV, Clark LN, Lebwohl M, Weinberg JM. Treatments for psoriasis and the risk of malignancy. J Am Acad Dermatol2009; 60:1001–1017.
Flytström I, Stenberg B, Svensson A, Bergbrant IM. Methotrexate vs. ciclosporin in psoriasis: effectiveness, quality of life and safety. A randomized controlled trial. Br J Dermatol2008; 158:116–121.
Kalb RE, Strober B, Weinstein G, Lebwohl M. Methotrexate and psoriasis: 2009 National Psoriasis Foundation Consensus Conference. J Am Acad Dermatol2009; 60:824–837.
Zachariae H, Heickendorff L, Søgaard H. The value of aminoterminal propeptide of type III procollagen in routine screening for methotrexate-induced liver fibrosis: a 10-year follow-up. Br J Dermatol2001; 144:100–103.
Lowe NJ, Wieder JM, Rosenbach A, et al. Long-term low-dose cyclosporine therapy for severe psoriasis: effects on renal function and structure. J Am Acad Dermatol1996; 35:710–719.
Gottlieb AB, Grossman RM, Khandke L, et al. Studies of the effect of cyclosporine in psoriasis in vivo: combined effects on activated T lymphocytes and epidermal regenerative maturation. J Invest Dermatol1992; 98:302–309.
Ellis CN, Fradin MS, Messana JM, et al. Cyclosporine for plaque-type psoriasis. Results of a multidose, double-blind trial. N Engl J Med1991; 324:277–284.
Faerber L, Braeutigam M, Weidinger G, et al. Cyclosporine in severe psoriasis. Results of a meta-analysis in 579 patients. Am J Clin Dermatol2001; 2:41–47.
Ozawa A, Ohkido M, Haruki Y, et al. Treatments of generalized pustular psoriasis: a multicenter study in Japan. J Dermatol1999; 26:141–149.
Krueger GG, Ellis CN. Alefacept therapy produces remission for patients with chronic plaque psoriasis. Br J Dermatol2003; 148:784–788.
Lebwohl M, Christophers E, Langley R, Ortonne JP, Roberts J, Griffiths CE; Alefacept Clinical Study Group. An international, randomized, double-blind, placebo-controlled phase 3 trial of intramuscular alefacept in patients with chronic plaque psoriasis. Arch Dermatol2003; 139:719–727.
Gottlieb AB, Matheson RT, Lowe N, et al. A randomized trial of etanercept as monotherapy for psoriasis. Arch Dermatol2003; 139:1627–1632.
Gottlieb AB, Masud S, Ramamurthi R, et al. Pharmacodynamic and pharmacokinetic response to anti-tumor necrosis factor-alpha monoclonal antibody (infliximab) treatment of moderate to severe psoriasis vulgaris. J Am Acad Dermatol2003; 48:68–75.
Reich K, Nestle FO, Papp K, et al; EXPRESS study investigators. Infliximab induction and maintenance therapy for moderate-to-severe psoriasis: a phase III, multicentre, double-blind trial. Lancet2005; 366:1367–1374.
Menter A, Feldman SR, Weinstein GD, et al. A randomized comparison of continuous vs. intermittent infliximab maintenance regimens over 1 year in the treatment of moderate-to-severe plaque psoriasis. J Am Acad Dermatol2007; 56:31.e1–31.e15.
Papp KA, Langley RG, Lebwohl M, et al; PHOENIX 2 study investigators. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2). Lancet2008; 371:1675–1684.
Leonardi CL, Kimball AB, Papp KA, et al; PHOENIX 1 study investigators. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1). Lancet2008; 371:1665–1674.
Griffiths CE, Strober BE, van de Kerkhof P, et al; ACCEPT Study Group. Comparison of ustekinumab and etanercept for moderate-to-severe psoriasis. N Engl J Med2010; 362:118–128.
Gottlieb A, Menter A, Mendelsohn A, et al. Ustekinumab, a human interleukin 12/23 monoclonal antibody, for psoriatic arthritis: randomised, double-blind, placebo-controlled, crossover trial. Lancet. 2009; 373:633–640.
References
Menter A, Gottlieb A, Feldman SR, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: section 1. Overview of psoriasis and guidelines of care for the treatment of psoriasis with biologics. J Am Acad Dermatol2008; 58:826–850.
Christophers E. Psoriasis—epidemiology and clinical spectrum. Clin Exp Dermatol2001; 26:314–320.
Rapp SR, Feldman SR, Exum ML, Fleischer AB, Reboussin DM. Psoriasis causes as much disability as other major medical diseases. J Am Acad Dermatol1999; 41:401–407.
Weiss SC, Kimball AB, Liewehr DJ, Blauvelt A, Turner ML, Emanuel EJ. Quantifying the harmful effect of psoriasis on health-related quality of life. J Am Acad Dermatol2002; 47:512–518.
Garg A, Gladman D. Recognizing psoriatic arthritis in the dermatology clinic. J Am Acad Dermatol2010; 63:733–748.
Kimball AB, Yu AP, Signorovitch J, et al. The effects of adalimumab treatment and psoriasis severity on self-reported work productivity and activity impairment for patients with moderate to severe psoriasis. J Am Acad Dermatol2012; 66:e67–e76.
Schmitt JM, Ford DE. Work limitations and productivity loss are associated with health-related quality of life but not with clinical severity in patients with psoriasis. Dermatology2006; 213:102–110.
Gelfand JM, Neimann AL, Shin DB, Wang X, Margolis DJ, Troxel AB. Risk of myocardial infarction in patients with psoriasis. JAMA2006; 296:1735–1741.
Abuabara K, Azfar RS, Shin DB, Neimann AL, Troxel AB, Gelfand JM. Cause-specific mortality in patients with severe psoriasis: a population-based cohort study in the U.K. Br J Dermatol2010; 163:586–592.
Ahlehoff O, Gislason GH, Charlot M, et al. Psoriasis is associated with clinically significant cardiovascular risk: a Danish nationwide cohort study. J Intern Med2011; 270:147–157.
Lin HW, Wang KH, Lin HC, Lin HC. Increased risk of acute myocardial infarction in patients with psoriasis: a 5-year population-based study in Taiwan. J Am Acad Dermatol2011; 64:495–501.
Bremmer S, Van Voorhees AS, Hsu S, et al; National Psoriasis Foundation. Obesity and psoriasis: from the Medical Board of the National Psoriasis Foundation. J Am Acad Dermatol2010; 63:1058–1069.
Tobin AM, Veale DJ, Fitzgerald O, et al. Cardiovascular disease and risk factors in patients with psoriasis and psoriatic arthritis. J Rheumatol2010; 37:1386–1394.
Najarian DJ, Gottlieb AB. Connections between psoriasis and Crohn’s disease. J Am Acad Dermatol2003; 48:805–821.
Neimann AL, Shin DB, Wang X, Margolis DJ, Troxel AB, Gelfand JM. Prevalence of cardiovascular risk factors in patients with psoriasis. J Am Acad Dermatol2006; 55:829–835.
Shapiro J, Cohen AD, Weitzman D, Tal R, David M. Psoriasis and cardiovascular risk factors: a case-control study on inpatients comparing psoriasis to dermatitis. J Am Acad Dermatol2012; 66:252–258.
Gelfand JM, Shin DB, Neimann AL, Wang X, Margolis DJ, Troxel AB. The risk of lymphoma in patients with psoriasis. J Invest Dermatol2006; 126:2194–2201.
Chen YJ, Wu CY, Chen TJ, et al. The risk of cancer in patients with psoriasis: a population-based cohort study in Taiwan. J Am Acad Dermatol2011; 65:84–91.
Friedewald VE, Cather JC, Gelfand JM, et al. AJC editor’s consensus: psoriasis and coronary artery disease. Am J Cardiol2008; 102:1631–1643.
American Academy of Dermatology Work Group; Menter A, Korman NJ, Elmets CA, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: section 6. Guidelines of care for the treatment of psoriasis and psoriatic arthritis: case-based presentations and evidence-based conclusions. J Am Acad Dermatol2011; 65:137–174.
Mallbris L, Larsson P, Bergqvist S, Vingård E, Granath F, Ståhle M. Psoriasis phenotype at disease onset: clinical characterization of 400 adult cases. J Invest Dermatol2005; 124:499–504.
Armstrong AW, Armstrong EJ, Fuller EN, Sockolov ME, Voyles SV. Smoking and pathogenesis of psoriasis: a review of oxidative, inflammatory and genetic mechanisms. Br J Dermatol2011; 165:1162–1168.
Qureshi AA, Dominguez PL, Choi HK, Han J, Curhan G. Alcohol intake and risk of incident psoriasis in US women: a prospective study. Arch Dermatol2010; 146:1364–1369.
Nestle FO, Kaplan DH, Barker J. Psoriasis. N Engl J Med2009; 361:496–509.
Genetic Analysis of Psoriasis Consortium & the Wellcome Trust Case Control Consortium 2; Strange A, Capon F, Spencer CC, et al. A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1. Nat Genet2010; 42:985–990.
Nair RP, Duffin KC, Helms C, et al; Collaborative Association Study of Psoriasis. Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways. Nat Genet2009; 41:199–204.
Griffiths CE, Christophers E, Barker JN, et al. A classification of psoriasis vulgaris according to phenotype. Br J Dermatol2007; 156:258–262.
Rosenbach M, Hsu S, Korman NJ, et al; National Psoriasis Foundation Medical Board. Treatment of erythrodermic psoriasis: from the medical board of the National Psoriasis Foundation. J Am Acad Dermatol2010; 62:655–662.
Mrowietz U, van de Kerkhof PC. Management of palmoplantar pustulosis: do we need to change?Br J Dermatol2011; 164:942–946.
Kluger N, Bessis D, Guillot B, Girard C. Acute respiratory distress syndrome complicating generalized pustular psoriasis (psoriasis-associated aseptic pneumonitis). J Am Acad Dermatol2011; 64:1154–1158.
Roth MM. Pregnancy dermatoses: diagnosis, management, and controversies. Am J Clin Dermatol2011; 12:25–41.
Gottlieb A, Korman NJ, Gordon KB, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: section 2. Psoriatic arthritis: overview and guidelines of care for treatment with an emphasis on the biologics. J Am Acad Dermatol2008; 58:851–864.
Ogdie A, Gelfand JM. Identification of risk factors for psoriatic arthritis: scientific opportunity meets clinical need. Arch Dermatol2010; 146:785–788.
Gelfand JM, Gladman DD, Mease PJ, et al. Epidemiology of psoriatic arthritis in the population of the United States. J Am Acad Dermatol2005; 53:573.
Moll JM, Wright V. Psoriatic arthritis. Semin Arthritis Rheum1973; 3:55–78.
McGonagle D. Enthesitis: an autoinflammatory lesion linking nail and joint involvement in psoriatic disease. J Eur Acad Dermatol Venereol2009; 23(suppl 1):9–13.
Feldman SR, Krueger GG. Psoriasis assessment tools in clinical trials. Ann Rheum Dis2005; 64(suppl 2):ii65–ii68.
Mason J, Mason AR, Cork MJ. Topical preparations for the treatment of psoriasis: a systematic review. Br J Dermatol2002; 146:351–364.
Menter A, Korman NJ, Elmets CA, et al; American Academy of Dermatology. Guidelines of care for the management of psoriasis and psoriatic arthritis. Section 3. Guidelines of care for the management and treatment of psoriasis with topical therapies. J Am Acad Dermatol2009; 60:643–659.
Zivkovich AH, Feldman SR. Are ointments better than other vehicles for corticosteroid treatment of psoriasis?J Drugs Dermatol2009; 8:570–572.
Menter A, Korman NJ, Elmets CA, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: section 5. Guidelines of care for the treatment of psoriasis with phototherapy and photochemotherapy. J Am Acad Dermatol2010; 62:114–135.
Menter A, Korman NJ, Elmets CA, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: section 4. Guidelines of care for the management and treatment of psoriasis with traditional systemic agents. J Am Acad Dermatol2009; 61:451–485.
Murase JE, Lee EE, Koo J. Effect of ethnicity on the risk of developing nonmelanoma skin cancer following long-term PUVA therapy. Int J Dermatol2005; 44:1016–1021.
Stern RS, Lunder EJ. Risk of squamous cell carcinoma and methoxsalen (psoralen) and UV-A radiation (PUVA). A meta-analysis. Arch Dermatol1998; 134:1582–1585.
Stern RS, Väkevä LH. Noncutaneous malignant tumors in the PUVA follow-up study: 1975–1996. J Invest Dermatol1997; 108:897–900.
Patel RV, Clark LN, Lebwohl M, Weinberg JM. Treatments for psoriasis and the risk of malignancy. J Am Acad Dermatol2009; 60:1001–1017.
Flytström I, Stenberg B, Svensson A, Bergbrant IM. Methotrexate vs. ciclosporin in psoriasis: effectiveness, quality of life and safety. A randomized controlled trial. Br J Dermatol2008; 158:116–121.
Kalb RE, Strober B, Weinstein G, Lebwohl M. Methotrexate and psoriasis: 2009 National Psoriasis Foundation Consensus Conference. J Am Acad Dermatol2009; 60:824–837.
Zachariae H, Heickendorff L, Søgaard H. The value of aminoterminal propeptide of type III procollagen in routine screening for methotrexate-induced liver fibrosis: a 10-year follow-up. Br J Dermatol2001; 144:100–103.
Lowe NJ, Wieder JM, Rosenbach A, et al. Long-term low-dose cyclosporine therapy for severe psoriasis: effects on renal function and structure. J Am Acad Dermatol1996; 35:710–719.
Gottlieb AB, Grossman RM, Khandke L, et al. Studies of the effect of cyclosporine in psoriasis in vivo: combined effects on activated T lymphocytes and epidermal regenerative maturation. J Invest Dermatol1992; 98:302–309.
Ellis CN, Fradin MS, Messana JM, et al. Cyclosporine for plaque-type psoriasis. Results of a multidose, double-blind trial. N Engl J Med1991; 324:277–284.
Faerber L, Braeutigam M, Weidinger G, et al. Cyclosporine in severe psoriasis. Results of a meta-analysis in 579 patients. Am J Clin Dermatol2001; 2:41–47.
Ozawa A, Ohkido M, Haruki Y, et al. Treatments of generalized pustular psoriasis: a multicenter study in Japan. J Dermatol1999; 26:141–149.
Krueger GG, Ellis CN. Alefacept therapy produces remission for patients with chronic plaque psoriasis. Br J Dermatol2003; 148:784–788.
Lebwohl M, Christophers E, Langley R, Ortonne JP, Roberts J, Griffiths CE; Alefacept Clinical Study Group. An international, randomized, double-blind, placebo-controlled phase 3 trial of intramuscular alefacept in patients with chronic plaque psoriasis. Arch Dermatol2003; 139:719–727.
Gottlieb AB, Matheson RT, Lowe N, et al. A randomized trial of etanercept as monotherapy for psoriasis. Arch Dermatol2003; 139:1627–1632.
Gottlieb AB, Masud S, Ramamurthi R, et al. Pharmacodynamic and pharmacokinetic response to anti-tumor necrosis factor-alpha monoclonal antibody (infliximab) treatment of moderate to severe psoriasis vulgaris. J Am Acad Dermatol2003; 48:68–75.
Reich K, Nestle FO, Papp K, et al; EXPRESS study investigators. Infliximab induction and maintenance therapy for moderate-to-severe psoriasis: a phase III, multicentre, double-blind trial. Lancet2005; 366:1367–1374.
Menter A, Feldman SR, Weinstein GD, et al. A randomized comparison of continuous vs. intermittent infliximab maintenance regimens over 1 year in the treatment of moderate-to-severe plaque psoriasis. J Am Acad Dermatol2007; 56:31.e1–31.e15.
Papp KA, Langley RG, Lebwohl M, et al; PHOENIX 2 study investigators. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2). Lancet2008; 371:1675–1684.
Leonardi CL, Kimball AB, Papp KA, et al; PHOENIX 1 study investigators. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1). Lancet2008; 371:1665–1674.
Griffiths CE, Strober BE, van de Kerkhof P, et al; ACCEPT Study Group. Comparison of ustekinumab and etanercept for moderate-to-severe psoriasis. N Engl J Med2010; 362:118–128.
Gottlieb A, Menter A, Mendelsohn A, et al. Ustekinumab, a human interleukin 12/23 monoclonal antibody, for psoriatic arthritis: randomised, double-blind, placebo-controlled, crossover trial. Lancet. 2009; 373:633–640.
Studies in the past 10 years have uncovered a link between psoriasis, metabolic syndrome, and cardiovascular disease. Interestingly, the risk grows less with age; patients at greatest risk are young men with severe psoriasis.
The most common presentation of psoriasis is plaque psoriasis. However, there are several other clinical variations of psoriasis, each of which has a distinct response to treatment and may be associated with significant systemic symptoms.
Tumor necrosis factor inhibitors should be considered first-line in the treatment of psoriatic arthritis.
Phototherapy and systemic medications including methotrexate, acitretin (Soriatane), cyclosporine (Gengraf, Neoral, Sandimmune), and biologic agents are the most effective treatments for moderate-to-severe psoriasis.
Screening is the testing of an individual who is at risk for a disease, but who does not exhibit signs or symptoms of the disease. The goal of screening is to detect disease at a stage when cure or control is possible, and an effective screening program should reduce the number of disease-specific deaths in the screened population. Screening should focus on diseases that are associated with potentially serious consequences and that are detectable in the preclinical phase, yet it should avoid identifying “pseudodisease” (ie, positive test findings that would not be expected to affect the patient’s health) or causing morbidity due to the test procedure itself.1 Finally, screening is only worthwhile when treatment of the disease is more effective when administered early.
Since lung cancer screening began in the 1950s,2,3 many studies have attempted to define the medical benefits and economic impact of widespread screening. Many important unresolved issues remain, including the effectiveness of lung cancer screening for reducing disease-specific mortality, the potential harms of screening, its cost-effectiveness, and the potential impact of new research methods on the early identification of lung cancer.
DOES LUNG CANCER SCREENING REDUCE DISEASE-SPECIFIC MORTALITY?
Early studies examined the usefulness of large-scale chest radiograph programs, either with or without sputum cytology, for lung cancer screening. Although several studies reported that radiographic screening identified patients with early lung cancer and reported higher survival rates, reviews and meta-analyses of these reports concluded that screening did not significantly reduce disease-specific mortality.4,5
The utility of chest radiography for the detection of early lung cancer is limited by several factors, including poor sensitivity for the detection of small or subtle nodules and a relatively high false-positive rate.6–8 More recently, several cohort studies and randomized, controlled trials have shown that computed tomography (CT) screening is effective for the identification of early lung cancer in high-risk patients (eg, individuals with chronic, heavy tobacco use or asbestos exposure).9–11 A recent meta-analysis concluded that CT-based screening significantly increases the number of early lung cancers identified, but also increases the number of false-positive findings (nodules) and unnecessary thoracotomies for benign lesions.12
Lung cancer screening should increase the number of patients identified at early disease stages. Treatment of early-stage lung cancer should decrease the number of patients identified with late-stage cancer, resulting in a stage shift toward earlier disease for the population as a whole. Although lung cancer screening cohort studies and randomized, controlled trials have demonstrated that screening increases the number of early-stage lung cancer cases identified, these studies have generally not demonstrated decreased rates of late-stage lung cancers or stage shifting in the populations studied. In the 1970s, the National Cancer Institute began three large-scale screening trials at Mayo Clinic, Memorial Sloan-Kettering Cancer Institute, and The Johns Hopkins University, each enrolling approximately 10,000 patients. In the Mayo trial, the incidence of advanced-stage tumors was nearly identical for the screened versus unscreened patients, with 303 cancer cases detected in the screened group versus 304 cases in the control group.13 CT-based cohort studies have also reported increased rates of early recognition of lung cancer and accompanying large increases in the number of diagnostic procedures performed. However, early controlled trials of CT screening showed no differences between screened and unscreened groups in the numbers of patients with late-stage tumors or deaths due to lung cancer.14
Results such as these have led some researchers to argue that survival benefits of screening largely reflect observational biases. For example:
Figure 1. Lead-time bias. Patients identified by screening may live longer with disease than patients diagnosed clinically, although overall survival time is not improved.Lead-time bias occurs when screening results in earlier recognition of disease, but does not change the patient’s eventual lifespan, creating the appearance that the patient’s survival time with the disease is longer (Figure 1).15 Longer lead times should be observed in a successful screening program even if eventual mortality remains exactly the same, and lead time bias is therefore an expected outcome of screening.
Figure 2. Length-time bias. Indolent tumors move more gradually from the detectable stage to the onset of symptoms. These tumors are therefore more likely to be identified by intermittent screening.Length-time bias arises from the observation that any screening test that is applied intermittently is more likely to detect indolent tumors than aggressive, fast-growing tumors that would result in clinical symptoms(Figure 2).15 Indolent tumors move more gradually from the detectable state to the onset of clinical symptoms, and are therefore especially likely to be identified by screening.
Overdiagnosis bias occurs when a screening test identifies disease that never would have affected the patient’s life in the absence of screening. This type of bias might occur if screening identifies a lesion that is so indolent that it would never cause clinical disease, or if the population is otherwise in such poor health that successfully screened patients would die from other causes.
There is no question that these biases affect reports of survival in lung cancer screening, although it is unclear whether they explain the reported benefit of screening observed in cohort studies. Screening advocates have argued that the failure to screen high-risk patients for lung cancer has the potential for significant harm. In contrast, opponents of screening have argued that there was a lack of data showing a reduction in the number of patients diagnosed with late-stage cancers or in cancer-related mortality.
IS LUNG CANCER OVERDIAGNOSED IN SCREENED POPULATIONS?
Although the apparent benefit of lung cancer screening is susceptible to different sources of bias, overdiagnosis has received the greatest attention on the basis of both theoretical concerns and observations from screening studies. Estimates of lung cancer growth suggest that a typical 10-cm tumor, which is usually large enough to be fatal, has progressed through approximately 40 volume doublings during the course of its existence. In contrast, a more survivable—and clinically detectable—1-cm tumor has progressed through approximately 30 volume doublings.16,17 A lung tumor therefore spends most of its existence relatively undetectable. It has been estimated that the median doubling time is approximately 181 days, and that 22% of lung cancers have doubling times more than 465 days.18 The appearance of tumors on CT may suggest the growth rate, with 1 study showing that solid malignant nodules had a mean doubling time of 149 days, compared with 457 days for partial ground-glass–opacity nodules, and 813 days for pure ground-glass nodules.19
These estimates suggest that if a 1-cm tumor with a history of 30 volume doublings continues to grow at a typical rate (ie, a 181-day doubling time), the patient will die of cancer within 5 years. If the tumor is among the 22% of those with a 465-day doubling time, the survival time would be 12.7 years. For malignant pure ground-glass nodules, the projected time to death is 22 years. Individuals with lung cancer are often elderly, long-term cigarette smokers with emphysema or other chronic health problems—many of whom would die of other causes before their lung cancers progressed enough to cause significant health problems.
Reprinted with permission from the American College of Chest Physicians (Raz DJ, et al. Natural history of stage I non-small cell lung cancer: implications for early detection. Chest 2007; 132:193–199).
Figure 3. Survival is worse in untreated than in treated non–small cell lung cancer patients, arguing against overdiagnosis bias. Blue line: patients receiving surgery; green line: untreated patients who refused surgery.
As an argument against the significance of overdiagnosis in lung cancer screening, it has been noted that outcomes are worse for patients identified with early-stage lung cancer in screening studies who do not receive treatment. For example, the results of a study of 1,432 patients with stage I non–small cell lung cancer (NSCLC) are illustrated in Figure 3. Survival was much better in screened patients who were treated than in those who were untreated, with almost all the untreated patients dying within 10 years of diagnosis.20 However, the subjects in this study were atypical of those in most screening studies. Thirty-three percent of the patients had squamous cell carcinoma and 61% had relatively large T2 lesions, compared with a typical screening study comprised of patients with more than 50% T1 lesions and a smaller percentage of squamous cell carcinoma.
Another argument against overdiagnosis comes from gene profiling studies that have compared genetic tumor markers for tumors identified by screening with tumors identified clinically. One study found that the expression profile of 3,231 genes was similar for patients with lung cancer identified by screening or by symptoms.21 However, these investigators also found that nine genes known to be important in tumor growth differed between screened and nonscreened populations.
The significance of overdiagnosis is supported by a long-term follow-up study from the Mayo Clinic chest radiography screening trial, which found that the number of lung cancer cases remained higher in the screening group than the control group (585 vs 500 cases) for up to 28 years after screening, suggesting an overdiagnosis of lung cancer by approximately 85 cases per 500 patients screened (approximately 17%).22 Several studies have also demonstrated that screening populations may have tumors with more favorable histology or clinical characteristics, including higher levels of bronchioloalveolar carcinoma or well-differentiated adenocarcinoma.23–25 Finally, autopsy series have found undiagnosed lung tumors in as many as 1% of patients who died from natural causes, with fewer advanced tumors found in the 1970s than in the 1950s.26,27
These arguments led most to believe randomized controlled trials of CT-based screening were needed. The largest of these, the National Lung Screening Trial (NLST), has recently reported results that will clarify the impact of lung cancer screening on cancer-related mortality.28 This study enrolled 53,456 subjects between the ages of 55 and 74 years with a history of at least 30 pack-years of smoking. Patients were randomized to baseline screening followed by annual screening for 2 years using either low-dose helical CT or chest radiography and outcome follow-up 5 years after randomization. Data analysis after 6 to 8 years of follow-up found 442 lung cancer deaths in the chest radiograph arm versus 354 in the CT arm, representing a 20.3% reduction with CT.29 Screening of 320 patients using low-dose helical CT would be required to avoid each lung cancer death. Thus, after years of debate, it has been demonstrated that it is possible to reduce lung cancer-specific mortality with CT-based screening.
ARE THERE SIGNIFICANT RISKS WITH CT-BASED SCREENING?
Reprinted with kind permission from Springer Science+Business Media (Fischbach F, et al. Detection of pulmonary nodules by multislice computed tomography: improved detection rate with reduced slice thickness. Eur Radiol 2003; 13:2378–2383).
Figure 4. Benign lung nodules visualized on computed tomography.Lung cancer screening using chest CT may be associated with certain risks. The detailed high-resolution images produced by contemporary CT reveal small benign lung nodules in as many as 74% of patients(Figure 4).24,30 Although these nodules rarely represent a significant health problem, they require follow-up procedures and contribute to patient anxiety.31 In one study, every 1,000 individuals screened with CT imaging resulted in the identification of nine cases of stage I NSCLC, 235 false-positive nodules measuring at least 5 mm, and four thoracotomies for benign lesions.12
Radiation from CT tests is a potential concern, although it is difficult to quantify the importance of this risk. One estimate of CT-related radiation exposure found that annual CT screening of 50% of the eligible population between 50 and 75 years of age in the United States would result in approximately 36,000 new cancers, or a 1.8% increase in the rate of cancer over the expected rate.32 Many patients and health care professionals are already concerned about the degree of radiation exposure from medical diagnostics. A recent study that examined cumulative radiation exposure due to medical imaging in 952,420 adults aged 18 to 64 years found that approximately 57.9% of men and 78.7% of women receive at least some annual health care-related radiation exposure.33 Radiation exposure was considered moderate (> 3–20 mSv/yr) for 18.1% of men and 20.3% of women, and was considered high (> 20–50 mSv/yr) or very high (>50 mSv/hr) for 2.3% of men and 2.1% of women.
IS SCREENING COST-EFFECTIVE?
It is difficult to calculate the cost-effectiveness of CT screening because the impact of screening on mortality and the economic implications of false-positive findings are not well understood. A cost-effectiveness analysis of helical CT screening assumed that screening would result in a 50% stage shift and a 13% reduction in mortality.34 Under these assumptions, the cost-effectiveness was greater among current smokers ($116,300 per quality-adjusted life year saved by screening) than among currently quitting smokers ($558,600) or former smokers ($2,322,700). These investigators concluded that lung cancer screening is unlikely to be cost-effective, especially among those with the lowest levels of current tobacco exposure (quitting or former smokers).
Larger stage shifts or reductions in mortality would be expected to translate into greater cost-effectiveness, although the real-world effects of screening on these parameters are uncertain. Data from a US nationwide survey suggested that only about one-half of all current smokers would opt for surgery following a positive screening result, which might significantly decrease the cost-effectiveness of treatment.35
It is unclear how well the methods used in screening studies such as the NLST would translate to actual clinical practice at a national level, or how the health care system would manage the many small lung nodules that would be identified using this approach.
HOW WILL FUTURE DEVELOPMENTS AFFECT LUNG CANCER SCREENING?
Ongoing studies will continue to refine our understanding of the impact of lung cancer screening. For example, the randomized Prostate, Lung, Colorectal, and Ovarian Screening Trial is examining chest radiograph screening versus control in both smokers and never-smokers between 55 and 74 years of age.36 It is anticipated that this study will provide important information about how well chest radiographs perform for the identification of lung cancer in high- and lower-risk populations. Large randomized trials in Europe are comparing CT with no imaging for lung cancer screening.37 Efforts to better characterize specific patient populations who are at the greatest risk of lung cancer may help to improve the efficiency and cost-effectiveness of screening. Advances in molecular testing may help to identify molecular and genetic tumor biomarkers that herald increased lung cancer risk and greater need for screening. More research is needed to better understand the optimal management of patients with small lung nodules on screening tests. Professional societies are poised to publish revised screening recommendations as data from the NLST become available. Finally, insurers will need to evaluate the evidence and develop reimbursement policies.
SUMMARY AND CONCLUSIONS
Lung cancer screening efforts conducted over the last several decades have shown that it is possible to identify early lung cancer in high-risk patient populations. However, demonstrating a clear improvement in cancer-related mortality has been more difficult. Biases inherent to noncontrolled trials of screening may explain some of the beneficial effects on survival observed in some studies. Recent results from the NLST have for the first time demonstrated a significant reduction in lung cancer mortality in high-risk patients screened for lung cancer with chest CT, although there are continuing concerns about the cost of screening, the risks from radiation exposure, and the additional testing resulting from the identification of small benign lung nodules. Ongoing research will help to maximize the benefit of lung cancer screening and minimize the related risks.
References
Holin SM, Dwork RE, Glaser S, Rikli AE, Stocklen JB. Solitary pulmonary nodules found in a community-wide chest roentgenographic survey: a five-year follow-up study. Am Rev Tuberc1959; 79:427–439.
Nash FA, Morgan JM, Tomkins JG. South London Lung Cancer Study. Br Med J1968; 2:715–721.
Obuchowski NA, Graham RJ, Baker ME, Powell KA. Ten criteria for effective screening: their application to multislice CT screening for pulmonary and colorectal cancers. AJR Am J Roentgenol2001; 176:1357–1362.
Eddy DM. Screening for lung cancer. Ann Intern Med1989; 111:232–237.
Manser RL, Irving LB, Byrnes G, Abramson MJ, Stone CA, Campbell DA. Screening for lung cancer: a systematic review and meta-analysis of controlled trials. Thorax2003; 58:784–789.
Krupinski EA, Berger WG, Dallas WJ, Roehrig H. Searching for nodules: what features attract attention and influence detection?Acad Radiol2003; 10:861–868.
Yoshida H. Local contralateral subtraction based on bilateral symmetry of lung for reduction of false positives in computerized detection of pulmonary nodules. IEEE Trans Biomed Eng2004; 51:778–789.
Shiraishi J, Abe H.Engelmann R, Doi K. Effect of high sensitivity in a computerized scheme for detecting extremely subtle solitary pulmonary nodules in chest radiographs: observer performance study. Acad Radiol2003; 10:1302–1311.
Veronesi G, Bellomi M, Scanagatta P, et al. Difficulties encountered managing nodules detected during a computed tomography lung cancer screening program. J Thorac Cardiovasc Surg2008; 136:611–617.
Wilson DO, Weissfeld JL, Fuhrman CR, et al. The Pittsburgh Lung Screening Study (PLuSS): outcomes within 3 years of a first computed tomography scan [published online ahead of print July 17, 2008]. Am J Respir Crit Care Med2008; 178:956–961. doi: 10.1164/rccm.200802-336OC
Fasola G, Belvedere O, Aita M, et al. Low-dose computed tomography screening for lung cancer and pleural mesothelioma in an asbestos-exposed population: baseline results of a prospective, nonrandomized feasibility trial—an Alpe-adria Thoracic Oncology Multidisciplinary Group Study (ATOM 002). Oncologist2007; 12:1215–1224.
Gopal M, Abdullah SE, Grady JJ, Goodwin JS. Screening for lung cancer with low-dose computed tomography: a systematic review and meta-analysis of the baseline findings of randomized controlled trials. J Thorac Oncol2010; 5:1233–1239.
Fontana RS, Sanderson DR, Woolner LB, et al. Screening for lung cancer: a critique of the Mayo Lung Project. Cancer1991; 67( suppl 4):1155–1164.
Bach PB, Jett JR, Pastorino U, Tockman MS, Swensen SJ, Begg CB. Computed tomography screening and lung cancer outcomes. JAMA2007; 297:953–961.
Patz EF, Goodman PC, Bepler G. Screening for lung cancer. N Engl J Med2000; 343:1627–1633.
Weiss W. Implications of tumor growth rate for the natural history of lung cancer. J Occup Med1984; 26:345–352.
Reich JM. A critical appraisal of overdiagnosis: estimates of its magnitude and implications for lung cancer screening. Thorax2008; 63:377–383.
Winer-Muram HT, Jennings SG, Tarver RD, et al. Volumetric growth rate of stage I lung cancer prior to treatment: serial CT scanning. Radiology2002; 223:798–805.
Hasegawa M, Sone S, Takashima S, et al. Growth rate of small lung cancers detected on mass CT screening. Br J Radiol2000; 73:1252–1259.
Raz DJ, Zell JA, Ou SH, Gandara DR, Anton-Culver H, Jablons DM. Natural history of stage I non-small cell lung cancer: implications for early detection [published online ahead of print May 15, 2007]. Chest2007; 132:193–199. doi: 10.1378/chest.06-3096
Bianchi F, Hu J, Pelosi G, et al. Lung cancers detected by screening with spiral computed tomography have a malignant phenotype when analyzed by cDNA microarray. Clin Cancer Res2004; 10( 18 Pt 1):6023–6028.
Marcus PM, Bergstralh EJ, Zweig MH, Harris A, Offord KP, Fontana RS. Extended lung cancer incidence follow-up in the Mayo Lung Project and overdiagnosis. J Natl Cancer Inst2006; 98:748–756.
Sone S, Li F, Yang ZG, et al. Results of three-year mass screening programme for lung cancer using mobile low-dose spiral computed tomography scanner. Br J Cancer2001; 84:25–32.
Swensen SJ, Jett JR, Hartman TE, et al. CT screening for lung cancer: five-year prospective experience [published online ahead of print February 4, 2005]. Radiology2005; 235:259–265. doi: 10.1148/radiol.2351041662
International Early Lung Cancer Action Program Investigators, Henschke CI, Yankelevitz DF, Libby DM, et al. Survival of patients with stage I lung cancer detected on CT screening. N Engl J Med2006; 355:1763–1771.
Manser RL, Dodd M, Byrnes G, Irving LB, Campbell DA. Incidental lung cancers identified at coronial autopsy: implications for overdiagnosis of lung cancer by screening. Respir Med2005; 99:501–507.
Chan CK, Wells CK, McFarlane MJ, Feinstein AR. More lung cancer but better survival: implications of secular trends in “necropsy surprise” rates. Chest1989; 96:291–296.
National Lung Screening Trial Research Team, Aberle DR, Adams AM, Berg CD, et al. Baseline characteristics of participants in the randomized national lung screening trial [published correction appears in J Natl Cancer Inst 2011; 103:1560]. J Natl Cancer Inst2010; 102:1771–1779.
Fischbach F, Knollmann F, Griesshaber V, Freund T, Akkol E, Felix R. Detection of pulmonary nodules by multislice computed tomography: improved detection rate with reduced slice thickness [published online ahead of print May 13, 2003]. Eur Radiol2003; 13:2378–2383. doi: 10.1007/s00330-003-1915-7
van den Bergh KA, Essink-Bot ML, Borsboom GJ, et al. Short-term health-related quality of life consequences in a lung cancer CT screening trial (NELSON) [published online ahead of pring November 24, 2009]. Br J Cancer2010; 102:27–34. doi: 10.1038/sj.bjc.6605459
Brenner DJ. Radiation risks potentially associated with low-dose CT screening of adult smokers for lung cancer. Radiology2004; 231:440–445.
Fazel R, Krumholz HM, Wang Y, et al. Exposure to low-dose ionizing radiation from medical imaging procedures. N Engl J Med2009; 361:849–857.
Mahadevia PJ, Fleisher LA, Frick KD, Eng J, Goodman SN, Powe NR. Lung cancer screening with helical computed tomography in older adult smokers: a decision and cost-effectiveness analysis. JAMA2003; 289:313–322.
Silvestri GA, Nietert PJ, Zoller J, Carter C, Bradford D. Attitudes towards screening for lung cancer among smokers and their nonsmoking counterparts. [published online ahead of print November 13, 2006]Thorax2007; 62:126–130. doi: 10.1136/thx.2005.056036
Tammemagi CM, Pinsky PF, Caporaso NE, et al. Lung cancer risk prediction: Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial models and validation [published online ahead of print May 23, 2011]. J Natl Cancer Inst2011; 103:1058–1068. doi: 10.1093/jnci/djr173
van Klaveren RJ, Oudkerk M, Prokop M, et al. Management of lung nodules detected by volume CT scanning. N Engl J Med2009; 361:2221–2229.
Peter Mazzone, MD, MPH, FCCP Director of Education, Lung Cancer Program, and Pulmonary Rehabilitation Program; Respiratory Institute, Cleveland Clinic, Cleveland, OH
Correspondence: Peter Mazzone, MD, MPH, FCCP, Critical Care Medicine, Cleveland Clinic, 9500 Euclid Avenue, A90, Cleveland, OH 44195; mazzonp@ccf.org
Dr. Mazzone reported that he has been a member of advisory committees for Boehringer Ingelheim and Oncimmune. He has research supported by Metabolomx.
This article was developed from an audio transcript of Dr. Mazzone’s presentation at the “Advances in Lung Cancer Evaluation and Management” symposium held in Cleveland, Ohio, on April 30, 2011. The transcript was formatted and edited by Cleveland Clinic Journal of Medicine staff for clarity and conciseness and was then reviewed, revised, and approved by Dr. Mazzone.
Peter Mazzone, MD, MPH, FCCP Director of Education, Lung Cancer Program, and Pulmonary Rehabilitation Program; Respiratory Institute, Cleveland Clinic, Cleveland, OH
Correspondence: Peter Mazzone, MD, MPH, FCCP, Critical Care Medicine, Cleveland Clinic, 9500 Euclid Avenue, A90, Cleveland, OH 44195; mazzonp@ccf.org
Dr. Mazzone reported that he has been a member of advisory committees for Boehringer Ingelheim and Oncimmune. He has research supported by Metabolomx.
This article was developed from an audio transcript of Dr. Mazzone’s presentation at the “Advances in Lung Cancer Evaluation and Management” symposium held in Cleveland, Ohio, on April 30, 2011. The transcript was formatted and edited by Cleveland Clinic Journal of Medicine staff for clarity and conciseness and was then reviewed, revised, and approved by Dr. Mazzone.
Author and Disclosure Information
Peter Mazzone, MD, MPH, FCCP Director of Education, Lung Cancer Program, and Pulmonary Rehabilitation Program; Respiratory Institute, Cleveland Clinic, Cleveland, OH
Correspondence: Peter Mazzone, MD, MPH, FCCP, Critical Care Medicine, Cleveland Clinic, 9500 Euclid Avenue, A90, Cleveland, OH 44195; mazzonp@ccf.org
Dr. Mazzone reported that he has been a member of advisory committees for Boehringer Ingelheim and Oncimmune. He has research supported by Metabolomx.
This article was developed from an audio transcript of Dr. Mazzone’s presentation at the “Advances in Lung Cancer Evaluation and Management” symposium held in Cleveland, Ohio, on April 30, 2011. The transcript was formatted and edited by Cleveland Clinic Journal of Medicine staff for clarity and conciseness and was then reviewed, revised, and approved by Dr. Mazzone.
Screening is the testing of an individual who is at risk for a disease, but who does not exhibit signs or symptoms of the disease. The goal of screening is to detect disease at a stage when cure or control is possible, and an effective screening program should reduce the number of disease-specific deaths in the screened population. Screening should focus on diseases that are associated with potentially serious consequences and that are detectable in the preclinical phase, yet it should avoid identifying “pseudodisease” (ie, positive test findings that would not be expected to affect the patient’s health) or causing morbidity due to the test procedure itself.1 Finally, screening is only worthwhile when treatment of the disease is more effective when administered early.
Since lung cancer screening began in the 1950s,2,3 many studies have attempted to define the medical benefits and economic impact of widespread screening. Many important unresolved issues remain, including the effectiveness of lung cancer screening for reducing disease-specific mortality, the potential harms of screening, its cost-effectiveness, and the potential impact of new research methods on the early identification of lung cancer.
DOES LUNG CANCER SCREENING REDUCE DISEASE-SPECIFIC MORTALITY?
Early studies examined the usefulness of large-scale chest radiograph programs, either with or without sputum cytology, for lung cancer screening. Although several studies reported that radiographic screening identified patients with early lung cancer and reported higher survival rates, reviews and meta-analyses of these reports concluded that screening did not significantly reduce disease-specific mortality.4,5
The utility of chest radiography for the detection of early lung cancer is limited by several factors, including poor sensitivity for the detection of small or subtle nodules and a relatively high false-positive rate.6–8 More recently, several cohort studies and randomized, controlled trials have shown that computed tomography (CT) screening is effective for the identification of early lung cancer in high-risk patients (eg, individuals with chronic, heavy tobacco use or asbestos exposure).9–11 A recent meta-analysis concluded that CT-based screening significantly increases the number of early lung cancers identified, but also increases the number of false-positive findings (nodules) and unnecessary thoracotomies for benign lesions.12
Lung cancer screening should increase the number of patients identified at early disease stages. Treatment of early-stage lung cancer should decrease the number of patients identified with late-stage cancer, resulting in a stage shift toward earlier disease for the population as a whole. Although lung cancer screening cohort studies and randomized, controlled trials have demonstrated that screening increases the number of early-stage lung cancer cases identified, these studies have generally not demonstrated decreased rates of late-stage lung cancers or stage shifting in the populations studied. In the 1970s, the National Cancer Institute began three large-scale screening trials at Mayo Clinic, Memorial Sloan-Kettering Cancer Institute, and The Johns Hopkins University, each enrolling approximately 10,000 patients. In the Mayo trial, the incidence of advanced-stage tumors was nearly identical for the screened versus unscreened patients, with 303 cancer cases detected in the screened group versus 304 cases in the control group.13 CT-based cohort studies have also reported increased rates of early recognition of lung cancer and accompanying large increases in the number of diagnostic procedures performed. However, early controlled trials of CT screening showed no differences between screened and unscreened groups in the numbers of patients with late-stage tumors or deaths due to lung cancer.14
Results such as these have led some researchers to argue that survival benefits of screening largely reflect observational biases. For example:
Figure 1. Lead-time bias. Patients identified by screening may live longer with disease than patients diagnosed clinically, although overall survival time is not improved.Lead-time bias occurs when screening results in earlier recognition of disease, but does not change the patient’s eventual lifespan, creating the appearance that the patient’s survival time with the disease is longer (Figure 1).15 Longer lead times should be observed in a successful screening program even if eventual mortality remains exactly the same, and lead time bias is therefore an expected outcome of screening.
Figure 2. Length-time bias. Indolent tumors move more gradually from the detectable stage to the onset of symptoms. These tumors are therefore more likely to be identified by intermittent screening.Length-time bias arises from the observation that any screening test that is applied intermittently is more likely to detect indolent tumors than aggressive, fast-growing tumors that would result in clinical symptoms(Figure 2).15 Indolent tumors move more gradually from the detectable state to the onset of clinical symptoms, and are therefore especially likely to be identified by screening.
Overdiagnosis bias occurs when a screening test identifies disease that never would have affected the patient’s life in the absence of screening. This type of bias might occur if screening identifies a lesion that is so indolent that it would never cause clinical disease, or if the population is otherwise in such poor health that successfully screened patients would die from other causes.
There is no question that these biases affect reports of survival in lung cancer screening, although it is unclear whether they explain the reported benefit of screening observed in cohort studies. Screening advocates have argued that the failure to screen high-risk patients for lung cancer has the potential for significant harm. In contrast, opponents of screening have argued that there was a lack of data showing a reduction in the number of patients diagnosed with late-stage cancers or in cancer-related mortality.
IS LUNG CANCER OVERDIAGNOSED IN SCREENED POPULATIONS?
Although the apparent benefit of lung cancer screening is susceptible to different sources of bias, overdiagnosis has received the greatest attention on the basis of both theoretical concerns and observations from screening studies. Estimates of lung cancer growth suggest that a typical 10-cm tumor, which is usually large enough to be fatal, has progressed through approximately 40 volume doublings during the course of its existence. In contrast, a more survivable—and clinically detectable—1-cm tumor has progressed through approximately 30 volume doublings.16,17 A lung tumor therefore spends most of its existence relatively undetectable. It has been estimated that the median doubling time is approximately 181 days, and that 22% of lung cancers have doubling times more than 465 days.18 The appearance of tumors on CT may suggest the growth rate, with 1 study showing that solid malignant nodules had a mean doubling time of 149 days, compared with 457 days for partial ground-glass–opacity nodules, and 813 days for pure ground-glass nodules.19
These estimates suggest that if a 1-cm tumor with a history of 30 volume doublings continues to grow at a typical rate (ie, a 181-day doubling time), the patient will die of cancer within 5 years. If the tumor is among the 22% of those with a 465-day doubling time, the survival time would be 12.7 years. For malignant pure ground-glass nodules, the projected time to death is 22 years. Individuals with lung cancer are often elderly, long-term cigarette smokers with emphysema or other chronic health problems—many of whom would die of other causes before their lung cancers progressed enough to cause significant health problems.
Reprinted with permission from the American College of Chest Physicians (Raz DJ, et al. Natural history of stage I non-small cell lung cancer: implications for early detection. Chest 2007; 132:193–199).
Figure 3. Survival is worse in untreated than in treated non–small cell lung cancer patients, arguing against overdiagnosis bias. Blue line: patients receiving surgery; green line: untreated patients who refused surgery.
As an argument against the significance of overdiagnosis in lung cancer screening, it has been noted that outcomes are worse for patients identified with early-stage lung cancer in screening studies who do not receive treatment. For example, the results of a study of 1,432 patients with stage I non–small cell lung cancer (NSCLC) are illustrated in Figure 3. Survival was much better in screened patients who were treated than in those who were untreated, with almost all the untreated patients dying within 10 years of diagnosis.20 However, the subjects in this study were atypical of those in most screening studies. Thirty-three percent of the patients had squamous cell carcinoma and 61% had relatively large T2 lesions, compared with a typical screening study comprised of patients with more than 50% T1 lesions and a smaller percentage of squamous cell carcinoma.
Another argument against overdiagnosis comes from gene profiling studies that have compared genetic tumor markers for tumors identified by screening with tumors identified clinically. One study found that the expression profile of 3,231 genes was similar for patients with lung cancer identified by screening or by symptoms.21 However, these investigators also found that nine genes known to be important in tumor growth differed between screened and nonscreened populations.
The significance of overdiagnosis is supported by a long-term follow-up study from the Mayo Clinic chest radiography screening trial, which found that the number of lung cancer cases remained higher in the screening group than the control group (585 vs 500 cases) for up to 28 years after screening, suggesting an overdiagnosis of lung cancer by approximately 85 cases per 500 patients screened (approximately 17%).22 Several studies have also demonstrated that screening populations may have tumors with more favorable histology or clinical characteristics, including higher levels of bronchioloalveolar carcinoma or well-differentiated adenocarcinoma.23–25 Finally, autopsy series have found undiagnosed lung tumors in as many as 1% of patients who died from natural causes, with fewer advanced tumors found in the 1970s than in the 1950s.26,27
These arguments led most to believe randomized controlled trials of CT-based screening were needed. The largest of these, the National Lung Screening Trial (NLST), has recently reported results that will clarify the impact of lung cancer screening on cancer-related mortality.28 This study enrolled 53,456 subjects between the ages of 55 and 74 years with a history of at least 30 pack-years of smoking. Patients were randomized to baseline screening followed by annual screening for 2 years using either low-dose helical CT or chest radiography and outcome follow-up 5 years after randomization. Data analysis after 6 to 8 years of follow-up found 442 lung cancer deaths in the chest radiograph arm versus 354 in the CT arm, representing a 20.3% reduction with CT.29 Screening of 320 patients using low-dose helical CT would be required to avoid each lung cancer death. Thus, after years of debate, it has been demonstrated that it is possible to reduce lung cancer-specific mortality with CT-based screening.
ARE THERE SIGNIFICANT RISKS WITH CT-BASED SCREENING?
Reprinted with kind permission from Springer Science+Business Media (Fischbach F, et al. Detection of pulmonary nodules by multislice computed tomography: improved detection rate with reduced slice thickness. Eur Radiol 2003; 13:2378–2383).
Figure 4. Benign lung nodules visualized on computed tomography.Lung cancer screening using chest CT may be associated with certain risks. The detailed high-resolution images produced by contemporary CT reveal small benign lung nodules in as many as 74% of patients(Figure 4).24,30 Although these nodules rarely represent a significant health problem, they require follow-up procedures and contribute to patient anxiety.31 In one study, every 1,000 individuals screened with CT imaging resulted in the identification of nine cases of stage I NSCLC, 235 false-positive nodules measuring at least 5 mm, and four thoracotomies for benign lesions.12
Radiation from CT tests is a potential concern, although it is difficult to quantify the importance of this risk. One estimate of CT-related radiation exposure found that annual CT screening of 50% of the eligible population between 50 and 75 years of age in the United States would result in approximately 36,000 new cancers, or a 1.8% increase in the rate of cancer over the expected rate.32 Many patients and health care professionals are already concerned about the degree of radiation exposure from medical diagnostics. A recent study that examined cumulative radiation exposure due to medical imaging in 952,420 adults aged 18 to 64 years found that approximately 57.9% of men and 78.7% of women receive at least some annual health care-related radiation exposure.33 Radiation exposure was considered moderate (> 3–20 mSv/yr) for 18.1% of men and 20.3% of women, and was considered high (> 20–50 mSv/yr) or very high (>50 mSv/hr) for 2.3% of men and 2.1% of women.
IS SCREENING COST-EFFECTIVE?
It is difficult to calculate the cost-effectiveness of CT screening because the impact of screening on mortality and the economic implications of false-positive findings are not well understood. A cost-effectiveness analysis of helical CT screening assumed that screening would result in a 50% stage shift and a 13% reduction in mortality.34 Under these assumptions, the cost-effectiveness was greater among current smokers ($116,300 per quality-adjusted life year saved by screening) than among currently quitting smokers ($558,600) or former smokers ($2,322,700). These investigators concluded that lung cancer screening is unlikely to be cost-effective, especially among those with the lowest levels of current tobacco exposure (quitting or former smokers).
Larger stage shifts or reductions in mortality would be expected to translate into greater cost-effectiveness, although the real-world effects of screening on these parameters are uncertain. Data from a US nationwide survey suggested that only about one-half of all current smokers would opt for surgery following a positive screening result, which might significantly decrease the cost-effectiveness of treatment.35
It is unclear how well the methods used in screening studies such as the NLST would translate to actual clinical practice at a national level, or how the health care system would manage the many small lung nodules that would be identified using this approach.
HOW WILL FUTURE DEVELOPMENTS AFFECT LUNG CANCER SCREENING?
Ongoing studies will continue to refine our understanding of the impact of lung cancer screening. For example, the randomized Prostate, Lung, Colorectal, and Ovarian Screening Trial is examining chest radiograph screening versus control in both smokers and never-smokers between 55 and 74 years of age.36 It is anticipated that this study will provide important information about how well chest radiographs perform for the identification of lung cancer in high- and lower-risk populations. Large randomized trials in Europe are comparing CT with no imaging for lung cancer screening.37 Efforts to better characterize specific patient populations who are at the greatest risk of lung cancer may help to improve the efficiency and cost-effectiveness of screening. Advances in molecular testing may help to identify molecular and genetic tumor biomarkers that herald increased lung cancer risk and greater need for screening. More research is needed to better understand the optimal management of patients with small lung nodules on screening tests. Professional societies are poised to publish revised screening recommendations as data from the NLST become available. Finally, insurers will need to evaluate the evidence and develop reimbursement policies.
SUMMARY AND CONCLUSIONS
Lung cancer screening efforts conducted over the last several decades have shown that it is possible to identify early lung cancer in high-risk patient populations. However, demonstrating a clear improvement in cancer-related mortality has been more difficult. Biases inherent to noncontrolled trials of screening may explain some of the beneficial effects on survival observed in some studies. Recent results from the NLST have for the first time demonstrated a significant reduction in lung cancer mortality in high-risk patients screened for lung cancer with chest CT, although there are continuing concerns about the cost of screening, the risks from radiation exposure, and the additional testing resulting from the identification of small benign lung nodules. Ongoing research will help to maximize the benefit of lung cancer screening and minimize the related risks.
Screening is the testing of an individual who is at risk for a disease, but who does not exhibit signs or symptoms of the disease. The goal of screening is to detect disease at a stage when cure or control is possible, and an effective screening program should reduce the number of disease-specific deaths in the screened population. Screening should focus on diseases that are associated with potentially serious consequences and that are detectable in the preclinical phase, yet it should avoid identifying “pseudodisease” (ie, positive test findings that would not be expected to affect the patient’s health) or causing morbidity due to the test procedure itself.1 Finally, screening is only worthwhile when treatment of the disease is more effective when administered early.
Since lung cancer screening began in the 1950s,2,3 many studies have attempted to define the medical benefits and economic impact of widespread screening. Many important unresolved issues remain, including the effectiveness of lung cancer screening for reducing disease-specific mortality, the potential harms of screening, its cost-effectiveness, and the potential impact of new research methods on the early identification of lung cancer.
DOES LUNG CANCER SCREENING REDUCE DISEASE-SPECIFIC MORTALITY?
Early studies examined the usefulness of large-scale chest radiograph programs, either with or without sputum cytology, for lung cancer screening. Although several studies reported that radiographic screening identified patients with early lung cancer and reported higher survival rates, reviews and meta-analyses of these reports concluded that screening did not significantly reduce disease-specific mortality.4,5
The utility of chest radiography for the detection of early lung cancer is limited by several factors, including poor sensitivity for the detection of small or subtle nodules and a relatively high false-positive rate.6–8 More recently, several cohort studies and randomized, controlled trials have shown that computed tomography (CT) screening is effective for the identification of early lung cancer in high-risk patients (eg, individuals with chronic, heavy tobacco use or asbestos exposure).9–11 A recent meta-analysis concluded that CT-based screening significantly increases the number of early lung cancers identified, but also increases the number of false-positive findings (nodules) and unnecessary thoracotomies for benign lesions.12
Lung cancer screening should increase the number of patients identified at early disease stages. Treatment of early-stage lung cancer should decrease the number of patients identified with late-stage cancer, resulting in a stage shift toward earlier disease for the population as a whole. Although lung cancer screening cohort studies and randomized, controlled trials have demonstrated that screening increases the number of early-stage lung cancer cases identified, these studies have generally not demonstrated decreased rates of late-stage lung cancers or stage shifting in the populations studied. In the 1970s, the National Cancer Institute began three large-scale screening trials at Mayo Clinic, Memorial Sloan-Kettering Cancer Institute, and The Johns Hopkins University, each enrolling approximately 10,000 patients. In the Mayo trial, the incidence of advanced-stage tumors was nearly identical for the screened versus unscreened patients, with 303 cancer cases detected in the screened group versus 304 cases in the control group.13 CT-based cohort studies have also reported increased rates of early recognition of lung cancer and accompanying large increases in the number of diagnostic procedures performed. However, early controlled trials of CT screening showed no differences between screened and unscreened groups in the numbers of patients with late-stage tumors or deaths due to lung cancer.14
Results such as these have led some researchers to argue that survival benefits of screening largely reflect observational biases. For example:
Figure 1. Lead-time bias. Patients identified by screening may live longer with disease than patients diagnosed clinically, although overall survival time is not improved.Lead-time bias occurs when screening results in earlier recognition of disease, but does not change the patient’s eventual lifespan, creating the appearance that the patient’s survival time with the disease is longer (Figure 1).15 Longer lead times should be observed in a successful screening program even if eventual mortality remains exactly the same, and lead time bias is therefore an expected outcome of screening.
Figure 2. Length-time bias. Indolent tumors move more gradually from the detectable stage to the onset of symptoms. These tumors are therefore more likely to be identified by intermittent screening.Length-time bias arises from the observation that any screening test that is applied intermittently is more likely to detect indolent tumors than aggressive, fast-growing tumors that would result in clinical symptoms(Figure 2).15 Indolent tumors move more gradually from the detectable state to the onset of clinical symptoms, and are therefore especially likely to be identified by screening.
Overdiagnosis bias occurs when a screening test identifies disease that never would have affected the patient’s life in the absence of screening. This type of bias might occur if screening identifies a lesion that is so indolent that it would never cause clinical disease, or if the population is otherwise in such poor health that successfully screened patients would die from other causes.
There is no question that these biases affect reports of survival in lung cancer screening, although it is unclear whether they explain the reported benefit of screening observed in cohort studies. Screening advocates have argued that the failure to screen high-risk patients for lung cancer has the potential for significant harm. In contrast, opponents of screening have argued that there was a lack of data showing a reduction in the number of patients diagnosed with late-stage cancers or in cancer-related mortality.
IS LUNG CANCER OVERDIAGNOSED IN SCREENED POPULATIONS?
Although the apparent benefit of lung cancer screening is susceptible to different sources of bias, overdiagnosis has received the greatest attention on the basis of both theoretical concerns and observations from screening studies. Estimates of lung cancer growth suggest that a typical 10-cm tumor, which is usually large enough to be fatal, has progressed through approximately 40 volume doublings during the course of its existence. In contrast, a more survivable—and clinically detectable—1-cm tumor has progressed through approximately 30 volume doublings.16,17 A lung tumor therefore spends most of its existence relatively undetectable. It has been estimated that the median doubling time is approximately 181 days, and that 22% of lung cancers have doubling times more than 465 days.18 The appearance of tumors on CT may suggest the growth rate, with 1 study showing that solid malignant nodules had a mean doubling time of 149 days, compared with 457 days for partial ground-glass–opacity nodules, and 813 days for pure ground-glass nodules.19
These estimates suggest that if a 1-cm tumor with a history of 30 volume doublings continues to grow at a typical rate (ie, a 181-day doubling time), the patient will die of cancer within 5 years. If the tumor is among the 22% of those with a 465-day doubling time, the survival time would be 12.7 years. For malignant pure ground-glass nodules, the projected time to death is 22 years. Individuals with lung cancer are often elderly, long-term cigarette smokers with emphysema or other chronic health problems—many of whom would die of other causes before their lung cancers progressed enough to cause significant health problems.
Reprinted with permission from the American College of Chest Physicians (Raz DJ, et al. Natural history of stage I non-small cell lung cancer: implications for early detection. Chest 2007; 132:193–199).
Figure 3. Survival is worse in untreated than in treated non–small cell lung cancer patients, arguing against overdiagnosis bias. Blue line: patients receiving surgery; green line: untreated patients who refused surgery.
As an argument against the significance of overdiagnosis in lung cancer screening, it has been noted that outcomes are worse for patients identified with early-stage lung cancer in screening studies who do not receive treatment. For example, the results of a study of 1,432 patients with stage I non–small cell lung cancer (NSCLC) are illustrated in Figure 3. Survival was much better in screened patients who were treated than in those who were untreated, with almost all the untreated patients dying within 10 years of diagnosis.20 However, the subjects in this study were atypical of those in most screening studies. Thirty-three percent of the patients had squamous cell carcinoma and 61% had relatively large T2 lesions, compared with a typical screening study comprised of patients with more than 50% T1 lesions and a smaller percentage of squamous cell carcinoma.
Another argument against overdiagnosis comes from gene profiling studies that have compared genetic tumor markers for tumors identified by screening with tumors identified clinically. One study found that the expression profile of 3,231 genes was similar for patients with lung cancer identified by screening or by symptoms.21 However, these investigators also found that nine genes known to be important in tumor growth differed between screened and nonscreened populations.
The significance of overdiagnosis is supported by a long-term follow-up study from the Mayo Clinic chest radiography screening trial, which found that the number of lung cancer cases remained higher in the screening group than the control group (585 vs 500 cases) for up to 28 years after screening, suggesting an overdiagnosis of lung cancer by approximately 85 cases per 500 patients screened (approximately 17%).22 Several studies have also demonstrated that screening populations may have tumors with more favorable histology or clinical characteristics, including higher levels of bronchioloalveolar carcinoma or well-differentiated adenocarcinoma.23–25 Finally, autopsy series have found undiagnosed lung tumors in as many as 1% of patients who died from natural causes, with fewer advanced tumors found in the 1970s than in the 1950s.26,27
These arguments led most to believe randomized controlled trials of CT-based screening were needed. The largest of these, the National Lung Screening Trial (NLST), has recently reported results that will clarify the impact of lung cancer screening on cancer-related mortality.28 This study enrolled 53,456 subjects between the ages of 55 and 74 years with a history of at least 30 pack-years of smoking. Patients were randomized to baseline screening followed by annual screening for 2 years using either low-dose helical CT or chest radiography and outcome follow-up 5 years after randomization. Data analysis after 6 to 8 years of follow-up found 442 lung cancer deaths in the chest radiograph arm versus 354 in the CT arm, representing a 20.3% reduction with CT.29 Screening of 320 patients using low-dose helical CT would be required to avoid each lung cancer death. Thus, after years of debate, it has been demonstrated that it is possible to reduce lung cancer-specific mortality with CT-based screening.
ARE THERE SIGNIFICANT RISKS WITH CT-BASED SCREENING?
Reprinted with kind permission from Springer Science+Business Media (Fischbach F, et al. Detection of pulmonary nodules by multislice computed tomography: improved detection rate with reduced slice thickness. Eur Radiol 2003; 13:2378–2383).
Figure 4. Benign lung nodules visualized on computed tomography.Lung cancer screening using chest CT may be associated with certain risks. The detailed high-resolution images produced by contemporary CT reveal small benign lung nodules in as many as 74% of patients(Figure 4).24,30 Although these nodules rarely represent a significant health problem, they require follow-up procedures and contribute to patient anxiety.31 In one study, every 1,000 individuals screened with CT imaging resulted in the identification of nine cases of stage I NSCLC, 235 false-positive nodules measuring at least 5 mm, and four thoracotomies for benign lesions.12
Radiation from CT tests is a potential concern, although it is difficult to quantify the importance of this risk. One estimate of CT-related radiation exposure found that annual CT screening of 50% of the eligible population between 50 and 75 years of age in the United States would result in approximately 36,000 new cancers, or a 1.8% increase in the rate of cancer over the expected rate.32 Many patients and health care professionals are already concerned about the degree of radiation exposure from medical diagnostics. A recent study that examined cumulative radiation exposure due to medical imaging in 952,420 adults aged 18 to 64 years found that approximately 57.9% of men and 78.7% of women receive at least some annual health care-related radiation exposure.33 Radiation exposure was considered moderate (> 3–20 mSv/yr) for 18.1% of men and 20.3% of women, and was considered high (> 20–50 mSv/yr) or very high (>50 mSv/hr) for 2.3% of men and 2.1% of women.
IS SCREENING COST-EFFECTIVE?
It is difficult to calculate the cost-effectiveness of CT screening because the impact of screening on mortality and the economic implications of false-positive findings are not well understood. A cost-effectiveness analysis of helical CT screening assumed that screening would result in a 50% stage shift and a 13% reduction in mortality.34 Under these assumptions, the cost-effectiveness was greater among current smokers ($116,300 per quality-adjusted life year saved by screening) than among currently quitting smokers ($558,600) or former smokers ($2,322,700). These investigators concluded that lung cancer screening is unlikely to be cost-effective, especially among those with the lowest levels of current tobacco exposure (quitting or former smokers).
Larger stage shifts or reductions in mortality would be expected to translate into greater cost-effectiveness, although the real-world effects of screening on these parameters are uncertain. Data from a US nationwide survey suggested that only about one-half of all current smokers would opt for surgery following a positive screening result, which might significantly decrease the cost-effectiveness of treatment.35
It is unclear how well the methods used in screening studies such as the NLST would translate to actual clinical practice at a national level, or how the health care system would manage the many small lung nodules that would be identified using this approach.
HOW WILL FUTURE DEVELOPMENTS AFFECT LUNG CANCER SCREENING?
Ongoing studies will continue to refine our understanding of the impact of lung cancer screening. For example, the randomized Prostate, Lung, Colorectal, and Ovarian Screening Trial is examining chest radiograph screening versus control in both smokers and never-smokers between 55 and 74 years of age.36 It is anticipated that this study will provide important information about how well chest radiographs perform for the identification of lung cancer in high- and lower-risk populations. Large randomized trials in Europe are comparing CT with no imaging for lung cancer screening.37 Efforts to better characterize specific patient populations who are at the greatest risk of lung cancer may help to improve the efficiency and cost-effectiveness of screening. Advances in molecular testing may help to identify molecular and genetic tumor biomarkers that herald increased lung cancer risk and greater need for screening. More research is needed to better understand the optimal management of patients with small lung nodules on screening tests. Professional societies are poised to publish revised screening recommendations as data from the NLST become available. Finally, insurers will need to evaluate the evidence and develop reimbursement policies.
SUMMARY AND CONCLUSIONS
Lung cancer screening efforts conducted over the last several decades have shown that it is possible to identify early lung cancer in high-risk patient populations. However, demonstrating a clear improvement in cancer-related mortality has been more difficult. Biases inherent to noncontrolled trials of screening may explain some of the beneficial effects on survival observed in some studies. Recent results from the NLST have for the first time demonstrated a significant reduction in lung cancer mortality in high-risk patients screened for lung cancer with chest CT, although there are continuing concerns about the cost of screening, the risks from radiation exposure, and the additional testing resulting from the identification of small benign lung nodules. Ongoing research will help to maximize the benefit of lung cancer screening and minimize the related risks.
References
Holin SM, Dwork RE, Glaser S, Rikli AE, Stocklen JB. Solitary pulmonary nodules found in a community-wide chest roentgenographic survey: a five-year follow-up study. Am Rev Tuberc1959; 79:427–439.
Nash FA, Morgan JM, Tomkins JG. South London Lung Cancer Study. Br Med J1968; 2:715–721.
Obuchowski NA, Graham RJ, Baker ME, Powell KA. Ten criteria for effective screening: their application to multislice CT screening for pulmonary and colorectal cancers. AJR Am J Roentgenol2001; 176:1357–1362.
Eddy DM. Screening for lung cancer. Ann Intern Med1989; 111:232–237.
Manser RL, Irving LB, Byrnes G, Abramson MJ, Stone CA, Campbell DA. Screening for lung cancer: a systematic review and meta-analysis of controlled trials. Thorax2003; 58:784–789.
Krupinski EA, Berger WG, Dallas WJ, Roehrig H. Searching for nodules: what features attract attention and influence detection?Acad Radiol2003; 10:861–868.
Yoshida H. Local contralateral subtraction based on bilateral symmetry of lung for reduction of false positives in computerized detection of pulmonary nodules. IEEE Trans Biomed Eng2004; 51:778–789.
Shiraishi J, Abe H.Engelmann R, Doi K. Effect of high sensitivity in a computerized scheme for detecting extremely subtle solitary pulmonary nodules in chest radiographs: observer performance study. Acad Radiol2003; 10:1302–1311.
Veronesi G, Bellomi M, Scanagatta P, et al. Difficulties encountered managing nodules detected during a computed tomography lung cancer screening program. J Thorac Cardiovasc Surg2008; 136:611–617.
Wilson DO, Weissfeld JL, Fuhrman CR, et al. The Pittsburgh Lung Screening Study (PLuSS): outcomes within 3 years of a first computed tomography scan [published online ahead of print July 17, 2008]. Am J Respir Crit Care Med2008; 178:956–961. doi: 10.1164/rccm.200802-336OC
Fasola G, Belvedere O, Aita M, et al. Low-dose computed tomography screening for lung cancer and pleural mesothelioma in an asbestos-exposed population: baseline results of a prospective, nonrandomized feasibility trial—an Alpe-adria Thoracic Oncology Multidisciplinary Group Study (ATOM 002). Oncologist2007; 12:1215–1224.
Gopal M, Abdullah SE, Grady JJ, Goodwin JS. Screening for lung cancer with low-dose computed tomography: a systematic review and meta-analysis of the baseline findings of randomized controlled trials. J Thorac Oncol2010; 5:1233–1239.
Fontana RS, Sanderson DR, Woolner LB, et al. Screening for lung cancer: a critique of the Mayo Lung Project. Cancer1991; 67( suppl 4):1155–1164.
Bach PB, Jett JR, Pastorino U, Tockman MS, Swensen SJ, Begg CB. Computed tomography screening and lung cancer outcomes. JAMA2007; 297:953–961.
Patz EF, Goodman PC, Bepler G. Screening for lung cancer. N Engl J Med2000; 343:1627–1633.
Weiss W. Implications of tumor growth rate for the natural history of lung cancer. J Occup Med1984; 26:345–352.
Reich JM. A critical appraisal of overdiagnosis: estimates of its magnitude and implications for lung cancer screening. Thorax2008; 63:377–383.
Winer-Muram HT, Jennings SG, Tarver RD, et al. Volumetric growth rate of stage I lung cancer prior to treatment: serial CT scanning. Radiology2002; 223:798–805.
Hasegawa M, Sone S, Takashima S, et al. Growth rate of small lung cancers detected on mass CT screening. Br J Radiol2000; 73:1252–1259.
Raz DJ, Zell JA, Ou SH, Gandara DR, Anton-Culver H, Jablons DM. Natural history of stage I non-small cell lung cancer: implications for early detection [published online ahead of print May 15, 2007]. Chest2007; 132:193–199. doi: 10.1378/chest.06-3096
Bianchi F, Hu J, Pelosi G, et al. Lung cancers detected by screening with spiral computed tomography have a malignant phenotype when analyzed by cDNA microarray. Clin Cancer Res2004; 10( 18 Pt 1):6023–6028.
Marcus PM, Bergstralh EJ, Zweig MH, Harris A, Offord KP, Fontana RS. Extended lung cancer incidence follow-up in the Mayo Lung Project and overdiagnosis. J Natl Cancer Inst2006; 98:748–756.
Sone S, Li F, Yang ZG, et al. Results of three-year mass screening programme for lung cancer using mobile low-dose spiral computed tomography scanner. Br J Cancer2001; 84:25–32.
Swensen SJ, Jett JR, Hartman TE, et al. CT screening for lung cancer: five-year prospective experience [published online ahead of print February 4, 2005]. Radiology2005; 235:259–265. doi: 10.1148/radiol.2351041662
International Early Lung Cancer Action Program Investigators, Henschke CI, Yankelevitz DF, Libby DM, et al. Survival of patients with stage I lung cancer detected on CT screening. N Engl J Med2006; 355:1763–1771.
Manser RL, Dodd M, Byrnes G, Irving LB, Campbell DA. Incidental lung cancers identified at coronial autopsy: implications for overdiagnosis of lung cancer by screening. Respir Med2005; 99:501–507.
Chan CK, Wells CK, McFarlane MJ, Feinstein AR. More lung cancer but better survival: implications of secular trends in “necropsy surprise” rates. Chest1989; 96:291–296.
National Lung Screening Trial Research Team, Aberle DR, Adams AM, Berg CD, et al. Baseline characteristics of participants in the randomized national lung screening trial [published correction appears in J Natl Cancer Inst 2011; 103:1560]. J Natl Cancer Inst2010; 102:1771–1779.
Fischbach F, Knollmann F, Griesshaber V, Freund T, Akkol E, Felix R. Detection of pulmonary nodules by multislice computed tomography: improved detection rate with reduced slice thickness [published online ahead of print May 13, 2003]. Eur Radiol2003; 13:2378–2383. doi: 10.1007/s00330-003-1915-7
van den Bergh KA, Essink-Bot ML, Borsboom GJ, et al. Short-term health-related quality of life consequences in a lung cancer CT screening trial (NELSON) [published online ahead of pring November 24, 2009]. Br J Cancer2010; 102:27–34. doi: 10.1038/sj.bjc.6605459
Brenner DJ. Radiation risks potentially associated with low-dose CT screening of adult smokers for lung cancer. Radiology2004; 231:440–445.
Fazel R, Krumholz HM, Wang Y, et al. Exposure to low-dose ionizing radiation from medical imaging procedures. N Engl J Med2009; 361:849–857.
Mahadevia PJ, Fleisher LA, Frick KD, Eng J, Goodman SN, Powe NR. Lung cancer screening with helical computed tomography in older adult smokers: a decision and cost-effectiveness analysis. JAMA2003; 289:313–322.
Silvestri GA, Nietert PJ, Zoller J, Carter C, Bradford D. Attitudes towards screening for lung cancer among smokers and their nonsmoking counterparts. [published online ahead of print November 13, 2006]Thorax2007; 62:126–130. doi: 10.1136/thx.2005.056036
Tammemagi CM, Pinsky PF, Caporaso NE, et al. Lung cancer risk prediction: Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial models and validation [published online ahead of print May 23, 2011]. J Natl Cancer Inst2011; 103:1058–1068. doi: 10.1093/jnci/djr173
van Klaveren RJ, Oudkerk M, Prokop M, et al. Management of lung nodules detected by volume CT scanning. N Engl J Med2009; 361:2221–2229.
References
Holin SM, Dwork RE, Glaser S, Rikli AE, Stocklen JB. Solitary pulmonary nodules found in a community-wide chest roentgenographic survey: a five-year follow-up study. Am Rev Tuberc1959; 79:427–439.
Nash FA, Morgan JM, Tomkins JG. South London Lung Cancer Study. Br Med J1968; 2:715–721.
Obuchowski NA, Graham RJ, Baker ME, Powell KA. Ten criteria for effective screening: their application to multislice CT screening for pulmonary and colorectal cancers. AJR Am J Roentgenol2001; 176:1357–1362.
Eddy DM. Screening for lung cancer. Ann Intern Med1989; 111:232–237.
Manser RL, Irving LB, Byrnes G, Abramson MJ, Stone CA, Campbell DA. Screening for lung cancer: a systematic review and meta-analysis of controlled trials. Thorax2003; 58:784–789.
Krupinski EA, Berger WG, Dallas WJ, Roehrig H. Searching for nodules: what features attract attention and influence detection?Acad Radiol2003; 10:861–868.
Yoshida H. Local contralateral subtraction based on bilateral symmetry of lung for reduction of false positives in computerized detection of pulmonary nodules. IEEE Trans Biomed Eng2004; 51:778–789.
Shiraishi J, Abe H.Engelmann R, Doi K. Effect of high sensitivity in a computerized scheme for detecting extremely subtle solitary pulmonary nodules in chest radiographs: observer performance study. Acad Radiol2003; 10:1302–1311.
Veronesi G, Bellomi M, Scanagatta P, et al. Difficulties encountered managing nodules detected during a computed tomography lung cancer screening program. J Thorac Cardiovasc Surg2008; 136:611–617.
Wilson DO, Weissfeld JL, Fuhrman CR, et al. The Pittsburgh Lung Screening Study (PLuSS): outcomes within 3 years of a first computed tomography scan [published online ahead of print July 17, 2008]. Am J Respir Crit Care Med2008; 178:956–961. doi: 10.1164/rccm.200802-336OC
Fasola G, Belvedere O, Aita M, et al. Low-dose computed tomography screening for lung cancer and pleural mesothelioma in an asbestos-exposed population: baseline results of a prospective, nonrandomized feasibility trial—an Alpe-adria Thoracic Oncology Multidisciplinary Group Study (ATOM 002). Oncologist2007; 12:1215–1224.
Gopal M, Abdullah SE, Grady JJ, Goodwin JS. Screening for lung cancer with low-dose computed tomography: a systematic review and meta-analysis of the baseline findings of randomized controlled trials. J Thorac Oncol2010; 5:1233–1239.
Fontana RS, Sanderson DR, Woolner LB, et al. Screening for lung cancer: a critique of the Mayo Lung Project. Cancer1991; 67( suppl 4):1155–1164.
Bach PB, Jett JR, Pastorino U, Tockman MS, Swensen SJ, Begg CB. Computed tomography screening and lung cancer outcomes. JAMA2007; 297:953–961.
Patz EF, Goodman PC, Bepler G. Screening for lung cancer. N Engl J Med2000; 343:1627–1633.
Weiss W. Implications of tumor growth rate for the natural history of lung cancer. J Occup Med1984; 26:345–352.
Reich JM. A critical appraisal of overdiagnosis: estimates of its magnitude and implications for lung cancer screening. Thorax2008; 63:377–383.
Winer-Muram HT, Jennings SG, Tarver RD, et al. Volumetric growth rate of stage I lung cancer prior to treatment: serial CT scanning. Radiology2002; 223:798–805.
Hasegawa M, Sone S, Takashima S, et al. Growth rate of small lung cancers detected on mass CT screening. Br J Radiol2000; 73:1252–1259.
Raz DJ, Zell JA, Ou SH, Gandara DR, Anton-Culver H, Jablons DM. Natural history of stage I non-small cell lung cancer: implications for early detection [published online ahead of print May 15, 2007]. Chest2007; 132:193–199. doi: 10.1378/chest.06-3096
Bianchi F, Hu J, Pelosi G, et al. Lung cancers detected by screening with spiral computed tomography have a malignant phenotype when analyzed by cDNA microarray. Clin Cancer Res2004; 10( 18 Pt 1):6023–6028.
Marcus PM, Bergstralh EJ, Zweig MH, Harris A, Offord KP, Fontana RS. Extended lung cancer incidence follow-up in the Mayo Lung Project and overdiagnosis. J Natl Cancer Inst2006; 98:748–756.
Sone S, Li F, Yang ZG, et al. Results of three-year mass screening programme for lung cancer using mobile low-dose spiral computed tomography scanner. Br J Cancer2001; 84:25–32.
Swensen SJ, Jett JR, Hartman TE, et al. CT screening for lung cancer: five-year prospective experience [published online ahead of print February 4, 2005]. Radiology2005; 235:259–265. doi: 10.1148/radiol.2351041662
International Early Lung Cancer Action Program Investigators, Henschke CI, Yankelevitz DF, Libby DM, et al. Survival of patients with stage I lung cancer detected on CT screening. N Engl J Med2006; 355:1763–1771.
Manser RL, Dodd M, Byrnes G, Irving LB, Campbell DA. Incidental lung cancers identified at coronial autopsy: implications for overdiagnosis of lung cancer by screening. Respir Med2005; 99:501–507.
Chan CK, Wells CK, McFarlane MJ, Feinstein AR. More lung cancer but better survival: implications of secular trends in “necropsy surprise” rates. Chest1989; 96:291–296.
National Lung Screening Trial Research Team, Aberle DR, Adams AM, Berg CD, et al. Baseline characteristics of participants in the randomized national lung screening trial [published correction appears in J Natl Cancer Inst 2011; 103:1560]. J Natl Cancer Inst2010; 102:1771–1779.
Fischbach F, Knollmann F, Griesshaber V, Freund T, Akkol E, Felix R. Detection of pulmonary nodules by multislice computed tomography: improved detection rate with reduced slice thickness [published online ahead of print May 13, 2003]. Eur Radiol2003; 13:2378–2383. doi: 10.1007/s00330-003-1915-7
van den Bergh KA, Essink-Bot ML, Borsboom GJ, et al. Short-term health-related quality of life consequences in a lung cancer CT screening trial (NELSON) [published online ahead of pring November 24, 2009]. Br J Cancer2010; 102:27–34. doi: 10.1038/sj.bjc.6605459
Brenner DJ. Radiation risks potentially associated with low-dose CT screening of adult smokers for lung cancer. Radiology2004; 231:440–445.
Fazel R, Krumholz HM, Wang Y, et al. Exposure to low-dose ionizing radiation from medical imaging procedures. N Engl J Med2009; 361:849–857.
Mahadevia PJ, Fleisher LA, Frick KD, Eng J, Goodman SN, Powe NR. Lung cancer screening with helical computed tomography in older adult smokers: a decision and cost-effectiveness analysis. JAMA2003; 289:313–322.
Silvestri GA, Nietert PJ, Zoller J, Carter C, Bradford D. Attitudes towards screening for lung cancer among smokers and their nonsmoking counterparts. [published online ahead of print November 13, 2006]Thorax2007; 62:126–130. doi: 10.1136/thx.2005.056036
Tammemagi CM, Pinsky PF, Caporaso NE, et al. Lung cancer risk prediction: Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial models and validation [published online ahead of print May 23, 2011]. J Natl Cancer Inst2011; 103:1058–1068. doi: 10.1093/jnci/djr173
van Klaveren RJ, Oudkerk M, Prokop M, et al. Management of lung nodules detected by volume CT scanning. N Engl J Med2009; 361:2221–2229.
The tumor, node, metastasis (TNM) staging system for lung cancer was first developed in 1973 using a sample of 2,155 patients who were treated at the MD Anderson Cancer Center in Houston, Texas.1 Important limitations of this first staging system included the relatively small number of patients studied, the geographic restriction of all patients to a single medical center, the limited generalizability to patients from other parts of the world, and the lack of external validation of TNM staging as a predictor of clinical outcome. This system was revised in 1997 using data from 5,319 patients at the MD Anderson Cancer Center, and it remained unchanged until the American Joint Committee on Cancer (AJCC) seventh edition was published in 2009.
The AJCC seventh edition TNM staging guidelines are the result of a multinational undertaking led by the International Association for the Study of Lung Cancer (IASLC), in which data from 100,869 patients were collected from study centers in North America, Asia, Australia, and Europe from 1990 to 2000.2 Staging recommendations for non–small cell lung cancer were developed using data from 67,725 patients. Of these, 53,640 were clinically staged, and 33,933 underwent pathologic staging. In 20,006 patients, both clinical and pathologic staging information were available.2 Approximately 95% of patients underwent follow-up for at least 2 years or until death.
The revised AJCC lung cancer staging system provided a much larger and more diverse patient database than the earlier TNM staging system, with robust long-term follow-up and rigorous validation of the prognostic significance of TNM groupings. The revised TNM descriptors were validated internally by confirming the consistency of Kaplan-Meier survival curves across different study centers. External validation of the staging system was performed by using patient survival data from the Surveillance, Epidemiology, and End Report (SEER) program of the National Cancer Institute.2 Data analysis was conducted by Cancer Research and Biostatistics, an independent statistical center in Seattle, Washington.
Potential limitations of the revised staging system included the lack of standardization of diagnostic technology across different regions and time periods, as well as the exclusion of patients from Africa, South America, and India.3 In addition, the AJCC seventh edition continues to classify patients entirely on the basis of anatomic characteristics. Certain tumor molecular markers are now recognized as both prognostic and predictive of the responses to certain treatments, but these have yet to be taken into consideration in lung cancer staging.
A summary of TNM descriptors in the sixth and seventh editions of the AJCC staging criteria, the use of the most recent criteria in lung cancer staging, and changes in staging from one edition to the next are summarized in Table 1.
T1 comprises two subcategories
In the previous AJCC staging system published in 2002 (sixth edition), the T1 tumor size classification was defined as a tumor measuring greater than 3 cm in size without invasion more proximal than the lobar bronchus.4 In the seventh edition TNM classification, the T1 category is separated into T1a, which is defined as tumor measuring greater than 2 cm, and T1b, ie, tumor measuring 2 to 3 cm.5 This new classification is based on data from both pathologic and clinical staging datasets, which demonstrate significant differences in median survival for tumors measuring smaller than 2 cm versus tumors that were 2 to 3 cm in size within the T1 category. These survival differences were subsequently validated using the SEER patient database.5
T2 also subdivided
A similar subdivision was performed for the T2 category. In the sixth edition TNM classification, a T2 tumor was defined either as a tumor greater than 3 cm in size, or with at least one of the following criteria: involvement of a mainstem bronchus 2 cm or more distal to the carina; invasion of the visceral pleura; or atelectasis extending to the hilar region, but not involving the entire lung.4 In the seventh edition, the T2 category is divided into T2a (tumor size, 3 to 5 cm) and T2b (tumor size, 5 to 7 cm).5 The median survival difference between these two subsets varied from approximately 10% to 27% across different study sites.2 Validation of the T2a and T2b classification using the SEER database demonstrated that the proportion of patients who survived 5 years was 14% higher for patients in the T2a than the T2b group (hazard ratio, 1.45; P < .0001), confirming the prognostic importance of these two subcategories.
T3 redefined
The investigators also made changes to the T3 classification in the AJCC seventh edition staging system. Tumors measuring greater than 7 cm (classified as T2 using the sixth edition) were reclassified as T3. Additionally, the subset of sixth edition T4 tumors that were defined by the presence of additional nodules in the same lobe were reclassified as T3. The revised AJCC seventh edition TNM classification, therefore, defines T3 tumors as those greater than 7 cm in size, or tumors of any size with the following characteristics: invasion of the chest wall, diaphragm, mediastinal pleura, or parietal pericardium; more than 2 cm from carina; atelectasis of entire lung; or satellite nodules in the same lobe.
T4 redefined based on survival outcomes
Finally, tumors that were previously classified as M1 because of additional nodules in different lobes of the ipsilateral lung are classified as T4 in the seventh edition. This change reflected the observation that 5-year survival outcomes for these patients differed markedly from other M1 tumors, but were similar to outcomes for patients with T4 tumors.2 The revised AJCC seventh edition criteria for T4 lesions includes tumors of any size with invasion of the mediastinum, heart, great vessels, trachea, esophagus, vertebral body, carina, or a satellite tumor nodule in the same lung.
N criteria unchanged
The N criteria subcommittee recommended that the existing N staging criteria should be retained without revision from the sixth edition.
M1 reclassified and subdivided
In the sixth edition, M1 disease was defined as any distant metastasis, including separate tumor nodules in a different lung lobe. In the seventh edition, pleural dissemination is reclassified from category T4 to M1 owing to significantly poorer survival among these subgroup of T4 patients.2 In addition, M1 disease is divided into two subcategories. M1a disease is defined as one or more tumor nodule(s) in a contralateral lobe, tumor with pleural nodules, or malignant pleural or pericardial effusion, whereas M1b disease is defined as any distant metastasis.
WHAT ARE THE IMPLICATIONS OF A NEW STAGING SYSTEM?
It is estimated that approximately 10% to 15% of newly diagnosed patients with lung cancer will be assigned to a different disease stage on the basis of this new classification system.6Table 2 compares cancer staging using the sixth and seventh edition TNM classification criteria and includes the proportion of patients in the IASLC database who would be upstaged or downstaged.6 For example, 3.8% of patients in the IASLC database would be upstaged from the former stage 1B to the new stage 2A, and approximately 4.4% of patients would be downstaged from 2B to 2A.
These changes to lung cancer staging may have significant implications for clinical decision-making. In a recent survey, clinicians who treat lung cancer were presented with three patient scenarios in which the lung cancer stage differed between the sixth and seventh AJCC editions.6 The clinicians were first presented with the clinical vignettes accompanied by their sixth edition designations, and then with their seventh edition designations. At each presentation, clinicians were asked to choose from several possible management options. Approximately 77% of clinicians surveyed changed their management strategy based on the change in staging classification.
SUMMARY AND CONCLUSIONS
The AJCC seventh edition TNM classification is based on internally and externally validated survival curves derived from tens of thousands of patients with different disease characteristics enrolled at study sites around the world. Because the treatments received by the patients are not included in this analysis, it is essential to exercise caution when using staging information to make treatment decisions. Prospective patient data will be required to determine whether this classification system significantly improves long-term treatment outcomes. In addition, it will be important to consider the potential effects of different staging systems when comparing the results of clinical trials.
References
Detterbeck FC, Boffa DJ, Tanoue LT. The new lung cancer staging system. Chest2009; 136:260–271.
Groome PA, Bolejack V, Crowley JJ, et al. The IASLC Lung Cancer Staging Project: validation of the proposals for revision of the T, N, and M descriptors and consequent stage groupings in the forthcoming (seventh) edition of the TNM classification of malignant tumours. J Thorac Oncol2007; 2:694–705.
Goldstraw P, Crowley J, Chansky K, et al. The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM Classification of malignant tumours. J Thorac Oncol2007; 2:706–714.
Sobin LH, Wittekind C. International Union Against Cancer (UICC), TNM Classification of Malignant Tumors. 6th ed. New York, NY: Wiley-Liss; 2002:99–103.
Rami-Porta R, Ball D, Crowley J, et al. The IASLC Lung Cancer Staging Project: proposals for the revision of the T descriptors in the forthcoming (seventh) edition of the TNM classification for lung cancer. J Thorac Oncol2007; 2:593–602.
Boffa DJ, Detterbeck FC, Smith EJ, et al. Should the 7th edition of the lung cancer stage classification system change treatment algorithms in non-small cell lung cancer?J Thorac Oncol2010; 5:1779–1783.
Rami-Porta R, Bolejack V, Goldstraw P. The new tumor, node, and metastasis staging system. Semin Respir Crit Care Med2011; 32:44–51.
Cristina P. Rodriguez, MD Division of Hematology & Medical Oncology, Oregon Health & Science University, Portland, OR
Correspondence: Cristina P. Rodriguez, MD, Assistant Professor, Division of Hematology & Medical Oncology, L586, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239; rodrigcr@ohsu.edu
Dr. Rodriguez reported that she has no relationships that pose a potential conflict of interest with this article.
This article was developed from an audio transcript of Dr. Rodriguez’s presentation at the “Advances in Lung Cancer Evaluation and Management” symposium held in Cleveland, Ohio, on April 30, 2011. The transcript was formatted and edited by Cleveland Clinic Journal of Medicine staff for clarity and conciseness and was then reviewed, revised, and approved by Dr. Rodriguez.
Cristina P. Rodriguez, MD Division of Hematology & Medical Oncology, Oregon Health & Science University, Portland, OR
Correspondence: Cristina P. Rodriguez, MD, Assistant Professor, Division of Hematology & Medical Oncology, L586, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239; rodrigcr@ohsu.edu
Dr. Rodriguez reported that she has no relationships that pose a potential conflict of interest with this article.
This article was developed from an audio transcript of Dr. Rodriguez’s presentation at the “Advances in Lung Cancer Evaluation and Management” symposium held in Cleveland, Ohio, on April 30, 2011. The transcript was formatted and edited by Cleveland Clinic Journal of Medicine staff for clarity and conciseness and was then reviewed, revised, and approved by Dr. Rodriguez.
Author and Disclosure Information
Cristina P. Rodriguez, MD Division of Hematology & Medical Oncology, Oregon Health & Science University, Portland, OR
Correspondence: Cristina P. Rodriguez, MD, Assistant Professor, Division of Hematology & Medical Oncology, L586, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239; rodrigcr@ohsu.edu
Dr. Rodriguez reported that she has no relationships that pose a potential conflict of interest with this article.
This article was developed from an audio transcript of Dr. Rodriguez’s presentation at the “Advances in Lung Cancer Evaluation and Management” symposium held in Cleveland, Ohio, on April 30, 2011. The transcript was formatted and edited by Cleveland Clinic Journal of Medicine staff for clarity and conciseness and was then reviewed, revised, and approved by Dr. Rodriguez.
The tumor, node, metastasis (TNM) staging system for lung cancer was first developed in 1973 using a sample of 2,155 patients who were treated at the MD Anderson Cancer Center in Houston, Texas.1 Important limitations of this first staging system included the relatively small number of patients studied, the geographic restriction of all patients to a single medical center, the limited generalizability to patients from other parts of the world, and the lack of external validation of TNM staging as a predictor of clinical outcome. This system was revised in 1997 using data from 5,319 patients at the MD Anderson Cancer Center, and it remained unchanged until the American Joint Committee on Cancer (AJCC) seventh edition was published in 2009.
The AJCC seventh edition TNM staging guidelines are the result of a multinational undertaking led by the International Association for the Study of Lung Cancer (IASLC), in which data from 100,869 patients were collected from study centers in North America, Asia, Australia, and Europe from 1990 to 2000.2 Staging recommendations for non–small cell lung cancer were developed using data from 67,725 patients. Of these, 53,640 were clinically staged, and 33,933 underwent pathologic staging. In 20,006 patients, both clinical and pathologic staging information were available.2 Approximately 95% of patients underwent follow-up for at least 2 years or until death.
The revised AJCC lung cancer staging system provided a much larger and more diverse patient database than the earlier TNM staging system, with robust long-term follow-up and rigorous validation of the prognostic significance of TNM groupings. The revised TNM descriptors were validated internally by confirming the consistency of Kaplan-Meier survival curves across different study centers. External validation of the staging system was performed by using patient survival data from the Surveillance, Epidemiology, and End Report (SEER) program of the National Cancer Institute.2 Data analysis was conducted by Cancer Research and Biostatistics, an independent statistical center in Seattle, Washington.
Potential limitations of the revised staging system included the lack of standardization of diagnostic technology across different regions and time periods, as well as the exclusion of patients from Africa, South America, and India.3 In addition, the AJCC seventh edition continues to classify patients entirely on the basis of anatomic characteristics. Certain tumor molecular markers are now recognized as both prognostic and predictive of the responses to certain treatments, but these have yet to be taken into consideration in lung cancer staging.
A summary of TNM descriptors in the sixth and seventh editions of the AJCC staging criteria, the use of the most recent criteria in lung cancer staging, and changes in staging from one edition to the next are summarized in Table 1.
T1 comprises two subcategories
In the previous AJCC staging system published in 2002 (sixth edition), the T1 tumor size classification was defined as a tumor measuring greater than 3 cm in size without invasion more proximal than the lobar bronchus.4 In the seventh edition TNM classification, the T1 category is separated into T1a, which is defined as tumor measuring greater than 2 cm, and T1b, ie, tumor measuring 2 to 3 cm.5 This new classification is based on data from both pathologic and clinical staging datasets, which demonstrate significant differences in median survival for tumors measuring smaller than 2 cm versus tumors that were 2 to 3 cm in size within the T1 category. These survival differences were subsequently validated using the SEER patient database.5
T2 also subdivided
A similar subdivision was performed for the T2 category. In the sixth edition TNM classification, a T2 tumor was defined either as a tumor greater than 3 cm in size, or with at least one of the following criteria: involvement of a mainstem bronchus 2 cm or more distal to the carina; invasion of the visceral pleura; or atelectasis extending to the hilar region, but not involving the entire lung.4 In the seventh edition, the T2 category is divided into T2a (tumor size, 3 to 5 cm) and T2b (tumor size, 5 to 7 cm).5 The median survival difference between these two subsets varied from approximately 10% to 27% across different study sites.2 Validation of the T2a and T2b classification using the SEER database demonstrated that the proportion of patients who survived 5 years was 14% higher for patients in the T2a than the T2b group (hazard ratio, 1.45; P < .0001), confirming the prognostic importance of these two subcategories.
T3 redefined
The investigators also made changes to the T3 classification in the AJCC seventh edition staging system. Tumors measuring greater than 7 cm (classified as T2 using the sixth edition) were reclassified as T3. Additionally, the subset of sixth edition T4 tumors that were defined by the presence of additional nodules in the same lobe were reclassified as T3. The revised AJCC seventh edition TNM classification, therefore, defines T3 tumors as those greater than 7 cm in size, or tumors of any size with the following characteristics: invasion of the chest wall, diaphragm, mediastinal pleura, or parietal pericardium; more than 2 cm from carina; atelectasis of entire lung; or satellite nodules in the same lobe.
T4 redefined based on survival outcomes
Finally, tumors that were previously classified as M1 because of additional nodules in different lobes of the ipsilateral lung are classified as T4 in the seventh edition. This change reflected the observation that 5-year survival outcomes for these patients differed markedly from other M1 tumors, but were similar to outcomes for patients with T4 tumors.2 The revised AJCC seventh edition criteria for T4 lesions includes tumors of any size with invasion of the mediastinum, heart, great vessels, trachea, esophagus, vertebral body, carina, or a satellite tumor nodule in the same lung.
N criteria unchanged
The N criteria subcommittee recommended that the existing N staging criteria should be retained without revision from the sixth edition.
M1 reclassified and subdivided
In the sixth edition, M1 disease was defined as any distant metastasis, including separate tumor nodules in a different lung lobe. In the seventh edition, pleural dissemination is reclassified from category T4 to M1 owing to significantly poorer survival among these subgroup of T4 patients.2 In addition, M1 disease is divided into two subcategories. M1a disease is defined as one or more tumor nodule(s) in a contralateral lobe, tumor with pleural nodules, or malignant pleural or pericardial effusion, whereas M1b disease is defined as any distant metastasis.
WHAT ARE THE IMPLICATIONS OF A NEW STAGING SYSTEM?
It is estimated that approximately 10% to 15% of newly diagnosed patients with lung cancer will be assigned to a different disease stage on the basis of this new classification system.6Table 2 compares cancer staging using the sixth and seventh edition TNM classification criteria and includes the proportion of patients in the IASLC database who would be upstaged or downstaged.6 For example, 3.8% of patients in the IASLC database would be upstaged from the former stage 1B to the new stage 2A, and approximately 4.4% of patients would be downstaged from 2B to 2A.
These changes to lung cancer staging may have significant implications for clinical decision-making. In a recent survey, clinicians who treat lung cancer were presented with three patient scenarios in which the lung cancer stage differed between the sixth and seventh AJCC editions.6 The clinicians were first presented with the clinical vignettes accompanied by their sixth edition designations, and then with their seventh edition designations. At each presentation, clinicians were asked to choose from several possible management options. Approximately 77% of clinicians surveyed changed their management strategy based on the change in staging classification.
SUMMARY AND CONCLUSIONS
The AJCC seventh edition TNM classification is based on internally and externally validated survival curves derived from tens of thousands of patients with different disease characteristics enrolled at study sites around the world. Because the treatments received by the patients are not included in this analysis, it is essential to exercise caution when using staging information to make treatment decisions. Prospective patient data will be required to determine whether this classification system significantly improves long-term treatment outcomes. In addition, it will be important to consider the potential effects of different staging systems when comparing the results of clinical trials.
The tumor, node, metastasis (TNM) staging system for lung cancer was first developed in 1973 using a sample of 2,155 patients who were treated at the MD Anderson Cancer Center in Houston, Texas.1 Important limitations of this first staging system included the relatively small number of patients studied, the geographic restriction of all patients to a single medical center, the limited generalizability to patients from other parts of the world, and the lack of external validation of TNM staging as a predictor of clinical outcome. This system was revised in 1997 using data from 5,319 patients at the MD Anderson Cancer Center, and it remained unchanged until the American Joint Committee on Cancer (AJCC) seventh edition was published in 2009.
The AJCC seventh edition TNM staging guidelines are the result of a multinational undertaking led by the International Association for the Study of Lung Cancer (IASLC), in which data from 100,869 patients were collected from study centers in North America, Asia, Australia, and Europe from 1990 to 2000.2 Staging recommendations for non–small cell lung cancer were developed using data from 67,725 patients. Of these, 53,640 were clinically staged, and 33,933 underwent pathologic staging. In 20,006 patients, both clinical and pathologic staging information were available.2 Approximately 95% of patients underwent follow-up for at least 2 years or until death.
The revised AJCC lung cancer staging system provided a much larger and more diverse patient database than the earlier TNM staging system, with robust long-term follow-up and rigorous validation of the prognostic significance of TNM groupings. The revised TNM descriptors were validated internally by confirming the consistency of Kaplan-Meier survival curves across different study centers. External validation of the staging system was performed by using patient survival data from the Surveillance, Epidemiology, and End Report (SEER) program of the National Cancer Institute.2 Data analysis was conducted by Cancer Research and Biostatistics, an independent statistical center in Seattle, Washington.
Potential limitations of the revised staging system included the lack of standardization of diagnostic technology across different regions and time periods, as well as the exclusion of patients from Africa, South America, and India.3 In addition, the AJCC seventh edition continues to classify patients entirely on the basis of anatomic characteristics. Certain tumor molecular markers are now recognized as both prognostic and predictive of the responses to certain treatments, but these have yet to be taken into consideration in lung cancer staging.
A summary of TNM descriptors in the sixth and seventh editions of the AJCC staging criteria, the use of the most recent criteria in lung cancer staging, and changes in staging from one edition to the next are summarized in Table 1.
T1 comprises two subcategories
In the previous AJCC staging system published in 2002 (sixth edition), the T1 tumor size classification was defined as a tumor measuring greater than 3 cm in size without invasion more proximal than the lobar bronchus.4 In the seventh edition TNM classification, the T1 category is separated into T1a, which is defined as tumor measuring greater than 2 cm, and T1b, ie, tumor measuring 2 to 3 cm.5 This new classification is based on data from both pathologic and clinical staging datasets, which demonstrate significant differences in median survival for tumors measuring smaller than 2 cm versus tumors that were 2 to 3 cm in size within the T1 category. These survival differences were subsequently validated using the SEER patient database.5
T2 also subdivided
A similar subdivision was performed for the T2 category. In the sixth edition TNM classification, a T2 tumor was defined either as a tumor greater than 3 cm in size, or with at least one of the following criteria: involvement of a mainstem bronchus 2 cm or more distal to the carina; invasion of the visceral pleura; or atelectasis extending to the hilar region, but not involving the entire lung.4 In the seventh edition, the T2 category is divided into T2a (tumor size, 3 to 5 cm) and T2b (tumor size, 5 to 7 cm).5 The median survival difference between these two subsets varied from approximately 10% to 27% across different study sites.2 Validation of the T2a and T2b classification using the SEER database demonstrated that the proportion of patients who survived 5 years was 14% higher for patients in the T2a than the T2b group (hazard ratio, 1.45; P < .0001), confirming the prognostic importance of these two subcategories.
T3 redefined
The investigators also made changes to the T3 classification in the AJCC seventh edition staging system. Tumors measuring greater than 7 cm (classified as T2 using the sixth edition) were reclassified as T3. Additionally, the subset of sixth edition T4 tumors that were defined by the presence of additional nodules in the same lobe were reclassified as T3. The revised AJCC seventh edition TNM classification, therefore, defines T3 tumors as those greater than 7 cm in size, or tumors of any size with the following characteristics: invasion of the chest wall, diaphragm, mediastinal pleura, or parietal pericardium; more than 2 cm from carina; atelectasis of entire lung; or satellite nodules in the same lobe.
T4 redefined based on survival outcomes
Finally, tumors that were previously classified as M1 because of additional nodules in different lobes of the ipsilateral lung are classified as T4 in the seventh edition. This change reflected the observation that 5-year survival outcomes for these patients differed markedly from other M1 tumors, but were similar to outcomes for patients with T4 tumors.2 The revised AJCC seventh edition criteria for T4 lesions includes tumors of any size with invasion of the mediastinum, heart, great vessels, trachea, esophagus, vertebral body, carina, or a satellite tumor nodule in the same lung.
N criteria unchanged
The N criteria subcommittee recommended that the existing N staging criteria should be retained without revision from the sixth edition.
M1 reclassified and subdivided
In the sixth edition, M1 disease was defined as any distant metastasis, including separate tumor nodules in a different lung lobe. In the seventh edition, pleural dissemination is reclassified from category T4 to M1 owing to significantly poorer survival among these subgroup of T4 patients.2 In addition, M1 disease is divided into two subcategories. M1a disease is defined as one or more tumor nodule(s) in a contralateral lobe, tumor with pleural nodules, or malignant pleural or pericardial effusion, whereas M1b disease is defined as any distant metastasis.
WHAT ARE THE IMPLICATIONS OF A NEW STAGING SYSTEM?
It is estimated that approximately 10% to 15% of newly diagnosed patients with lung cancer will be assigned to a different disease stage on the basis of this new classification system.6Table 2 compares cancer staging using the sixth and seventh edition TNM classification criteria and includes the proportion of patients in the IASLC database who would be upstaged or downstaged.6 For example, 3.8% of patients in the IASLC database would be upstaged from the former stage 1B to the new stage 2A, and approximately 4.4% of patients would be downstaged from 2B to 2A.
These changes to lung cancer staging may have significant implications for clinical decision-making. In a recent survey, clinicians who treat lung cancer were presented with three patient scenarios in which the lung cancer stage differed between the sixth and seventh AJCC editions.6 The clinicians were first presented with the clinical vignettes accompanied by their sixth edition designations, and then with their seventh edition designations. At each presentation, clinicians were asked to choose from several possible management options. Approximately 77% of clinicians surveyed changed their management strategy based on the change in staging classification.
SUMMARY AND CONCLUSIONS
The AJCC seventh edition TNM classification is based on internally and externally validated survival curves derived from tens of thousands of patients with different disease characteristics enrolled at study sites around the world. Because the treatments received by the patients are not included in this analysis, it is essential to exercise caution when using staging information to make treatment decisions. Prospective patient data will be required to determine whether this classification system significantly improves long-term treatment outcomes. In addition, it will be important to consider the potential effects of different staging systems when comparing the results of clinical trials.
References
Detterbeck FC, Boffa DJ, Tanoue LT. The new lung cancer staging system. Chest2009; 136:260–271.
Groome PA, Bolejack V, Crowley JJ, et al. The IASLC Lung Cancer Staging Project: validation of the proposals for revision of the T, N, and M descriptors and consequent stage groupings in the forthcoming (seventh) edition of the TNM classification of malignant tumours. J Thorac Oncol2007; 2:694–705.
Goldstraw P, Crowley J, Chansky K, et al. The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM Classification of malignant tumours. J Thorac Oncol2007; 2:706–714.
Sobin LH, Wittekind C. International Union Against Cancer (UICC), TNM Classification of Malignant Tumors. 6th ed. New York, NY: Wiley-Liss; 2002:99–103.
Rami-Porta R, Ball D, Crowley J, et al. The IASLC Lung Cancer Staging Project: proposals for the revision of the T descriptors in the forthcoming (seventh) edition of the TNM classification for lung cancer. J Thorac Oncol2007; 2:593–602.
Boffa DJ, Detterbeck FC, Smith EJ, et al. Should the 7th edition of the lung cancer stage classification system change treatment algorithms in non-small cell lung cancer?J Thorac Oncol2010; 5:1779–1783.
Rami-Porta R, Bolejack V, Goldstraw P. The new tumor, node, and metastasis staging system. Semin Respir Crit Care Med2011; 32:44–51.
References
Detterbeck FC, Boffa DJ, Tanoue LT. The new lung cancer staging system. Chest2009; 136:260–271.
Groome PA, Bolejack V, Crowley JJ, et al. The IASLC Lung Cancer Staging Project: validation of the proposals for revision of the T, N, and M descriptors and consequent stage groupings in the forthcoming (seventh) edition of the TNM classification of malignant tumours. J Thorac Oncol2007; 2:694–705.
Goldstraw P, Crowley J, Chansky K, et al. The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM Classification of malignant tumours. J Thorac Oncol2007; 2:706–714.
Sobin LH, Wittekind C. International Union Against Cancer (UICC), TNM Classification of Malignant Tumors. 6th ed. New York, NY: Wiley-Liss; 2002:99–103.
Rami-Porta R, Ball D, Crowley J, et al. The IASLC Lung Cancer Staging Project: proposals for the revision of the T descriptors in the forthcoming (seventh) edition of the TNM classification for lung cancer. J Thorac Oncol2007; 2:593–602.
Boffa DJ, Detterbeck FC, Smith EJ, et al. Should the 7th edition of the lung cancer stage classification system change treatment algorithms in non-small cell lung cancer?J Thorac Oncol2010; 5:1779–1783.
Rami-Porta R, Bolejack V, Goldstraw P. The new tumor, node, and metastasis staging system. Semin Respir Crit Care Med2011; 32:44–51.
Several techniques are available for the diagnosis of suspected lung cancer, including standard flexible bronchoscopy, transthoracic needle aspiration, and sputum cytology. Mediastinal staging of lung cancer is essential for treatment planning and assessment of prognosis, and has traditionally been performed surgically. Although cervical mediastinoscopy is regarded as the “gold standard” for sampling mediastinal lymph nodes, this procedure typically requires hospitalization and general anesthesia.1 Current endobronchial ultrasound (EBUS) techniques provide less invasive lung cancer diagnosis and staging. Recent research has examined the application of endobronchial ultrasound-based assessment for initial diagnosis of lung cancer, mediastinal staging and restaging after neoadjuvant therapy, and evaluation of tumor genetic markers.
BRONCHOSCOPIC LUNG CANCER DIAGNOSIS
Evidence-based clinical guidelines for the diagnosis of lung cancer developed by the American College of Chest Physicians reviewed the sensitivity of standard bronchoscopy (ie, without EBUS or electromagnetic navigation) and ancillary procedures that are often performed in combination with flexible bronchoscopy, such as endobronchial biopsy, brushing, washing, and standard transbronchial needle aspiration (TBNA).2 A comprehensive review of published studies from 1971 to 2004 was included in the analysis. Overall, the sensitivity of standard flexible bronchoscopy was 88% (67% to 97%) for the diagnosis of central bronchogenic carcinoma and 78% (36% to 88%) for the diagnosis of peripheral bronchogenic carcinoma. Newer techniques have been developed that appear to provide more consistent diagnosis of primary lesions.
Electromagnetic navigation bronchoscopy (ENB) is a functional tool in biopsy planning that uses computed tomography (CT) mapping to precisely locate peripheral lesions. After real-time navigation to the peripheral lesion with a steerable probe, tissue collection may be optimized by guiding sampling instruments directly to the lesion through an extendable working channel.3 A prospective pilot study examined the feasibility and safety of ENB to reach peripheral lesions and lymph nodes in patients with suspected lung cancer lesions or enlarged mediastinal lymph nodes.3 Diagnostic tissue was obtained in 80.3% of attempts, including 74% of procedures involving peripheral lung lesions and 100% of procedures involving lymph nodes.
IMPROVING DIAGNOSIS WITH ULTRASOUND
Another diagnostic method is EBUS, which uses reflected sound waves to better visualize lesions at the time of biopsy.4 Radial probe endobronchial ultrasound (RP-EBUS) employs a rotating ultrasound transducer at the end of a probe, and is used either with or without a water-filled balloon to improve ultrasound transduction and image quality. Convex-probe ultrasound uses a curvilinear ultrasound probe at the end of a bronchoscope, which allows for real-time TBNA visualization.4 A recent meta-analysis examined the yield of RP-EBUS for the evaluation of peripheral pulmonary lesions in 16 studies with a combined population of 1,420 patients.5 The overall sensitivity of RP-EBUS for the detection of lung cancer was 73%, and the specificity was 100%. In a prospective, randomized clinical trial of patients with peripheral lung lesions, the combination of ENB and RP-EBUS produced a diagnostic yield of 88%, compared with 69% with RP-EBUS alone and 59% with ENB alone (P = .02).6 Although this finding suggests that a multimodal approach combining ENB and RP-EBUS may improve lung cancer diagnosis, the sample size was relatively small (118 patients).
ENDOBRONCHIAL ULTRASOUND FOR LUNG CANCER STAGING
Reproduced with permission from the American College of Chest Physicians (Yasufuku K, et al. Comparison of endobronchial ultrasound, positron emission tomography, and CT for lymph node staging of lung cancer. Chest 2006; 130:10–18).
Figure 1. The diagnostic reach of various ultrasound sampling techniques is shown with 1, highest mediastinal; 2, upper paratracheal; 4, lower paratracheal; 5, subaortic; , subcarinal; 8, paraesophageal; 9, pulmonary ligament; 10, hilar; 11, interlobar; and 12, lobar. Endobronchial ultrasound with transbronchial needle aspiration (EBUS-TBNA) is performed via the airway as opposed to endo-scopic ultrasound with fine-needle aspiration (EUS-FNA), which is carried out in the esophagus.7A promising application for EBUS is its use as a less invasive method for confirming metastatic mediastinal lymph nodes in the staging of lung cancer. Figure 1 shows the distribution of the mediastinal lymph nodes and the various diagnostic techniques that may be used to sample different lymph node stations.7
In a prospective study of potentially operable patients from Japan with proven (n = 96) or suspected (n = 6) lung cancer, investigators compared CT, positron emission tomography (PET), and EBUS-TBNA for mediastinal lymph node staging using surgical histology as the reference standard.7 The accuracy of staging was significantly greater with EBUS-TBNA (98%) than either PET (72.5%) or CT (60.8%) (P < .00001).
A recent retrospective study examined the use of EBUS-TBNA for clarification of 127 PET-positive hilar or mediastinal lymph nodes from 109 patients with suspected lung cancer.1 In 77 patients (71%), EBUS-TBNA successfully identified cancerous lymph nodes and obviated the need for further surgical biopsy. In 96 patients with definitive reference pathology, the sensitivity of EBUS-TBNA was 91%, specificity was 100%, and diagnostic accuracy was 92%. The positive predictive value of EBUS was 100%, but the negative predictive value (ie, the proportion of patients with negative EBUS-TBNA who were also negative on surgical pathology) was only 60%. This suggests a relatively high rate of false-negative EBUS-TBNA findings in this PET-positive group of patients.
Another recent study prospectively evaluated the usefulness of EBUS-TBNA after PET-CT for mediastinal staging in 117 patients with potentially operable non–small cell lung cancer (NSCLC).8 Patients were classified as either N2- or N3-positive or -negative using EBUS-TBNA, and patients who were N2- or N3-negative underwent surgical staging with lymph node dissection. Mediastinal node metastasis was confirmed by EBUS-TBNA in 37 nodal stations of 27 patients. Ninety patients who were negative by EBUS-TBNA underwent surgery with lymph node dissection. Three were reclassified as positive and 87 as negative. The overall sensitivity of EBUS-TBNA for the detection of mediastinal metastases was 90% versus 70% with PET-CT (P = .052). For the subgroup of 61 patients who had a normal mediastinum by PET-CT, nine were found to have mediastinal metastases at surgical evaluation. Six of these nine false-negatives were correctly identified by EBUS-TBNA.
Similar results were found in a study examining the use of EBUS-TBNA in 97 patients with confirmed NSCLC, no enlarged lymph nodes on CT (ie, no lymph nodes larger than 1 cm in short axis), and no abnormal mediastinal PET findings.9 Lymph nodes as small as 5 mm by ultrasound imaging at stations 2R, 2L, 4R, 4L, 7, 10R, 10L, 11R, and 11L were aspirated, and all patients underwent surgical staging. Malignant lymph nodes were detected by surgical staging in nine patients, and eight of these were identified by EBUS-TBNA. The sensitivity of EBUS-TBNA for the detection of mediastinal metastases was 89%; the specificity was 100%; and the negative predictive value was 99%.
Guided fine-needle aspiration with ultrasound bronchoscopy
An additional approach to mediastinal lung cancer staging is endoscopic ultrasound with bronchoscope-guided fine-needle aspiration (EUS-B-FNA) and EBUS-TBNA in a single procedure. The use of EBUS-TBNA and EUS-B-FNA for NSCLC staging was examined in a prospective study of 150 patients with confirmed or strongly suspected NSCLC.10 Patients underwent EBUS-TBNA, and EUS-B-FNA then was used for nodes that were inaccessible through the airways. EBUS-TBNA diagnosed mediastinal metastases in 38 of 143 patients, and three more patients were identified by additional EUS-B-FNA. Surgery identified four additional patients with mediastinal metastases that were negative by both EBUS-TBNA and EUS-B-FNA. Overall sensitivity for the detection of mediastinal metastases was 84.4% with EBUS-TBNA alone versus 91.1% with EBUS-TBNA followed by EUS-B-FNA, but this was not statistically significant (P = .332).
A second study of 139 patients with confirmed NSCLC reported similar results when EBUS-TBNA and EUS-B-FNA were performed using a single ultrasound bronchoscope.11 The sensitivity for detection of mediastinal metastases was 89% with EUS-FNA, 92% with EBUS-TBNA, and 96% with the combined approach. The specificity was 100% for all three approaches. The negative predictive values were 82% for the esophageal approach, 92% for the endobronchial approach, and 86% for the combined approach.
Meta-analyses support EBUS-TBNA for staging
The usefulness of EBUS-TBNA for NSCLC staging has been examined in two recent meta-analyses. The first included data from 11 studies of EBUS-TBNA with 1,299 patients.12 Overall, the included studies yielded a pooled sensitivity of 93% and a specificity of 100% for the detection of metastatic mediastinal lymph nodes (95% CI). The sensitivity was higher for patients who were selected for evaluation on the basis of positive PET or CT findings than for patients without selection by PET or CT (0.94 vs 0.76) (P < .05). The authors concluded that EBUS-TBNA for lung cancer staging is accurate, safe, and cost-effective, and that selection of patients based on CT or PET findings resulted in higher sensitivity.
The second meta-analysis examined data from 10 studies evaluating the utility of EBUS-TBNA for lung cancer staging.13 This meta-analysis also yielded high sensitivity (88%) and specificity (100%) of EBUS-TBNA for the identification of metastatic mediastinal lymph nodes.
EVALUATION OF EBUS VERSUS MEDIASTINOSCOPY AND OTHER INVASIVE TESTS
Although several studies suggest that EBUS-TBNA provides an accurate and less invasive method for assessment of mediastinal lymph nodes in the mediastinal staging of patients with NSCLC, few studies have directly compared EBUS-TBNA with mediastinoscopy. In a prospective crossover trial, 66 patients with suspected NSCLC underwent mediastinal staging using EBUS-TBNA followed by mediastinoscopy, with surgical lymph node dissection as the reference standard.14 The overall diagnostic yield for all lymph nodes was significantly higher with EBUS-TBNA than with mediastinoscopy (91% vs 78%) (P = .007). However, this difference was primarily due to a higher success rate in the diagnosis of subcarinal lymph nodes (98% vs 78%) (P = .007), which can be difficult to evaluate with mediastinoscopy. Differences between the two methods at other node stations were not statistically significant (Table). In the 57 patients who were diagnosed with NSCLC, the prediction of the correct pathologic stage did not differ significantly between the two approaches (93% with EBUS-TBNA vs 82% with mediastinoscopy) (P = .083).
A more recent randomized, multicenter clinical trial compared endosonographical staging (EUS-FNA and EBUS-TBNA) with mediastinoscopy in 241 patients with resectable suspected NSCLC.15 Patients were randomized to either surgical staging or to endosonography followed by surgical staging for those without nodal metastases using ultrasound-guided FNA. The sensitivity for detection of nodal metastases was 79% with surgical staging and 94% with endosonography and surgical staging (P = .02). Comparing the sensitivity of the two procedures alone, without follow-up surgical staging when ultrasound was negative, the sensitivities of the two approaches were similar: 79% with mediastinoscopy and 85% with endosonographic staging alone.
Another retrospective study examined the results of EBUS-TBNA for the initial diagnosis and staging of 88 patients with known or suspected lung cancer who underwent at least one invasive diagnostic or staging procedure before EBUS-TBNA.16 The selection of EBUS-TBNA and bronchoscopy as the initial test for diagnosis and staging could have prevented at least one invasive test in 50% of patients, and could have been the only invasive test procedure in 47.7% of individuals. In 27 patients who underwent two or more invasive tests, EBUS-TBNA could have avoided at least one invasive test in 16 patients (59%).
PATHWAYS TO DIAGNOSIS
Reprinted with permission from Current Opinion in Pulmonary Medicine (Almeida FA, et al. Initial evaluation of the nonsmall cell lung cancer patient: diagnosis and staging. Curr Opin Pulm Med 2010; 16:307–314).
Figure 2. This diagnostic algorithm should be followed for patients with suspected non–small cell lung cancer (NSCLC).17 CBC = complete blood count; COPD = chronic obstructive pulmonary disease; CT = computed tomography; Dlco = diffusion capacity of the lung for carbon monoxide; EBUS-TBNA = endobronchial ultrasound-guided trans-bronchial needle aspiration; PET = positron emission tomographyA proposed diagnostic algorithm for suspected NSCLC is shown in Figure 2.17 When lung cancer is highly suspected on the basis of focused patient history and physical examination, the patient should undergo CT-PET or chest CT with contrast that also should assess the liver and adrenal glands. If the patient has radiographic evidence of metastatic disease, the next step is biopsy of the most accessible, most advanced lesion for tissue diagnosis and staging. In patients without evidence of metastatic disease, the next step is to evaluate the mediastinal lymph nodes. Patients with evidence of nodal involvement on PET-CT or without evidence of nodal involvement but with larger tumors (eg, stage T1b or larger) may be evaluated using EBUS-TBNA as the first invasive test if available or mediastinoscopy. Standard bronchoscopy in conjunction with EBUS-TBNA has the capability of sampling the primary lesion when the mediastinal staging fails to demonstrate malignant disease. Therefore, it can provide a definitive diagnosis in addition to mediastinal staging during one single procedure, whereas mediastinoscopy typically cannot assess the primary lesion if necessary.
APPLICATIONS IN MOLECULAR TUMOR PROFILING
Genetic profiling of lung cancer tissue samples is essential to identify biomarkers that significantly influence treatment responses, and EBUS-TBNA has been used to obtain biopsy tissue samples for genetic analysis. One study examined the detection of EGFR gene mutations in biopsy tissue samples obtained from 46 patients with metastatic adenocarcinoma to the hilar or mediastinal lymph nodes diagnosed by EBUS-TBNA.18 Recut sections of the paraffin-embedded samples yielded tumor cells in 43 patients, and tissue samples were examined for mutations of EGFR exons 19 and 21. Five patients underwent surgical resection, and three of these yielded samples with EGFR mutations at exon 21. Examination of the 43 EBUS-TBNA specimens revealed EGFR mutations in 11. These included three of the mutations that were identified from surgical specimens. A more recent study examined the concordance between mutations of KRAS, EGFR, BRAF, and PIK3CA obtained by EBUS-TBNA, EUS-B-FNA, and histologic samples obtained during surgical staging from 43 patients.19KRAS mutations were identified in six patients, EGFR mutation in one patient, and PIK3CA mutation in one patient. The investigators observed 100% concordance between cytologic fine-needle aspirates and histologic specimens, suggesting no additional benefit of more invasive procedures for the evaluation of tumor biomarkers.
EBUS RESTAGING OF LUNG CANCER
The utility of EBUS-TBNA has also been investigated for restaging of lung cancer following neoadjuvant chemotherapy. Mediastinal restaging using EBUS-TBNA was performed in 124 consecutive patients with stage IIIA-N2 NSCLC who had received chemotherapy induction.20 CT evaluation revealed partial responses for 66 patients and stable disease in 58. All patients subsequently underwent thoracotomy and attempted curative resection with lymph node dissection. Of 58 patients with stable disease on CT, 41 were EBUS-TBNA–positive for mediastinal metastasis, and all were thoracotomy-positive. However, in 17 patients who were EBUS-TBNA–negative, 14 were thoracotomy-positive and only three were thoracotomy-negative. Similarly, in 66 patients with partial response to treatment on CT, 48 were EBUS-TNA–positive and thoracotomy-positive. In 18 patients who were EBUS-TBNA–negative, 14 were thoracotomy-positive and only four were also thoracotomy-negative. Overall, the sensitivity of EBUS-TBNA was 77% in patients with partial responses and 75% in those with stable disease. The negative predictive value of EBUS-TBNA in this series was very low: 22% in the partial response group and 18% in the stable disease group.
Similar results were obtained in a European study that examined EBUS-TBNA mediastinal restaging after neoadjuvant therapy in patients with pathologically confirmed N2 disease.21 Patients with negative or uncertain EBUS-TBNA were reexamined using transcervical extended bilateral mediastinal lymphadenectomy, a surgical staging procedure that is not widely used in the United States. Of 85 mediastinal lymph nodes from 61 patients that were examined using EBUS-TBNA, nine patients (15%) had a false-negative result with EBUS-TBNA, and three patients (5%) had a false-positive result. On a per-patient basis, the sensitivity of EBUS-TBNA was 67% and the negative predictive value was 78%.
SUMMARY AND CONCLUSIONS
Newer technologies such as EBUS-TBNA make it possible to simplify the diagnosis and staging of lung cancer. Bronchoscopy with EBUS may be the preferred method for the initial diagnosis and staging of patients who have disease limited to the chest. EBUS is clearly superior to current modalities for mediastinum staging such as CT and PET, and appears to be similar to mediastinoscopy. Standard bronchoscopy with EBUS followed by mediastinoscopy, if necessary, appears to be the best strategy for initial diagnosis and staging of patients with suspected lung cancer radiographically limited to the chest. However, at this time, diagnosis and staging should rely on local expertise rather than a particular methodology. Patients with T1B lesions or higher should be considered for invasive mediastinal staging regardless of their PET or CT results. The available evidence suggests that EBUS is a reasonable initial test for mediastinal restaging following neoadjuvant chemotherapy. However, a negative EBUS in this setting should prompt additional invasive tests to confirm its findings.
References
Rintoul RC, Tournoy KG, El Daly H, et al. EBUS-TBNA for the clarification of PET positive intra-thoracic lymph nodes: an international multi-centre experience. J Thorac Oncol2009; 4:44–48.
Rivera P, Metha A, American College of Chest Physicians. Initial diagnosis of lung cancer: ACCP evidence-based clinical practice guidelines( 2nd edition). Chest2007; 132:131S–148S.
Gildea TR, Mazzone PJ, Karnak D, Meziane M, Mehta AC. Electromagnetic navigation diagnostic bronchoscopy: a prospective study. Am J Respir Crit Care Med2006; 174:982–989.
Steinfort DP, Khor YH, Manser RL, Irving LB. Radial probe endobronchial ultrasound for the diagnosis of peripheral lung cancer: systematic review and meta-analysis. Eur Respir J2011; 37:902–910.
Eberhardt R, Anantham D, Ernst A, Feller-Kopman D, Herth F. Multimodality bronchoscopic diagnosis of peripheral lung lesions: a randomized controlled trial. Am J Respir Crit Care Med2007; 176:36–41.
Yasufuku K, Nakajima T, Motoori K, et al. Comparison of endobronchial ultrasound, positron emission tomography, and CT for lymph node staging of lung cancer. Chest2006; 130:710–718.
Hwangbo B, Kim SK, Lee HS, et al. Application of endobronchial ultrasound-guided transbronchial needle aspiration following integrated PET/CT in mediastinal staging of potentially operable non-small cell lung cancer. Chest2009; 135:1280–1287.
Herth FJ, Eberhardt R, Krasnik M, Ernst A. Endobronchial ultrasound-guided transbronchial needle aspiration of lymph nodes in the radiologically and positron emission tomography-normal mediastinum in patients with lung cancer. Chest2008; 133:887–891.
Hwangbo B, Lee GK, Lee HS, et al. Transbronchial and transesophageal fine-needle aspiration using an ultrasound bronchoscope in mediastinal staging of potentially operable lung cancer. Chest2010; 138:795–802.
Herth FJ, Krasnik M, Kahn N, Eberhardt R, Ernst A. Combined endoscopic-endobronchial ultrasound-guided fine-needle aspiration of mediastinal lymph nodes through a single bronchoscope in 150 patients with suspected lung cancer. Chest2010; 138:790–794.
Gu P, Zhao YZ, Jiang LY, Zhang W, Xin Y, Han BH. Endobronchial ultrasound-guided transbronchial needle aspiration for staging of lung cancer: a systematic review and meta-analysis [published online ahead of print January 3, 3009]. Eur J Cancer2009; 45:1389–1396. doi: 10.1016/j.ejca2009.06.023
Adams K, Shah PL, Edmonds L, Lim E. Test performance of endobronchial ultrasound and transbronchial needle aspiration biopsy for mediastinal staging in patients with lung cancer: systematic review and meta-analysis [published online ahead of print May 18, 2009]. Thorax2009; 64:757–762. doi: 10.1136/thx.2008.109868
Ernst A, Anantham D, Eberhardt R, Krasnik M, Herth FJ. Diagnosis of mediastinal adenopathy-real-time endobronchial ultrasound guided needle aspiration versus mediastinoscopy. J Thorac Oncol2008; 3:577–582.
Annema JT, van Meerbeeck JP, Rintoul RC, et al. Mediastinoscopy vs endosonography for mediastinal nodal staging of lung cancer: a randomized trial. JAMA2010; 304:2245–2252.
Almeida FA, Uzbeck M, Jimenez C, et al. Flexible bronchoscopy and endobronchial ultrasound-transbronchial needle aspiration (EBUS-TBNA) vs other invasive modalities in the initial diagnosis and staging of suspected or confirmed lung cancer. Chest2010; 138:423A. Abstract.
Almeida FA, Uzbeck M, Ost D. Initial evaluation of the nonsmall cell lung cancer patient: diagnosis and staging. Curr Opin Pulm Med2010; 16:307–314.
Nakajima T, Yasufuku K, Suzuki M, et al. Assessment of epidermal growth factor receptor mutation by endobronchial ultrasound-guided transbronchial needle aspiration [published online ahead of print June 15, 2007. Chest2007; 132:597–602. doi: 10.1378/chest.07-0095
van Eijk R, Licht J, Schrumpf M, et al. Rapid KRAS, EGFR, BRAF and PIK3CA mutation analysis of fine needle aspirates from non-small-cell lung cancer using allele-specific qPCR. PLoS One2011; 6:e17791.
Herth FJ, Annema JT, Eberhardt R, et al. Endobronchial ultrasound with transbronchial needle aspiration for restaging the mediastinum in lung cancer [published online ahead of print June 2, 2008]. J Clin Oncol2008; 26:3346–3350. doi: 10.1200/JCO.2007.14.9229
Szlubowski A, Herth FJ, Soja J, et al. Endobronchial ultrasound-guided needle aspiration in non-small-cell lung cancer restaging verified by the transcervical bilateral extended mediastinal lymphadenectomy—a prospective study [published online ahead of print December 22, 2009]. Eur J Cardiothorac Surg2010; 37:1180–1184. doi: 10.1016/j.ejcts.2009.11.014
Francisco Aécio Almedia, MD, MS, FCCP Associate Staff Member, Director, Interventional Pulmonary Medicine Fellowship Program, Respiratory Institute, Cleveland Clinic, Cleveland, OH
Correspondence: Francisco Aécio Almeida, MD, MS, FCCP, Critical Care Medicine, Cleveland Clinic, 9500 Euclid Avenue, A90, Cleveland, OH 44195; almeidf@ccf.org
Dr. Almeida reported that he has no financial relationships that pose a potential conflict of interest with this article.
This article was developed from an audio transcript of Dr. Almeida’s presentation at the “Advances in Lung Cancer Evaluation and Management” symposium held in Cleveland, Ohio, on April 30, 2011. The transcript was formatted and edited by Cleveland Clinic Journal of Medicine staff for clarity and consciseness and was then reviewed, revised, and approved by Dr. Almeida.
Francisco Aécio Almedia, MD, MS, FCCP Associate Staff Member, Director, Interventional Pulmonary Medicine Fellowship Program, Respiratory Institute, Cleveland Clinic, Cleveland, OH
Correspondence: Francisco Aécio Almeida, MD, MS, FCCP, Critical Care Medicine, Cleveland Clinic, 9500 Euclid Avenue, A90, Cleveland, OH 44195; almeidf@ccf.org
Dr. Almeida reported that he has no financial relationships that pose a potential conflict of interest with this article.
This article was developed from an audio transcript of Dr. Almeida’s presentation at the “Advances in Lung Cancer Evaluation and Management” symposium held in Cleveland, Ohio, on April 30, 2011. The transcript was formatted and edited by Cleveland Clinic Journal of Medicine staff for clarity and consciseness and was then reviewed, revised, and approved by Dr. Almeida.
Author and Disclosure Information
Francisco Aécio Almedia, MD, MS, FCCP Associate Staff Member, Director, Interventional Pulmonary Medicine Fellowship Program, Respiratory Institute, Cleveland Clinic, Cleveland, OH
Correspondence: Francisco Aécio Almeida, MD, MS, FCCP, Critical Care Medicine, Cleveland Clinic, 9500 Euclid Avenue, A90, Cleveland, OH 44195; almeidf@ccf.org
Dr. Almeida reported that he has no financial relationships that pose a potential conflict of interest with this article.
This article was developed from an audio transcript of Dr. Almeida’s presentation at the “Advances in Lung Cancer Evaluation and Management” symposium held in Cleveland, Ohio, on April 30, 2011. The transcript was formatted and edited by Cleveland Clinic Journal of Medicine staff for clarity and consciseness and was then reviewed, revised, and approved by Dr. Almeida.
Several techniques are available for the diagnosis of suspected lung cancer, including standard flexible bronchoscopy, transthoracic needle aspiration, and sputum cytology. Mediastinal staging of lung cancer is essential for treatment planning and assessment of prognosis, and has traditionally been performed surgically. Although cervical mediastinoscopy is regarded as the “gold standard” for sampling mediastinal lymph nodes, this procedure typically requires hospitalization and general anesthesia.1 Current endobronchial ultrasound (EBUS) techniques provide less invasive lung cancer diagnosis and staging. Recent research has examined the application of endobronchial ultrasound-based assessment for initial diagnosis of lung cancer, mediastinal staging and restaging after neoadjuvant therapy, and evaluation of tumor genetic markers.
BRONCHOSCOPIC LUNG CANCER DIAGNOSIS
Evidence-based clinical guidelines for the diagnosis of lung cancer developed by the American College of Chest Physicians reviewed the sensitivity of standard bronchoscopy (ie, without EBUS or electromagnetic navigation) and ancillary procedures that are often performed in combination with flexible bronchoscopy, such as endobronchial biopsy, brushing, washing, and standard transbronchial needle aspiration (TBNA).2 A comprehensive review of published studies from 1971 to 2004 was included in the analysis. Overall, the sensitivity of standard flexible bronchoscopy was 88% (67% to 97%) for the diagnosis of central bronchogenic carcinoma and 78% (36% to 88%) for the diagnosis of peripheral bronchogenic carcinoma. Newer techniques have been developed that appear to provide more consistent diagnosis of primary lesions.
Electromagnetic navigation bronchoscopy (ENB) is a functional tool in biopsy planning that uses computed tomography (CT) mapping to precisely locate peripheral lesions. After real-time navigation to the peripheral lesion with a steerable probe, tissue collection may be optimized by guiding sampling instruments directly to the lesion through an extendable working channel.3 A prospective pilot study examined the feasibility and safety of ENB to reach peripheral lesions and lymph nodes in patients with suspected lung cancer lesions or enlarged mediastinal lymph nodes.3 Diagnostic tissue was obtained in 80.3% of attempts, including 74% of procedures involving peripheral lung lesions and 100% of procedures involving lymph nodes.
IMPROVING DIAGNOSIS WITH ULTRASOUND
Another diagnostic method is EBUS, which uses reflected sound waves to better visualize lesions at the time of biopsy.4 Radial probe endobronchial ultrasound (RP-EBUS) employs a rotating ultrasound transducer at the end of a probe, and is used either with or without a water-filled balloon to improve ultrasound transduction and image quality. Convex-probe ultrasound uses a curvilinear ultrasound probe at the end of a bronchoscope, which allows for real-time TBNA visualization.4 A recent meta-analysis examined the yield of RP-EBUS for the evaluation of peripheral pulmonary lesions in 16 studies with a combined population of 1,420 patients.5 The overall sensitivity of RP-EBUS for the detection of lung cancer was 73%, and the specificity was 100%. In a prospective, randomized clinical trial of patients with peripheral lung lesions, the combination of ENB and RP-EBUS produced a diagnostic yield of 88%, compared with 69% with RP-EBUS alone and 59% with ENB alone (P = .02).6 Although this finding suggests that a multimodal approach combining ENB and RP-EBUS may improve lung cancer diagnosis, the sample size was relatively small (118 patients).
ENDOBRONCHIAL ULTRASOUND FOR LUNG CANCER STAGING
Reproduced with permission from the American College of Chest Physicians (Yasufuku K, et al. Comparison of endobronchial ultrasound, positron emission tomography, and CT for lymph node staging of lung cancer. Chest 2006; 130:10–18).
Figure 1. The diagnostic reach of various ultrasound sampling techniques is shown with 1, highest mediastinal; 2, upper paratracheal; 4, lower paratracheal; 5, subaortic; , subcarinal; 8, paraesophageal; 9, pulmonary ligament; 10, hilar; 11, interlobar; and 12, lobar. Endobronchial ultrasound with transbronchial needle aspiration (EBUS-TBNA) is performed via the airway as opposed to endo-scopic ultrasound with fine-needle aspiration (EUS-FNA), which is carried out in the esophagus.7A promising application for EBUS is its use as a less invasive method for confirming metastatic mediastinal lymph nodes in the staging of lung cancer. Figure 1 shows the distribution of the mediastinal lymph nodes and the various diagnostic techniques that may be used to sample different lymph node stations.7
In a prospective study of potentially operable patients from Japan with proven (n = 96) or suspected (n = 6) lung cancer, investigators compared CT, positron emission tomography (PET), and EBUS-TBNA for mediastinal lymph node staging using surgical histology as the reference standard.7 The accuracy of staging was significantly greater with EBUS-TBNA (98%) than either PET (72.5%) or CT (60.8%) (P < .00001).
A recent retrospective study examined the use of EBUS-TBNA for clarification of 127 PET-positive hilar or mediastinal lymph nodes from 109 patients with suspected lung cancer.1 In 77 patients (71%), EBUS-TBNA successfully identified cancerous lymph nodes and obviated the need for further surgical biopsy. In 96 patients with definitive reference pathology, the sensitivity of EBUS-TBNA was 91%, specificity was 100%, and diagnostic accuracy was 92%. The positive predictive value of EBUS was 100%, but the negative predictive value (ie, the proportion of patients with negative EBUS-TBNA who were also negative on surgical pathology) was only 60%. This suggests a relatively high rate of false-negative EBUS-TBNA findings in this PET-positive group of patients.
Another recent study prospectively evaluated the usefulness of EBUS-TBNA after PET-CT for mediastinal staging in 117 patients with potentially operable non–small cell lung cancer (NSCLC).8 Patients were classified as either N2- or N3-positive or -negative using EBUS-TBNA, and patients who were N2- or N3-negative underwent surgical staging with lymph node dissection. Mediastinal node metastasis was confirmed by EBUS-TBNA in 37 nodal stations of 27 patients. Ninety patients who were negative by EBUS-TBNA underwent surgery with lymph node dissection. Three were reclassified as positive and 87 as negative. The overall sensitivity of EBUS-TBNA for the detection of mediastinal metastases was 90% versus 70% with PET-CT (P = .052). For the subgroup of 61 patients who had a normal mediastinum by PET-CT, nine were found to have mediastinal metastases at surgical evaluation. Six of these nine false-negatives were correctly identified by EBUS-TBNA.
Similar results were found in a study examining the use of EBUS-TBNA in 97 patients with confirmed NSCLC, no enlarged lymph nodes on CT (ie, no lymph nodes larger than 1 cm in short axis), and no abnormal mediastinal PET findings.9 Lymph nodes as small as 5 mm by ultrasound imaging at stations 2R, 2L, 4R, 4L, 7, 10R, 10L, 11R, and 11L were aspirated, and all patients underwent surgical staging. Malignant lymph nodes were detected by surgical staging in nine patients, and eight of these were identified by EBUS-TBNA. The sensitivity of EBUS-TBNA for the detection of mediastinal metastases was 89%; the specificity was 100%; and the negative predictive value was 99%.
Guided fine-needle aspiration with ultrasound bronchoscopy
An additional approach to mediastinal lung cancer staging is endoscopic ultrasound with bronchoscope-guided fine-needle aspiration (EUS-B-FNA) and EBUS-TBNA in a single procedure. The use of EBUS-TBNA and EUS-B-FNA for NSCLC staging was examined in a prospective study of 150 patients with confirmed or strongly suspected NSCLC.10 Patients underwent EBUS-TBNA, and EUS-B-FNA then was used for nodes that were inaccessible through the airways. EBUS-TBNA diagnosed mediastinal metastases in 38 of 143 patients, and three more patients were identified by additional EUS-B-FNA. Surgery identified four additional patients with mediastinal metastases that were negative by both EBUS-TBNA and EUS-B-FNA. Overall sensitivity for the detection of mediastinal metastases was 84.4% with EBUS-TBNA alone versus 91.1% with EBUS-TBNA followed by EUS-B-FNA, but this was not statistically significant (P = .332).
A second study of 139 patients with confirmed NSCLC reported similar results when EBUS-TBNA and EUS-B-FNA were performed using a single ultrasound bronchoscope.11 The sensitivity for detection of mediastinal metastases was 89% with EUS-FNA, 92% with EBUS-TBNA, and 96% with the combined approach. The specificity was 100% for all three approaches. The negative predictive values were 82% for the esophageal approach, 92% for the endobronchial approach, and 86% for the combined approach.
Meta-analyses support EBUS-TBNA for staging
The usefulness of EBUS-TBNA for NSCLC staging has been examined in two recent meta-analyses. The first included data from 11 studies of EBUS-TBNA with 1,299 patients.12 Overall, the included studies yielded a pooled sensitivity of 93% and a specificity of 100% for the detection of metastatic mediastinal lymph nodes (95% CI). The sensitivity was higher for patients who were selected for evaluation on the basis of positive PET or CT findings than for patients without selection by PET or CT (0.94 vs 0.76) (P < .05). The authors concluded that EBUS-TBNA for lung cancer staging is accurate, safe, and cost-effective, and that selection of patients based on CT or PET findings resulted in higher sensitivity.
The second meta-analysis examined data from 10 studies evaluating the utility of EBUS-TBNA for lung cancer staging.13 This meta-analysis also yielded high sensitivity (88%) and specificity (100%) of EBUS-TBNA for the identification of metastatic mediastinal lymph nodes.
EVALUATION OF EBUS VERSUS MEDIASTINOSCOPY AND OTHER INVASIVE TESTS
Although several studies suggest that EBUS-TBNA provides an accurate and less invasive method for assessment of mediastinal lymph nodes in the mediastinal staging of patients with NSCLC, few studies have directly compared EBUS-TBNA with mediastinoscopy. In a prospective crossover trial, 66 patients with suspected NSCLC underwent mediastinal staging using EBUS-TBNA followed by mediastinoscopy, with surgical lymph node dissection as the reference standard.14 The overall diagnostic yield for all lymph nodes was significantly higher with EBUS-TBNA than with mediastinoscopy (91% vs 78%) (P = .007). However, this difference was primarily due to a higher success rate in the diagnosis of subcarinal lymph nodes (98% vs 78%) (P = .007), which can be difficult to evaluate with mediastinoscopy. Differences between the two methods at other node stations were not statistically significant (Table). In the 57 patients who were diagnosed with NSCLC, the prediction of the correct pathologic stage did not differ significantly between the two approaches (93% with EBUS-TBNA vs 82% with mediastinoscopy) (P = .083).
A more recent randomized, multicenter clinical trial compared endosonographical staging (EUS-FNA and EBUS-TBNA) with mediastinoscopy in 241 patients with resectable suspected NSCLC.15 Patients were randomized to either surgical staging or to endosonography followed by surgical staging for those without nodal metastases using ultrasound-guided FNA. The sensitivity for detection of nodal metastases was 79% with surgical staging and 94% with endosonography and surgical staging (P = .02). Comparing the sensitivity of the two procedures alone, without follow-up surgical staging when ultrasound was negative, the sensitivities of the two approaches were similar: 79% with mediastinoscopy and 85% with endosonographic staging alone.
Another retrospective study examined the results of EBUS-TBNA for the initial diagnosis and staging of 88 patients with known or suspected lung cancer who underwent at least one invasive diagnostic or staging procedure before EBUS-TBNA.16 The selection of EBUS-TBNA and bronchoscopy as the initial test for diagnosis and staging could have prevented at least one invasive test in 50% of patients, and could have been the only invasive test procedure in 47.7% of individuals. In 27 patients who underwent two or more invasive tests, EBUS-TBNA could have avoided at least one invasive test in 16 patients (59%).
PATHWAYS TO DIAGNOSIS
Reprinted with permission from Current Opinion in Pulmonary Medicine (Almeida FA, et al. Initial evaluation of the nonsmall cell lung cancer patient: diagnosis and staging. Curr Opin Pulm Med 2010; 16:307–314).
Figure 2. This diagnostic algorithm should be followed for patients with suspected non–small cell lung cancer (NSCLC).17 CBC = complete blood count; COPD = chronic obstructive pulmonary disease; CT = computed tomography; Dlco = diffusion capacity of the lung for carbon monoxide; EBUS-TBNA = endobronchial ultrasound-guided trans-bronchial needle aspiration; PET = positron emission tomographyA proposed diagnostic algorithm for suspected NSCLC is shown in Figure 2.17 When lung cancer is highly suspected on the basis of focused patient history and physical examination, the patient should undergo CT-PET or chest CT with contrast that also should assess the liver and adrenal glands. If the patient has radiographic evidence of metastatic disease, the next step is biopsy of the most accessible, most advanced lesion for tissue diagnosis and staging. In patients without evidence of metastatic disease, the next step is to evaluate the mediastinal lymph nodes. Patients with evidence of nodal involvement on PET-CT or without evidence of nodal involvement but with larger tumors (eg, stage T1b or larger) may be evaluated using EBUS-TBNA as the first invasive test if available or mediastinoscopy. Standard bronchoscopy in conjunction with EBUS-TBNA has the capability of sampling the primary lesion when the mediastinal staging fails to demonstrate malignant disease. Therefore, it can provide a definitive diagnosis in addition to mediastinal staging during one single procedure, whereas mediastinoscopy typically cannot assess the primary lesion if necessary.
APPLICATIONS IN MOLECULAR TUMOR PROFILING
Genetic profiling of lung cancer tissue samples is essential to identify biomarkers that significantly influence treatment responses, and EBUS-TBNA has been used to obtain biopsy tissue samples for genetic analysis. One study examined the detection of EGFR gene mutations in biopsy tissue samples obtained from 46 patients with metastatic adenocarcinoma to the hilar or mediastinal lymph nodes diagnosed by EBUS-TBNA.18 Recut sections of the paraffin-embedded samples yielded tumor cells in 43 patients, and tissue samples were examined for mutations of EGFR exons 19 and 21. Five patients underwent surgical resection, and three of these yielded samples with EGFR mutations at exon 21. Examination of the 43 EBUS-TBNA specimens revealed EGFR mutations in 11. These included three of the mutations that were identified from surgical specimens. A more recent study examined the concordance between mutations of KRAS, EGFR, BRAF, and PIK3CA obtained by EBUS-TBNA, EUS-B-FNA, and histologic samples obtained during surgical staging from 43 patients.19KRAS mutations were identified in six patients, EGFR mutation in one patient, and PIK3CA mutation in one patient. The investigators observed 100% concordance between cytologic fine-needle aspirates and histologic specimens, suggesting no additional benefit of more invasive procedures for the evaluation of tumor biomarkers.
EBUS RESTAGING OF LUNG CANCER
The utility of EBUS-TBNA has also been investigated for restaging of lung cancer following neoadjuvant chemotherapy. Mediastinal restaging using EBUS-TBNA was performed in 124 consecutive patients with stage IIIA-N2 NSCLC who had received chemotherapy induction.20 CT evaluation revealed partial responses for 66 patients and stable disease in 58. All patients subsequently underwent thoracotomy and attempted curative resection with lymph node dissection. Of 58 patients with stable disease on CT, 41 were EBUS-TBNA–positive for mediastinal metastasis, and all were thoracotomy-positive. However, in 17 patients who were EBUS-TBNA–negative, 14 were thoracotomy-positive and only three were thoracotomy-negative. Similarly, in 66 patients with partial response to treatment on CT, 48 were EBUS-TNA–positive and thoracotomy-positive. In 18 patients who were EBUS-TBNA–negative, 14 were thoracotomy-positive and only four were also thoracotomy-negative. Overall, the sensitivity of EBUS-TBNA was 77% in patients with partial responses and 75% in those with stable disease. The negative predictive value of EBUS-TBNA in this series was very low: 22% in the partial response group and 18% in the stable disease group.
Similar results were obtained in a European study that examined EBUS-TBNA mediastinal restaging after neoadjuvant therapy in patients with pathologically confirmed N2 disease.21 Patients with negative or uncertain EBUS-TBNA were reexamined using transcervical extended bilateral mediastinal lymphadenectomy, a surgical staging procedure that is not widely used in the United States. Of 85 mediastinal lymph nodes from 61 patients that were examined using EBUS-TBNA, nine patients (15%) had a false-negative result with EBUS-TBNA, and three patients (5%) had a false-positive result. On a per-patient basis, the sensitivity of EBUS-TBNA was 67% and the negative predictive value was 78%.
SUMMARY AND CONCLUSIONS
Newer technologies such as EBUS-TBNA make it possible to simplify the diagnosis and staging of lung cancer. Bronchoscopy with EBUS may be the preferred method for the initial diagnosis and staging of patients who have disease limited to the chest. EBUS is clearly superior to current modalities for mediastinum staging such as CT and PET, and appears to be similar to mediastinoscopy. Standard bronchoscopy with EBUS followed by mediastinoscopy, if necessary, appears to be the best strategy for initial diagnosis and staging of patients with suspected lung cancer radiographically limited to the chest. However, at this time, diagnosis and staging should rely on local expertise rather than a particular methodology. Patients with T1B lesions or higher should be considered for invasive mediastinal staging regardless of their PET or CT results. The available evidence suggests that EBUS is a reasonable initial test for mediastinal restaging following neoadjuvant chemotherapy. However, a negative EBUS in this setting should prompt additional invasive tests to confirm its findings.
Several techniques are available for the diagnosis of suspected lung cancer, including standard flexible bronchoscopy, transthoracic needle aspiration, and sputum cytology. Mediastinal staging of lung cancer is essential for treatment planning and assessment of prognosis, and has traditionally been performed surgically. Although cervical mediastinoscopy is regarded as the “gold standard” for sampling mediastinal lymph nodes, this procedure typically requires hospitalization and general anesthesia.1 Current endobronchial ultrasound (EBUS) techniques provide less invasive lung cancer diagnosis and staging. Recent research has examined the application of endobronchial ultrasound-based assessment for initial diagnosis of lung cancer, mediastinal staging and restaging after neoadjuvant therapy, and evaluation of tumor genetic markers.
BRONCHOSCOPIC LUNG CANCER DIAGNOSIS
Evidence-based clinical guidelines for the diagnosis of lung cancer developed by the American College of Chest Physicians reviewed the sensitivity of standard bronchoscopy (ie, without EBUS or electromagnetic navigation) and ancillary procedures that are often performed in combination with flexible bronchoscopy, such as endobronchial biopsy, brushing, washing, and standard transbronchial needle aspiration (TBNA).2 A comprehensive review of published studies from 1971 to 2004 was included in the analysis. Overall, the sensitivity of standard flexible bronchoscopy was 88% (67% to 97%) for the diagnosis of central bronchogenic carcinoma and 78% (36% to 88%) for the diagnosis of peripheral bronchogenic carcinoma. Newer techniques have been developed that appear to provide more consistent diagnosis of primary lesions.
Electromagnetic navigation bronchoscopy (ENB) is a functional tool in biopsy planning that uses computed tomography (CT) mapping to precisely locate peripheral lesions. After real-time navigation to the peripheral lesion with a steerable probe, tissue collection may be optimized by guiding sampling instruments directly to the lesion through an extendable working channel.3 A prospective pilot study examined the feasibility and safety of ENB to reach peripheral lesions and lymph nodes in patients with suspected lung cancer lesions or enlarged mediastinal lymph nodes.3 Diagnostic tissue was obtained in 80.3% of attempts, including 74% of procedures involving peripheral lung lesions and 100% of procedures involving lymph nodes.
IMPROVING DIAGNOSIS WITH ULTRASOUND
Another diagnostic method is EBUS, which uses reflected sound waves to better visualize lesions at the time of biopsy.4 Radial probe endobronchial ultrasound (RP-EBUS) employs a rotating ultrasound transducer at the end of a probe, and is used either with or without a water-filled balloon to improve ultrasound transduction and image quality. Convex-probe ultrasound uses a curvilinear ultrasound probe at the end of a bronchoscope, which allows for real-time TBNA visualization.4 A recent meta-analysis examined the yield of RP-EBUS for the evaluation of peripheral pulmonary lesions in 16 studies with a combined population of 1,420 patients.5 The overall sensitivity of RP-EBUS for the detection of lung cancer was 73%, and the specificity was 100%. In a prospective, randomized clinical trial of patients with peripheral lung lesions, the combination of ENB and RP-EBUS produced a diagnostic yield of 88%, compared with 69% with RP-EBUS alone and 59% with ENB alone (P = .02).6 Although this finding suggests that a multimodal approach combining ENB and RP-EBUS may improve lung cancer diagnosis, the sample size was relatively small (118 patients).
ENDOBRONCHIAL ULTRASOUND FOR LUNG CANCER STAGING
Reproduced with permission from the American College of Chest Physicians (Yasufuku K, et al. Comparison of endobronchial ultrasound, positron emission tomography, and CT for lymph node staging of lung cancer. Chest 2006; 130:10–18).
Figure 1. The diagnostic reach of various ultrasound sampling techniques is shown with 1, highest mediastinal; 2, upper paratracheal; 4, lower paratracheal; 5, subaortic; , subcarinal; 8, paraesophageal; 9, pulmonary ligament; 10, hilar; 11, interlobar; and 12, lobar. Endobronchial ultrasound with transbronchial needle aspiration (EBUS-TBNA) is performed via the airway as opposed to endo-scopic ultrasound with fine-needle aspiration (EUS-FNA), which is carried out in the esophagus.7A promising application for EBUS is its use as a less invasive method for confirming metastatic mediastinal lymph nodes in the staging of lung cancer. Figure 1 shows the distribution of the mediastinal lymph nodes and the various diagnostic techniques that may be used to sample different lymph node stations.7
In a prospective study of potentially operable patients from Japan with proven (n = 96) or suspected (n = 6) lung cancer, investigators compared CT, positron emission tomography (PET), and EBUS-TBNA for mediastinal lymph node staging using surgical histology as the reference standard.7 The accuracy of staging was significantly greater with EBUS-TBNA (98%) than either PET (72.5%) or CT (60.8%) (P < .00001).
A recent retrospective study examined the use of EBUS-TBNA for clarification of 127 PET-positive hilar or mediastinal lymph nodes from 109 patients with suspected lung cancer.1 In 77 patients (71%), EBUS-TBNA successfully identified cancerous lymph nodes and obviated the need for further surgical biopsy. In 96 patients with definitive reference pathology, the sensitivity of EBUS-TBNA was 91%, specificity was 100%, and diagnostic accuracy was 92%. The positive predictive value of EBUS was 100%, but the negative predictive value (ie, the proportion of patients with negative EBUS-TBNA who were also negative on surgical pathology) was only 60%. This suggests a relatively high rate of false-negative EBUS-TBNA findings in this PET-positive group of patients.
Another recent study prospectively evaluated the usefulness of EBUS-TBNA after PET-CT for mediastinal staging in 117 patients with potentially operable non–small cell lung cancer (NSCLC).8 Patients were classified as either N2- or N3-positive or -negative using EBUS-TBNA, and patients who were N2- or N3-negative underwent surgical staging with lymph node dissection. Mediastinal node metastasis was confirmed by EBUS-TBNA in 37 nodal stations of 27 patients. Ninety patients who were negative by EBUS-TBNA underwent surgery with lymph node dissection. Three were reclassified as positive and 87 as negative. The overall sensitivity of EBUS-TBNA for the detection of mediastinal metastases was 90% versus 70% with PET-CT (P = .052). For the subgroup of 61 patients who had a normal mediastinum by PET-CT, nine were found to have mediastinal metastases at surgical evaluation. Six of these nine false-negatives were correctly identified by EBUS-TBNA.
Similar results were found in a study examining the use of EBUS-TBNA in 97 patients with confirmed NSCLC, no enlarged lymph nodes on CT (ie, no lymph nodes larger than 1 cm in short axis), and no abnormal mediastinal PET findings.9 Lymph nodes as small as 5 mm by ultrasound imaging at stations 2R, 2L, 4R, 4L, 7, 10R, 10L, 11R, and 11L were aspirated, and all patients underwent surgical staging. Malignant lymph nodes were detected by surgical staging in nine patients, and eight of these were identified by EBUS-TBNA. The sensitivity of EBUS-TBNA for the detection of mediastinal metastases was 89%; the specificity was 100%; and the negative predictive value was 99%.
Guided fine-needle aspiration with ultrasound bronchoscopy
An additional approach to mediastinal lung cancer staging is endoscopic ultrasound with bronchoscope-guided fine-needle aspiration (EUS-B-FNA) and EBUS-TBNA in a single procedure. The use of EBUS-TBNA and EUS-B-FNA for NSCLC staging was examined in a prospective study of 150 patients with confirmed or strongly suspected NSCLC.10 Patients underwent EBUS-TBNA, and EUS-B-FNA then was used for nodes that were inaccessible through the airways. EBUS-TBNA diagnosed mediastinal metastases in 38 of 143 patients, and three more patients were identified by additional EUS-B-FNA. Surgery identified four additional patients with mediastinal metastases that were negative by both EBUS-TBNA and EUS-B-FNA. Overall sensitivity for the detection of mediastinal metastases was 84.4% with EBUS-TBNA alone versus 91.1% with EBUS-TBNA followed by EUS-B-FNA, but this was not statistically significant (P = .332).
A second study of 139 patients with confirmed NSCLC reported similar results when EBUS-TBNA and EUS-B-FNA were performed using a single ultrasound bronchoscope.11 The sensitivity for detection of mediastinal metastases was 89% with EUS-FNA, 92% with EBUS-TBNA, and 96% with the combined approach. The specificity was 100% for all three approaches. The negative predictive values were 82% for the esophageal approach, 92% for the endobronchial approach, and 86% for the combined approach.
Meta-analyses support EBUS-TBNA for staging
The usefulness of EBUS-TBNA for NSCLC staging has been examined in two recent meta-analyses. The first included data from 11 studies of EBUS-TBNA with 1,299 patients.12 Overall, the included studies yielded a pooled sensitivity of 93% and a specificity of 100% for the detection of metastatic mediastinal lymph nodes (95% CI). The sensitivity was higher for patients who were selected for evaluation on the basis of positive PET or CT findings than for patients without selection by PET or CT (0.94 vs 0.76) (P < .05). The authors concluded that EBUS-TBNA for lung cancer staging is accurate, safe, and cost-effective, and that selection of patients based on CT or PET findings resulted in higher sensitivity.
The second meta-analysis examined data from 10 studies evaluating the utility of EBUS-TBNA for lung cancer staging.13 This meta-analysis also yielded high sensitivity (88%) and specificity (100%) of EBUS-TBNA for the identification of metastatic mediastinal lymph nodes.
EVALUATION OF EBUS VERSUS MEDIASTINOSCOPY AND OTHER INVASIVE TESTS
Although several studies suggest that EBUS-TBNA provides an accurate and less invasive method for assessment of mediastinal lymph nodes in the mediastinal staging of patients with NSCLC, few studies have directly compared EBUS-TBNA with mediastinoscopy. In a prospective crossover trial, 66 patients with suspected NSCLC underwent mediastinal staging using EBUS-TBNA followed by mediastinoscopy, with surgical lymph node dissection as the reference standard.14 The overall diagnostic yield for all lymph nodes was significantly higher with EBUS-TBNA than with mediastinoscopy (91% vs 78%) (P = .007). However, this difference was primarily due to a higher success rate in the diagnosis of subcarinal lymph nodes (98% vs 78%) (P = .007), which can be difficult to evaluate with mediastinoscopy. Differences between the two methods at other node stations were not statistically significant (Table). In the 57 patients who were diagnosed with NSCLC, the prediction of the correct pathologic stage did not differ significantly between the two approaches (93% with EBUS-TBNA vs 82% with mediastinoscopy) (P = .083).
A more recent randomized, multicenter clinical trial compared endosonographical staging (EUS-FNA and EBUS-TBNA) with mediastinoscopy in 241 patients with resectable suspected NSCLC.15 Patients were randomized to either surgical staging or to endosonography followed by surgical staging for those without nodal metastases using ultrasound-guided FNA. The sensitivity for detection of nodal metastases was 79% with surgical staging and 94% with endosonography and surgical staging (P = .02). Comparing the sensitivity of the two procedures alone, without follow-up surgical staging when ultrasound was negative, the sensitivities of the two approaches were similar: 79% with mediastinoscopy and 85% with endosonographic staging alone.
Another retrospective study examined the results of EBUS-TBNA for the initial diagnosis and staging of 88 patients with known or suspected lung cancer who underwent at least one invasive diagnostic or staging procedure before EBUS-TBNA.16 The selection of EBUS-TBNA and bronchoscopy as the initial test for diagnosis and staging could have prevented at least one invasive test in 50% of patients, and could have been the only invasive test procedure in 47.7% of individuals. In 27 patients who underwent two or more invasive tests, EBUS-TBNA could have avoided at least one invasive test in 16 patients (59%).
PATHWAYS TO DIAGNOSIS
Reprinted with permission from Current Opinion in Pulmonary Medicine (Almeida FA, et al. Initial evaluation of the nonsmall cell lung cancer patient: diagnosis and staging. Curr Opin Pulm Med 2010; 16:307–314).
Figure 2. This diagnostic algorithm should be followed for patients with suspected non–small cell lung cancer (NSCLC).17 CBC = complete blood count; COPD = chronic obstructive pulmonary disease; CT = computed tomography; Dlco = diffusion capacity of the lung for carbon monoxide; EBUS-TBNA = endobronchial ultrasound-guided trans-bronchial needle aspiration; PET = positron emission tomographyA proposed diagnostic algorithm for suspected NSCLC is shown in Figure 2.17 When lung cancer is highly suspected on the basis of focused patient history and physical examination, the patient should undergo CT-PET or chest CT with contrast that also should assess the liver and adrenal glands. If the patient has radiographic evidence of metastatic disease, the next step is biopsy of the most accessible, most advanced lesion for tissue diagnosis and staging. In patients without evidence of metastatic disease, the next step is to evaluate the mediastinal lymph nodes. Patients with evidence of nodal involvement on PET-CT or without evidence of nodal involvement but with larger tumors (eg, stage T1b or larger) may be evaluated using EBUS-TBNA as the first invasive test if available or mediastinoscopy. Standard bronchoscopy in conjunction with EBUS-TBNA has the capability of sampling the primary lesion when the mediastinal staging fails to demonstrate malignant disease. Therefore, it can provide a definitive diagnosis in addition to mediastinal staging during one single procedure, whereas mediastinoscopy typically cannot assess the primary lesion if necessary.
APPLICATIONS IN MOLECULAR TUMOR PROFILING
Genetic profiling of lung cancer tissue samples is essential to identify biomarkers that significantly influence treatment responses, and EBUS-TBNA has been used to obtain biopsy tissue samples for genetic analysis. One study examined the detection of EGFR gene mutations in biopsy tissue samples obtained from 46 patients with metastatic adenocarcinoma to the hilar or mediastinal lymph nodes diagnosed by EBUS-TBNA.18 Recut sections of the paraffin-embedded samples yielded tumor cells in 43 patients, and tissue samples were examined for mutations of EGFR exons 19 and 21. Five patients underwent surgical resection, and three of these yielded samples with EGFR mutations at exon 21. Examination of the 43 EBUS-TBNA specimens revealed EGFR mutations in 11. These included three of the mutations that were identified from surgical specimens. A more recent study examined the concordance between mutations of KRAS, EGFR, BRAF, and PIK3CA obtained by EBUS-TBNA, EUS-B-FNA, and histologic samples obtained during surgical staging from 43 patients.19KRAS mutations were identified in six patients, EGFR mutation in one patient, and PIK3CA mutation in one patient. The investigators observed 100% concordance between cytologic fine-needle aspirates and histologic specimens, suggesting no additional benefit of more invasive procedures for the evaluation of tumor biomarkers.
EBUS RESTAGING OF LUNG CANCER
The utility of EBUS-TBNA has also been investigated for restaging of lung cancer following neoadjuvant chemotherapy. Mediastinal restaging using EBUS-TBNA was performed in 124 consecutive patients with stage IIIA-N2 NSCLC who had received chemotherapy induction.20 CT evaluation revealed partial responses for 66 patients and stable disease in 58. All patients subsequently underwent thoracotomy and attempted curative resection with lymph node dissection. Of 58 patients with stable disease on CT, 41 were EBUS-TBNA–positive for mediastinal metastasis, and all were thoracotomy-positive. However, in 17 patients who were EBUS-TBNA–negative, 14 were thoracotomy-positive and only three were thoracotomy-negative. Similarly, in 66 patients with partial response to treatment on CT, 48 were EBUS-TNA–positive and thoracotomy-positive. In 18 patients who were EBUS-TBNA–negative, 14 were thoracotomy-positive and only four were also thoracotomy-negative. Overall, the sensitivity of EBUS-TBNA was 77% in patients with partial responses and 75% in those with stable disease. The negative predictive value of EBUS-TBNA in this series was very low: 22% in the partial response group and 18% in the stable disease group.
Similar results were obtained in a European study that examined EBUS-TBNA mediastinal restaging after neoadjuvant therapy in patients with pathologically confirmed N2 disease.21 Patients with negative or uncertain EBUS-TBNA were reexamined using transcervical extended bilateral mediastinal lymphadenectomy, a surgical staging procedure that is not widely used in the United States. Of 85 mediastinal lymph nodes from 61 patients that were examined using EBUS-TBNA, nine patients (15%) had a false-negative result with EBUS-TBNA, and three patients (5%) had a false-positive result. On a per-patient basis, the sensitivity of EBUS-TBNA was 67% and the negative predictive value was 78%.
SUMMARY AND CONCLUSIONS
Newer technologies such as EBUS-TBNA make it possible to simplify the diagnosis and staging of lung cancer. Bronchoscopy with EBUS may be the preferred method for the initial diagnosis and staging of patients who have disease limited to the chest. EBUS is clearly superior to current modalities for mediastinum staging such as CT and PET, and appears to be similar to mediastinoscopy. Standard bronchoscopy with EBUS followed by mediastinoscopy, if necessary, appears to be the best strategy for initial diagnosis and staging of patients with suspected lung cancer radiographically limited to the chest. However, at this time, diagnosis and staging should rely on local expertise rather than a particular methodology. Patients with T1B lesions or higher should be considered for invasive mediastinal staging regardless of their PET or CT results. The available evidence suggests that EBUS is a reasonable initial test for mediastinal restaging following neoadjuvant chemotherapy. However, a negative EBUS in this setting should prompt additional invasive tests to confirm its findings.
References
Rintoul RC, Tournoy KG, El Daly H, et al. EBUS-TBNA for the clarification of PET positive intra-thoracic lymph nodes: an international multi-centre experience. J Thorac Oncol2009; 4:44–48.
Rivera P, Metha A, American College of Chest Physicians. Initial diagnosis of lung cancer: ACCP evidence-based clinical practice guidelines( 2nd edition). Chest2007; 132:131S–148S.
Gildea TR, Mazzone PJ, Karnak D, Meziane M, Mehta AC. Electromagnetic navigation diagnostic bronchoscopy: a prospective study. Am J Respir Crit Care Med2006; 174:982–989.
Steinfort DP, Khor YH, Manser RL, Irving LB. Radial probe endobronchial ultrasound for the diagnosis of peripheral lung cancer: systematic review and meta-analysis. Eur Respir J2011; 37:902–910.
Eberhardt R, Anantham D, Ernst A, Feller-Kopman D, Herth F. Multimodality bronchoscopic diagnosis of peripheral lung lesions: a randomized controlled trial. Am J Respir Crit Care Med2007; 176:36–41.
Yasufuku K, Nakajima T, Motoori K, et al. Comparison of endobronchial ultrasound, positron emission tomography, and CT for lymph node staging of lung cancer. Chest2006; 130:710–718.
Hwangbo B, Kim SK, Lee HS, et al. Application of endobronchial ultrasound-guided transbronchial needle aspiration following integrated PET/CT in mediastinal staging of potentially operable non-small cell lung cancer. Chest2009; 135:1280–1287.
Herth FJ, Eberhardt R, Krasnik M, Ernst A. Endobronchial ultrasound-guided transbronchial needle aspiration of lymph nodes in the radiologically and positron emission tomography-normal mediastinum in patients with lung cancer. Chest2008; 133:887–891.
Hwangbo B, Lee GK, Lee HS, et al. Transbronchial and transesophageal fine-needle aspiration using an ultrasound bronchoscope in mediastinal staging of potentially operable lung cancer. Chest2010; 138:795–802.
Herth FJ, Krasnik M, Kahn N, Eberhardt R, Ernst A. Combined endoscopic-endobronchial ultrasound-guided fine-needle aspiration of mediastinal lymph nodes through a single bronchoscope in 150 patients with suspected lung cancer. Chest2010; 138:790–794.
Gu P, Zhao YZ, Jiang LY, Zhang W, Xin Y, Han BH. Endobronchial ultrasound-guided transbronchial needle aspiration for staging of lung cancer: a systematic review and meta-analysis [published online ahead of print January 3, 3009]. Eur J Cancer2009; 45:1389–1396. doi: 10.1016/j.ejca2009.06.023
Adams K, Shah PL, Edmonds L, Lim E. Test performance of endobronchial ultrasound and transbronchial needle aspiration biopsy for mediastinal staging in patients with lung cancer: systematic review and meta-analysis [published online ahead of print May 18, 2009]. Thorax2009; 64:757–762. doi: 10.1136/thx.2008.109868
Ernst A, Anantham D, Eberhardt R, Krasnik M, Herth FJ. Diagnosis of mediastinal adenopathy-real-time endobronchial ultrasound guided needle aspiration versus mediastinoscopy. J Thorac Oncol2008; 3:577–582.
Annema JT, van Meerbeeck JP, Rintoul RC, et al. Mediastinoscopy vs endosonography for mediastinal nodal staging of lung cancer: a randomized trial. JAMA2010; 304:2245–2252.
Almeida FA, Uzbeck M, Jimenez C, et al. Flexible bronchoscopy and endobronchial ultrasound-transbronchial needle aspiration (EBUS-TBNA) vs other invasive modalities in the initial diagnosis and staging of suspected or confirmed lung cancer. Chest2010; 138:423A. Abstract.
Almeida FA, Uzbeck M, Ost D. Initial evaluation of the nonsmall cell lung cancer patient: diagnosis and staging. Curr Opin Pulm Med2010; 16:307–314.
Nakajima T, Yasufuku K, Suzuki M, et al. Assessment of epidermal growth factor receptor mutation by endobronchial ultrasound-guided transbronchial needle aspiration [published online ahead of print June 15, 2007. Chest2007; 132:597–602. doi: 10.1378/chest.07-0095
van Eijk R, Licht J, Schrumpf M, et al. Rapid KRAS, EGFR, BRAF and PIK3CA mutation analysis of fine needle aspirates from non-small-cell lung cancer using allele-specific qPCR. PLoS One2011; 6:e17791.
Herth FJ, Annema JT, Eberhardt R, et al. Endobronchial ultrasound with transbronchial needle aspiration for restaging the mediastinum in lung cancer [published online ahead of print June 2, 2008]. J Clin Oncol2008; 26:3346–3350. doi: 10.1200/JCO.2007.14.9229
Szlubowski A, Herth FJ, Soja J, et al. Endobronchial ultrasound-guided needle aspiration in non-small-cell lung cancer restaging verified by the transcervical bilateral extended mediastinal lymphadenectomy—a prospective study [published online ahead of print December 22, 2009]. Eur J Cardiothorac Surg2010; 37:1180–1184. doi: 10.1016/j.ejcts.2009.11.014
References
Rintoul RC, Tournoy KG, El Daly H, et al. EBUS-TBNA for the clarification of PET positive intra-thoracic lymph nodes: an international multi-centre experience. J Thorac Oncol2009; 4:44–48.
Rivera P, Metha A, American College of Chest Physicians. Initial diagnosis of lung cancer: ACCP evidence-based clinical practice guidelines( 2nd edition). Chest2007; 132:131S–148S.
Gildea TR, Mazzone PJ, Karnak D, Meziane M, Mehta AC. Electromagnetic navigation diagnostic bronchoscopy: a prospective study. Am J Respir Crit Care Med2006; 174:982–989.
Steinfort DP, Khor YH, Manser RL, Irving LB. Radial probe endobronchial ultrasound for the diagnosis of peripheral lung cancer: systematic review and meta-analysis. Eur Respir J2011; 37:902–910.
Eberhardt R, Anantham D, Ernst A, Feller-Kopman D, Herth F. Multimodality bronchoscopic diagnosis of peripheral lung lesions: a randomized controlled trial. Am J Respir Crit Care Med2007; 176:36–41.
Yasufuku K, Nakajima T, Motoori K, et al. Comparison of endobronchial ultrasound, positron emission tomography, and CT for lymph node staging of lung cancer. Chest2006; 130:710–718.
Hwangbo B, Kim SK, Lee HS, et al. Application of endobronchial ultrasound-guided transbronchial needle aspiration following integrated PET/CT in mediastinal staging of potentially operable non-small cell lung cancer. Chest2009; 135:1280–1287.
Herth FJ, Eberhardt R, Krasnik M, Ernst A. Endobronchial ultrasound-guided transbronchial needle aspiration of lymph nodes in the radiologically and positron emission tomography-normal mediastinum in patients with lung cancer. Chest2008; 133:887–891.
Hwangbo B, Lee GK, Lee HS, et al. Transbronchial and transesophageal fine-needle aspiration using an ultrasound bronchoscope in mediastinal staging of potentially operable lung cancer. Chest2010; 138:795–802.
Herth FJ, Krasnik M, Kahn N, Eberhardt R, Ernst A. Combined endoscopic-endobronchial ultrasound-guided fine-needle aspiration of mediastinal lymph nodes through a single bronchoscope in 150 patients with suspected lung cancer. Chest2010; 138:790–794.
Gu P, Zhao YZ, Jiang LY, Zhang W, Xin Y, Han BH. Endobronchial ultrasound-guided transbronchial needle aspiration for staging of lung cancer: a systematic review and meta-analysis [published online ahead of print January 3, 3009]. Eur J Cancer2009; 45:1389–1396. doi: 10.1016/j.ejca2009.06.023
Adams K, Shah PL, Edmonds L, Lim E. Test performance of endobronchial ultrasound and transbronchial needle aspiration biopsy for mediastinal staging in patients with lung cancer: systematic review and meta-analysis [published online ahead of print May 18, 2009]. Thorax2009; 64:757–762. doi: 10.1136/thx.2008.109868
Ernst A, Anantham D, Eberhardt R, Krasnik M, Herth FJ. Diagnosis of mediastinal adenopathy-real-time endobronchial ultrasound guided needle aspiration versus mediastinoscopy. J Thorac Oncol2008; 3:577–582.
Annema JT, van Meerbeeck JP, Rintoul RC, et al. Mediastinoscopy vs endosonography for mediastinal nodal staging of lung cancer: a randomized trial. JAMA2010; 304:2245–2252.
Almeida FA, Uzbeck M, Jimenez C, et al. Flexible bronchoscopy and endobronchial ultrasound-transbronchial needle aspiration (EBUS-TBNA) vs other invasive modalities in the initial diagnosis and staging of suspected or confirmed lung cancer. Chest2010; 138:423A. Abstract.
Almeida FA, Uzbeck M, Ost D. Initial evaluation of the nonsmall cell lung cancer patient: diagnosis and staging. Curr Opin Pulm Med2010; 16:307–314.
Nakajima T, Yasufuku K, Suzuki M, et al. Assessment of epidermal growth factor receptor mutation by endobronchial ultrasound-guided transbronchial needle aspiration [published online ahead of print June 15, 2007. Chest2007; 132:597–602. doi: 10.1378/chest.07-0095
van Eijk R, Licht J, Schrumpf M, et al. Rapid KRAS, EGFR, BRAF and PIK3CA mutation analysis of fine needle aspirates from non-small-cell lung cancer using allele-specific qPCR. PLoS One2011; 6:e17791.
Herth FJ, Annema JT, Eberhardt R, et al. Endobronchial ultrasound with transbronchial needle aspiration for restaging the mediastinum in lung cancer [published online ahead of print June 2, 2008]. J Clin Oncol2008; 26:3346–3350. doi: 10.1200/JCO.2007.14.9229
Szlubowski A, Herth FJ, Soja J, et al. Endobronchial ultrasound-guided needle aspiration in non-small-cell lung cancer restaging verified by the transcervical bilateral extended mediastinal lymphadenectomy—a prospective study [published online ahead of print December 22, 2009]. Eur J Cardiothorac Surg2010; 37:1180–1184. doi: 10.1016/j.ejcts.2009.11.014
For patients with localized lung cancer, lung resection provides the highest likelihood of a cure. However, only about 20% to 30% of patients are potential candidates for surgical resection because of the stage at which the disease is diagnosed or because of comorbid conditions.1,2 In one study, poor lung function alone ruled out more than 37% of patients who presented with anatomically resectable disease.3 The poor prognosis for patients who do not undergo surgery, the likelihood of early mortality from lung resection, and the potential for loss of lung function following resection are all important considerations in the preoperative pulmonary evaluation of candidates for anatomical lung resection.
PROGNOSIS OF LUNG CANCER POOR WITHOUT SURGICAL RESECTION
Several studies support the poor prognosis of lung cancer patients who do not undergo resection. In one study of 1,297 screen- and symptom-detected patients, the median duration of survival without surgery was 25 months for patients with screen-detected stage I lung cancer (n = 42) and 13 months for those with symptom-detected stage I disease (n = 27).4 Another study of 799 patients with stage I lung cancer who were not treated surgically reported 5- and 10-year survival rates of 16.6% (n = 49) and 7.4% (n = 49), respectively.5 In a study of 251 patients with squamous cell carcinoma on sputum cytology, yet negative chest imaging, the 5-year and 10-year survival rates were 53.2% and 33.5%.6 Another study of 57 patients with potentially resectable disease who did not undergo surgery reported a median survival of 15.6 months, compared with 30.9 months for a group of 346 patients who underwent resection.7
PREDICTORS OF SURGICAL MORTALITY
Several large patient series describe perioperative mortality and the rate of complications for patients undergoing surgical resection for lung cancer. Reported surgical mortality rates in these studies vary from approximately 1% to 5%.2,8–10 The median age of patients in most of these studies was 65 to 70 years, and many patients had significant medical comorbidity. Predictors of increased surgical mortality include pneumonectomy, bilobectomy, American Society of Anesthesiologists (ASA) Physical Status Scale rating, Zubrod performance status score, renal dysfunction, induction chemoradiation therapy, steroid use, older age, urgent procedures, male gender, forced expiratory volume in 1 second (FEV1), and body mass index.11 In France, a thoracic surgery scoring system for in-hospital mortality (Thoracoscore) was developed using data obtained from more than 15,000 patients who were enrolled in a nationally representative thoracic surgery database. Mortality risk factors included in the model were patient age, sex, dyspnea score, ASA score, performance status, priority of surgery, diagnosis, procedure class, and comorbid disease.12 The model was highly accurate for the prediction of mortality, with a C statistic of 0.86. (1.00 corresponds to perfect outcome prediction.) The model was subsequently validated on 1,675 patients from the United States, where a similar accuracy was noted.13 The online version of the Thoracoscore risk assessment tool is available at: http://www.sfar.org/scores2/thoracoscore2.php.
REDUCED PULMONARY FUNCTION AFTER RESECTION
Several outcome measures have been used to assess the impact of resection on pulmonary function and quality of life after surgery. Across various studies, postoperative FEV1 values, diffusing capacity of the lung for carbon monoxide (Dlco) values, and peak oxygen consumption (VO2 peak) were assessed at various time intervals after lobectomy or pneumonectomy. FEV1 varied from 84% to 91% of preoperative values for lobectomy,14–16 and 64% to 66% for pneumonectomy.14–16 The Dlco was 89% to 96% of preoperative values after lobectomy and 72% to 80% after pneumonectomy.14,16 VO2 peak varied from 87% to 100% of preoperative values after lobectomy,14–16 and 71% to 89% after pneumonectomy.14–16
Patients with chronic obstructive pulmonary disease (COPD) typically experience smaller declines in FEV1 after lobectomy (0% to 8%) than those without COPD (16% to 20%). Declines in Dlco and VO2 peak are more variable, with reported decreases of 3% to 20% in those with COPD, and 0% to 21% for those without the disease.17–19
Lobectomy patients continue to recover pulmonary function for approximately 6 months after surgery. In patients who undergo pneumonectomy, improvement is generally limited after 3 months.14–16 Loss of lung function may vary significantly with the location of the resection. For example, resection of an emphysematous portion of the lung will probably result in less loss of function.
Few studies specifically examine quality of life after lung resection in patients with lung cancer. In general, patients who undergo resection have a lower quality of life before surgery than the general population.20 Postsurgical decline in physical measures of health-related quality of life has been reported during the month after surgery, with a return to baseline after 3 months. Mental quality of life scores did not decrease after surgery, and there was little correlation between quality of life outcomes and measures of pulmonary function.20
LUNG FUNCTION TESTING
Lung function testing helps predict the risk of postoperative complications, including mortality. The two most commonly used measures of pulmonary function are FEV1 and Dlco.
Both absolute FEV1 value and percent of predicted FEV1 strongly predict the risk of postoperative complications. It has been difficult to identify one cutoff value below which resection should not be considered. Studies have suggested preoperative absolute FEV1 values of 2 L for pneumonectomy and 1.5 L for lobectomy as cutoffs signifying increased short- and long-term surgical risk.21,22 Percent predicted FEV1, which incorporates patient age, sex, and height, is more commonly used to individualize treatment, since absolute values do not take into consideration other patient-related variables. An FEV1 of 80% predicted or higher has been proposed as a cutoff to proceed with resection without additional testing,23 but this decision must be individualized to each patient.
Similarly, it has been difficult to identify one cutoff value for the Dlco. As one might expect, the lower the value the higher the risk for a given patient. Patients with Dlco values less than 60% predicted normal24 had an increased mortality risk, longer hospital stay, and greater hospital costs in one report.
FEV1 and Dlco are only modestly correlated with one another.25 In one study, 43% of patients with FEV1 greater than 80% of predicted had Dlco less than 80% of predicted.26
According to guidelines developed by the American College of Chest Physicians (ACCP), spirometry is recommended for patients being considered for lung cancer resection.27 Patients with FEV1 that is greater than 80% predicted or greater than 2 L and without evidence of dyspnea or interstitial lung disease are considered suitable candidates for resection, including pneumonectomy, without further testing. Lobectomy without further evaluation may be performed if the FEV1 is greater than 1.5 L and there is no evidence of dyspnea or interstitial lung disease.
Although assessing FEV1 values alone may be adequate in patients being considered for lung cancer resection who have no evidence of either undue dyspnea on exertion or interstitial lung disease, the ACCP recommends also measuring Dlco when these signs are present. Guidelines from the European Respiratory Society (ERS) and the European Society of Thoracic Surgeons (ESTS) recommend routinely measuring Dlco during preoperative evaluation regardless of whether the spirometric evaluation is abnormal.28 Similarly, the British Thoracic Society (BTS) recommends measuring transfer factor of the lung for carbon monoxide (Tlco) in all patients regardless of spirometric values.29
PREDICTING POSTOPERATIVE LUNG FUNCTION
Several methods have been used to predict postoperative lung function.
Segment method
The segment method estimates postoperative lung function by multiplying baseline function by the percentage of lung sections that will remain after resection.30 For example, if preoperative FEV1 is 1 L and surgery will result in the loss of 25% of lung segments, the predicted postoperative FEV1 is 750 mL. In a study using 19 lung segments in the calculation, the predicted postoperative lung function correlated well with actual postoperative lung function for patients undergoing lobectomy, but only modestly for patients undergoing pneumonectomy.30 Another method using 42 subsegments for the calculation, and correcting for segments that were obstructed by tumor, produced very similar results.31
Radionuclide scanning
In other studies, quantitative radionuclide scanning to identify the proportion of lung with poor perfusion produced fair to good correlations between predicted and actual postoperative FEV1.32–35 Techniques that are used less often include quantitative computed tomography (CT) and measurement of airway vibration during respiration.
Studies comparing different methods for predicting postoperative pulmonary function have found that perfusion imaging outperformed other approaches, and that the segment method is not a good predictor of outcome for patients undergoing pneumonectomy.17,36
Additional testing needed
For potential lung resection patients, the ACCP guidelines recommend that if either the FEV1 or Dlco is less than 80% of the predicted value, postoperative lung function should be predicted through additional testing.27 The ERS recommends that predicted postoperative FEV1 should not be used alone to select lung cancer patients for lung resection, especially those with moderate to severe COPD.28 These guidelines also recommend that the first estimate of residual lung function should be calculated based on segment counting, that only segments not totally obstructed should be counted, and that the patency of bronchus and segment structure should be preserved. In addition, patients with borderline function should undergo imaging-based calculation of residual lung function, including ventilation or perfusion scintigraphy before pneumonectomy, or quantitative CT scan before either lobectomy or pneumonectomy.28 The BTS recommends the use of segment counting to estimate postoperative lung function as part of risk assessment for postoperative dyspnea. Ventilation or perfusion scintigraphy should be considered to predict postoperative lung function if a ventilation or perfusion mismatch is suspected. Quantitative CT or MRI may be considered to predict postoperative lung function if the facility is available.29
Predicting mortality and complications: FEV1 and Dlco
The predicted postoperative FEV1 value is an independent predictor of postoperative mortality and other complications. Although there is no absolute cut-off value, studies identify an increased risk of complications below predicted postoperative FEV1 values ranging from 30%37 to 40%.38,39 Predicted postoperative Dlco is another outcome measure that can independently identify increased mortality risk in lung cancer resection patients. Dlco less than 40% has been associated with increased risk of postoperative respiratory complications even in those with predicted postoperative FEV1 values above 40%.26,39 One study stated that a combination of the two values, predicted postoperative FEV1 and predicted postoperative Dlco—called the predicted postoperative product (PPP)—is the best predictor of surgical mortality.40 Another study examined the utility of a prediction rule for pulmonary complications after lung surgery using a point system in which points were assigned based on predicted postoperative Dlco (1 point for each 5% decrement below 100%) plus 2 points for preoperative chemotherapy.41 The risk of complications was 9% for those with scores less than 11, 14% for those with scores of 11 to 13, and 26% for those with scores greater than 13.
When surgery is considered, ACCP guidelines state an increased risk of perioperative mortality in those lung cancer patients with either a PPP less than 1,650, or a predicted postoperative FEV1 less than 30%.27 These patients should be counseled about nonstandard surgery and nonsurgical treatment options. The ERS guidelines consider a predicted postoperative FEV1 value less than 30% to be a high-risk threshold when assessing pulmonary reserve before surgery.28
EXERCISE TESTING
In general, standardized cardiopulmonary exercise testing using VO2 peak has been shown to predict postoperative complications, including perioperative and long-term morbidity and mortality.42,43 Lower values are associated with a greater risk of poor outcome. Peak VO2 may not add significantly to the risk stratification of patients who have both FEV1 and Dlco values greater than 80%.44
According to ACCP recommendations for exercise testing in patients who are being evaluated for surgery, either an FEV1 or Dlco less than 40% of predicted postoperative (PPO) indicates increased risk for perioperative death and cardiopulmonary complications with standard lung resection. Preoperative exercise testing is recommended for these patients.27 Maximal oxygen consumption (VO2 max) less than 10 mL/kg/min, or the combination of VO2 max less than 15 mL/kg/min with both FEV1 and Dlco less than 40% PPO, also indicates increased risk for death and complications; these patients should be counseled about nonstandard surgery or nonsurgical treatment options. Guidelines from the ERS recommend exercise testing for all patients undergoing lung cancer surgery who have FEV1 or Dlco less than 80% of normal values.28 The VO2 peak measured during incremental exercise on a treadmill or cycle should be regarded as the most important parameter.
Figure. Distance walked during a shuttle walking test is strongly related to maximal oxygen consumption (VO2 max).
Several studies have found that distance traveled during walking tests predicts postoperative complications and can be related to VO2 max (Figure).45 According to ACCP guidelines, lung cancer patients who are potential candidates for standard lung resection are at increased risk for perioperative death and cardiopulmonary complications if they walk less than 25 shuttles on 2 shuttle walk tests or less than 1 flight of stairs. These patients should be counseled about nonstandard surgery and nonsurgical treatment options.27
Conversely, ERS/ESTS guidelines state that the shuttle walk test distance underestimates exercise capacity at the lower range, and does not discriminate between patients with and without complications.28 These guidelines state that shuttle walk test distance should not be used alone to select patients for resection. It may be used as a screening test, since patients walking less than 400 m are likely to also have VO2 peak less than 15 mL/kg/min. A standardized symptom-limited stair climbing test can be a cost-effective screening method to identify those who need more sophisticated exercise tests in order to optimize their perioperative management. The 6-minute walk test is not recommended.
British Thoracic Society guidelines recommend the use of the shuttle walk test as a functional assessment in patients with moderate to high risk of postoperative dyspnea.29 A distance walk of more than 400 m is recommended as a cutoff for acceptable pulmonary function. These guidelines recommend against using pulmonary function and exercise tests as the sole surrogates for a quality of life evaluation.
ALGORITHMS FOR TESTING
The ACCP, ERS/ESTS, and BTS guidelines all include algorithms for the preoperative evaluation of candidates for lung cancer resection.27–29 The guidelines differ from each other in many ways, including when to obtain a Dlco and cardiopulmonary exercise test, and in some of the cutoff values for various pulmonary function measures. ACCP guidelines begin with spirometry testing, supporting lobectomy in patients with spirometry results above the cutoff value of FEV1 greater than 1.5 L and pneumonectomy in those with a cutoff value of FEV1 greater than 2 L, and greater than 80% of predicted, unless the patient has dyspnea or evidence of interstitial lung disease. Measurement of the Dlco is recommended for those who do not meet the FEV1 cutoffs, or in those with unexplained dyspnea or diffuse parenchymal disease on chest radiograph or CT.27
A systematic review and set of treatment recommendations for high-risk patients with stage I lung cancer, developed by the Thoracic Oncology Network of the ACCP and the Workforce on Evidence-Based Surgery of the Society of Thoracic Surgeons, currently under review, will provide additional guidance regarding the use of lung function testing to evaluate risk of morbidity and mortality. These guidelines note that FEV1, Dlco, and peak VO2 all predict morbidity and mortality following major lung resection. Assessment of FEV1 and Dlco, including calculation of the estimated postoperative value, is strongly recommended before resection. The predictive value of peak VO2 is strongest in patients with impaired FEV1 or Dlco, and assessment of peak VO2 before major lung resection is recommended for these patients.
INTERVENTIONS TO DECREASE PERIOPERATIVE RISK
The impact of smoking cessation on perioperative outcome has been a matter of considerable debate. One large study found that the incidence of postoperative complications was actually greater when patients stopped smoking within 8 weeks before cardiac surgery.46 However, a recent meta-analysis including lung resection patients found no relationship between smoking cessation in the weeks before surgery and worse clinical outcomes.47 When a shorter duration of smoking cessation is examined, thoracotomy studies note that patients who continue to smoke within 1 month of pneumonectomy are at increased risk of major pulmonary events.48,49 An examination of perioperative mortality or major complications using data from the Society of Thoracic Surgeons found that smoking cessation within 1 month preceding surgery did not significantly affect perioperative morbidity or mortality, whereas longer abstention from tobacco use was associated with better surgical outcomes.50 The ACCP recommends that all patients with lung cancer be counseled regarding smoking cessation.27 ERS/ESTS guidelines recommend smoking cessation for at least 2 to 4 weeks before surgery, since this may change perioperative smoking behavior and decrease the risk of postoperative complications.28 Pulmonary rehabiliatation in the perioperative period has been shown to improve measures of activity tolerance, allowing resection of marginal candidates, and improving functional outcomes after resection.51 The ERS/ESTS guidelines state that early pre- and postoperative rehabilitation may produce functional benefits in resectable lung cancer patients.28
SUMMARY AND CONCLUSIONS
Lung function testing helps predict the risk of postoperative mortality, perioperative complications, and long-term dyspnea for patients with lung cancer undergoing surgical resection. Predicted postoperative FEV1 and Dlco should be evaluated in most resection candidates. Exercise testing adds to standard lung function testing in those with borderline values, discordance between standard measures, or discordance between subjective and objective lung function. Algorithms for preoperative assessment have been developed by the ACCP, the ERS/ESTS, and the BTS, which differ somewhat in the order of testing and specific testing cutoff values. Smoking cessation and pulmonary rehabilitation can help to reduce perioperative and long-term risks.
References
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Peter Mazzone, MD, MPH, FCCP Director of Education, Lung Cancer Program, and Pulmonary Rehabilitation Program; Respiratory Institute, Cleveland Clinic, Cleveland, OH
Correspondence: Peter Mazzone, MD, MPH, FCCP, Critical Care Medicine, Cleveland Clinic, 9500 Euclid Avenue, A90, Cleveland, OH 44195; mazzonp@ccf.org
Dr. Mazzone reported that he has been a member of advisory committees for Boehringer Ingelheim and Oncimmune. He has research supported by Metabolomx.
This article was developed from an audio transcript of Dr. Mazzone’s presentation at the “Advances in Lung Cancer Evaluation and Management” symposium held in Cleveland, Ohio, on April 30, 2011. The transcript was formatted and edited by Cleveland Clinic Journal of Medicine staff for clarity and conciseness and was then reviewed, revised, and approved by Dr. Mazzone.
Peter Mazzone, MD, MPH, FCCP Director of Education, Lung Cancer Program, and Pulmonary Rehabilitation Program; Respiratory Institute, Cleveland Clinic, Cleveland, OH
Correspondence: Peter Mazzone, MD, MPH, FCCP, Critical Care Medicine, Cleveland Clinic, 9500 Euclid Avenue, A90, Cleveland, OH 44195; mazzonp@ccf.org
Dr. Mazzone reported that he has been a member of advisory committees for Boehringer Ingelheim and Oncimmune. He has research supported by Metabolomx.
This article was developed from an audio transcript of Dr. Mazzone’s presentation at the “Advances in Lung Cancer Evaluation and Management” symposium held in Cleveland, Ohio, on April 30, 2011. The transcript was formatted and edited by Cleveland Clinic Journal of Medicine staff for clarity and conciseness and was then reviewed, revised, and approved by Dr. Mazzone.
Author and Disclosure Information
Peter Mazzone, MD, MPH, FCCP Director of Education, Lung Cancer Program, and Pulmonary Rehabilitation Program; Respiratory Institute, Cleveland Clinic, Cleveland, OH
Correspondence: Peter Mazzone, MD, MPH, FCCP, Critical Care Medicine, Cleveland Clinic, 9500 Euclid Avenue, A90, Cleveland, OH 44195; mazzonp@ccf.org
Dr. Mazzone reported that he has been a member of advisory committees for Boehringer Ingelheim and Oncimmune. He has research supported by Metabolomx.
This article was developed from an audio transcript of Dr. Mazzone’s presentation at the “Advances in Lung Cancer Evaluation and Management” symposium held in Cleveland, Ohio, on April 30, 2011. The transcript was formatted and edited by Cleveland Clinic Journal of Medicine staff for clarity and conciseness and was then reviewed, revised, and approved by Dr. Mazzone.
For patients with localized lung cancer, lung resection provides the highest likelihood of a cure. However, only about 20% to 30% of patients are potential candidates for surgical resection because of the stage at which the disease is diagnosed or because of comorbid conditions.1,2 In one study, poor lung function alone ruled out more than 37% of patients who presented with anatomically resectable disease.3 The poor prognosis for patients who do not undergo surgery, the likelihood of early mortality from lung resection, and the potential for loss of lung function following resection are all important considerations in the preoperative pulmonary evaluation of candidates for anatomical lung resection.
PROGNOSIS OF LUNG CANCER POOR WITHOUT SURGICAL RESECTION
Several studies support the poor prognosis of lung cancer patients who do not undergo resection. In one study of 1,297 screen- and symptom-detected patients, the median duration of survival without surgery was 25 months for patients with screen-detected stage I lung cancer (n = 42) and 13 months for those with symptom-detected stage I disease (n = 27).4 Another study of 799 patients with stage I lung cancer who were not treated surgically reported 5- and 10-year survival rates of 16.6% (n = 49) and 7.4% (n = 49), respectively.5 In a study of 251 patients with squamous cell carcinoma on sputum cytology, yet negative chest imaging, the 5-year and 10-year survival rates were 53.2% and 33.5%.6 Another study of 57 patients with potentially resectable disease who did not undergo surgery reported a median survival of 15.6 months, compared with 30.9 months for a group of 346 patients who underwent resection.7
PREDICTORS OF SURGICAL MORTALITY
Several large patient series describe perioperative mortality and the rate of complications for patients undergoing surgical resection for lung cancer. Reported surgical mortality rates in these studies vary from approximately 1% to 5%.2,8–10 The median age of patients in most of these studies was 65 to 70 years, and many patients had significant medical comorbidity. Predictors of increased surgical mortality include pneumonectomy, bilobectomy, American Society of Anesthesiologists (ASA) Physical Status Scale rating, Zubrod performance status score, renal dysfunction, induction chemoradiation therapy, steroid use, older age, urgent procedures, male gender, forced expiratory volume in 1 second (FEV1), and body mass index.11 In France, a thoracic surgery scoring system for in-hospital mortality (Thoracoscore) was developed using data obtained from more than 15,000 patients who were enrolled in a nationally representative thoracic surgery database. Mortality risk factors included in the model were patient age, sex, dyspnea score, ASA score, performance status, priority of surgery, diagnosis, procedure class, and comorbid disease.12 The model was highly accurate for the prediction of mortality, with a C statistic of 0.86. (1.00 corresponds to perfect outcome prediction.) The model was subsequently validated on 1,675 patients from the United States, where a similar accuracy was noted.13 The online version of the Thoracoscore risk assessment tool is available at: http://www.sfar.org/scores2/thoracoscore2.php.
REDUCED PULMONARY FUNCTION AFTER RESECTION
Several outcome measures have been used to assess the impact of resection on pulmonary function and quality of life after surgery. Across various studies, postoperative FEV1 values, diffusing capacity of the lung for carbon monoxide (Dlco) values, and peak oxygen consumption (VO2 peak) were assessed at various time intervals after lobectomy or pneumonectomy. FEV1 varied from 84% to 91% of preoperative values for lobectomy,14–16 and 64% to 66% for pneumonectomy.14–16 The Dlco was 89% to 96% of preoperative values after lobectomy and 72% to 80% after pneumonectomy.14,16 VO2 peak varied from 87% to 100% of preoperative values after lobectomy,14–16 and 71% to 89% after pneumonectomy.14–16
Patients with chronic obstructive pulmonary disease (COPD) typically experience smaller declines in FEV1 after lobectomy (0% to 8%) than those without COPD (16% to 20%). Declines in Dlco and VO2 peak are more variable, with reported decreases of 3% to 20% in those with COPD, and 0% to 21% for those without the disease.17–19
Lobectomy patients continue to recover pulmonary function for approximately 6 months after surgery. In patients who undergo pneumonectomy, improvement is generally limited after 3 months.14–16 Loss of lung function may vary significantly with the location of the resection. For example, resection of an emphysematous portion of the lung will probably result in less loss of function.
Few studies specifically examine quality of life after lung resection in patients with lung cancer. In general, patients who undergo resection have a lower quality of life before surgery than the general population.20 Postsurgical decline in physical measures of health-related quality of life has been reported during the month after surgery, with a return to baseline after 3 months. Mental quality of life scores did not decrease after surgery, and there was little correlation between quality of life outcomes and measures of pulmonary function.20
LUNG FUNCTION TESTING
Lung function testing helps predict the risk of postoperative complications, including mortality. The two most commonly used measures of pulmonary function are FEV1 and Dlco.
Both absolute FEV1 value and percent of predicted FEV1 strongly predict the risk of postoperative complications. It has been difficult to identify one cutoff value below which resection should not be considered. Studies have suggested preoperative absolute FEV1 values of 2 L for pneumonectomy and 1.5 L for lobectomy as cutoffs signifying increased short- and long-term surgical risk.21,22 Percent predicted FEV1, which incorporates patient age, sex, and height, is more commonly used to individualize treatment, since absolute values do not take into consideration other patient-related variables. An FEV1 of 80% predicted or higher has been proposed as a cutoff to proceed with resection without additional testing,23 but this decision must be individualized to each patient.
Similarly, it has been difficult to identify one cutoff value for the Dlco. As one might expect, the lower the value the higher the risk for a given patient. Patients with Dlco values less than 60% predicted normal24 had an increased mortality risk, longer hospital stay, and greater hospital costs in one report.
FEV1 and Dlco are only modestly correlated with one another.25 In one study, 43% of patients with FEV1 greater than 80% of predicted had Dlco less than 80% of predicted.26
According to guidelines developed by the American College of Chest Physicians (ACCP), spirometry is recommended for patients being considered for lung cancer resection.27 Patients with FEV1 that is greater than 80% predicted or greater than 2 L and without evidence of dyspnea or interstitial lung disease are considered suitable candidates for resection, including pneumonectomy, without further testing. Lobectomy without further evaluation may be performed if the FEV1 is greater than 1.5 L and there is no evidence of dyspnea or interstitial lung disease.
Although assessing FEV1 values alone may be adequate in patients being considered for lung cancer resection who have no evidence of either undue dyspnea on exertion or interstitial lung disease, the ACCP recommends also measuring Dlco when these signs are present. Guidelines from the European Respiratory Society (ERS) and the European Society of Thoracic Surgeons (ESTS) recommend routinely measuring Dlco during preoperative evaluation regardless of whether the spirometric evaluation is abnormal.28 Similarly, the British Thoracic Society (BTS) recommends measuring transfer factor of the lung for carbon monoxide (Tlco) in all patients regardless of spirometric values.29
PREDICTING POSTOPERATIVE LUNG FUNCTION
Several methods have been used to predict postoperative lung function.
Segment method
The segment method estimates postoperative lung function by multiplying baseline function by the percentage of lung sections that will remain after resection.30 For example, if preoperative FEV1 is 1 L and surgery will result in the loss of 25% of lung segments, the predicted postoperative FEV1 is 750 mL. In a study using 19 lung segments in the calculation, the predicted postoperative lung function correlated well with actual postoperative lung function for patients undergoing lobectomy, but only modestly for patients undergoing pneumonectomy.30 Another method using 42 subsegments for the calculation, and correcting for segments that were obstructed by tumor, produced very similar results.31
Radionuclide scanning
In other studies, quantitative radionuclide scanning to identify the proportion of lung with poor perfusion produced fair to good correlations between predicted and actual postoperative FEV1.32–35 Techniques that are used less often include quantitative computed tomography (CT) and measurement of airway vibration during respiration.
Studies comparing different methods for predicting postoperative pulmonary function have found that perfusion imaging outperformed other approaches, and that the segment method is not a good predictor of outcome for patients undergoing pneumonectomy.17,36
Additional testing needed
For potential lung resection patients, the ACCP guidelines recommend that if either the FEV1 or Dlco is less than 80% of the predicted value, postoperative lung function should be predicted through additional testing.27 The ERS recommends that predicted postoperative FEV1 should not be used alone to select lung cancer patients for lung resection, especially those with moderate to severe COPD.28 These guidelines also recommend that the first estimate of residual lung function should be calculated based on segment counting, that only segments not totally obstructed should be counted, and that the patency of bronchus and segment structure should be preserved. In addition, patients with borderline function should undergo imaging-based calculation of residual lung function, including ventilation or perfusion scintigraphy before pneumonectomy, or quantitative CT scan before either lobectomy or pneumonectomy.28 The BTS recommends the use of segment counting to estimate postoperative lung function as part of risk assessment for postoperative dyspnea. Ventilation or perfusion scintigraphy should be considered to predict postoperative lung function if a ventilation or perfusion mismatch is suspected. Quantitative CT or MRI may be considered to predict postoperative lung function if the facility is available.29
Predicting mortality and complications: FEV1 and Dlco
The predicted postoperative FEV1 value is an independent predictor of postoperative mortality and other complications. Although there is no absolute cut-off value, studies identify an increased risk of complications below predicted postoperative FEV1 values ranging from 30%37 to 40%.38,39 Predicted postoperative Dlco is another outcome measure that can independently identify increased mortality risk in lung cancer resection patients. Dlco less than 40% has been associated with increased risk of postoperative respiratory complications even in those with predicted postoperative FEV1 values above 40%.26,39 One study stated that a combination of the two values, predicted postoperative FEV1 and predicted postoperative Dlco—called the predicted postoperative product (PPP)—is the best predictor of surgical mortality.40 Another study examined the utility of a prediction rule for pulmonary complications after lung surgery using a point system in which points were assigned based on predicted postoperative Dlco (1 point for each 5% decrement below 100%) plus 2 points for preoperative chemotherapy.41 The risk of complications was 9% for those with scores less than 11, 14% for those with scores of 11 to 13, and 26% for those with scores greater than 13.
When surgery is considered, ACCP guidelines state an increased risk of perioperative mortality in those lung cancer patients with either a PPP less than 1,650, or a predicted postoperative FEV1 less than 30%.27 These patients should be counseled about nonstandard surgery and nonsurgical treatment options. The ERS guidelines consider a predicted postoperative FEV1 value less than 30% to be a high-risk threshold when assessing pulmonary reserve before surgery.28
EXERCISE TESTING
In general, standardized cardiopulmonary exercise testing using VO2 peak has been shown to predict postoperative complications, including perioperative and long-term morbidity and mortality.42,43 Lower values are associated with a greater risk of poor outcome. Peak VO2 may not add significantly to the risk stratification of patients who have both FEV1 and Dlco values greater than 80%.44
According to ACCP recommendations for exercise testing in patients who are being evaluated for surgery, either an FEV1 or Dlco less than 40% of predicted postoperative (PPO) indicates increased risk for perioperative death and cardiopulmonary complications with standard lung resection. Preoperative exercise testing is recommended for these patients.27 Maximal oxygen consumption (VO2 max) less than 10 mL/kg/min, or the combination of VO2 max less than 15 mL/kg/min with both FEV1 and Dlco less than 40% PPO, also indicates increased risk for death and complications; these patients should be counseled about nonstandard surgery or nonsurgical treatment options. Guidelines from the ERS recommend exercise testing for all patients undergoing lung cancer surgery who have FEV1 or Dlco less than 80% of normal values.28 The VO2 peak measured during incremental exercise on a treadmill or cycle should be regarded as the most important parameter.
Figure. Distance walked during a shuttle walking test is strongly related to maximal oxygen consumption (VO2 max).
Several studies have found that distance traveled during walking tests predicts postoperative complications and can be related to VO2 max (Figure).45 According to ACCP guidelines, lung cancer patients who are potential candidates for standard lung resection are at increased risk for perioperative death and cardiopulmonary complications if they walk less than 25 shuttles on 2 shuttle walk tests or less than 1 flight of stairs. These patients should be counseled about nonstandard surgery and nonsurgical treatment options.27
Conversely, ERS/ESTS guidelines state that the shuttle walk test distance underestimates exercise capacity at the lower range, and does not discriminate between patients with and without complications.28 These guidelines state that shuttle walk test distance should not be used alone to select patients for resection. It may be used as a screening test, since patients walking less than 400 m are likely to also have VO2 peak less than 15 mL/kg/min. A standardized symptom-limited stair climbing test can be a cost-effective screening method to identify those who need more sophisticated exercise tests in order to optimize their perioperative management. The 6-minute walk test is not recommended.
British Thoracic Society guidelines recommend the use of the shuttle walk test as a functional assessment in patients with moderate to high risk of postoperative dyspnea.29 A distance walk of more than 400 m is recommended as a cutoff for acceptable pulmonary function. These guidelines recommend against using pulmonary function and exercise tests as the sole surrogates for a quality of life evaluation.
ALGORITHMS FOR TESTING
The ACCP, ERS/ESTS, and BTS guidelines all include algorithms for the preoperative evaluation of candidates for lung cancer resection.27–29 The guidelines differ from each other in many ways, including when to obtain a Dlco and cardiopulmonary exercise test, and in some of the cutoff values for various pulmonary function measures. ACCP guidelines begin with spirometry testing, supporting lobectomy in patients with spirometry results above the cutoff value of FEV1 greater than 1.5 L and pneumonectomy in those with a cutoff value of FEV1 greater than 2 L, and greater than 80% of predicted, unless the patient has dyspnea or evidence of interstitial lung disease. Measurement of the Dlco is recommended for those who do not meet the FEV1 cutoffs, or in those with unexplained dyspnea or diffuse parenchymal disease on chest radiograph or CT.27
A systematic review and set of treatment recommendations for high-risk patients with stage I lung cancer, developed by the Thoracic Oncology Network of the ACCP and the Workforce on Evidence-Based Surgery of the Society of Thoracic Surgeons, currently under review, will provide additional guidance regarding the use of lung function testing to evaluate risk of morbidity and mortality. These guidelines note that FEV1, Dlco, and peak VO2 all predict morbidity and mortality following major lung resection. Assessment of FEV1 and Dlco, including calculation of the estimated postoperative value, is strongly recommended before resection. The predictive value of peak VO2 is strongest in patients with impaired FEV1 or Dlco, and assessment of peak VO2 before major lung resection is recommended for these patients.
INTERVENTIONS TO DECREASE PERIOPERATIVE RISK
The impact of smoking cessation on perioperative outcome has been a matter of considerable debate. One large study found that the incidence of postoperative complications was actually greater when patients stopped smoking within 8 weeks before cardiac surgery.46 However, a recent meta-analysis including lung resection patients found no relationship between smoking cessation in the weeks before surgery and worse clinical outcomes.47 When a shorter duration of smoking cessation is examined, thoracotomy studies note that patients who continue to smoke within 1 month of pneumonectomy are at increased risk of major pulmonary events.48,49 An examination of perioperative mortality or major complications using data from the Society of Thoracic Surgeons found that smoking cessation within 1 month preceding surgery did not significantly affect perioperative morbidity or mortality, whereas longer abstention from tobacco use was associated with better surgical outcomes.50 The ACCP recommends that all patients with lung cancer be counseled regarding smoking cessation.27 ERS/ESTS guidelines recommend smoking cessation for at least 2 to 4 weeks before surgery, since this may change perioperative smoking behavior and decrease the risk of postoperative complications.28 Pulmonary rehabiliatation in the perioperative period has been shown to improve measures of activity tolerance, allowing resection of marginal candidates, and improving functional outcomes after resection.51 The ERS/ESTS guidelines state that early pre- and postoperative rehabilitation may produce functional benefits in resectable lung cancer patients.28
SUMMARY AND CONCLUSIONS
Lung function testing helps predict the risk of postoperative mortality, perioperative complications, and long-term dyspnea for patients with lung cancer undergoing surgical resection. Predicted postoperative FEV1 and Dlco should be evaluated in most resection candidates. Exercise testing adds to standard lung function testing in those with borderline values, discordance between standard measures, or discordance between subjective and objective lung function. Algorithms for preoperative assessment have been developed by the ACCP, the ERS/ESTS, and the BTS, which differ somewhat in the order of testing and specific testing cutoff values. Smoking cessation and pulmonary rehabilitation can help to reduce perioperative and long-term risks.
For patients with localized lung cancer, lung resection provides the highest likelihood of a cure. However, only about 20% to 30% of patients are potential candidates for surgical resection because of the stage at which the disease is diagnosed or because of comorbid conditions.1,2 In one study, poor lung function alone ruled out more than 37% of patients who presented with anatomically resectable disease.3 The poor prognosis for patients who do not undergo surgery, the likelihood of early mortality from lung resection, and the potential for loss of lung function following resection are all important considerations in the preoperative pulmonary evaluation of candidates for anatomical lung resection.
PROGNOSIS OF LUNG CANCER POOR WITHOUT SURGICAL RESECTION
Several studies support the poor prognosis of lung cancer patients who do not undergo resection. In one study of 1,297 screen- and symptom-detected patients, the median duration of survival without surgery was 25 months for patients with screen-detected stage I lung cancer (n = 42) and 13 months for those with symptom-detected stage I disease (n = 27).4 Another study of 799 patients with stage I lung cancer who were not treated surgically reported 5- and 10-year survival rates of 16.6% (n = 49) and 7.4% (n = 49), respectively.5 In a study of 251 patients with squamous cell carcinoma on sputum cytology, yet negative chest imaging, the 5-year and 10-year survival rates were 53.2% and 33.5%.6 Another study of 57 patients with potentially resectable disease who did not undergo surgery reported a median survival of 15.6 months, compared with 30.9 months for a group of 346 patients who underwent resection.7
PREDICTORS OF SURGICAL MORTALITY
Several large patient series describe perioperative mortality and the rate of complications for patients undergoing surgical resection for lung cancer. Reported surgical mortality rates in these studies vary from approximately 1% to 5%.2,8–10 The median age of patients in most of these studies was 65 to 70 years, and many patients had significant medical comorbidity. Predictors of increased surgical mortality include pneumonectomy, bilobectomy, American Society of Anesthesiologists (ASA) Physical Status Scale rating, Zubrod performance status score, renal dysfunction, induction chemoradiation therapy, steroid use, older age, urgent procedures, male gender, forced expiratory volume in 1 second (FEV1), and body mass index.11 In France, a thoracic surgery scoring system for in-hospital mortality (Thoracoscore) was developed using data obtained from more than 15,000 patients who were enrolled in a nationally representative thoracic surgery database. Mortality risk factors included in the model were patient age, sex, dyspnea score, ASA score, performance status, priority of surgery, diagnosis, procedure class, and comorbid disease.12 The model was highly accurate for the prediction of mortality, with a C statistic of 0.86. (1.00 corresponds to perfect outcome prediction.) The model was subsequently validated on 1,675 patients from the United States, where a similar accuracy was noted.13 The online version of the Thoracoscore risk assessment tool is available at: http://www.sfar.org/scores2/thoracoscore2.php.
REDUCED PULMONARY FUNCTION AFTER RESECTION
Several outcome measures have been used to assess the impact of resection on pulmonary function and quality of life after surgery. Across various studies, postoperative FEV1 values, diffusing capacity of the lung for carbon monoxide (Dlco) values, and peak oxygen consumption (VO2 peak) were assessed at various time intervals after lobectomy or pneumonectomy. FEV1 varied from 84% to 91% of preoperative values for lobectomy,14–16 and 64% to 66% for pneumonectomy.14–16 The Dlco was 89% to 96% of preoperative values after lobectomy and 72% to 80% after pneumonectomy.14,16 VO2 peak varied from 87% to 100% of preoperative values after lobectomy,14–16 and 71% to 89% after pneumonectomy.14–16
Patients with chronic obstructive pulmonary disease (COPD) typically experience smaller declines in FEV1 after lobectomy (0% to 8%) than those without COPD (16% to 20%). Declines in Dlco and VO2 peak are more variable, with reported decreases of 3% to 20% in those with COPD, and 0% to 21% for those without the disease.17–19
Lobectomy patients continue to recover pulmonary function for approximately 6 months after surgery. In patients who undergo pneumonectomy, improvement is generally limited after 3 months.14–16 Loss of lung function may vary significantly with the location of the resection. For example, resection of an emphysematous portion of the lung will probably result in less loss of function.
Few studies specifically examine quality of life after lung resection in patients with lung cancer. In general, patients who undergo resection have a lower quality of life before surgery than the general population.20 Postsurgical decline in physical measures of health-related quality of life has been reported during the month after surgery, with a return to baseline after 3 months. Mental quality of life scores did not decrease after surgery, and there was little correlation between quality of life outcomes and measures of pulmonary function.20
LUNG FUNCTION TESTING
Lung function testing helps predict the risk of postoperative complications, including mortality. The two most commonly used measures of pulmonary function are FEV1 and Dlco.
Both absolute FEV1 value and percent of predicted FEV1 strongly predict the risk of postoperative complications. It has been difficult to identify one cutoff value below which resection should not be considered. Studies have suggested preoperative absolute FEV1 values of 2 L for pneumonectomy and 1.5 L for lobectomy as cutoffs signifying increased short- and long-term surgical risk.21,22 Percent predicted FEV1, which incorporates patient age, sex, and height, is more commonly used to individualize treatment, since absolute values do not take into consideration other patient-related variables. An FEV1 of 80% predicted or higher has been proposed as a cutoff to proceed with resection without additional testing,23 but this decision must be individualized to each patient.
Similarly, it has been difficult to identify one cutoff value for the Dlco. As one might expect, the lower the value the higher the risk for a given patient. Patients with Dlco values less than 60% predicted normal24 had an increased mortality risk, longer hospital stay, and greater hospital costs in one report.
FEV1 and Dlco are only modestly correlated with one another.25 In one study, 43% of patients with FEV1 greater than 80% of predicted had Dlco less than 80% of predicted.26
According to guidelines developed by the American College of Chest Physicians (ACCP), spirometry is recommended for patients being considered for lung cancer resection.27 Patients with FEV1 that is greater than 80% predicted or greater than 2 L and without evidence of dyspnea or interstitial lung disease are considered suitable candidates for resection, including pneumonectomy, without further testing. Lobectomy without further evaluation may be performed if the FEV1 is greater than 1.5 L and there is no evidence of dyspnea or interstitial lung disease.
Although assessing FEV1 values alone may be adequate in patients being considered for lung cancer resection who have no evidence of either undue dyspnea on exertion or interstitial lung disease, the ACCP recommends also measuring Dlco when these signs are present. Guidelines from the European Respiratory Society (ERS) and the European Society of Thoracic Surgeons (ESTS) recommend routinely measuring Dlco during preoperative evaluation regardless of whether the spirometric evaluation is abnormal.28 Similarly, the British Thoracic Society (BTS) recommends measuring transfer factor of the lung for carbon monoxide (Tlco) in all patients regardless of spirometric values.29
PREDICTING POSTOPERATIVE LUNG FUNCTION
Several methods have been used to predict postoperative lung function.
Segment method
The segment method estimates postoperative lung function by multiplying baseline function by the percentage of lung sections that will remain after resection.30 For example, if preoperative FEV1 is 1 L and surgery will result in the loss of 25% of lung segments, the predicted postoperative FEV1 is 750 mL. In a study using 19 lung segments in the calculation, the predicted postoperative lung function correlated well with actual postoperative lung function for patients undergoing lobectomy, but only modestly for patients undergoing pneumonectomy.30 Another method using 42 subsegments for the calculation, and correcting for segments that were obstructed by tumor, produced very similar results.31
Radionuclide scanning
In other studies, quantitative radionuclide scanning to identify the proportion of lung with poor perfusion produced fair to good correlations between predicted and actual postoperative FEV1.32–35 Techniques that are used less often include quantitative computed tomography (CT) and measurement of airway vibration during respiration.
Studies comparing different methods for predicting postoperative pulmonary function have found that perfusion imaging outperformed other approaches, and that the segment method is not a good predictor of outcome for patients undergoing pneumonectomy.17,36
Additional testing needed
For potential lung resection patients, the ACCP guidelines recommend that if either the FEV1 or Dlco is less than 80% of the predicted value, postoperative lung function should be predicted through additional testing.27 The ERS recommends that predicted postoperative FEV1 should not be used alone to select lung cancer patients for lung resection, especially those with moderate to severe COPD.28 These guidelines also recommend that the first estimate of residual lung function should be calculated based on segment counting, that only segments not totally obstructed should be counted, and that the patency of bronchus and segment structure should be preserved. In addition, patients with borderline function should undergo imaging-based calculation of residual lung function, including ventilation or perfusion scintigraphy before pneumonectomy, or quantitative CT scan before either lobectomy or pneumonectomy.28 The BTS recommends the use of segment counting to estimate postoperative lung function as part of risk assessment for postoperative dyspnea. Ventilation or perfusion scintigraphy should be considered to predict postoperative lung function if a ventilation or perfusion mismatch is suspected. Quantitative CT or MRI may be considered to predict postoperative lung function if the facility is available.29
Predicting mortality and complications: FEV1 and Dlco
The predicted postoperative FEV1 value is an independent predictor of postoperative mortality and other complications. Although there is no absolute cut-off value, studies identify an increased risk of complications below predicted postoperative FEV1 values ranging from 30%37 to 40%.38,39 Predicted postoperative Dlco is another outcome measure that can independently identify increased mortality risk in lung cancer resection patients. Dlco less than 40% has been associated with increased risk of postoperative respiratory complications even in those with predicted postoperative FEV1 values above 40%.26,39 One study stated that a combination of the two values, predicted postoperative FEV1 and predicted postoperative Dlco—called the predicted postoperative product (PPP)—is the best predictor of surgical mortality.40 Another study examined the utility of a prediction rule for pulmonary complications after lung surgery using a point system in which points were assigned based on predicted postoperative Dlco (1 point for each 5% decrement below 100%) plus 2 points for preoperative chemotherapy.41 The risk of complications was 9% for those with scores less than 11, 14% for those with scores of 11 to 13, and 26% for those with scores greater than 13.
When surgery is considered, ACCP guidelines state an increased risk of perioperative mortality in those lung cancer patients with either a PPP less than 1,650, or a predicted postoperative FEV1 less than 30%.27 These patients should be counseled about nonstandard surgery and nonsurgical treatment options. The ERS guidelines consider a predicted postoperative FEV1 value less than 30% to be a high-risk threshold when assessing pulmonary reserve before surgery.28
EXERCISE TESTING
In general, standardized cardiopulmonary exercise testing using VO2 peak has been shown to predict postoperative complications, including perioperative and long-term morbidity and mortality.42,43 Lower values are associated with a greater risk of poor outcome. Peak VO2 may not add significantly to the risk stratification of patients who have both FEV1 and Dlco values greater than 80%.44
According to ACCP recommendations for exercise testing in patients who are being evaluated for surgery, either an FEV1 or Dlco less than 40% of predicted postoperative (PPO) indicates increased risk for perioperative death and cardiopulmonary complications with standard lung resection. Preoperative exercise testing is recommended for these patients.27 Maximal oxygen consumption (VO2 max) less than 10 mL/kg/min, or the combination of VO2 max less than 15 mL/kg/min with both FEV1 and Dlco less than 40% PPO, also indicates increased risk for death and complications; these patients should be counseled about nonstandard surgery or nonsurgical treatment options. Guidelines from the ERS recommend exercise testing for all patients undergoing lung cancer surgery who have FEV1 or Dlco less than 80% of normal values.28 The VO2 peak measured during incremental exercise on a treadmill or cycle should be regarded as the most important parameter.
Figure. Distance walked during a shuttle walking test is strongly related to maximal oxygen consumption (VO2 max).
Several studies have found that distance traveled during walking tests predicts postoperative complications and can be related to VO2 max (Figure).45 According to ACCP guidelines, lung cancer patients who are potential candidates for standard lung resection are at increased risk for perioperative death and cardiopulmonary complications if they walk less than 25 shuttles on 2 shuttle walk tests or less than 1 flight of stairs. These patients should be counseled about nonstandard surgery and nonsurgical treatment options.27
Conversely, ERS/ESTS guidelines state that the shuttle walk test distance underestimates exercise capacity at the lower range, and does not discriminate between patients with and without complications.28 These guidelines state that shuttle walk test distance should not be used alone to select patients for resection. It may be used as a screening test, since patients walking less than 400 m are likely to also have VO2 peak less than 15 mL/kg/min. A standardized symptom-limited stair climbing test can be a cost-effective screening method to identify those who need more sophisticated exercise tests in order to optimize their perioperative management. The 6-minute walk test is not recommended.
British Thoracic Society guidelines recommend the use of the shuttle walk test as a functional assessment in patients with moderate to high risk of postoperative dyspnea.29 A distance walk of more than 400 m is recommended as a cutoff for acceptable pulmonary function. These guidelines recommend against using pulmonary function and exercise tests as the sole surrogates for a quality of life evaluation.
ALGORITHMS FOR TESTING
The ACCP, ERS/ESTS, and BTS guidelines all include algorithms for the preoperative evaluation of candidates for lung cancer resection.27–29 The guidelines differ from each other in many ways, including when to obtain a Dlco and cardiopulmonary exercise test, and in some of the cutoff values for various pulmonary function measures. ACCP guidelines begin with spirometry testing, supporting lobectomy in patients with spirometry results above the cutoff value of FEV1 greater than 1.5 L and pneumonectomy in those with a cutoff value of FEV1 greater than 2 L, and greater than 80% of predicted, unless the patient has dyspnea or evidence of interstitial lung disease. Measurement of the Dlco is recommended for those who do not meet the FEV1 cutoffs, or in those with unexplained dyspnea or diffuse parenchymal disease on chest radiograph or CT.27
A systematic review and set of treatment recommendations for high-risk patients with stage I lung cancer, developed by the Thoracic Oncology Network of the ACCP and the Workforce on Evidence-Based Surgery of the Society of Thoracic Surgeons, currently under review, will provide additional guidance regarding the use of lung function testing to evaluate risk of morbidity and mortality. These guidelines note that FEV1, Dlco, and peak VO2 all predict morbidity and mortality following major lung resection. Assessment of FEV1 and Dlco, including calculation of the estimated postoperative value, is strongly recommended before resection. The predictive value of peak VO2 is strongest in patients with impaired FEV1 or Dlco, and assessment of peak VO2 before major lung resection is recommended for these patients.
INTERVENTIONS TO DECREASE PERIOPERATIVE RISK
The impact of smoking cessation on perioperative outcome has been a matter of considerable debate. One large study found that the incidence of postoperative complications was actually greater when patients stopped smoking within 8 weeks before cardiac surgery.46 However, a recent meta-analysis including lung resection patients found no relationship between smoking cessation in the weeks before surgery and worse clinical outcomes.47 When a shorter duration of smoking cessation is examined, thoracotomy studies note that patients who continue to smoke within 1 month of pneumonectomy are at increased risk of major pulmonary events.48,49 An examination of perioperative mortality or major complications using data from the Society of Thoracic Surgeons found that smoking cessation within 1 month preceding surgery did not significantly affect perioperative morbidity or mortality, whereas longer abstention from tobacco use was associated with better surgical outcomes.50 The ACCP recommends that all patients with lung cancer be counseled regarding smoking cessation.27 ERS/ESTS guidelines recommend smoking cessation for at least 2 to 4 weeks before surgery, since this may change perioperative smoking behavior and decrease the risk of postoperative complications.28 Pulmonary rehabiliatation in the perioperative period has been shown to improve measures of activity tolerance, allowing resection of marginal candidates, and improving functional outcomes after resection.51 The ERS/ESTS guidelines state that early pre- and postoperative rehabilitation may produce functional benefits in resectable lung cancer patients.28
SUMMARY AND CONCLUSIONS
Lung function testing helps predict the risk of postoperative mortality, perioperative complications, and long-term dyspnea for patients with lung cancer undergoing surgical resection. Predicted postoperative FEV1 and Dlco should be evaluated in most resection candidates. Exercise testing adds to standard lung function testing in those with borderline values, discordance between standard measures, or discordance between subjective and objective lung function. Algorithms for preoperative assessment have been developed by the ACCP, the ERS/ESTS, and the BTS, which differ somewhat in the order of testing and specific testing cutoff values. Smoking cessation and pulmonary rehabilitation can help to reduce perioperative and long-term risks.
References
Damhuis RA, Schütte PR. Resection rates and postoperative mortality in 7,899 patients with lung cancer. Eur Respir J1996; 9:7–10.
Little AG, Rusch VW, Bonner JA, et al. Patterns of surgical care of lung cancer patients. Ann Thorac Surg2005; 80:2051–2056.
Baser S, Shannon VR, Eapen GA, et al. Pulmonary dysfunction as a major cause of inoperability among patients with non-small-cell lung cancer. Clin Lung Cancer2006; 7:344–349.
Sobue T, Suzuki T, Matsuda M, Kuroishi T, Ikeda S, Naruke T. Survival for clinical stage I lung cancer not surgically treated: comparison between screen-detected and symptom-detected cases. The Japanese Lung Cancer Screening Research Group. Cancer1992; 69:685–692.
Motohiro A, Ueda H, Komatsu H, Yanai N, Mori T; National Chest Hospital Study Group for Lung Cancer. Prognosis of nonsurgically treated, clinical stage I lung cancer patients in Japan. Lung Cancer2002; 36:65–69.
Sato M, Saito Y, Endo C, et al. The natural history of radiographically occult bronchogenic squamous cell carcinoma: a retrospective study of overdiagnosis bias. Chest2004; 126:108–113.
Loewen GM, Watson D, Kohman L, et al. Preoperative exercise Vo2 measurement for lung resection candidates: results of Cancer and Leukemia Group B Protocol 9238. J Thorac Oncol2007; 2:619–625.
Allen MS, Darling GE, Pechet TT, et al. Morbidity and mortality of major pulmonary resections in patients with early-stage lung cancer: initial results of the randomized, prospective ACOSOG Z0030 trial. Ann Thorac Surg2006; 81:1013–1020.
Meguid RA, Brooke BS, Chang DC, Sherwood JT, Brock MV, Yang SC. Are surgical outcomes for lung cancer resections improved at teaching hospitals?Ann Thorac Surg2008; 85:1015–1025.
Memtsoudis SG, Besculides MC, Zellos L, Patil N, Rogers SO. Trends in lung surgery: United States 1988 to 2002. Chest2006; 130:1462–1470.
Kozower BD, Sheng S, O’Brien SM, et al. STS database risk models: predictors of mortality and major morbidity for lung cancer resection. Ann Thorac Surg2010; 90:875–883.
Falcoz PE, Conti M, Brouchet L, et al. The Thoracic Surgery Scoring System (Thoracoscore): risk model for in-hospital death in 15,183 patients requiring thoracic surgery [published online ahead of print January 9, 2007]. J Thorac Cardiovasc Surg2007; 133:325–332. doi: 10.1016/j.jtcvs.2006.09.020
Bolliger CT, Jordan P, Solèr M, et al. Pulmonary function and exercise capacity after lung resection. Eur Respir J1996; 9:415–421.
Nezu K, Kushibe K, Tojo T, Takahama M, Kitamura S. Recovery and limitation of exercise capacity after lung resection for lung cancer. Chest1998; 113:1511–1516.
Brunelli A, Xiumé F, Refai M, et al. Evaluation of expiratory volume, diffusion capacity, and exercise tolerance following major lung resection: a prospective follow-up analysis. Chest2007; 131:141–147.
Smulders SA, Smeenk FW, Janssen-Heijnen ML, Postmus PE. Actual and predicted postoperative changes in lung function after pneumonectomy: a retrospective analysis. Chest2004; 125:1735–1741.
Edwards JG, Duthie DJ, Waller DA. Lobar volume reduction surgery: a method of increasing the lung cancer resection rate in patients with emphysema. Thorax2001; 56:791–795.
Bobbio A, Chetta A, Carbognani P, et al. Changes in pulmonary function test and cardiopulmonary exercise capacity in COPD patients after lobar pulmonary resection [published online ahead of print September 6, 2005]. Eur J Cardiothorac Surg2005; 28:754–758. doi: 10.1016/j.ejcts.2005.08.001
Brunelli A, Refai M, Salati M, Xiumé F, Sabbatini A. Predicted versus observed FEV1 and Dlco after major lung resection: a prospective evaluation at different postoperative periods. Ann Thorac Surg2007; 83:1134–1139.
Boushy SF, Billig DM, North LB, Helgason AH. Clinical course related to preoperative and postoperative pulmonary function in patients with bronchogenic carcinoma. Chest1971; 59:383–391.
Wernly JA, DeMeester TR, Kirchner PT, Myerowitz PD, Oxford DE, Golomb HM. Clinical value of quantitative ventilation-perfusion lung scans in the surgical management of bronchogenic carcinoma. J Thorac Cardiovasc Surg1980; 80:535–543.
Wyser C, Stulz P, Solèr M, et al. Prospective evaluation of an algorithm for the functional assessment of lung resection candidates. Am J Respir Crit Care Med1999; 159:1450–1456.
Bousamra M, Presberg KW, Chammas JH, et al. Early and late morbidity in patients undergoing pulmonary resection with low diffusion capacity. Ann Thorac Surg1996; 62:968–975.
Ferguson MK, Little L, Rizzo L, et al. Diffusing capacity predicts morbidity and mortality after pulmonary resection. J Thorac Cardiovasc Surg1988; 96:894–900.
Brunelli A, Refai MA, Salati M, Sabbatini A, Morgan-Hughes NJ, Rocco G. Carbon monoxide lung diffusion capacity improves risk stratification in patients without airflow limitation: evidence for systematic measurement before lung resection [published online ahead of print February 14, 2006]. Eur J Cardiothorac Surg2006; 29:567–570. doi: 10.1016/j.ejcts.2006.01.014
Colice GL, Shafazand S, Griffin JP, Keenan R, Bolliger CT; American College of Chest Physicians. Physiologic evaluation of the patient with lung cancer being considered for resectional surgery: ACCP evidenced-based clinical practice guidelines (2nd edition). Chest2007; 132( suppl 3):161S–177S.
Brunelli A, Charloux A, Bolliger CT, et al. ERS/ESTS clinical guidelines on fitness for radical therapy in lung cancer patients (surgery and chemo-radiotherapy). Eur Respir J2009; 34:17–41.
Lim E, Baldwin D, Beckles M, et al. Guidelines on the radical management of patients with lung cancer. Thorax2010; 65( suppl 3):iii1–iii27.
Nakahara K, Monden Y, Ohno K, Miyoshi S, Maeda H, Kawashima Y. A method for predicting postoperative lung function and its relation to postoperative complications in patients with lung cancer. Ann Thorac Surg1985; 39:260–265.
Kristersson S, Lindell SE, Svanberg L. Prediction of pulmonary function loss due to pneumonectomy using 133 Xe-radiospirometry. Chest1972; 62:694–698.
Bria WF, Kanarek DJ, Kazemi H. Prediction of postoperative pulmonary function following thoracic operations: value of ventilation-perfusion scanning. J Thorac Cardiovasc Surg1983; 86:186–192.
Ali MK, Mountain CF, Ewer MS, Johnston D, Haynie TP. Predicting loss of pulmonary function after pulmonary resection for bronchogenic carcinoma. Chest1980; 77:337–342.
Corris PA, Ellis DA, Hawkins T, Gibson GJ. Use of radionuclide scanning in the preoperative estimation of pulmonary function after pneumonectomy. Thorax1987; 42:285–291.
Bolliger CT, Gückel C, Engel H, et al. Prediction of functional reserves after lung resection: comparison between quantitative computed tomography, scintigraphy, and anatomy. Respiration2002; 69:482–489.
Nakahara K, Ohno K, Hashimoto J, et al. Prediction of postoperative respiratory failure in patients undergoing lung resection for lung cancer. Ann Thorac Surg1988; 46:549–552.
Markos J, Mullan BP, Hillman DR, et al. Preoperative assessment as a predictor of mortality and morbidity after lung resection. Am Rev Respir Dis1989; 139:902–910.
Ribas J, Diaz O, Barberà JA, et al. Invasive exercise testing in the evaluation of patients at high-risk for lung resection. Eur Respir J1998; 12:1429–1435.
Pierce RJ, Copland JM, Sharpe K, Barter CE. Preoperative risk evaluation for lung cancer resection: predicted postoperative product as a predictor of surgical mortality. Am J Respir Crit Care Med1994; 150:947–955.
Amar D, Munoz D, Shi W, Zhang H, Thaler HT. A clinical prediction rule for pulmonary complications after thoracic surgery for primary lung cancer [published online ahead of print October 27, 2009]. Anesth Analg2010; 110:1343–1348. doi: 10.1213/ANE.0b013e3181bf5c99
Benzo R, Kelley GA, Recchi L, Hofman A, Sciurba F. Complications of lung resection and exercise capacity: a meta-analysis [published online ahead of print April 3, 2007]. Respir Med2007; 101:1790–1797. doi: 10.1016/j.rmed.2007.02.012
Jones LW, Eves ND, Kraus WE, et al. The lung cancer exercise training study: a randomized trial of aerobic training, resistance training, or both in postsurgical lung cancer patients: rationale and design. BMC Cancer2010; 10:155.
Larsen KR, Svendsen UG, Milman N, Brenøe J, Petersen BN. Exercise testing in the preoperative evaluation of patients with bronchogenic carcinoma. Eur Respir J1997; 10:1559–1565.
Singh SJ, Morgan MDL, Hardman AE, Rowe C, Bardsley PA. Comparison of oxygen uptake during a conventional treadmill test and the shuttle walking test in chronic airflow limitation. Eur Respir J1994; 7:2016–2020.
Warner MA, Divertie MB, Tinker JH. Preoperative cessation of smoking and pulmonary complications in coronary artery bypass patients. Anesthesiology1984; 60:380–383.
Myers K, Hajek P, Hinds C, McRobbie H. Stopping smoking shortly before surgery and postoperative complications: a systematic review and meta-analysis [published online ahead of print March 14, 2011]. Arch Intern Med2011; 171:983–989. doi: 10.1001/archinternmed.2011.97
Vaporciyan AA, Merriman KW, Ece F, et al. Incidence of major pulmonary morbidity after pneumonectomy: association with timing of smoking cessation. Ann Thorac Surg2002; 73:420–426.
Barrera R, Shi W, Amar D, et al. Smoking and timing of cessation: impact on pulmonary complications after thoracotomy. Chest2005; 127:1977–1983.
Mason DP, Subramanian S, Nowicki ER, et al. Impact of smoking cessation before resection of lung cancer. A Society of Thoracic Surgeons General Thoracic Surgery Database study. Ann Thorac Surg2009; 88:362–371.
Cesario A, Ferri L, Galetta D, et al. Pre-operative pulmonary rehabilitation and surgery for lung cancer. Lung Cancer2007; 57:118–119.
References
Damhuis RA, Schütte PR. Resection rates and postoperative mortality in 7,899 patients with lung cancer. Eur Respir J1996; 9:7–10.
Little AG, Rusch VW, Bonner JA, et al. Patterns of surgical care of lung cancer patients. Ann Thorac Surg2005; 80:2051–2056.
Baser S, Shannon VR, Eapen GA, et al. Pulmonary dysfunction as a major cause of inoperability among patients with non-small-cell lung cancer. Clin Lung Cancer2006; 7:344–349.
Sobue T, Suzuki T, Matsuda M, Kuroishi T, Ikeda S, Naruke T. Survival for clinical stage I lung cancer not surgically treated: comparison between screen-detected and symptom-detected cases. The Japanese Lung Cancer Screening Research Group. Cancer1992; 69:685–692.
Motohiro A, Ueda H, Komatsu H, Yanai N, Mori T; National Chest Hospital Study Group for Lung Cancer. Prognosis of nonsurgically treated, clinical stage I lung cancer patients in Japan. Lung Cancer2002; 36:65–69.
Sato M, Saito Y, Endo C, et al. The natural history of radiographically occult bronchogenic squamous cell carcinoma: a retrospective study of overdiagnosis bias. Chest2004; 126:108–113.
Loewen GM, Watson D, Kohman L, et al. Preoperative exercise Vo2 measurement for lung resection candidates: results of Cancer and Leukemia Group B Protocol 9238. J Thorac Oncol2007; 2:619–625.
Allen MS, Darling GE, Pechet TT, et al. Morbidity and mortality of major pulmonary resections in patients with early-stage lung cancer: initial results of the randomized, prospective ACOSOG Z0030 trial. Ann Thorac Surg2006; 81:1013–1020.
Meguid RA, Brooke BS, Chang DC, Sherwood JT, Brock MV, Yang SC. Are surgical outcomes for lung cancer resections improved at teaching hospitals?Ann Thorac Surg2008; 85:1015–1025.
Memtsoudis SG, Besculides MC, Zellos L, Patil N, Rogers SO. Trends in lung surgery: United States 1988 to 2002. Chest2006; 130:1462–1470.
Kozower BD, Sheng S, O’Brien SM, et al. STS database risk models: predictors of mortality and major morbidity for lung cancer resection. Ann Thorac Surg2010; 90:875–883.
Falcoz PE, Conti M, Brouchet L, et al. The Thoracic Surgery Scoring System (Thoracoscore): risk model for in-hospital death in 15,183 patients requiring thoracic surgery [published online ahead of print January 9, 2007]. J Thorac Cardiovasc Surg2007; 133:325–332. doi: 10.1016/j.jtcvs.2006.09.020
Bolliger CT, Jordan P, Solèr M, et al. Pulmonary function and exercise capacity after lung resection. Eur Respir J1996; 9:415–421.
Nezu K, Kushibe K, Tojo T, Takahama M, Kitamura S. Recovery and limitation of exercise capacity after lung resection for lung cancer. Chest1998; 113:1511–1516.
Brunelli A, Xiumé F, Refai M, et al. Evaluation of expiratory volume, diffusion capacity, and exercise tolerance following major lung resection: a prospective follow-up analysis. Chest2007; 131:141–147.
Smulders SA, Smeenk FW, Janssen-Heijnen ML, Postmus PE. Actual and predicted postoperative changes in lung function after pneumonectomy: a retrospective analysis. Chest2004; 125:1735–1741.
Edwards JG, Duthie DJ, Waller DA. Lobar volume reduction surgery: a method of increasing the lung cancer resection rate in patients with emphysema. Thorax2001; 56:791–795.
Bobbio A, Chetta A, Carbognani P, et al. Changes in pulmonary function test and cardiopulmonary exercise capacity in COPD patients after lobar pulmonary resection [published online ahead of print September 6, 2005]. Eur J Cardiothorac Surg2005; 28:754–758. doi: 10.1016/j.ejcts.2005.08.001
Brunelli A, Refai M, Salati M, Xiumé F, Sabbatini A. Predicted versus observed FEV1 and Dlco after major lung resection: a prospective evaluation at different postoperative periods. Ann Thorac Surg2007; 83:1134–1139.
Boushy SF, Billig DM, North LB, Helgason AH. Clinical course related to preoperative and postoperative pulmonary function in patients with bronchogenic carcinoma. Chest1971; 59:383–391.
Wernly JA, DeMeester TR, Kirchner PT, Myerowitz PD, Oxford DE, Golomb HM. Clinical value of quantitative ventilation-perfusion lung scans in the surgical management of bronchogenic carcinoma. J Thorac Cardiovasc Surg1980; 80:535–543.
Wyser C, Stulz P, Solèr M, et al. Prospective evaluation of an algorithm for the functional assessment of lung resection candidates. Am J Respir Crit Care Med1999; 159:1450–1456.
Bousamra M, Presberg KW, Chammas JH, et al. Early and late morbidity in patients undergoing pulmonary resection with low diffusion capacity. Ann Thorac Surg1996; 62:968–975.
Ferguson MK, Little L, Rizzo L, et al. Diffusing capacity predicts morbidity and mortality after pulmonary resection. J Thorac Cardiovasc Surg1988; 96:894–900.
Brunelli A, Refai MA, Salati M, Sabbatini A, Morgan-Hughes NJ, Rocco G. Carbon monoxide lung diffusion capacity improves risk stratification in patients without airflow limitation: evidence for systematic measurement before lung resection [published online ahead of print February 14, 2006]. Eur J Cardiothorac Surg2006; 29:567–570. doi: 10.1016/j.ejcts.2006.01.014
Colice GL, Shafazand S, Griffin JP, Keenan R, Bolliger CT; American College of Chest Physicians. Physiologic evaluation of the patient with lung cancer being considered for resectional surgery: ACCP evidenced-based clinical practice guidelines (2nd edition). Chest2007; 132( suppl 3):161S–177S.
Brunelli A, Charloux A, Bolliger CT, et al. ERS/ESTS clinical guidelines on fitness for radical therapy in lung cancer patients (surgery and chemo-radiotherapy). Eur Respir J2009; 34:17–41.
Lim E, Baldwin D, Beckles M, et al. Guidelines on the radical management of patients with lung cancer. Thorax2010; 65( suppl 3):iii1–iii27.
Nakahara K, Monden Y, Ohno K, Miyoshi S, Maeda H, Kawashima Y. A method for predicting postoperative lung function and its relation to postoperative complications in patients with lung cancer. Ann Thorac Surg1985; 39:260–265.
Kristersson S, Lindell SE, Svanberg L. Prediction of pulmonary function loss due to pneumonectomy using 133 Xe-radiospirometry. Chest1972; 62:694–698.
Bria WF, Kanarek DJ, Kazemi H. Prediction of postoperative pulmonary function following thoracic operations: value of ventilation-perfusion scanning. J Thorac Cardiovasc Surg1983; 86:186–192.
Ali MK, Mountain CF, Ewer MS, Johnston D, Haynie TP. Predicting loss of pulmonary function after pulmonary resection for bronchogenic carcinoma. Chest1980; 77:337–342.
Corris PA, Ellis DA, Hawkins T, Gibson GJ. Use of radionuclide scanning in the preoperative estimation of pulmonary function after pneumonectomy. Thorax1987; 42:285–291.
Bolliger CT, Gückel C, Engel H, et al. Prediction of functional reserves after lung resection: comparison between quantitative computed tomography, scintigraphy, and anatomy. Respiration2002; 69:482–489.
Nakahara K, Ohno K, Hashimoto J, et al. Prediction of postoperative respiratory failure in patients undergoing lung resection for lung cancer. Ann Thorac Surg1988; 46:549–552.
Markos J, Mullan BP, Hillman DR, et al. Preoperative assessment as a predictor of mortality and morbidity after lung resection. Am Rev Respir Dis1989; 139:902–910.
Ribas J, Diaz O, Barberà JA, et al. Invasive exercise testing in the evaluation of patients at high-risk for lung resection. Eur Respir J1998; 12:1429–1435.
Pierce RJ, Copland JM, Sharpe K, Barter CE. Preoperative risk evaluation for lung cancer resection: predicted postoperative product as a predictor of surgical mortality. Am J Respir Crit Care Med1994; 150:947–955.
Amar D, Munoz D, Shi W, Zhang H, Thaler HT. A clinical prediction rule for pulmonary complications after thoracic surgery for primary lung cancer [published online ahead of print October 27, 2009]. Anesth Analg2010; 110:1343–1348. doi: 10.1213/ANE.0b013e3181bf5c99
Benzo R, Kelley GA, Recchi L, Hofman A, Sciurba F. Complications of lung resection and exercise capacity: a meta-analysis [published online ahead of print April 3, 2007]. Respir Med2007; 101:1790–1797. doi: 10.1016/j.rmed.2007.02.012
Jones LW, Eves ND, Kraus WE, et al. The lung cancer exercise training study: a randomized trial of aerobic training, resistance training, or both in postsurgical lung cancer patients: rationale and design. BMC Cancer2010; 10:155.
Larsen KR, Svendsen UG, Milman N, Brenøe J, Petersen BN. Exercise testing in the preoperative evaluation of patients with bronchogenic carcinoma. Eur Respir J1997; 10:1559–1565.
Singh SJ, Morgan MDL, Hardman AE, Rowe C, Bardsley PA. Comparison of oxygen uptake during a conventional treadmill test and the shuttle walking test in chronic airflow limitation. Eur Respir J1994; 7:2016–2020.
Warner MA, Divertie MB, Tinker JH. Preoperative cessation of smoking and pulmonary complications in coronary artery bypass patients. Anesthesiology1984; 60:380–383.
Myers K, Hajek P, Hinds C, McRobbie H. Stopping smoking shortly before surgery and postoperative complications: a systematic review and meta-analysis [published online ahead of print March 14, 2011]. Arch Intern Med2011; 171:983–989. doi: 10.1001/archinternmed.2011.97
Vaporciyan AA, Merriman KW, Ece F, et al. Incidence of major pulmonary morbidity after pneumonectomy: association with timing of smoking cessation. Ann Thorac Surg2002; 73:420–426.
Barrera R, Shi W, Amar D, et al. Smoking and timing of cessation: impact on pulmonary complications after thoracotomy. Chest2005; 127:1977–1983.
Mason DP, Subramanian S, Nowicki ER, et al. Impact of smoking cessation before resection of lung cancer. A Society of Thoracic Surgeons General Thoracic Surgery Database study. Ann Thorac Surg2009; 88:362–371.
Cesario A, Ferri L, Galetta D, et al. Pre-operative pulmonary rehabilitation and surgery for lung cancer. Lung Cancer2007; 57:118–119.
Video-assisted thoracoscopic surgery (VATS) is emerging as a therapeutic option for a variety of thoracic applications. When applied to the patient with lung cancer, the therapeutic benefit of VATS lobectomy appears to be confined to node-negative, relatively small tumors. Operable patients with larger tumors are currently best served by thoracotomy and mediastinal lymph node dissection. As an alternative to thoracotomy for stage I lung cancer, VATS lobectomy is associated with less postoperative pain, less surgical morbidity, fewer complications, and shorter hospitalization.1–4
LIMITED SPECIALIZED INSTRUMENTATION REQUIRED
Technologic innovation in minimally invasive surgery applied to the lung has lagged behind that of radiation oncology and interventional cardiology. VATS lobectomy requires relatively limited specialized instrumentation beyond standard minimally invasive surgical instruments commonly used for a variety of nonthoracic operations.
Video-assisted thoracoscopic surgery takes advantage of the reproducible anatomy of the lungs. However, knowledge of the vascular and bronchial anatomy is essential to avoid compromise of critical structures during VATS lobectomy.
The indication for VATS lobectomy at Cleveland Clinic is suspected clinical stage I lung cancer with pulmonary function sufficient to tolerate resection. A peripheral cancer or nodule of 3 cm or less is preferable for minimally invasive thoracic surgery.
Until 2007, the definition of a VATS lobectomy lacked uniformity. A standardized definition of VATS was provided by the Cancer and Leukemia Group B, which conducted a prospective multiinstitutional feasibility study of VATS lobectomy. It defined a true VATS lobectomy as one with individual identification and ligation of lobar vessels and bronchus, with accompanying hilar and mediastinal lymph node sampling or dissection, and performed without rib spreading.5
VATS OUTCOMES: FEWER COMPLICATIONS, SHORTER LENGTH OF STAY
The proportion of lung resections by VATS has increased steadily in the United States over the past decade, reaching 29% in 2007.1 The obvious question is whether thoracoscopic lobectomy holds an advantage over thoracotomy in terms of morbidity. Park documented significantly less postoperative atrial fibrillation, blood transfusion, renal failure, and other complications when VATS lobectomy was compared with thoracotomy (Table).4
In a propensity-matched analysis, Paul et al1 found an overall lower rate of complications with VATS compared with open lobectomy (26.2% vs 34.7%; P < .0001), including a lower incidence of arrhythmia (7.3% vs 11.5%; P = .0004), a lower frequency of blood transfusion (2.4% vs 4.7%; P = .0028), a reduced need for reintubation (1.4% vs 3.1%; P = .0046), and a shorter length of stay (4.0 vs 6.0 days; P < .0001) and chest tube duration (3.0 vs 4.0 days; P < .0001). At Cleveland Clinic, length of hospital stay has been shortened by about 1 day in patients undergoing VATS compared with open lobectomy.
The advantage of thoracoscopic lobectomy compared with thoracotomy may be limited to reduction in associated morbidity alone. Five-year survival was 78% in a series of 411 patients with clinical stage I non–small cell lung cancer (NSCLC) who underwent VATS lobectomy and the more technically difficult VATS segmentectomy.6 This rate of survival is equivalent to or better than any other reported series of patients with stage I NSCLC.
A potential oncologic benefit to the VATS approach through preservation of host immunity has also been suggested. Release of inflammatory mediators such as interleukin (IL)-6, IL-8, and IL-10 has been observed following thoracotomy and a subsequent immunosuppressive effect proposed. Liberation of these inflammatory cytokines appears attenuated by the VATS approach. Cellular proliferation and stimulation of tumor growth may be consequences of postoperative cytokine release, and limiting liberation of these products may have a direct beneficial tumor effect.7
MEDIASTINAL LYMPHADENECTOMY
Meticulous clinical staging of lung cancer directs clinical decision-making and has prognostic value. Imaging with computed tomography (CT) and fluorodeoxyglucose (FDG) positron emission tomography (PET) is neither sensitive nor specific for nodal metastases. The increasing popularity of less invasive staging and operative approaches for lung cancer imparts the risk of obtaining inadequate mediastinal information and the potential for undertreatment or overtreatment. At a minimum, systematic lymph node sampling is an essential component of any surgical approach (minimally invasive or open). Lymph node sampling should not be compromised by VATS, although more expertise is required for a complete VATS lymphadenectomy.
In patients with early-stage lung cancer, thorough lymphadenectomy may confer an important survival benefit even if sampled lymph nodes are found to be negative.8 Resection of occult (undetected) disease is one potential explanation for this survival benefit.
CASE STUDY: LYMPHADENECTOMY VIA MINIMALLY INVASIVE TECHNIQUE
A 45-year-old man with a 15 pack-year history of tobacco use presented with chest pain. He quit smoking 3 years previously. Although his chest pain resolved, a lesion in the right chest was incidentally found on chest radiograph.
The patient underwent spirometry and had normal values. A follow-up CT revealed a 2.1-cm spiculated right upper lobe nodule. There was no significant nodule uptake of FDG (standardized uptake value: 1.5 to 1.8) on PET. Percutaneous fine-needle aspiration biopsy demonstrated atypical cells of unclear significance. Navigational bronchoscopy-directed biopsy also revealed atypical cells but was nondiagnostic. The concern was that because the size of the mass was 2.1 cm, surveillance was not a viable option.
Ultimately, because of the biopsy ambiguity, large nodule size, and excellent patient performance status, VATS resection was offered. As a prelude, the mediastinum was staged with mediastinoscopy. The entire central (N2) compartment was surveyed with this technique and all samples were found to be free of cancer.
A VATS lobectomy was then performed. One utility incision (4 cm) was made and two to three ports (1 cm each) were placed within the thorax. No rib-spreading was utilized. An anatomic lobectomy with division of major vascular structures and the bronchus was performed similarly to an open procedure. When fully mobilized, the specimen (the right upper lobe in this case) was placed in a protective bag and delivered through the utility incision. Regional lymph nodes were also harvested for pathologic examination.
This patient was found to have a T1aN0M0 NSCLC and had an uneventful 3-day hospital course. Based on this final pathology and on institutional data, his projected survival was approximately 85%, 10% to 15% higher than national averages.8
SUMMARY
VATS lung resection is slowly becoming the standard of care for patients with stage I lung cancer. Advantages to the VATS approach compared with open lobectomy are less morbidity and shorter hospitalization. The perioperative stress response is attenuated with VATS, which suggests a potential superior oncologic outcome, although this remains to be proved. A complete mediastinal lymphadenectomy, regardless of the approach, may confer a survival advantage in early-stage lung cancer.
References
Paul S, Altorki NK, Sheng S, et al. Thoracoscopic lobectomy is associated with lower morbidity than open lobectomy: a propensity-matched analysis from the STS database. J Thorac Cardiovasc Surg2010; 139:366–378.
Villamizar NR, Darrabie MD, Burfeind WR, et al. Thoracoscopic lobectomy is associated with lower morbidity compared with thoracotomy. J Thorac Cardiovasc Surg2009; 138:419–425.
Swanson SJ, Meyers BF, Gunnarsson CL, et al. Video-assisted thoracoscopic surgical lobectomy is less costly and morbid than open lobectomy: a retrospective multiinstitutional database analysis [published online ahead of print November 28, 2011]. Ann Thorac Surg. doi: 10.1016/j.athoracsur.2011.06.007.
Park BJ. Is surgical morbidity decreased with minimally invasive lobectomy?Cancer J2011; 17:18–22.
Swanson SJ, Herndon JE, D’Amico TA, et al. Video-assisted thoracic surgery lobectomy: report of CALGB 39802—a prospective, multi-institution feasibility study. J Clin Oncol2007; 25:4993–4997.
Nakamura H, Taniguchi Y, Miwa K, et al. Comparison of the surgical outcomes of thoracoscopic lobectomy, segmentectomy, and wedge resection for clinical stage I non-small cell lung cancer. Thorac Cardiov Surg2011; 59:137–141.
Whitson BA, D’Cunha J. Video-assisted thoracoscopic surgical lobectomy: the potential oncological benefit of surgical immunomodulation. Semin Thorac Cardiovasc Surg2010; 22:113–115.
Murthy SC, Reznik SI, Ogwudu UC, et al. Winning the battle, losing the war: the noncurative “curative” resection for stage I adenocarcinoma of the lung. Ann Thorac Surg2010; 90:1067–1074.
Sudish Murthy, MD, PhD Department of Thoracic and Cardiovascular Surgery, Cleveland Clinic, Cleveland, OH
Correspondence: Sudish Murthy, MD, PhD, Department of Thoracic and Cardiovascular Surgery, Cleveland Clinic, 9500 Euclid Avenue, J4-1, Cleveland, OH 44195; MURTHYS1@ccf.org
Dr. Murthy reported that he has received royalties from Hood Laboratories.
This article was developed from an audio transcript of Dr. Murthy’s presentation at the “Advances in Lung Cancer Evaluation and Management” symposium held in Cleveland, Ohio, on April 30, 2011. The transcript was formatted and edited by Cleveland Clinic Journal of Medicine staff for clarity and conciseness and was then reviewed, revised, and approved by Dr. Murthy.
Sudish Murthy, MD, PhD Department of Thoracic and Cardiovascular Surgery, Cleveland Clinic, Cleveland, OH
Correspondence: Sudish Murthy, MD, PhD, Department of Thoracic and Cardiovascular Surgery, Cleveland Clinic, 9500 Euclid Avenue, J4-1, Cleveland, OH 44195; MURTHYS1@ccf.org
Dr. Murthy reported that he has received royalties from Hood Laboratories.
This article was developed from an audio transcript of Dr. Murthy’s presentation at the “Advances in Lung Cancer Evaluation and Management” symposium held in Cleveland, Ohio, on April 30, 2011. The transcript was formatted and edited by Cleveland Clinic Journal of Medicine staff for clarity and conciseness and was then reviewed, revised, and approved by Dr. Murthy.
Author and Disclosure Information
Sudish Murthy, MD, PhD Department of Thoracic and Cardiovascular Surgery, Cleveland Clinic, Cleveland, OH
Correspondence: Sudish Murthy, MD, PhD, Department of Thoracic and Cardiovascular Surgery, Cleveland Clinic, 9500 Euclid Avenue, J4-1, Cleveland, OH 44195; MURTHYS1@ccf.org
Dr. Murthy reported that he has received royalties from Hood Laboratories.
This article was developed from an audio transcript of Dr. Murthy’s presentation at the “Advances in Lung Cancer Evaluation and Management” symposium held in Cleveland, Ohio, on April 30, 2011. The transcript was formatted and edited by Cleveland Clinic Journal of Medicine staff for clarity and conciseness and was then reviewed, revised, and approved by Dr. Murthy.
Video-assisted thoracoscopic surgery (VATS) is emerging as a therapeutic option for a variety of thoracic applications. When applied to the patient with lung cancer, the therapeutic benefit of VATS lobectomy appears to be confined to node-negative, relatively small tumors. Operable patients with larger tumors are currently best served by thoracotomy and mediastinal lymph node dissection. As an alternative to thoracotomy for stage I lung cancer, VATS lobectomy is associated with less postoperative pain, less surgical morbidity, fewer complications, and shorter hospitalization.1–4
LIMITED SPECIALIZED INSTRUMENTATION REQUIRED
Technologic innovation in minimally invasive surgery applied to the lung has lagged behind that of radiation oncology and interventional cardiology. VATS lobectomy requires relatively limited specialized instrumentation beyond standard minimally invasive surgical instruments commonly used for a variety of nonthoracic operations.
Video-assisted thoracoscopic surgery takes advantage of the reproducible anatomy of the lungs. However, knowledge of the vascular and bronchial anatomy is essential to avoid compromise of critical structures during VATS lobectomy.
The indication for VATS lobectomy at Cleveland Clinic is suspected clinical stage I lung cancer with pulmonary function sufficient to tolerate resection. A peripheral cancer or nodule of 3 cm or less is preferable for minimally invasive thoracic surgery.
Until 2007, the definition of a VATS lobectomy lacked uniformity. A standardized definition of VATS was provided by the Cancer and Leukemia Group B, which conducted a prospective multiinstitutional feasibility study of VATS lobectomy. It defined a true VATS lobectomy as one with individual identification and ligation of lobar vessels and bronchus, with accompanying hilar and mediastinal lymph node sampling or dissection, and performed without rib spreading.5
VATS OUTCOMES: FEWER COMPLICATIONS, SHORTER LENGTH OF STAY
The proportion of lung resections by VATS has increased steadily in the United States over the past decade, reaching 29% in 2007.1 The obvious question is whether thoracoscopic lobectomy holds an advantage over thoracotomy in terms of morbidity. Park documented significantly less postoperative atrial fibrillation, blood transfusion, renal failure, and other complications when VATS lobectomy was compared with thoracotomy (Table).4
In a propensity-matched analysis, Paul et al1 found an overall lower rate of complications with VATS compared with open lobectomy (26.2% vs 34.7%; P < .0001), including a lower incidence of arrhythmia (7.3% vs 11.5%; P = .0004), a lower frequency of blood transfusion (2.4% vs 4.7%; P = .0028), a reduced need for reintubation (1.4% vs 3.1%; P = .0046), and a shorter length of stay (4.0 vs 6.0 days; P < .0001) and chest tube duration (3.0 vs 4.0 days; P < .0001). At Cleveland Clinic, length of hospital stay has been shortened by about 1 day in patients undergoing VATS compared with open lobectomy.
The advantage of thoracoscopic lobectomy compared with thoracotomy may be limited to reduction in associated morbidity alone. Five-year survival was 78% in a series of 411 patients with clinical stage I non–small cell lung cancer (NSCLC) who underwent VATS lobectomy and the more technically difficult VATS segmentectomy.6 This rate of survival is equivalent to or better than any other reported series of patients with stage I NSCLC.
A potential oncologic benefit to the VATS approach through preservation of host immunity has also been suggested. Release of inflammatory mediators such as interleukin (IL)-6, IL-8, and IL-10 has been observed following thoracotomy and a subsequent immunosuppressive effect proposed. Liberation of these inflammatory cytokines appears attenuated by the VATS approach. Cellular proliferation and stimulation of tumor growth may be consequences of postoperative cytokine release, and limiting liberation of these products may have a direct beneficial tumor effect.7
MEDIASTINAL LYMPHADENECTOMY
Meticulous clinical staging of lung cancer directs clinical decision-making and has prognostic value. Imaging with computed tomography (CT) and fluorodeoxyglucose (FDG) positron emission tomography (PET) is neither sensitive nor specific for nodal metastases. The increasing popularity of less invasive staging and operative approaches for lung cancer imparts the risk of obtaining inadequate mediastinal information and the potential for undertreatment or overtreatment. At a minimum, systematic lymph node sampling is an essential component of any surgical approach (minimally invasive or open). Lymph node sampling should not be compromised by VATS, although more expertise is required for a complete VATS lymphadenectomy.
In patients with early-stage lung cancer, thorough lymphadenectomy may confer an important survival benefit even if sampled lymph nodes are found to be negative.8 Resection of occult (undetected) disease is one potential explanation for this survival benefit.
CASE STUDY: LYMPHADENECTOMY VIA MINIMALLY INVASIVE TECHNIQUE
A 45-year-old man with a 15 pack-year history of tobacco use presented with chest pain. He quit smoking 3 years previously. Although his chest pain resolved, a lesion in the right chest was incidentally found on chest radiograph.
The patient underwent spirometry and had normal values. A follow-up CT revealed a 2.1-cm spiculated right upper lobe nodule. There was no significant nodule uptake of FDG (standardized uptake value: 1.5 to 1.8) on PET. Percutaneous fine-needle aspiration biopsy demonstrated atypical cells of unclear significance. Navigational bronchoscopy-directed biopsy also revealed atypical cells but was nondiagnostic. The concern was that because the size of the mass was 2.1 cm, surveillance was not a viable option.
Ultimately, because of the biopsy ambiguity, large nodule size, and excellent patient performance status, VATS resection was offered. As a prelude, the mediastinum was staged with mediastinoscopy. The entire central (N2) compartment was surveyed with this technique and all samples were found to be free of cancer.
A VATS lobectomy was then performed. One utility incision (4 cm) was made and two to three ports (1 cm each) were placed within the thorax. No rib-spreading was utilized. An anatomic lobectomy with division of major vascular structures and the bronchus was performed similarly to an open procedure. When fully mobilized, the specimen (the right upper lobe in this case) was placed in a protective bag and delivered through the utility incision. Regional lymph nodes were also harvested for pathologic examination.
This patient was found to have a T1aN0M0 NSCLC and had an uneventful 3-day hospital course. Based on this final pathology and on institutional data, his projected survival was approximately 85%, 10% to 15% higher than national averages.8
SUMMARY
VATS lung resection is slowly becoming the standard of care for patients with stage I lung cancer. Advantages to the VATS approach compared with open lobectomy are less morbidity and shorter hospitalization. The perioperative stress response is attenuated with VATS, which suggests a potential superior oncologic outcome, although this remains to be proved. A complete mediastinal lymphadenectomy, regardless of the approach, may confer a survival advantage in early-stage lung cancer.
Video-assisted thoracoscopic surgery (VATS) is emerging as a therapeutic option for a variety of thoracic applications. When applied to the patient with lung cancer, the therapeutic benefit of VATS lobectomy appears to be confined to node-negative, relatively small tumors. Operable patients with larger tumors are currently best served by thoracotomy and mediastinal lymph node dissection. As an alternative to thoracotomy for stage I lung cancer, VATS lobectomy is associated with less postoperative pain, less surgical morbidity, fewer complications, and shorter hospitalization.1–4
LIMITED SPECIALIZED INSTRUMENTATION REQUIRED
Technologic innovation in minimally invasive surgery applied to the lung has lagged behind that of radiation oncology and interventional cardiology. VATS lobectomy requires relatively limited specialized instrumentation beyond standard minimally invasive surgical instruments commonly used for a variety of nonthoracic operations.
Video-assisted thoracoscopic surgery takes advantage of the reproducible anatomy of the lungs. However, knowledge of the vascular and bronchial anatomy is essential to avoid compromise of critical structures during VATS lobectomy.
The indication for VATS lobectomy at Cleveland Clinic is suspected clinical stage I lung cancer with pulmonary function sufficient to tolerate resection. A peripheral cancer or nodule of 3 cm or less is preferable for minimally invasive thoracic surgery.
Until 2007, the definition of a VATS lobectomy lacked uniformity. A standardized definition of VATS was provided by the Cancer and Leukemia Group B, which conducted a prospective multiinstitutional feasibility study of VATS lobectomy. It defined a true VATS lobectomy as one with individual identification and ligation of lobar vessels and bronchus, with accompanying hilar and mediastinal lymph node sampling or dissection, and performed without rib spreading.5
VATS OUTCOMES: FEWER COMPLICATIONS, SHORTER LENGTH OF STAY
The proportion of lung resections by VATS has increased steadily in the United States over the past decade, reaching 29% in 2007.1 The obvious question is whether thoracoscopic lobectomy holds an advantage over thoracotomy in terms of morbidity. Park documented significantly less postoperative atrial fibrillation, blood transfusion, renal failure, and other complications when VATS lobectomy was compared with thoracotomy (Table).4
In a propensity-matched analysis, Paul et al1 found an overall lower rate of complications with VATS compared with open lobectomy (26.2% vs 34.7%; P < .0001), including a lower incidence of arrhythmia (7.3% vs 11.5%; P = .0004), a lower frequency of blood transfusion (2.4% vs 4.7%; P = .0028), a reduced need for reintubation (1.4% vs 3.1%; P = .0046), and a shorter length of stay (4.0 vs 6.0 days; P < .0001) and chest tube duration (3.0 vs 4.0 days; P < .0001). At Cleveland Clinic, length of hospital stay has been shortened by about 1 day in patients undergoing VATS compared with open lobectomy.
The advantage of thoracoscopic lobectomy compared with thoracotomy may be limited to reduction in associated morbidity alone. Five-year survival was 78% in a series of 411 patients with clinical stage I non–small cell lung cancer (NSCLC) who underwent VATS lobectomy and the more technically difficult VATS segmentectomy.6 This rate of survival is equivalent to or better than any other reported series of patients with stage I NSCLC.
A potential oncologic benefit to the VATS approach through preservation of host immunity has also been suggested. Release of inflammatory mediators such as interleukin (IL)-6, IL-8, and IL-10 has been observed following thoracotomy and a subsequent immunosuppressive effect proposed. Liberation of these inflammatory cytokines appears attenuated by the VATS approach. Cellular proliferation and stimulation of tumor growth may be consequences of postoperative cytokine release, and limiting liberation of these products may have a direct beneficial tumor effect.7
MEDIASTINAL LYMPHADENECTOMY
Meticulous clinical staging of lung cancer directs clinical decision-making and has prognostic value. Imaging with computed tomography (CT) and fluorodeoxyglucose (FDG) positron emission tomography (PET) is neither sensitive nor specific for nodal metastases. The increasing popularity of less invasive staging and operative approaches for lung cancer imparts the risk of obtaining inadequate mediastinal information and the potential for undertreatment or overtreatment. At a minimum, systematic lymph node sampling is an essential component of any surgical approach (minimally invasive or open). Lymph node sampling should not be compromised by VATS, although more expertise is required for a complete VATS lymphadenectomy.
In patients with early-stage lung cancer, thorough lymphadenectomy may confer an important survival benefit even if sampled lymph nodes are found to be negative.8 Resection of occult (undetected) disease is one potential explanation for this survival benefit.
CASE STUDY: LYMPHADENECTOMY VIA MINIMALLY INVASIVE TECHNIQUE
A 45-year-old man with a 15 pack-year history of tobacco use presented with chest pain. He quit smoking 3 years previously. Although his chest pain resolved, a lesion in the right chest was incidentally found on chest radiograph.
The patient underwent spirometry and had normal values. A follow-up CT revealed a 2.1-cm spiculated right upper lobe nodule. There was no significant nodule uptake of FDG (standardized uptake value: 1.5 to 1.8) on PET. Percutaneous fine-needle aspiration biopsy demonstrated atypical cells of unclear significance. Navigational bronchoscopy-directed biopsy also revealed atypical cells but was nondiagnostic. The concern was that because the size of the mass was 2.1 cm, surveillance was not a viable option.
Ultimately, because of the biopsy ambiguity, large nodule size, and excellent patient performance status, VATS resection was offered. As a prelude, the mediastinum was staged with mediastinoscopy. The entire central (N2) compartment was surveyed with this technique and all samples were found to be free of cancer.
A VATS lobectomy was then performed. One utility incision (4 cm) was made and two to three ports (1 cm each) were placed within the thorax. No rib-spreading was utilized. An anatomic lobectomy with division of major vascular structures and the bronchus was performed similarly to an open procedure. When fully mobilized, the specimen (the right upper lobe in this case) was placed in a protective bag and delivered through the utility incision. Regional lymph nodes were also harvested for pathologic examination.
This patient was found to have a T1aN0M0 NSCLC and had an uneventful 3-day hospital course. Based on this final pathology and on institutional data, his projected survival was approximately 85%, 10% to 15% higher than national averages.8
SUMMARY
VATS lung resection is slowly becoming the standard of care for patients with stage I lung cancer. Advantages to the VATS approach compared with open lobectomy are less morbidity and shorter hospitalization. The perioperative stress response is attenuated with VATS, which suggests a potential superior oncologic outcome, although this remains to be proved. A complete mediastinal lymphadenectomy, regardless of the approach, may confer a survival advantage in early-stage lung cancer.
References
Paul S, Altorki NK, Sheng S, et al. Thoracoscopic lobectomy is associated with lower morbidity than open lobectomy: a propensity-matched analysis from the STS database. J Thorac Cardiovasc Surg2010; 139:366–378.
Villamizar NR, Darrabie MD, Burfeind WR, et al. Thoracoscopic lobectomy is associated with lower morbidity compared with thoracotomy. J Thorac Cardiovasc Surg2009; 138:419–425.
Swanson SJ, Meyers BF, Gunnarsson CL, et al. Video-assisted thoracoscopic surgical lobectomy is less costly and morbid than open lobectomy: a retrospective multiinstitutional database analysis [published online ahead of print November 28, 2011]. Ann Thorac Surg. doi: 10.1016/j.athoracsur.2011.06.007.
Park BJ. Is surgical morbidity decreased with minimally invasive lobectomy?Cancer J2011; 17:18–22.
Swanson SJ, Herndon JE, D’Amico TA, et al. Video-assisted thoracic surgery lobectomy: report of CALGB 39802—a prospective, multi-institution feasibility study. J Clin Oncol2007; 25:4993–4997.
Nakamura H, Taniguchi Y, Miwa K, et al. Comparison of the surgical outcomes of thoracoscopic lobectomy, segmentectomy, and wedge resection for clinical stage I non-small cell lung cancer. Thorac Cardiov Surg2011; 59:137–141.
Whitson BA, D’Cunha J. Video-assisted thoracoscopic surgical lobectomy: the potential oncological benefit of surgical immunomodulation. Semin Thorac Cardiovasc Surg2010; 22:113–115.
Murthy SC, Reznik SI, Ogwudu UC, et al. Winning the battle, losing the war: the noncurative “curative” resection for stage I adenocarcinoma of the lung. Ann Thorac Surg2010; 90:1067–1074.
References
Paul S, Altorki NK, Sheng S, et al. Thoracoscopic lobectomy is associated with lower morbidity than open lobectomy: a propensity-matched analysis from the STS database. J Thorac Cardiovasc Surg2010; 139:366–378.
Villamizar NR, Darrabie MD, Burfeind WR, et al. Thoracoscopic lobectomy is associated with lower morbidity compared with thoracotomy. J Thorac Cardiovasc Surg2009; 138:419–425.
Swanson SJ, Meyers BF, Gunnarsson CL, et al. Video-assisted thoracoscopic surgical lobectomy is less costly and morbid than open lobectomy: a retrospective multiinstitutional database analysis [published online ahead of print November 28, 2011]. Ann Thorac Surg. doi: 10.1016/j.athoracsur.2011.06.007.
Park BJ. Is surgical morbidity decreased with minimally invasive lobectomy?Cancer J2011; 17:18–22.
Swanson SJ, Herndon JE, D’Amico TA, et al. Video-assisted thoracic surgery lobectomy: report of CALGB 39802—a prospective, multi-institution feasibility study. J Clin Oncol2007; 25:4993–4997.
Nakamura H, Taniguchi Y, Miwa K, et al. Comparison of the surgical outcomes of thoracoscopic lobectomy, segmentectomy, and wedge resection for clinical stage I non-small cell lung cancer. Thorac Cardiov Surg2011; 59:137–141.
Whitson BA, D’Cunha J. Video-assisted thoracoscopic surgical lobectomy: the potential oncological benefit of surgical immunomodulation. Semin Thorac Cardiovasc Surg2010; 22:113–115.
Murthy SC, Reznik SI, Ogwudu UC, et al. Winning the battle, losing the war: the noncurative “curative” resection for stage I adenocarcinoma of the lung. Ann Thorac Surg2010; 90:1067–1074.
Surgical resection for patients with stage I non–small cell lung cancer (NSCLC) is typically associated with survival rates of 60% to 70% after 5 years, and as high as 80% in some series.1 Although lobectomy or pneumonectomy improves outcomes compared with sublobar resection for many patients, a substantial number are ineligible for standard surgical resection because of cardiovascular disease or other conditions that are associated with unacceptably high perioperative risk. Observation alone is not a good strategy for patients who are ineligible for surgery. Studies comparing treatment outcomes associated with resection, radiation, and observation have demonstrated much shorter survival times and higher mortality for patients treated with observation only.2
Stereotactic body radiotherapy (SBRT) is the new standard of care for patients with medically inoperable stage I NSCLC. SBRT differs from standard radiation therapy in terms of dose, fractionation, field size, and targeting. Compared with standard radiation, SBRT offers a shorter and more convenient treatment regimen with improved local control and survival while lowering treatment cost.3,4 Although cancer-specific outcomes of patients in SBRT series are similar to those in surgical groups, they are not truly comparable because of dissimilarities between the two populations. The inoperable group has higher rates of comorbidity and death compared with the medically operable group; as many as one-third die from comorbid conditions rather than cancer, leading to short follow-up in many SBRT series. Surgical resection remains the standard of care for operable stage I NSCLC.
STEREOTACTIC RADIATION FOR PATIENTS WITH INOPERABLE LUNG CANCER
Figure 1. Recurrence-free survival at 30 months as a function of increasing radiation dose.31Standard external beam radiation has had disappointing outcomes for stage I NSCLC, likely because of inadequate treatment doses. Delivery of 60 Gy (in two consecutive courses of 30 Gy in 10 fractions) was associated with a 5-year survival rate of 38% for patients with primary tumors less than 2 cm in size, 22% for tumors 2 to 3 cm in size, 5% for tumors 3 to 4 cm in size, and 0% for larger tumors.5 Most studies, but not all, have reported improved treatment outcomes for patients receiving higher radiation doses.6 Biologic and statistical modeling of tumor responses across different radiation dose levels suggests that doses as high as 80 to 90 Gy are needed to achieve a recurrence-free survival rate of 50% (Figure 1), though this level is beyond the dose achieved by most standard external beam regimens.7
Modern standard external beam radiation doses without chemotherapy for stage I lung cancer are approximately 60 to 74 Gy. The dose fractionation schedule used with SBRT delivers much higher equivalent doses (83 Gy to 150 Gy), although the true biologically equivalent dose (BED) is not yet perfectly understood.8 Most clinical studies that have examined the effectiveness of SBRT have demonstrated local control rates in excess of 90% to 95% when an adequate dose (BED ≥ 100 Gy) is utilized, since the dose-response curve appears to plateau at this level.9 These response rates are higher than the 50% to 60% rate observed with conventional radiation.3,4 Efforts to confirm these comparative results in randomized trials have been largely abandoned because of the perceived advantage with SBRT.
PERIPHERAL VERSUS CENTRAL TUMORS
Stereotactic body radiotherapy has been referred to as “radiosurgery,” in part because the extremely high doses used to treat tumor are ablative to the immediate surrounding tissue. The consequences of ablation depend on whether the treatment involves parallel or serial tissue. Parallel tissue, such as lung, kidney, or liver, remains functional after the ablation or removal of small subunits if adequate volume of functional organ remains. With serial tissue such as the spinal cord or bowel, damage to one section results in loss of function at distal sites. Although the lung is parallel tissue, it includes serial structures such as the trachea and proximal bronchial tree. Tumors located within 2 cm of the proximal bronchial tree are classified as central, whereas tumors outside this zone are peripheral.
Peripheral tumors
Peripheral lung tumors are surrounded by only parallel tissue, and no maximum point-dose limit has been identified for their treatment. A recent cooperative group study (Radiation Therapy Oncology Group [RTOG] 0236) enrolled 55 patients, 80% with tumor stage IA (T1 N0) and 20% with stage IB (T2 N0).10 Patients with bronchoalveolar histology were excluded from the study. Patients received three radiation treatments of 20 Gy each (BED of 180 Gy) to their known tumor with a small margin, and were followed with serial computed tomography (CT). After a median follow-up of 34 months, only one of the 55 evaluable patients had a local tumor failure, for a local control rate of 97.6%. Three patients had recurrences in the initially involved lobe for a 3-year local control rate of 90.6%; two patients had nodal failures for a 3-year local regional control rate of 87.2%; and 11 patients had disseminated recurrences, for a 3-year distant failure rate of 22.1%.
Survival after 3 years was approximately 50%, which is much better than the survival rate typically attained with standard radiation therapy. Further, only 10 of the 26 deaths were attributed to lung cancer while 16 patients died of comorbid conditions such as stroke or myocardial infarction, illustrating the difficulty in tracking overall survival as a measure of efficacy in this medically fragile population.
Adverse events in this study were relatively rare. Seven patients had grade 3 or higher pulmonary complications, including hypoxia, pneumonitis, and pulmonary function test changes. Of note, the study scored changes in pulmonary function as toxicity; however, in this population, where nearly all patients have underlying lung disease, chronic obstructive pulmonary disease (COPD) exacerbations are also common.
Our own analysis of pulmonary function changes in patients treated with SBRT at Cleveland Clinic demonstrated that while there was no significant change in average baseline, pulmonary function in almost 10% of patients met criteria for a grade 3 pulmonary toxicity. A similar number of patients had a proportional improvement in pulmonary function, however. Given a nearly comparable distribution of pulmonary function changes in both directions with no significant deviation from baseline in aggregate, most of these fluctuations may be related to changes in the patient’s underlying comorbidities rather than effects of treatment.
RTOG 0236 demonstrated an excellent level of local control (97.6%) using 3 fractions of 20 Gy each (BED 180 Gy total). As noted, the dose response may plateau at 100 Gy BED,9 which raises the question of whether the radiation dose levels used in this study were higher than necessary. A recently completed randomized phase 2 clinical trial conducted by the RTOG compared 34 Gy in a single fraction versus 48 Gy in 4 fractions, and a similar study by Roswell Park Cancer Institute, Buffalo, New York, and Cleveland Clinic is comparing 60 Gy in 3 fractions versus 30 Gy in a single fraction. These studies, once mature, should help define the optimal radiation dose and treatment schedule for patients with inoperable peripheral tumors.
Central tumors
Centrally located tumors are in proximity to both parallel tissues (normal lung) and serial tissues (trachea, bronchial tree, or esophagus), as well as imperfectly categorized tissues (heart and great vessels). An important question is whether it is possible to reach a radiation dose level of 100 Gy BED or higher in these tumors without causing excessive toxicity to normal tissues. Although there is a potential risk of cardiotoxicity with chest radiotherapy, clinical studies of SBRT for lung cancer have not demonstrated any evidence of toxicity to the heart or the great vessels with focal radiation. Some studies have suggested that radiotherapy of central lung tumors may be associated with other adverse events.
Awareness of central versus peripheral tumor locations was first raised in an early phase 2 study in which patients were treated with 60 to 66 Gy in 3 fractions over a period of 1 to 2 weeks. Grade 3 or higher toxicity during 2 years of follow-up was noted for 46% of patients with central tumors and 17% of patients with peripheral tumors.11 Six deaths that occurred during the study were considered to be possibly treatment-related, including four cases of bacterial pneumonia, one patient with pericardial effusion, and one patient with hemoptysis that was later ascribed to carinal recurrence.
Other studies using lower fraction sizes, however, have demonstrated excellent efficacy and safety in treating central tumors with SBRT. In early Japanese studies12,13 that used smaller fractions without tissue constraints, no differences in toxicity were noted with treatment of central versus peripheral tumors. A European study similarly demonstrated more than 90% local control at 3 years for a regimen of 60 Gy in 8 fractions (7.5 Gy/fraction).14 Currently the RTOG is conducting a dose escalation study examining doses from 50 Gy to 60 Gy (10 Gy to 12 Gy per fraction in 5 fractions). The study has reached its highest level (60 Gy in 5 fractions) with no evidence of excessive toxicity reported.
SAFETY AND TOLERABILITY
Reprinted with permission from Journal of Thoracic Oncology (Stephans KL, et al. Comprehensive analysis of pulmonary function test (PFT) changes after stereotactic body radiotherapy (SBRT) for stage I lung cancer in medically inoperable patients. J Thorac
Figure 2. Although pulmonary function does not change significantly as a result of stereotactic body radiotherapy, some patients, as in this study, may exhibit increases in forced expiratory volume in 1 second (FEV1) (A) or diffusing capacity of the lung for carbon monoxide (DLCO) (B).Overall, the data suggest that for both central and peripheral tumors, SBRT is well tolerated in the medically inoperable population. On average, studies that have examined the effects of radiation therapy on pulmonary function have demonstrated little or no loss of function with SBRT. Some studies have described transient decreases in function with subsequent return to baseline.15,16 Even if overall group median lung function scores do not change significantly as a result of SBRT, individual patients may exhibit large increases or decreases in forced expiratory volume in 1 second (FEV1) or diffusing capacity of the lung for carbon monoxide (Dlco) after radiation therapy (Figure 2). These changes may be a function of underlying comorbidities as well as SBRT, given the minimal change in the average pulmonary function test measures.17
Radiation pneumonitis (an inflammatory complication of radiation frequently characterized by cough, fever, and shortness of breath) is rare—less than 5% in most series. An outlier is a single series that utilized 48 Gy in 4 fractions, a common and well-tolerated dose; the investigators reported a 30% rate of grade 2 through 5 (symptomatic) pneumonitis.18 Pneumonitis was significantly associated with the conformality index, a measure of how tightly the radiation beam is focused on the target tumor, emphasizing the importance of treatment technique on outcomes.
Other notes of caution for patients receiving SBRT include chest wall toxicity and neuropathy. Chest wall toxicity may include a variety of adverse events such as rib fractures, chest wall pain, and skin changes. These events have been described at chest wall radiation doses greater than 30 Gy.19 One study reported brachial plexopathy in 7 of 37 patients who received doses above 100 Gy BED delivered to the brachial plexus.20 Another recent study found that the probability of chest wall toxicity increased as the volume of chest wall receiving a 60 Gy dose increased above 15 to 20 cc.21 Esophagitis and skin reactions are rare except in cases where the patient is being treated for a tumor in extremely close proximity to the esophagus or skin.22
Computed tomography after SBRT often reveals substantial focal fibrosis in the region of high-dose lung radiation.23,24 Despite the often striking radiographic appearance, symptoms are rare and fibrosis may sometimes be mistaken for tumor recurrence. CT images should be read by those experienced in following post-SBRT changes. Findings suspicious for recurrence are typically evaluated by positron emission tomography (PET) followed by biopsy only if PET demonstrates sufficient hypermetabolism.
OPERABLE PATIENTS
Surgical resection is the standard of care for operable patients with lung cancer. Some studies are beginning to examine whether SBRT may also be useful in potentially operable patients. A Japanese study examined outcomes for 87 operable patients who underwent SBRT for stage I NSCLC and who were followed over a 55-month period.25 The local control rate was 92% for T1 tumors, a success rate approaching that of lobectomy. The success rate decreased to 73% for T2 tumors. Five-year overall survival rates were 72% for stage IA and 62% for stage IB, paralleling the surgical experience. Similar early results have been reported from the Netherlands.26 An RTOG study of medically operable patients recently completed enrollment after accruing 33 patients, with final results pending maturation of the data.
A major barrier to the introduction of SBRT to the operable population is the limited nature of the available data; SBRT technology has been implemented only recently and follow-up has been modest, owing to the nature of the medically inoperable population. In addition, it is difficult to determine during the first few months after SBRT which patients will be well controlled. Waiting for response to become apparent is an appropriate strategy for an inoperable patient with no alternatives, but operable patients need a trigger to indicate initiation of salvage therapies.27 In addition, lymph node dissection during surgery often provides information that is essential to tumor staging, and this information might be unavailable for patients treated with SBRT. It is also difficult to weigh the efficacy and tolerability of SBRT against surgical management because the two patient populations are not comparable.
High-risk operable patients
Comparisons of surgery and SBRT for stage I NSCLC are in their infancy and subject to extreme selection bias. Some attempts to create matched populations have demonstrated similar outcomes in matched patients.28,29 Markov modeling suggests improved efficacy for surgery overall, but the model turns in favor of SBRT in patients whose predicted surgical mortality exceeds 4%.30
High-risk operable patients are currently eligible for the American College of Surgeons Oncology group (ACOSOG)/RTOG 0870/Cancer and Leukemia Group B (CALGB) 140503 study; a randomized phase 3 clinical trial that is comparing lobectomy versus sublobar resection for small (< 2 cm) peripheral NSCLC. This study should help to clarify how this higher-risk patient group should be managed.
CLEVELAND CLINIC EXPERIENCE
At Cleveland Clinic, more than 700 patients with stage I NSCLC have been treated with SBRT since 2003. Peripheral tumors are typically treated with a radiation dose of 60 Gy in 3 fractions spaced over 8 to 14 days, or alternatively 30 Gy to 34 Gy in a single fraction. Occasional large tumors near the chest wall or spinal cord are treated with doses up to 50 Gy in 5 fractions over 5 consecutive days. For central tumors, radiation dose regimens include 50 Gy (5 fractions over 5 consecutive days) or 60 Gy (8 fractions over 10 days), depending upon tumor size and proximity to critical structures.
SUMMARY AND CONCLUSIONS
Many patients with NSCLC are ineligible for surgery because of COPD, cardiovascular disease, or other conditions associated with unacceptably high perioperative risk. SBRT is the standard of care for patients with medically inoperable stage I NSCLC. Modern standard radiation doses are typically between 50 to 60 Gy in 3 to 5 fractions. Local control rates in excess of 90% to 95% have been reported with these doses. SBRT is generally well tolerated by patients with both peripheral and centrally located tumors. On average, lung function is not substantially altered by SBRT, although individual patients may exhibit increased or decreased FEV1 and Dlco values after treatment. Pneumonitis has been relatively rare in most studies, with typical rates of 0% to 5%. SBRT has been shown to produce reasonable rates of local control in potentially operable patients, although data are extremely limited in this population and there are important questions about salvage therapy and postprocedural evaluation in these patients. Several ongoing clinical trials are continuing to define the efficacy and safety of different radiation dosing procedures for patients with inoperable NSCLC.
References
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McGarry RC, Song G, des Rosiers P, Timmerman R. Observationonly management of early stage, medically inoperable lung cancer: poor outcome. Chest2002; 121:1155–1158.
Lanni TB, Grills IS, Kestin LL, Robertson JM. Stereotactic radiotherapy reduces treatment cost while improving overall survival and local control over standard fractionated radiation therapy for medically inoperable non-small-cell lung cancer. Am J Clin Oncol2011; 34:494–498.
Grutters JP, Kessels AG, Pijls-Johannesma M, De Ruysscher D, Joore MA, Lambin P. Comparison of the effectiveness of radiotherapy with photons, protons and carbon-ions for non-small cell lung cancer: a meta-analysis [published online ahead of print September 3, 2009]. Radiother Oncol2010; 95:32–40. doi: 10.1016/jradonc.2009.08.003
Noordijk EM, vd Poest Clement E, Hermans J, Wever AMJ, Leer JWH. Radiotherapy as an alternative to surgery in elderly patients with resectable lung cancer. Radiother Oncol1988; 13:83–89.
Sibley GS. Radiotherapy for patients with medically inoperable stage I nonsmall cell lung carcinoma: smaller volumes and higher doses—a review. Cancer1998; 82:433–438.
Mehta M, Manon R. Are more aggressive therapies able to improve treatment of locally advanced non-small cell lung cancer: combined modality treatment?Semin Oncol2005; 32 (2 suppl 3):S25–S34.
Park C, Papiez L, Zhang S, Story M, Timmerman RD. Universal survival curve and single fraction equivalent dose: useful tools in understanding potency of ablative radiotherapy. Int J Radiat Oncol Biol Phys2008; 70:847–852.
Wulf J, Baier K, Mueller G, Flentje MP. Dose-response in stereotactic irradiation of lung tumors. Radiother Oncol2005; 77:83–87.
Timmerman R, Paulus R, Galvin J, et al. Stereotactic body radiation therapy for inoperable early stage lung cancer. JAMA2010; 303:1070–1076.
Timmerman R, McGarry R, Yiannoutsos C, et al. Excessive toxicity when treating central tumors in a phase II study of stereotactic body radiation therapy for medically inoperable early-stage lung cancer. J Clin Oncol2006; 24:4833–4839.
Onishi H, Shirato H, Nagata Y, et al. Hypofractionated stereotactic radiotherapy (HypoFXSRT) for stage I non-small cell lung cancer: updated results of 257 patients in a Japanese multi-institutional study. J Thorac Oncol2007; 2 (7 suppl 3):S94–S100.
Nagata Y, Takayama K, Matsuo Y, et al. Clinical outcomes of a phase I/II study of 48 Gy of stereotactic body radiotherapy in 4 fractions for primary lung cancer using a stereotactic body frame [published online ahead of print September 19, 2005]. Int J Radiat Oncol Biol Phys2005; 63:1427–1431. doi: 10.1016/j.ijrobp.2005.05.034
Haasbeek CJ, Lagerwaard FJ, Slotman BJ, Senan S. Outcomes of stereotactic ablative radiotherapy for centrally located early-stage lung cancer. J Thorac Oncol2011; 6:2036–2043.
Timmerman R, Papiez L, McGarry R, et al. Extracranial stereotactic radioablation: results of a phase I study in medically inoperable stage I non-small cell lung cancer. Chest2003; 124:1946–1955.
Henderson M, McGarry R, Yiannoutsos C, et al. Baseline pulmonary function as a predictor for survival and decline in pulmonary function over time in patients undergoing stereotactic body radiotherapy for the treatment of stage I non-small-cell lung cancer. Int J Radiat Oncol Biol Phys2008; 72:404–409.
Stephans KL, Djemil T, Reddy CA, et al. Comprehensive analysis of pulmonary function test (PFT) changes after stereotactic body radiotherapy (SBRT) for stage I lung cancer in medically inoperable patients. J Thorac Oncol2009; 4:838–844.
Yamashita H, Nakagawa K, Nakamura N, et al. Exceptionally high incidence of symptomatic grade 2–5 radiation pneumonitis after stereotactic radiation therapy for lung tumors. Radiat Oncol2007; 2:21.
Dunlap NE, Cai J, Biedermann GB, et al. Chest wall volume receiving > 30 Gy predicts risk of severe pain and/or rib fracture after lung stereotactic body radiotherapy. Int J Radiat Oncol Biol Phys2010; 76:796–801.
Forquer JA, Fakiris AJ, Timmerman RD, et al. Brachial plexopathy from stereotactic body radiotherapy in early-stage NSCLC: dose-limiting toxicity in apical tumor sites. Radiother Oncol2009; 93:408–413.
Stephans KL, Djemil T, Tendulkar RD, Robinson CG, Reddy CA, Videtic GM. Prediction of chest wall toxicity from lung stereotactic body radiotherapy (SBRT) [published online ahead of print February 6, 2011]. Int J Radiat Oncol Biol Phys2012; 82:974–980. doi: 10.1016/j.ijrobp.2010.12.002
Hoppe BS, Laser B, Kowalski AV, et al. Acute skin toxicity following stereotactic body radiation therapy for stage I non-small-cell lung cancer: who’s at risk?Int J Radiat Oncol Biol Phys2008; 72:1283–1286.
Bradley J. Radiographic response and clinical toxicity following SBRT for stage I lung cancer. J Thorac Oncol2007; 2 (7 suppl 3):S118–S124.
Linda A, Trovo M, Bradley JD. Radiation injury of the lung after stereotactic body radiation therapy (SBRT) for lung cancer: a timeline and pattern of CT changes [published online ahead of print December 1, 2009]. Eur J Radiol2011; 79:147–154. doi: 10.1016/j.ejrad.2009.10.029
Onishi H, Shirato H, Nagata Y, et al. Stereotactic body radiotherapy (SBRT) for operable stage I non-small-cell lung cancer: can SBRT be comparable to surgery [published online ahead of print July 16, 2011]?Int J Radiat Oncol Biol Phys2011; 81:1352–1358. doi: 10.1016/j.ijrobp.2009.07.1751
Lagerwaard FJ, Verstegen NE, Haasbeek CJ, et al. Outcomes of stereotactic ablative radiotherapy in patients with potentially operable stage I non-small-cell lung cancer [published online ahead of print November 19, 2011.]Int J Radiat Oncol Biol Phys. doi: 10.1016/j.ijrobp.2011.06.2003.
Neri S, Takahashi Y, Terashi T, et al. Surgical treatment of local recurrence after stereotactic body radiotherapy for primary and metastatic lung cancers. J Thorac Oncol2010; 5:2003–2007.
Crabtree TD, Denlinger CE, Meyers BF, et al. Stereotactic body radiation therapy versus surgical resection for stage I non-small cell lung cancer [published online ahead of print April 18, 2010]. J Thorac Cardiovasc Surg2010; 140:377–386. doi: 10.1016/j.jtcvs.2009.12.054
Palma D, Lagerwaard F, Rodrigues G, Haasbeek C, Senan S. Curative treatment of stage I non-small-cell lung acancer in patients with severe COPD: stereotactic radiotherapy outcomes and systematic review [published online ahead of print June 2, 2011]. Int J Radiat Oncol Biol Phys2012; 82:1149–1156. doi: 10.1016/j.ijrobp.2011.03.005
Louie AV, Rodrigues G, Hannouf M, et al. Stereotactic body radiotherapy versus surgery for medically operable stage I non-small-cell lung cancer: a Markov model-based decision analysis [published online ahead of print October 6, 2010]. Int J Radiat Oncol Biol Phys2011; 81:964–973. doi: 10.1016/j.ijrobp.2010.06.040
Martel MK, Ten Haken RK, Hazuka MB, et al. Estimation of tumor control probability model parameters from 3-D dose distributions of non-small cell lung cancer patients. Lung Cancer1999; 24:31–37.
Kevin Stephans, MD Department of Radiation Oncology, Cleveland Clinic, Cleveland, OH
Correspondence: Kevin Stephans, MD, Department of Radiation Oncology, Cleveland Clinic, 9500 Euclid Avenue, T28, Cleveland, OH 44195; stephak@ccf.org
Dr. Stephans reported that he has no financial relationships that pose a potential conflict of interest with this article.
This article was developed from an audio transcript of Dr. Stephans’s presentation at the “Advances in Lung Cancer Evaluation and Management” symposium held in Cleveland, Ohio, on April 30, 2011. The transcript was formatted and edited by Cleveland Clinic Journal of Medicine staff for clarity and conciseness and was then reviewed, revised, and approved by Dr. Stephans.
Kevin Stephans, MD Department of Radiation Oncology, Cleveland Clinic, Cleveland, OH
Correspondence: Kevin Stephans, MD, Department of Radiation Oncology, Cleveland Clinic, 9500 Euclid Avenue, T28, Cleveland, OH 44195; stephak@ccf.org
Dr. Stephans reported that he has no financial relationships that pose a potential conflict of interest with this article.
This article was developed from an audio transcript of Dr. Stephans’s presentation at the “Advances in Lung Cancer Evaluation and Management” symposium held in Cleveland, Ohio, on April 30, 2011. The transcript was formatted and edited by Cleveland Clinic Journal of Medicine staff for clarity and conciseness and was then reviewed, revised, and approved by Dr. Stephans.
Author and Disclosure Information
Kevin Stephans, MD Department of Radiation Oncology, Cleveland Clinic, Cleveland, OH
Correspondence: Kevin Stephans, MD, Department of Radiation Oncology, Cleveland Clinic, 9500 Euclid Avenue, T28, Cleveland, OH 44195; stephak@ccf.org
Dr. Stephans reported that he has no financial relationships that pose a potential conflict of interest with this article.
This article was developed from an audio transcript of Dr. Stephans’s presentation at the “Advances in Lung Cancer Evaluation and Management” symposium held in Cleveland, Ohio, on April 30, 2011. The transcript was formatted and edited by Cleveland Clinic Journal of Medicine staff for clarity and conciseness and was then reviewed, revised, and approved by Dr. Stephans.
Surgical resection for patients with stage I non–small cell lung cancer (NSCLC) is typically associated with survival rates of 60% to 70% after 5 years, and as high as 80% in some series.1 Although lobectomy or pneumonectomy improves outcomes compared with sublobar resection for many patients, a substantial number are ineligible for standard surgical resection because of cardiovascular disease or other conditions that are associated with unacceptably high perioperative risk. Observation alone is not a good strategy for patients who are ineligible for surgery. Studies comparing treatment outcomes associated with resection, radiation, and observation have demonstrated much shorter survival times and higher mortality for patients treated with observation only.2
Stereotactic body radiotherapy (SBRT) is the new standard of care for patients with medically inoperable stage I NSCLC. SBRT differs from standard radiation therapy in terms of dose, fractionation, field size, and targeting. Compared with standard radiation, SBRT offers a shorter and more convenient treatment regimen with improved local control and survival while lowering treatment cost.3,4 Although cancer-specific outcomes of patients in SBRT series are similar to those in surgical groups, they are not truly comparable because of dissimilarities between the two populations. The inoperable group has higher rates of comorbidity and death compared with the medically operable group; as many as one-third die from comorbid conditions rather than cancer, leading to short follow-up in many SBRT series. Surgical resection remains the standard of care for operable stage I NSCLC.
STEREOTACTIC RADIATION FOR PATIENTS WITH INOPERABLE LUNG CANCER
Figure 1. Recurrence-free survival at 30 months as a function of increasing radiation dose.31Standard external beam radiation has had disappointing outcomes for stage I NSCLC, likely because of inadequate treatment doses. Delivery of 60 Gy (in two consecutive courses of 30 Gy in 10 fractions) was associated with a 5-year survival rate of 38% for patients with primary tumors less than 2 cm in size, 22% for tumors 2 to 3 cm in size, 5% for tumors 3 to 4 cm in size, and 0% for larger tumors.5 Most studies, but not all, have reported improved treatment outcomes for patients receiving higher radiation doses.6 Biologic and statistical modeling of tumor responses across different radiation dose levels suggests that doses as high as 80 to 90 Gy are needed to achieve a recurrence-free survival rate of 50% (Figure 1), though this level is beyond the dose achieved by most standard external beam regimens.7
Modern standard external beam radiation doses without chemotherapy for stage I lung cancer are approximately 60 to 74 Gy. The dose fractionation schedule used with SBRT delivers much higher equivalent doses (83 Gy to 150 Gy), although the true biologically equivalent dose (BED) is not yet perfectly understood.8 Most clinical studies that have examined the effectiveness of SBRT have demonstrated local control rates in excess of 90% to 95% when an adequate dose (BED ≥ 100 Gy) is utilized, since the dose-response curve appears to plateau at this level.9 These response rates are higher than the 50% to 60% rate observed with conventional radiation.3,4 Efforts to confirm these comparative results in randomized trials have been largely abandoned because of the perceived advantage with SBRT.
PERIPHERAL VERSUS CENTRAL TUMORS
Stereotactic body radiotherapy has been referred to as “radiosurgery,” in part because the extremely high doses used to treat tumor are ablative to the immediate surrounding tissue. The consequences of ablation depend on whether the treatment involves parallel or serial tissue. Parallel tissue, such as lung, kidney, or liver, remains functional after the ablation or removal of small subunits if adequate volume of functional organ remains. With serial tissue such as the spinal cord or bowel, damage to one section results in loss of function at distal sites. Although the lung is parallel tissue, it includes serial structures such as the trachea and proximal bronchial tree. Tumors located within 2 cm of the proximal bronchial tree are classified as central, whereas tumors outside this zone are peripheral.
Peripheral tumors
Peripheral lung tumors are surrounded by only parallel tissue, and no maximum point-dose limit has been identified for their treatment. A recent cooperative group study (Radiation Therapy Oncology Group [RTOG] 0236) enrolled 55 patients, 80% with tumor stage IA (T1 N0) and 20% with stage IB (T2 N0).10 Patients with bronchoalveolar histology were excluded from the study. Patients received three radiation treatments of 20 Gy each (BED of 180 Gy) to their known tumor with a small margin, and were followed with serial computed tomography (CT). After a median follow-up of 34 months, only one of the 55 evaluable patients had a local tumor failure, for a local control rate of 97.6%. Three patients had recurrences in the initially involved lobe for a 3-year local control rate of 90.6%; two patients had nodal failures for a 3-year local regional control rate of 87.2%; and 11 patients had disseminated recurrences, for a 3-year distant failure rate of 22.1%.
Survival after 3 years was approximately 50%, which is much better than the survival rate typically attained with standard radiation therapy. Further, only 10 of the 26 deaths were attributed to lung cancer while 16 patients died of comorbid conditions such as stroke or myocardial infarction, illustrating the difficulty in tracking overall survival as a measure of efficacy in this medically fragile population.
Adverse events in this study were relatively rare. Seven patients had grade 3 or higher pulmonary complications, including hypoxia, pneumonitis, and pulmonary function test changes. Of note, the study scored changes in pulmonary function as toxicity; however, in this population, where nearly all patients have underlying lung disease, chronic obstructive pulmonary disease (COPD) exacerbations are also common.
Our own analysis of pulmonary function changes in patients treated with SBRT at Cleveland Clinic demonstrated that while there was no significant change in average baseline, pulmonary function in almost 10% of patients met criteria for a grade 3 pulmonary toxicity. A similar number of patients had a proportional improvement in pulmonary function, however. Given a nearly comparable distribution of pulmonary function changes in both directions with no significant deviation from baseline in aggregate, most of these fluctuations may be related to changes in the patient’s underlying comorbidities rather than effects of treatment.
RTOG 0236 demonstrated an excellent level of local control (97.6%) using 3 fractions of 20 Gy each (BED 180 Gy total). As noted, the dose response may plateau at 100 Gy BED,9 which raises the question of whether the radiation dose levels used in this study were higher than necessary. A recently completed randomized phase 2 clinical trial conducted by the RTOG compared 34 Gy in a single fraction versus 48 Gy in 4 fractions, and a similar study by Roswell Park Cancer Institute, Buffalo, New York, and Cleveland Clinic is comparing 60 Gy in 3 fractions versus 30 Gy in a single fraction. These studies, once mature, should help define the optimal radiation dose and treatment schedule for patients with inoperable peripheral tumors.
Central tumors
Centrally located tumors are in proximity to both parallel tissues (normal lung) and serial tissues (trachea, bronchial tree, or esophagus), as well as imperfectly categorized tissues (heart and great vessels). An important question is whether it is possible to reach a radiation dose level of 100 Gy BED or higher in these tumors without causing excessive toxicity to normal tissues. Although there is a potential risk of cardiotoxicity with chest radiotherapy, clinical studies of SBRT for lung cancer have not demonstrated any evidence of toxicity to the heart or the great vessels with focal radiation. Some studies have suggested that radiotherapy of central lung tumors may be associated with other adverse events.
Awareness of central versus peripheral tumor locations was first raised in an early phase 2 study in which patients were treated with 60 to 66 Gy in 3 fractions over a period of 1 to 2 weeks. Grade 3 or higher toxicity during 2 years of follow-up was noted for 46% of patients with central tumors and 17% of patients with peripheral tumors.11 Six deaths that occurred during the study were considered to be possibly treatment-related, including four cases of bacterial pneumonia, one patient with pericardial effusion, and one patient with hemoptysis that was later ascribed to carinal recurrence.
Other studies using lower fraction sizes, however, have demonstrated excellent efficacy and safety in treating central tumors with SBRT. In early Japanese studies12,13 that used smaller fractions without tissue constraints, no differences in toxicity were noted with treatment of central versus peripheral tumors. A European study similarly demonstrated more than 90% local control at 3 years for a regimen of 60 Gy in 8 fractions (7.5 Gy/fraction).14 Currently the RTOG is conducting a dose escalation study examining doses from 50 Gy to 60 Gy (10 Gy to 12 Gy per fraction in 5 fractions). The study has reached its highest level (60 Gy in 5 fractions) with no evidence of excessive toxicity reported.
SAFETY AND TOLERABILITY
Reprinted with permission from Journal of Thoracic Oncology (Stephans KL, et al. Comprehensive analysis of pulmonary function test (PFT) changes after stereotactic body radiotherapy (SBRT) for stage I lung cancer in medically inoperable patients. J Thorac
Figure 2. Although pulmonary function does not change significantly as a result of stereotactic body radiotherapy, some patients, as in this study, may exhibit increases in forced expiratory volume in 1 second (FEV1) (A) or diffusing capacity of the lung for carbon monoxide (DLCO) (B).Overall, the data suggest that for both central and peripheral tumors, SBRT is well tolerated in the medically inoperable population. On average, studies that have examined the effects of radiation therapy on pulmonary function have demonstrated little or no loss of function with SBRT. Some studies have described transient decreases in function with subsequent return to baseline.15,16 Even if overall group median lung function scores do not change significantly as a result of SBRT, individual patients may exhibit large increases or decreases in forced expiratory volume in 1 second (FEV1) or diffusing capacity of the lung for carbon monoxide (Dlco) after radiation therapy (Figure 2). These changes may be a function of underlying comorbidities as well as SBRT, given the minimal change in the average pulmonary function test measures.17
Radiation pneumonitis (an inflammatory complication of radiation frequently characterized by cough, fever, and shortness of breath) is rare—less than 5% in most series. An outlier is a single series that utilized 48 Gy in 4 fractions, a common and well-tolerated dose; the investigators reported a 30% rate of grade 2 through 5 (symptomatic) pneumonitis.18 Pneumonitis was significantly associated with the conformality index, a measure of how tightly the radiation beam is focused on the target tumor, emphasizing the importance of treatment technique on outcomes.
Other notes of caution for patients receiving SBRT include chest wall toxicity and neuropathy. Chest wall toxicity may include a variety of adverse events such as rib fractures, chest wall pain, and skin changes. These events have been described at chest wall radiation doses greater than 30 Gy.19 One study reported brachial plexopathy in 7 of 37 patients who received doses above 100 Gy BED delivered to the brachial plexus.20 Another recent study found that the probability of chest wall toxicity increased as the volume of chest wall receiving a 60 Gy dose increased above 15 to 20 cc.21 Esophagitis and skin reactions are rare except in cases where the patient is being treated for a tumor in extremely close proximity to the esophagus or skin.22
Computed tomography after SBRT often reveals substantial focal fibrosis in the region of high-dose lung radiation.23,24 Despite the often striking radiographic appearance, symptoms are rare and fibrosis may sometimes be mistaken for tumor recurrence. CT images should be read by those experienced in following post-SBRT changes. Findings suspicious for recurrence are typically evaluated by positron emission tomography (PET) followed by biopsy only if PET demonstrates sufficient hypermetabolism.
OPERABLE PATIENTS
Surgical resection is the standard of care for operable patients with lung cancer. Some studies are beginning to examine whether SBRT may also be useful in potentially operable patients. A Japanese study examined outcomes for 87 operable patients who underwent SBRT for stage I NSCLC and who were followed over a 55-month period.25 The local control rate was 92% for T1 tumors, a success rate approaching that of lobectomy. The success rate decreased to 73% for T2 tumors. Five-year overall survival rates were 72% for stage IA and 62% for stage IB, paralleling the surgical experience. Similar early results have been reported from the Netherlands.26 An RTOG study of medically operable patients recently completed enrollment after accruing 33 patients, with final results pending maturation of the data.
A major barrier to the introduction of SBRT to the operable population is the limited nature of the available data; SBRT technology has been implemented only recently and follow-up has been modest, owing to the nature of the medically inoperable population. In addition, it is difficult to determine during the first few months after SBRT which patients will be well controlled. Waiting for response to become apparent is an appropriate strategy for an inoperable patient with no alternatives, but operable patients need a trigger to indicate initiation of salvage therapies.27 In addition, lymph node dissection during surgery often provides information that is essential to tumor staging, and this information might be unavailable for patients treated with SBRT. It is also difficult to weigh the efficacy and tolerability of SBRT against surgical management because the two patient populations are not comparable.
High-risk operable patients
Comparisons of surgery and SBRT for stage I NSCLC are in their infancy and subject to extreme selection bias. Some attempts to create matched populations have demonstrated similar outcomes in matched patients.28,29 Markov modeling suggests improved efficacy for surgery overall, but the model turns in favor of SBRT in patients whose predicted surgical mortality exceeds 4%.30
High-risk operable patients are currently eligible for the American College of Surgeons Oncology group (ACOSOG)/RTOG 0870/Cancer and Leukemia Group B (CALGB) 140503 study; a randomized phase 3 clinical trial that is comparing lobectomy versus sublobar resection for small (< 2 cm) peripheral NSCLC. This study should help to clarify how this higher-risk patient group should be managed.
CLEVELAND CLINIC EXPERIENCE
At Cleveland Clinic, more than 700 patients with stage I NSCLC have been treated with SBRT since 2003. Peripheral tumors are typically treated with a radiation dose of 60 Gy in 3 fractions spaced over 8 to 14 days, or alternatively 30 Gy to 34 Gy in a single fraction. Occasional large tumors near the chest wall or spinal cord are treated with doses up to 50 Gy in 5 fractions over 5 consecutive days. For central tumors, radiation dose regimens include 50 Gy (5 fractions over 5 consecutive days) or 60 Gy (8 fractions over 10 days), depending upon tumor size and proximity to critical structures.
SUMMARY AND CONCLUSIONS
Many patients with NSCLC are ineligible for surgery because of COPD, cardiovascular disease, or other conditions associated with unacceptably high perioperative risk. SBRT is the standard of care for patients with medically inoperable stage I NSCLC. Modern standard radiation doses are typically between 50 to 60 Gy in 3 to 5 fractions. Local control rates in excess of 90% to 95% have been reported with these doses. SBRT is generally well tolerated by patients with both peripheral and centrally located tumors. On average, lung function is not substantially altered by SBRT, although individual patients may exhibit increased or decreased FEV1 and Dlco values after treatment. Pneumonitis has been relatively rare in most studies, with typical rates of 0% to 5%. SBRT has been shown to produce reasonable rates of local control in potentially operable patients, although data are extremely limited in this population and there are important questions about salvage therapy and postprocedural evaluation in these patients. Several ongoing clinical trials are continuing to define the efficacy and safety of different radiation dosing procedures for patients with inoperable NSCLC.
Surgical resection for patients with stage I non–small cell lung cancer (NSCLC) is typically associated with survival rates of 60% to 70% after 5 years, and as high as 80% in some series.1 Although lobectomy or pneumonectomy improves outcomes compared with sublobar resection for many patients, a substantial number are ineligible for standard surgical resection because of cardiovascular disease or other conditions that are associated with unacceptably high perioperative risk. Observation alone is not a good strategy for patients who are ineligible for surgery. Studies comparing treatment outcomes associated with resection, radiation, and observation have demonstrated much shorter survival times and higher mortality for patients treated with observation only.2
Stereotactic body radiotherapy (SBRT) is the new standard of care for patients with medically inoperable stage I NSCLC. SBRT differs from standard radiation therapy in terms of dose, fractionation, field size, and targeting. Compared with standard radiation, SBRT offers a shorter and more convenient treatment regimen with improved local control and survival while lowering treatment cost.3,4 Although cancer-specific outcomes of patients in SBRT series are similar to those in surgical groups, they are not truly comparable because of dissimilarities between the two populations. The inoperable group has higher rates of comorbidity and death compared with the medically operable group; as many as one-third die from comorbid conditions rather than cancer, leading to short follow-up in many SBRT series. Surgical resection remains the standard of care for operable stage I NSCLC.
STEREOTACTIC RADIATION FOR PATIENTS WITH INOPERABLE LUNG CANCER
Figure 1. Recurrence-free survival at 30 months as a function of increasing radiation dose.31Standard external beam radiation has had disappointing outcomes for stage I NSCLC, likely because of inadequate treatment doses. Delivery of 60 Gy (in two consecutive courses of 30 Gy in 10 fractions) was associated with a 5-year survival rate of 38% for patients with primary tumors less than 2 cm in size, 22% for tumors 2 to 3 cm in size, 5% for tumors 3 to 4 cm in size, and 0% for larger tumors.5 Most studies, but not all, have reported improved treatment outcomes for patients receiving higher radiation doses.6 Biologic and statistical modeling of tumor responses across different radiation dose levels suggests that doses as high as 80 to 90 Gy are needed to achieve a recurrence-free survival rate of 50% (Figure 1), though this level is beyond the dose achieved by most standard external beam regimens.7
Modern standard external beam radiation doses without chemotherapy for stage I lung cancer are approximately 60 to 74 Gy. The dose fractionation schedule used with SBRT delivers much higher equivalent doses (83 Gy to 150 Gy), although the true biologically equivalent dose (BED) is not yet perfectly understood.8 Most clinical studies that have examined the effectiveness of SBRT have demonstrated local control rates in excess of 90% to 95% when an adequate dose (BED ≥ 100 Gy) is utilized, since the dose-response curve appears to plateau at this level.9 These response rates are higher than the 50% to 60% rate observed with conventional radiation.3,4 Efforts to confirm these comparative results in randomized trials have been largely abandoned because of the perceived advantage with SBRT.
PERIPHERAL VERSUS CENTRAL TUMORS
Stereotactic body radiotherapy has been referred to as “radiosurgery,” in part because the extremely high doses used to treat tumor are ablative to the immediate surrounding tissue. The consequences of ablation depend on whether the treatment involves parallel or serial tissue. Parallel tissue, such as lung, kidney, or liver, remains functional after the ablation or removal of small subunits if adequate volume of functional organ remains. With serial tissue such as the spinal cord or bowel, damage to one section results in loss of function at distal sites. Although the lung is parallel tissue, it includes serial structures such as the trachea and proximal bronchial tree. Tumors located within 2 cm of the proximal bronchial tree are classified as central, whereas tumors outside this zone are peripheral.
Peripheral tumors
Peripheral lung tumors are surrounded by only parallel tissue, and no maximum point-dose limit has been identified for their treatment. A recent cooperative group study (Radiation Therapy Oncology Group [RTOG] 0236) enrolled 55 patients, 80% with tumor stage IA (T1 N0) and 20% with stage IB (T2 N0).10 Patients with bronchoalveolar histology were excluded from the study. Patients received three radiation treatments of 20 Gy each (BED of 180 Gy) to their known tumor with a small margin, and were followed with serial computed tomography (CT). After a median follow-up of 34 months, only one of the 55 evaluable patients had a local tumor failure, for a local control rate of 97.6%. Three patients had recurrences in the initially involved lobe for a 3-year local control rate of 90.6%; two patients had nodal failures for a 3-year local regional control rate of 87.2%; and 11 patients had disseminated recurrences, for a 3-year distant failure rate of 22.1%.
Survival after 3 years was approximately 50%, which is much better than the survival rate typically attained with standard radiation therapy. Further, only 10 of the 26 deaths were attributed to lung cancer while 16 patients died of comorbid conditions such as stroke or myocardial infarction, illustrating the difficulty in tracking overall survival as a measure of efficacy in this medically fragile population.
Adverse events in this study were relatively rare. Seven patients had grade 3 or higher pulmonary complications, including hypoxia, pneumonitis, and pulmonary function test changes. Of note, the study scored changes in pulmonary function as toxicity; however, in this population, where nearly all patients have underlying lung disease, chronic obstructive pulmonary disease (COPD) exacerbations are also common.
Our own analysis of pulmonary function changes in patients treated with SBRT at Cleveland Clinic demonstrated that while there was no significant change in average baseline, pulmonary function in almost 10% of patients met criteria for a grade 3 pulmonary toxicity. A similar number of patients had a proportional improvement in pulmonary function, however. Given a nearly comparable distribution of pulmonary function changes in both directions with no significant deviation from baseline in aggregate, most of these fluctuations may be related to changes in the patient’s underlying comorbidities rather than effects of treatment.
RTOG 0236 demonstrated an excellent level of local control (97.6%) using 3 fractions of 20 Gy each (BED 180 Gy total). As noted, the dose response may plateau at 100 Gy BED,9 which raises the question of whether the radiation dose levels used in this study were higher than necessary. A recently completed randomized phase 2 clinical trial conducted by the RTOG compared 34 Gy in a single fraction versus 48 Gy in 4 fractions, and a similar study by Roswell Park Cancer Institute, Buffalo, New York, and Cleveland Clinic is comparing 60 Gy in 3 fractions versus 30 Gy in a single fraction. These studies, once mature, should help define the optimal radiation dose and treatment schedule for patients with inoperable peripheral tumors.
Central tumors
Centrally located tumors are in proximity to both parallel tissues (normal lung) and serial tissues (trachea, bronchial tree, or esophagus), as well as imperfectly categorized tissues (heart and great vessels). An important question is whether it is possible to reach a radiation dose level of 100 Gy BED or higher in these tumors without causing excessive toxicity to normal tissues. Although there is a potential risk of cardiotoxicity with chest radiotherapy, clinical studies of SBRT for lung cancer have not demonstrated any evidence of toxicity to the heart or the great vessels with focal radiation. Some studies have suggested that radiotherapy of central lung tumors may be associated with other adverse events.
Awareness of central versus peripheral tumor locations was first raised in an early phase 2 study in which patients were treated with 60 to 66 Gy in 3 fractions over a period of 1 to 2 weeks. Grade 3 or higher toxicity during 2 years of follow-up was noted for 46% of patients with central tumors and 17% of patients with peripheral tumors.11 Six deaths that occurred during the study were considered to be possibly treatment-related, including four cases of bacterial pneumonia, one patient with pericardial effusion, and one patient with hemoptysis that was later ascribed to carinal recurrence.
Other studies using lower fraction sizes, however, have demonstrated excellent efficacy and safety in treating central tumors with SBRT. In early Japanese studies12,13 that used smaller fractions without tissue constraints, no differences in toxicity were noted with treatment of central versus peripheral tumors. A European study similarly demonstrated more than 90% local control at 3 years for a regimen of 60 Gy in 8 fractions (7.5 Gy/fraction).14 Currently the RTOG is conducting a dose escalation study examining doses from 50 Gy to 60 Gy (10 Gy to 12 Gy per fraction in 5 fractions). The study has reached its highest level (60 Gy in 5 fractions) with no evidence of excessive toxicity reported.
SAFETY AND TOLERABILITY
Reprinted with permission from Journal of Thoracic Oncology (Stephans KL, et al. Comprehensive analysis of pulmonary function test (PFT) changes after stereotactic body radiotherapy (SBRT) for stage I lung cancer in medically inoperable patients. J Thorac
Figure 2. Although pulmonary function does not change significantly as a result of stereotactic body radiotherapy, some patients, as in this study, may exhibit increases in forced expiratory volume in 1 second (FEV1) (A) or diffusing capacity of the lung for carbon monoxide (DLCO) (B).Overall, the data suggest that for both central and peripheral tumors, SBRT is well tolerated in the medically inoperable population. On average, studies that have examined the effects of radiation therapy on pulmonary function have demonstrated little or no loss of function with SBRT. Some studies have described transient decreases in function with subsequent return to baseline.15,16 Even if overall group median lung function scores do not change significantly as a result of SBRT, individual patients may exhibit large increases or decreases in forced expiratory volume in 1 second (FEV1) or diffusing capacity of the lung for carbon monoxide (Dlco) after radiation therapy (Figure 2). These changes may be a function of underlying comorbidities as well as SBRT, given the minimal change in the average pulmonary function test measures.17
Radiation pneumonitis (an inflammatory complication of radiation frequently characterized by cough, fever, and shortness of breath) is rare—less than 5% in most series. An outlier is a single series that utilized 48 Gy in 4 fractions, a common and well-tolerated dose; the investigators reported a 30% rate of grade 2 through 5 (symptomatic) pneumonitis.18 Pneumonitis was significantly associated with the conformality index, a measure of how tightly the radiation beam is focused on the target tumor, emphasizing the importance of treatment technique on outcomes.
Other notes of caution for patients receiving SBRT include chest wall toxicity and neuropathy. Chest wall toxicity may include a variety of adverse events such as rib fractures, chest wall pain, and skin changes. These events have been described at chest wall radiation doses greater than 30 Gy.19 One study reported brachial plexopathy in 7 of 37 patients who received doses above 100 Gy BED delivered to the brachial plexus.20 Another recent study found that the probability of chest wall toxicity increased as the volume of chest wall receiving a 60 Gy dose increased above 15 to 20 cc.21 Esophagitis and skin reactions are rare except in cases where the patient is being treated for a tumor in extremely close proximity to the esophagus or skin.22
Computed tomography after SBRT often reveals substantial focal fibrosis in the region of high-dose lung radiation.23,24 Despite the often striking radiographic appearance, symptoms are rare and fibrosis may sometimes be mistaken for tumor recurrence. CT images should be read by those experienced in following post-SBRT changes. Findings suspicious for recurrence are typically evaluated by positron emission tomography (PET) followed by biopsy only if PET demonstrates sufficient hypermetabolism.
OPERABLE PATIENTS
Surgical resection is the standard of care for operable patients with lung cancer. Some studies are beginning to examine whether SBRT may also be useful in potentially operable patients. A Japanese study examined outcomes for 87 operable patients who underwent SBRT for stage I NSCLC and who were followed over a 55-month period.25 The local control rate was 92% for T1 tumors, a success rate approaching that of lobectomy. The success rate decreased to 73% for T2 tumors. Five-year overall survival rates were 72% for stage IA and 62% for stage IB, paralleling the surgical experience. Similar early results have been reported from the Netherlands.26 An RTOG study of medically operable patients recently completed enrollment after accruing 33 patients, with final results pending maturation of the data.
A major barrier to the introduction of SBRT to the operable population is the limited nature of the available data; SBRT technology has been implemented only recently and follow-up has been modest, owing to the nature of the medically inoperable population. In addition, it is difficult to determine during the first few months after SBRT which patients will be well controlled. Waiting for response to become apparent is an appropriate strategy for an inoperable patient with no alternatives, but operable patients need a trigger to indicate initiation of salvage therapies.27 In addition, lymph node dissection during surgery often provides information that is essential to tumor staging, and this information might be unavailable for patients treated with SBRT. It is also difficult to weigh the efficacy and tolerability of SBRT against surgical management because the two patient populations are not comparable.
High-risk operable patients
Comparisons of surgery and SBRT for stage I NSCLC are in their infancy and subject to extreme selection bias. Some attempts to create matched populations have demonstrated similar outcomes in matched patients.28,29 Markov modeling suggests improved efficacy for surgery overall, but the model turns in favor of SBRT in patients whose predicted surgical mortality exceeds 4%.30
High-risk operable patients are currently eligible for the American College of Surgeons Oncology group (ACOSOG)/RTOG 0870/Cancer and Leukemia Group B (CALGB) 140503 study; a randomized phase 3 clinical trial that is comparing lobectomy versus sublobar resection for small (< 2 cm) peripheral NSCLC. This study should help to clarify how this higher-risk patient group should be managed.
CLEVELAND CLINIC EXPERIENCE
At Cleveland Clinic, more than 700 patients with stage I NSCLC have been treated with SBRT since 2003. Peripheral tumors are typically treated with a radiation dose of 60 Gy in 3 fractions spaced over 8 to 14 days, or alternatively 30 Gy to 34 Gy in a single fraction. Occasional large tumors near the chest wall or spinal cord are treated with doses up to 50 Gy in 5 fractions over 5 consecutive days. For central tumors, radiation dose regimens include 50 Gy (5 fractions over 5 consecutive days) or 60 Gy (8 fractions over 10 days), depending upon tumor size and proximity to critical structures.
SUMMARY AND CONCLUSIONS
Many patients with NSCLC are ineligible for surgery because of COPD, cardiovascular disease, or other conditions associated with unacceptably high perioperative risk. SBRT is the standard of care for patients with medically inoperable stage I NSCLC. Modern standard radiation doses are typically between 50 to 60 Gy in 3 to 5 fractions. Local control rates in excess of 90% to 95% have been reported with these doses. SBRT is generally well tolerated by patients with both peripheral and centrally located tumors. On average, lung function is not substantially altered by SBRT, although individual patients may exhibit increased or decreased FEV1 and Dlco values after treatment. Pneumonitis has been relatively rare in most studies, with typical rates of 0% to 5%. SBRT has been shown to produce reasonable rates of local control in potentially operable patients, although data are extremely limited in this population and there are important questions about salvage therapy and postprocedural evaluation in these patients. Several ongoing clinical trials are continuing to define the efficacy and safety of different radiation dosing procedures for patients with inoperable NSCLC.
References
Smolle-Juettner FM, Maier A, Lindenmann J, Matzi V, Neuböck N. Resection in stage I/II non-small cell lung cancer. In:Heide J, Schmittel A, Kaiser D, Hinkelbein W, eds. Controversies in the Treatment of Lung Cancer. Basel, Switzerland: Karger; 2010:71–77.
McGarry RC, Song G, des Rosiers P, Timmerman R. Observationonly management of early stage, medically inoperable lung cancer: poor outcome. Chest2002; 121:1155–1158.
Lanni TB, Grills IS, Kestin LL, Robertson JM. Stereotactic radiotherapy reduces treatment cost while improving overall survival and local control over standard fractionated radiation therapy for medically inoperable non-small-cell lung cancer. Am J Clin Oncol2011; 34:494–498.
Grutters JP, Kessels AG, Pijls-Johannesma M, De Ruysscher D, Joore MA, Lambin P. Comparison of the effectiveness of radiotherapy with photons, protons and carbon-ions for non-small cell lung cancer: a meta-analysis [published online ahead of print September 3, 2009]. Radiother Oncol2010; 95:32–40. doi: 10.1016/jradonc.2009.08.003
Noordijk EM, vd Poest Clement E, Hermans J, Wever AMJ, Leer JWH. Radiotherapy as an alternative to surgery in elderly patients with resectable lung cancer. Radiother Oncol1988; 13:83–89.
Sibley GS. Radiotherapy for patients with medically inoperable stage I nonsmall cell lung carcinoma: smaller volumes and higher doses—a review. Cancer1998; 82:433–438.
Mehta M, Manon R. Are more aggressive therapies able to improve treatment of locally advanced non-small cell lung cancer: combined modality treatment?Semin Oncol2005; 32 (2 suppl 3):S25–S34.
Park C, Papiez L, Zhang S, Story M, Timmerman RD. Universal survival curve and single fraction equivalent dose: useful tools in understanding potency of ablative radiotherapy. Int J Radiat Oncol Biol Phys2008; 70:847–852.
Wulf J, Baier K, Mueller G, Flentje MP. Dose-response in stereotactic irradiation of lung tumors. Radiother Oncol2005; 77:83–87.
Timmerman R, Paulus R, Galvin J, et al. Stereotactic body radiation therapy for inoperable early stage lung cancer. JAMA2010; 303:1070–1076.
Timmerman R, McGarry R, Yiannoutsos C, et al. Excessive toxicity when treating central tumors in a phase II study of stereotactic body radiation therapy for medically inoperable early-stage lung cancer. J Clin Oncol2006; 24:4833–4839.
Onishi H, Shirato H, Nagata Y, et al. Hypofractionated stereotactic radiotherapy (HypoFXSRT) for stage I non-small cell lung cancer: updated results of 257 patients in a Japanese multi-institutional study. J Thorac Oncol2007; 2 (7 suppl 3):S94–S100.
Nagata Y, Takayama K, Matsuo Y, et al. Clinical outcomes of a phase I/II study of 48 Gy of stereotactic body radiotherapy in 4 fractions for primary lung cancer using a stereotactic body frame [published online ahead of print September 19, 2005]. Int J Radiat Oncol Biol Phys2005; 63:1427–1431. doi: 10.1016/j.ijrobp.2005.05.034
Haasbeek CJ, Lagerwaard FJ, Slotman BJ, Senan S. Outcomes of stereotactic ablative radiotherapy for centrally located early-stage lung cancer. J Thorac Oncol2011; 6:2036–2043.
Timmerman R, Papiez L, McGarry R, et al. Extracranial stereotactic radioablation: results of a phase I study in medically inoperable stage I non-small cell lung cancer. Chest2003; 124:1946–1955.
Henderson M, McGarry R, Yiannoutsos C, et al. Baseline pulmonary function as a predictor for survival and decline in pulmonary function over time in patients undergoing stereotactic body radiotherapy for the treatment of stage I non-small-cell lung cancer. Int J Radiat Oncol Biol Phys2008; 72:404–409.
Stephans KL, Djemil T, Reddy CA, et al. Comprehensive analysis of pulmonary function test (PFT) changes after stereotactic body radiotherapy (SBRT) for stage I lung cancer in medically inoperable patients. J Thorac Oncol2009; 4:838–844.
Yamashita H, Nakagawa K, Nakamura N, et al. Exceptionally high incidence of symptomatic grade 2–5 radiation pneumonitis after stereotactic radiation therapy for lung tumors. Radiat Oncol2007; 2:21.
Dunlap NE, Cai J, Biedermann GB, et al. Chest wall volume receiving > 30 Gy predicts risk of severe pain and/or rib fracture after lung stereotactic body radiotherapy. Int J Radiat Oncol Biol Phys2010; 76:796–801.
Forquer JA, Fakiris AJ, Timmerman RD, et al. Brachial plexopathy from stereotactic body radiotherapy in early-stage NSCLC: dose-limiting toxicity in apical tumor sites. Radiother Oncol2009; 93:408–413.
Stephans KL, Djemil T, Tendulkar RD, Robinson CG, Reddy CA, Videtic GM. Prediction of chest wall toxicity from lung stereotactic body radiotherapy (SBRT) [published online ahead of print February 6, 2011]. Int J Radiat Oncol Biol Phys2012; 82:974–980. doi: 10.1016/j.ijrobp.2010.12.002
Hoppe BS, Laser B, Kowalski AV, et al. Acute skin toxicity following stereotactic body radiation therapy for stage I non-small-cell lung cancer: who’s at risk?Int J Radiat Oncol Biol Phys2008; 72:1283–1286.
Bradley J. Radiographic response and clinical toxicity following SBRT for stage I lung cancer. J Thorac Oncol2007; 2 (7 suppl 3):S118–S124.
Linda A, Trovo M, Bradley JD. Radiation injury of the lung after stereotactic body radiation therapy (SBRT) for lung cancer: a timeline and pattern of CT changes [published online ahead of print December 1, 2009]. Eur J Radiol2011; 79:147–154. doi: 10.1016/j.ejrad.2009.10.029
Onishi H, Shirato H, Nagata Y, et al. Stereotactic body radiotherapy (SBRT) for operable stage I non-small-cell lung cancer: can SBRT be comparable to surgery [published online ahead of print July 16, 2011]?Int J Radiat Oncol Biol Phys2011; 81:1352–1358. doi: 10.1016/j.ijrobp.2009.07.1751
Lagerwaard FJ, Verstegen NE, Haasbeek CJ, et al. Outcomes of stereotactic ablative radiotherapy in patients with potentially operable stage I non-small-cell lung cancer [published online ahead of print November 19, 2011.]Int J Radiat Oncol Biol Phys. doi: 10.1016/j.ijrobp.2011.06.2003.
Neri S, Takahashi Y, Terashi T, et al. Surgical treatment of local recurrence after stereotactic body radiotherapy for primary and metastatic lung cancers. J Thorac Oncol2010; 5:2003–2007.
Crabtree TD, Denlinger CE, Meyers BF, et al. Stereotactic body radiation therapy versus surgical resection for stage I non-small cell lung cancer [published online ahead of print April 18, 2010]. J Thorac Cardiovasc Surg2010; 140:377–386. doi: 10.1016/j.jtcvs.2009.12.054
Palma D, Lagerwaard F, Rodrigues G, Haasbeek C, Senan S. Curative treatment of stage I non-small-cell lung acancer in patients with severe COPD: stereotactic radiotherapy outcomes and systematic review [published online ahead of print June 2, 2011]. Int J Radiat Oncol Biol Phys2012; 82:1149–1156. doi: 10.1016/j.ijrobp.2011.03.005
Louie AV, Rodrigues G, Hannouf M, et al. Stereotactic body radiotherapy versus surgery for medically operable stage I non-small-cell lung cancer: a Markov model-based decision analysis [published online ahead of print October 6, 2010]. Int J Radiat Oncol Biol Phys2011; 81:964–973. doi: 10.1016/j.ijrobp.2010.06.040
Martel MK, Ten Haken RK, Hazuka MB, et al. Estimation of tumor control probability model parameters from 3-D dose distributions of non-small cell lung cancer patients. Lung Cancer1999; 24:31–37.
References
Smolle-Juettner FM, Maier A, Lindenmann J, Matzi V, Neuböck N. Resection in stage I/II non-small cell lung cancer. In:Heide J, Schmittel A, Kaiser D, Hinkelbein W, eds. Controversies in the Treatment of Lung Cancer. Basel, Switzerland: Karger; 2010:71–77.
McGarry RC, Song G, des Rosiers P, Timmerman R. Observationonly management of early stage, medically inoperable lung cancer: poor outcome. Chest2002; 121:1155–1158.
Lanni TB, Grills IS, Kestin LL, Robertson JM. Stereotactic radiotherapy reduces treatment cost while improving overall survival and local control over standard fractionated radiation therapy for medically inoperable non-small-cell lung cancer. Am J Clin Oncol2011; 34:494–498.
Grutters JP, Kessels AG, Pijls-Johannesma M, De Ruysscher D, Joore MA, Lambin P. Comparison of the effectiveness of radiotherapy with photons, protons and carbon-ions for non-small cell lung cancer: a meta-analysis [published online ahead of print September 3, 2009]. Radiother Oncol2010; 95:32–40. doi: 10.1016/jradonc.2009.08.003
Noordijk EM, vd Poest Clement E, Hermans J, Wever AMJ, Leer JWH. Radiotherapy as an alternative to surgery in elderly patients with resectable lung cancer. Radiother Oncol1988; 13:83–89.
Sibley GS. Radiotherapy for patients with medically inoperable stage I nonsmall cell lung carcinoma: smaller volumes and higher doses—a review. Cancer1998; 82:433–438.
Mehta M, Manon R. Are more aggressive therapies able to improve treatment of locally advanced non-small cell lung cancer: combined modality treatment?Semin Oncol2005; 32 (2 suppl 3):S25–S34.
Park C, Papiez L, Zhang S, Story M, Timmerman RD. Universal survival curve and single fraction equivalent dose: useful tools in understanding potency of ablative radiotherapy. Int J Radiat Oncol Biol Phys2008; 70:847–852.
Wulf J, Baier K, Mueller G, Flentje MP. Dose-response in stereotactic irradiation of lung tumors. Radiother Oncol2005; 77:83–87.
Timmerman R, Paulus R, Galvin J, et al. Stereotactic body radiation therapy for inoperable early stage lung cancer. JAMA2010; 303:1070–1076.
Timmerman R, McGarry R, Yiannoutsos C, et al. Excessive toxicity when treating central tumors in a phase II study of stereotactic body radiation therapy for medically inoperable early-stage lung cancer. J Clin Oncol2006; 24:4833–4839.
Onishi H, Shirato H, Nagata Y, et al. Hypofractionated stereotactic radiotherapy (HypoFXSRT) for stage I non-small cell lung cancer: updated results of 257 patients in a Japanese multi-institutional study. J Thorac Oncol2007; 2 (7 suppl 3):S94–S100.
Nagata Y, Takayama K, Matsuo Y, et al. Clinical outcomes of a phase I/II study of 48 Gy of stereotactic body radiotherapy in 4 fractions for primary lung cancer using a stereotactic body frame [published online ahead of print September 19, 2005]. Int J Radiat Oncol Biol Phys2005; 63:1427–1431. doi: 10.1016/j.ijrobp.2005.05.034
Haasbeek CJ, Lagerwaard FJ, Slotman BJ, Senan S. Outcomes of stereotactic ablative radiotherapy for centrally located early-stage lung cancer. J Thorac Oncol2011; 6:2036–2043.
Timmerman R, Papiez L, McGarry R, et al. Extracranial stereotactic radioablation: results of a phase I study in medically inoperable stage I non-small cell lung cancer. Chest2003; 124:1946–1955.
Henderson M, McGarry R, Yiannoutsos C, et al. Baseline pulmonary function as a predictor for survival and decline in pulmonary function over time in patients undergoing stereotactic body radiotherapy for the treatment of stage I non-small-cell lung cancer. Int J Radiat Oncol Biol Phys2008; 72:404–409.
Stephans KL, Djemil T, Reddy CA, et al. Comprehensive analysis of pulmonary function test (PFT) changes after stereotactic body radiotherapy (SBRT) for stage I lung cancer in medically inoperable patients. J Thorac Oncol2009; 4:838–844.
Yamashita H, Nakagawa K, Nakamura N, et al. Exceptionally high incidence of symptomatic grade 2–5 radiation pneumonitis after stereotactic radiation therapy for lung tumors. Radiat Oncol2007; 2:21.
Dunlap NE, Cai J, Biedermann GB, et al. Chest wall volume receiving > 30 Gy predicts risk of severe pain and/or rib fracture after lung stereotactic body radiotherapy. Int J Radiat Oncol Biol Phys2010; 76:796–801.
Forquer JA, Fakiris AJ, Timmerman RD, et al. Brachial plexopathy from stereotactic body radiotherapy in early-stage NSCLC: dose-limiting toxicity in apical tumor sites. Radiother Oncol2009; 93:408–413.
Stephans KL, Djemil T, Tendulkar RD, Robinson CG, Reddy CA, Videtic GM. Prediction of chest wall toxicity from lung stereotactic body radiotherapy (SBRT) [published online ahead of print February 6, 2011]. Int J Radiat Oncol Biol Phys2012; 82:974–980. doi: 10.1016/j.ijrobp.2010.12.002
Hoppe BS, Laser B, Kowalski AV, et al. Acute skin toxicity following stereotactic body radiation therapy for stage I non-small-cell lung cancer: who’s at risk?Int J Radiat Oncol Biol Phys2008; 72:1283–1286.
Bradley J. Radiographic response and clinical toxicity following SBRT for stage I lung cancer. J Thorac Oncol2007; 2 (7 suppl 3):S118–S124.
Linda A, Trovo M, Bradley JD. Radiation injury of the lung after stereotactic body radiation therapy (SBRT) for lung cancer: a timeline and pattern of CT changes [published online ahead of print December 1, 2009]. Eur J Radiol2011; 79:147–154. doi: 10.1016/j.ejrad.2009.10.029
Onishi H, Shirato H, Nagata Y, et al. Stereotactic body radiotherapy (SBRT) for operable stage I non-small-cell lung cancer: can SBRT be comparable to surgery [published online ahead of print July 16, 2011]?Int J Radiat Oncol Biol Phys2011; 81:1352–1358. doi: 10.1016/j.ijrobp.2009.07.1751
Lagerwaard FJ, Verstegen NE, Haasbeek CJ, et al. Outcomes of stereotactic ablative radiotherapy in patients with potentially operable stage I non-small-cell lung cancer [published online ahead of print November 19, 2011.]Int J Radiat Oncol Biol Phys. doi: 10.1016/j.ijrobp.2011.06.2003.
Neri S, Takahashi Y, Terashi T, et al. Surgical treatment of local recurrence after stereotactic body radiotherapy for primary and metastatic lung cancers. J Thorac Oncol2010; 5:2003–2007.
Crabtree TD, Denlinger CE, Meyers BF, et al. Stereotactic body radiation therapy versus surgical resection for stage I non-small cell lung cancer [published online ahead of print April 18, 2010]. J Thorac Cardiovasc Surg2010; 140:377–386. doi: 10.1016/j.jtcvs.2009.12.054
Palma D, Lagerwaard F, Rodrigues G, Haasbeek C, Senan S. Curative treatment of stage I non-small-cell lung acancer in patients with severe COPD: stereotactic radiotherapy outcomes and systematic review [published online ahead of print June 2, 2011]. Int J Radiat Oncol Biol Phys2012; 82:1149–1156. doi: 10.1016/j.ijrobp.2011.03.005
Louie AV, Rodrigues G, Hannouf M, et al. Stereotactic body radiotherapy versus surgery for medically operable stage I non-small-cell lung cancer: a Markov model-based decision analysis [published online ahead of print October 6, 2010]. Int J Radiat Oncol Biol Phys2011; 81:964–973. doi: 10.1016/j.ijrobp.2010.06.040
Martel MK, Ten Haken RK, Hazuka MB, et al. Estimation of tumor control probability model parameters from 3-D dose distributions of non-small cell lung cancer patients. Lung Cancer1999; 24:31–37.
The population of patients with stage III non–small cell lung cancer (NSCLC) presents a management challenge for clinicians. The standard of care for locally advanced NSCLC is chemotherapy plus radiation, but the optimal chemoradiation regimen is a work in progress, building upon decades of clinical trial research. Optimal therapy may require patient participation in a current phase 3 clinical trial.
Understanding the background behind the design of phase 3 clinical trials may permit better understanding of optimal chemoradiation. Most recent research has focused on optimization of chemotherapy with less attention paid to radiation dose and technique, the use of targeted agents, and imaging and planning.
A dilemma in the management of stage III NSCLC is how best to combine the correct treatments in the right sequence to achieve simultaneous local, regional, and distant control, as the disease occurs at multiple levels and cure is not possible without local disease control. Another dilemma concerns administration of radiation therapy when the lung, heart, esophagus, or spinal cord may impede delivery of treatment. Additionally, patients may not present with symptoms until an advanced stage of disease, and their performance status is frequently impaired and often influenced by comorbidities such as smoking.
FACTORS RELATED TO PROGNOSIS AND CHOICE OF TREATMENT
Most potentially curable patients with NSCLC present with locally advanced mediastinal disease. Despite improvements in staging procedures and therapy, however, the prognosis of locally advanced NSCLC remains poor with a survival rate of less than 20% at 5 years.
Prognostic indicators
Poor outcomes can be attributed to the heterogeneity of locally advanced stage III NSCLC and the factors that influence this heterogeneity. Within stage IIIA and stage IIIB, subdivisions vary considerably depending on tumor size, tumor location, and nodal involvement. With routine positron emission tomography (PET) and assessment of intracranial dissemination, a significant number of “stage III” patients are identified with advanced-stage disease and upstaged. Revisions in the staging system that define clinically distinct subsets within stage III attempt to bring more coherence to patient subsets (Table).1
Factors that affect treatment choice
Clinical and patient factors can influence the choice of concurrent chemoradiation therapy. Weight loss, performance status, comorbidity, and pulmonary reserve influence survival and patient outcome. Comorbidities are frequently observed in elderly patients and smokers. More than one-half of patients with stage III NSCLC are currently thought to be ineligible for concurrent regimens if inclusion is restricted to patients younger than 75 years and those with fewer than two serious comorbidities. The exact contribution of comorbidity, age, and other clinical parameters to the reported toxicity is unclear.
Tumor biology
The biology of different types of NSCLC can vary considerably (eg, bronchoalveolar vs squamous cell vs adenocarcinoma). Sometimes cancer grows indolently, even with nodal presentations. Molecular profiling to understand this phenomenon is still in its infancy.
CURRENT APPROACHES TO CHEMORADIATION
Treatment of unresectable stage III NSCLC requires control of local disease and distant metastases. Much work has been undertaken to determine the safety and efficacy of sequential chemoradiation (chemotherapy followed by radiation therapy) and concurrent chemoradiation (chemotherapy during radiation therapy).
Sequential chemoradiation
Dillman et al2,3 ushered in an era of combined modality therapy when in 1990 they demonstrated that a 5-week course of induction chemotherapy followed by radiotherapy in stage III NSCLC resulted in improved median survival compared with radiotherapy alone (13.8 months vs 9.7 months) in a randomized trial.
Sause et al4,5 later showed that in “good risk” patients (Karnofsky Performance Status > 70) with surgically unresectable NSCLC, induction chemotherapy followed by radiation therapy produced superior short-term survival compared with hyperfractionated radiation therapy or standard radiation therapy alone.
Concurrent chemoradiation
The next step in the search for optimal sequencing was the study of concurrent chemotherapy and radiation. In phase 3 studies that compared sequential chemoradiation with concurrent chemoradiation, a consistent advantage in overall survival was conferred by concurrent chemoradiation therapy. Even with concurrent chemoradiation, however, survival was still modest (16% and 21% to 5 years in the two largest comparisons), and median survival improved only from 14.5 months with sequential therapy to 17.1 months with concurrent therapy in the largest comparison.6
Further support for concurrent chemoradiation on the end point of overall survival comes from two meta-analyses. A Cochrane meta-analysis demonstrated a significant 14% reduction in the risk of death with concurrent chemoradiation compared with sequential treatment.7 The NSCLC Collaborative Group discovered a significant survival advantage with concurrent chemoradiation compared with sequential treatment (hazard ratio: 0.84) with an absolute benefit of 5.7% at 3 years (3-year survival of 18.1% with sequential chemoradiation vs 23.8% with concurrent chemoradiation).8
Applying the results of clinical trials to appropriate patients offers the best chance to improve outcomes. The heterogeneity of the NSCLC population makes application of therapeutic advances challenging. One must consider that the selection criteria used in clinical trials, including performance status, weight loss, disease stage, and volume of disease have a great bearing on the results achieved.
When toxicity between the two multimodality approaches was compared, the risk of grade 3 or 4 acute esophagitis was found to increase from 4% with sequential chemoradiation therapy to 18% with concurrent treatment, but no difference in acute pulmonary toxicity has been observed.8
Some investigators used lower doses of chemotherapy in the concurrent chemoradiation arms to minimize radiation toxicity. However, the dose intensity in sequential treatment should be maintained so that the advantage of controlling micrometastatic disease is not lost.
These clinical trials highlight that timing of chemoradiation precludes a significant proportion of patients from receiving uninterrupted radiation therapy, either because of toxicity from chemotherapy, leading to a reduction in performance status, or disease progression during sequential chemotherapy.
ATTEMPTS TO IMPROVE RADIOTHERAPY
Methods to improve radiotherapy have centered on evolving radiologic imaging and computer technology, with the objective of enhanced precision of radiation delivery. The routine use of PET in planning radiotherapy allows for dose escalation and control of toxicity.
Radiotherapy dose and outcomes
Three-dimensional (3D) conformal radiation techniques permit the use of higher doses of targeted radiation to spare normal tissue. A meta-analysis of six trials of concurrent chemoradiation therapy concluded that an increased dose of radiation improves both local control and survival.9 A better understanding of normal lung tolerability to radiation therapy is needed to optimize radiation dose.
A clinical trial to test the efficacy of high-dose conformal radiation therapy is in progress. Patients with unresectable stage IIIA or IIIB NSCLC are being randomized to concurrent chemoradiation therapy with carboplatin and weekly paclitaxel with either 74 Gy of radiation in 37 fractions over 7.5 weeks, or 60 Gy of radiation in 30 fractions over 6 weeks. Results will be stratified by radiation therapy technique (3D conformal radiation or intensity-modulated radiation therapy). Following an impressive survival rate (median overall survival: 22.7 months) obtained with the addition of cetuximab to the chemoradiation regimen in the phase 2 Radiation Therapy Oncology Group 0324 trial, an amendment to the design further randomized patients in each radiotherapy group to cetuximab or no cetuximab.10 Those randomized to cetuximab will continue on consolidation therapy with carboplatin, paclitaxel, and cetuximab, while the group randomized to no cetuximab will receive consolidation therapy with carboplatin and paclitaxel only.
Another approach in stage III NSCLC is the use of molecular biomarkers to predict response. Tumor typing for specific molecular sensitivities is generally thought to help predict response to systemic chemotherapy, but within the setting of radiotherapy, patients with a mutation of the epidermal growth factor receptor (EGFR) were found to have more radiosensitive tumors and decreased local recurrence rates than those without the EGFR mutation.11,12 Interactions between systemic therapy and radiation may also prove to be important in response to therapy and prognosis.
Figure 1. At median follow-up of 38 months among patients with non–small cell lung cancer, there was no statistically significant difference in median survival between those randomized to immediate concurrent radiotherapy and those who received induction chemotherapy followed by identical chemoradiation (12 months vs 14 months, respectively).Induction chemotherapy followed by chemoradiation was proposed as an alternative to concurrent chemotherapy as a way to potentially improve systemic control in patients with unresectable stage III NSCLC. Induction chemotherapy provided no survival benefit over concurrent chemoradiation alone in a randomized controlled comparison by Vokes et al (Figure 1).13 There was no significant difference in nonhematologic toxicity between the treatment groups, although the incidence of grade 3/4 esophagitis was very high (about 30%) in both arms. The patient selection may have influenced median survival in this trial; approximately 25% of patients enrolled had weight loss in excess of 5%, which has been shown to be a poor prognostic factor.
A three-arm study compared sequential chemotherapy/radiotherapy, induction chemotherapy followed by concurrent chemoradiation, and concurrent chemoradiation followed by consolidation chemotherapy.14 In the sequential and induction arms, paclitaxel and carboplatin were administered for two cycles prior to radiation therapy; in the consolidation arm, the drugs were given following radiation therapy. The median survival was 16.3 months in the consolidation arm, 12.7 months in the induction arm, and 13.0 months in the sequential arm. The induction and consolidation arms were associated with greater toxicity. The incidences of grade 3/4 esophagitis and pulmonary toxicity were highest in the consolidation arm (28% and 16%, respectively). Although the study was not powered for direct comparison of the three treatment arms, the prolonged median survival for concurrent treatment followed by consolidation chemotherapy adds support to the argument that providing the definitive treatment up front followed by systemically active doses of chemotherapy is the preferred therapeutic approach in stage III NSCLC.
The Southwest Oncology Group (SWOG) study 9504 conducted in patients with stage IIIB NSCLC adds to the evidence of a benefit with consolidation chemotherapy after definitive chemoradiation.15 In this trial, consolidation with docetaxel following concurrent cisplatin-etoposide and radiotherapy extended median overall survival to 26 months.
Figure 2. The Hoosier Oncology Group found that no survival advantage was conferred by consolidation docetaxel after cisplatin-etoposide (median survival: 21.1 months), over cisplatin-etoposide and concurrent radiation alone (observation arm, median survival: 23.2 months) in patients with stage III inoperable NSCLC.
In the Hoosier Oncology Group (HOG) LUN 01-24 study, consolidation with docetaxel after cisplatin-etoposide did not have a survival advantage over cisplatin-etoposide and concurrent radiation alone, but it was associated with increased toxicity in patients with stage III inoperable NSCLC (Figure 2).16
The dose intensity and delivery of consolidation docetaxel were similar in the SWOG 9504 and the HOG LUN 01-24 studies. Although no difference in median survival was observed between the consolidation and observation arms in HOG LUN 01-24, the median survival for the observation arm in this trial was much higher than the 15 months demonstrated with the same concurrent regimen (cisplatin-etoposide and chest radiotherapy) in the SWOG 9019 trial.17 A difference in stage distribution across the two trials might explain the differences in survival in the observation arms.
LITTLE PROGRESS WITH BIOLOGIC THERAPIES
The improvements observed when combining chemotherapy with radiation therapy in sequence with systemically active doses of third-generation agents have come at a price of increased toxicity, and most patients will still suffer relapse and ultimately die of metastatic disease. A significant proportion of patients will not be fit enough for more aggressive regimens.
The addition of thalidomide as an immunomodulator agent to chemoradiation did not improve overall or progression-free survival; it was also associated with a higher rate of grade 3+ toxicities in patients with stage IIIA/B NSCLC.18
In CALBG 30407, a regimen of pemetrexed disodium and carboplatin together with radiation therapy with or without cetuximab was studied in patients with stage III unresectable NSCLC.19 Median survival was 22.3 months with pemetrexed-carboplatin; the addition of cetuximab conferred no significant benefit, with maintenance beyond 4 cycles being unfeasible in nearly 50% the patients enrolled.
Integrating the vascular endothelial growth factor inhibitor bevacizumab into combined modality therapy was tested in SWOG 0533. The study consisted of 3 treatment arms in which bevacizumab was introduced at different times in the concurrent chemoradiation setting in patients with stage III NSCLC. Accrual into the trial was terminated because of an unacceptable level of toxicity. Despite the risk stratification, restrictive eligibility criteria, and careful bevacizumab deployment, the approach still proved to be unfeasible.
The small-molecule epidermal tyrosine kinase inhibitors gefitinib and erlotinib had demonstrated efficacy as single agents, but the randomized SWOG 0023 trial of maintenance gefitinib after concurrent chemoradiation and consolidation therapy with docetaxel was terminated early when an interim analysis suggested lack of efficacy of maintenance gefitinib.
CONCLUSIONS
Stage III NSCLC is a heterogeneous disease with considerable variations in prognosis and treatment options. The goals of treatment are local control through the use of radiation therapy and chemotherapy and eradication of distant micrometastases through chemotherapy. For patients with good performance status, concurrent chemoradiation is the standard of care.
Phase 3 trials of full-dose chemotherapy, as either induction or consolidation, have not optimized outcomes. Integration of targeted agents is now under investigation. Any future progress will likely rely on molecular selection, which will require accruing a large number of patients into many clinical trials.
References
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Dillman RO, Seagren SL, Propert KJ, et al. A randomized trial of induction chemotherapy plus high-dose radiation versus radiation alone in stage III non-small-cell lung cancer. N Engl J Med1990; 323:940–945.
Dillman RO, Herndon J, Seagren SL, Eaton WL, Green MR. Improved survival in stage III non-small-cell lung cancer: seven-year follow-up of Cancer and Leukemia Group B (CALGB) 8433 trial. J Natl Cancer Inst1996; 88:1210–1215.
Sause WT, Scott C, Taylor S, et al. Radiation Therapy Oncology Group (RTOG) 88-08 and Eastern Cooperative Oncology Group (ECOG) 4588: preliminary results of a phase III trial in regionally advanced, unresectable non-small-cell lung cancer. J Natl Cancer Inst1995; 87:198–205.
Sause W, Kolesar P, Taylor S, et al. Final results of phase III trial in regionally advanced, unresectable non-small-cell lung cancer*: Radiation Therapy Oncology Group, Eastern Cooperative Oncology Group, and Southwest Oncology Group. Chest2000; 117:358–364.
Bayman NA, Blackhall F, Jain P, et al. Management of unresectable stage III non-small-cell lung cancer with combined-modality therapy: a review of the current literature and recommendations for treatment. Clin Lung Cancer2008; 9:92–101.
Rowell NP, O’Rourke NP. Concurrent chemoradiotherapy in non-small cell lung cancer. Cochrane Database Syst Rev2004; 18:CD002140.
Aupérin A, Le Pechoux C, Rolland E, et al. Meta-analysis of concomitant versus sequential radiochemotheapy in locally advanced non-small-cell lung cancer. J Clin Oncol2010; 28:2181–2190.
Machtay M, Swann S, Komaki R, et al. Higher BED is associated with improved local-regional control and survival for NSCLC treated with chemoradiotherapy [ASTRO abstract]. Int J Radiat Oncol Biol Phys2005; 63( suppl 1):S40.
Blumenschein GR, Paulus R, Curran WJ, et al. A phase II study of cetuximab (C225) in combination with chemoradiation (CRT) in patients (PTS) with stage IIIA/B non-small cell lung cancer (NSCLC): a report of the 2 year and median survival (MS) for the RTOG 0324 trial. J Clin Oncol2008; 26( suppl). Abstract 7516.
Riesterer O, Milas L, Ang KK. Use of molecular biomarkers for predicting the response to radiotherapy with or without chemotherapy. J Clin Oncol2007; 26:4075–4083.
Mak RH, Doran E, Muzikansky A, et al. Thoracic radiation therapy in locally advanced NSCLC patients (pts) with EGFR mutations. J Clin Oncol2010; 28( suppl). Abstract 7016.
Vokes EE, Herndon JE, Kelley MJ, et al. Induction chemotherapy followed by chemoradiotherapy compared with chemoradiotherapy alone for regionally advanced unresectable stage III non-small-cell lung cancer: Cancer and Leukemia Group B. J Clin Oncol2007; 25:1698–1704.
Belani CP, Choy H, Bonomi P, et al. Combined chemoradiotherapy regimens of paclitaxel and carboplatin for locally advanced non-small-cell lung cancer: a randomized phase II locally advanced multi-modality protocol. J Clin Oncol2005; 23:5883–5891.
Gandara DR, Chansky K, Gaspar LE, Albain KS, Lara PN, Crowley J. Long term survival in stage IIIb non-small cell lung cancer (NSCLC) treated with consolidation docetaxel following concurrent chemoradiotherapy (SWOG S9504). J Clin Oncol2005; 23( suppl). Abstract 7059.
Hanna N, Neubauer M, Yiannoutsos C, et al. Phase III study of cisplatin, etoposide, and concurrent chest radiation with or without consolidation docetaxel in patients with inoperable stage III non-small-cell lung cancer: the Hoosier Oncology Group and U.S. Oncology. J Clin Oncol2008; 35:5755–5760.
Albain KS, Crowley JJ, Turrisi AT, et al. Concurrent cisplatin, etoposide, and chest radiotherapy in pathologic stage IIIB non-small-cell lung cancer: a Southwest Oncology Group phase II study, SWOG 9019. J Clin Oncol2002; 20:3454–3460.
Schiller JH, Dahlberg SE, Mehta M, et al. A phase III trial of carboplatin, paclitaxel, and thoracic radiation therapy with or without thalidomide in patients with stage III non-small cell carcinoma of the lung (NSCLC): E3598. J Clin Oncol2009; 27 (suppl). Abstract 7503.
Govindan R, Bogart J, Wang X, et al. Phase II study of pemetrexed, carboplatin, and thoracic radiation with or without cetuximab in patients with locally advanced unresectable non-small cell lung cancer: CALGB 30407. J Clin Oncol2009; 27 (suppl). Abstract 7505.
Correspondence: Gregory M.M. Videtic, MD, CM, FRCPC, Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, 9500 Euclid Avenue, T28, Cleveland, OH 44195; videtig@ccf.org
Dr. Videtic reported that he has no financial relationships that pose a potential conflict of interest with this article.
This article was developed from an audio transcript of Dr. Videtic’s presentation at the “Advances in Lung Cancer Evaluation and Management” symposium held in Cleveland, Ohio, on April 30, 2011. The transcript was formatted and edited by Cleveland Clinic Journal of Medicine staff for clarity and conciseness and was then reviewed, revised, and approved by Dr. Videtic.
Correspondence: Gregory M.M. Videtic, MD, CM, FRCPC, Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, 9500 Euclid Avenue, T28, Cleveland, OH 44195; videtig@ccf.org
Dr. Videtic reported that he has no financial relationships that pose a potential conflict of interest with this article.
This article was developed from an audio transcript of Dr. Videtic’s presentation at the “Advances in Lung Cancer Evaluation and Management” symposium held in Cleveland, Ohio, on April 30, 2011. The transcript was formatted and edited by Cleveland Clinic Journal of Medicine staff for clarity and conciseness and was then reviewed, revised, and approved by Dr. Videtic.
Correspondence: Gregory M.M. Videtic, MD, CM, FRCPC, Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, 9500 Euclid Avenue, T28, Cleveland, OH 44195; videtig@ccf.org
Dr. Videtic reported that he has no financial relationships that pose a potential conflict of interest with this article.
This article was developed from an audio transcript of Dr. Videtic’s presentation at the “Advances in Lung Cancer Evaluation and Management” symposium held in Cleveland, Ohio, on April 30, 2011. The transcript was formatted and edited by Cleveland Clinic Journal of Medicine staff for clarity and conciseness and was then reviewed, revised, and approved by Dr. Videtic.
The population of patients with stage III non–small cell lung cancer (NSCLC) presents a management challenge for clinicians. The standard of care for locally advanced NSCLC is chemotherapy plus radiation, but the optimal chemoradiation regimen is a work in progress, building upon decades of clinical trial research. Optimal therapy may require patient participation in a current phase 3 clinical trial.
Understanding the background behind the design of phase 3 clinical trials may permit better understanding of optimal chemoradiation. Most recent research has focused on optimization of chemotherapy with less attention paid to radiation dose and technique, the use of targeted agents, and imaging and planning.
A dilemma in the management of stage III NSCLC is how best to combine the correct treatments in the right sequence to achieve simultaneous local, regional, and distant control, as the disease occurs at multiple levels and cure is not possible without local disease control. Another dilemma concerns administration of radiation therapy when the lung, heart, esophagus, or spinal cord may impede delivery of treatment. Additionally, patients may not present with symptoms until an advanced stage of disease, and their performance status is frequently impaired and often influenced by comorbidities such as smoking.
FACTORS RELATED TO PROGNOSIS AND CHOICE OF TREATMENT
Most potentially curable patients with NSCLC present with locally advanced mediastinal disease. Despite improvements in staging procedures and therapy, however, the prognosis of locally advanced NSCLC remains poor with a survival rate of less than 20% at 5 years.
Prognostic indicators
Poor outcomes can be attributed to the heterogeneity of locally advanced stage III NSCLC and the factors that influence this heterogeneity. Within stage IIIA and stage IIIB, subdivisions vary considerably depending on tumor size, tumor location, and nodal involvement. With routine positron emission tomography (PET) and assessment of intracranial dissemination, a significant number of “stage III” patients are identified with advanced-stage disease and upstaged. Revisions in the staging system that define clinically distinct subsets within stage III attempt to bring more coherence to patient subsets (Table).1
Factors that affect treatment choice
Clinical and patient factors can influence the choice of concurrent chemoradiation therapy. Weight loss, performance status, comorbidity, and pulmonary reserve influence survival and patient outcome. Comorbidities are frequently observed in elderly patients and smokers. More than one-half of patients with stage III NSCLC are currently thought to be ineligible for concurrent regimens if inclusion is restricted to patients younger than 75 years and those with fewer than two serious comorbidities. The exact contribution of comorbidity, age, and other clinical parameters to the reported toxicity is unclear.
Tumor biology
The biology of different types of NSCLC can vary considerably (eg, bronchoalveolar vs squamous cell vs adenocarcinoma). Sometimes cancer grows indolently, even with nodal presentations. Molecular profiling to understand this phenomenon is still in its infancy.
CURRENT APPROACHES TO CHEMORADIATION
Treatment of unresectable stage III NSCLC requires control of local disease and distant metastases. Much work has been undertaken to determine the safety and efficacy of sequential chemoradiation (chemotherapy followed by radiation therapy) and concurrent chemoradiation (chemotherapy during radiation therapy).
Sequential chemoradiation
Dillman et al2,3 ushered in an era of combined modality therapy when in 1990 they demonstrated that a 5-week course of induction chemotherapy followed by radiotherapy in stage III NSCLC resulted in improved median survival compared with radiotherapy alone (13.8 months vs 9.7 months) in a randomized trial.
Sause et al4,5 later showed that in “good risk” patients (Karnofsky Performance Status > 70) with surgically unresectable NSCLC, induction chemotherapy followed by radiation therapy produced superior short-term survival compared with hyperfractionated radiation therapy or standard radiation therapy alone.
Concurrent chemoradiation
The next step in the search for optimal sequencing was the study of concurrent chemotherapy and radiation. In phase 3 studies that compared sequential chemoradiation with concurrent chemoradiation, a consistent advantage in overall survival was conferred by concurrent chemoradiation therapy. Even with concurrent chemoradiation, however, survival was still modest (16% and 21% to 5 years in the two largest comparisons), and median survival improved only from 14.5 months with sequential therapy to 17.1 months with concurrent therapy in the largest comparison.6
Further support for concurrent chemoradiation on the end point of overall survival comes from two meta-analyses. A Cochrane meta-analysis demonstrated a significant 14% reduction in the risk of death with concurrent chemoradiation compared with sequential treatment.7 The NSCLC Collaborative Group discovered a significant survival advantage with concurrent chemoradiation compared with sequential treatment (hazard ratio: 0.84) with an absolute benefit of 5.7% at 3 years (3-year survival of 18.1% with sequential chemoradiation vs 23.8% with concurrent chemoradiation).8
Applying the results of clinical trials to appropriate patients offers the best chance to improve outcomes. The heterogeneity of the NSCLC population makes application of therapeutic advances challenging. One must consider that the selection criteria used in clinical trials, including performance status, weight loss, disease stage, and volume of disease have a great bearing on the results achieved.
When toxicity between the two multimodality approaches was compared, the risk of grade 3 or 4 acute esophagitis was found to increase from 4% with sequential chemoradiation therapy to 18% with concurrent treatment, but no difference in acute pulmonary toxicity has been observed.8
Some investigators used lower doses of chemotherapy in the concurrent chemoradiation arms to minimize radiation toxicity. However, the dose intensity in sequential treatment should be maintained so that the advantage of controlling micrometastatic disease is not lost.
These clinical trials highlight that timing of chemoradiation precludes a significant proportion of patients from receiving uninterrupted radiation therapy, either because of toxicity from chemotherapy, leading to a reduction in performance status, or disease progression during sequential chemotherapy.
ATTEMPTS TO IMPROVE RADIOTHERAPY
Methods to improve radiotherapy have centered on evolving radiologic imaging and computer technology, with the objective of enhanced precision of radiation delivery. The routine use of PET in planning radiotherapy allows for dose escalation and control of toxicity.
Radiotherapy dose and outcomes
Three-dimensional (3D) conformal radiation techniques permit the use of higher doses of targeted radiation to spare normal tissue. A meta-analysis of six trials of concurrent chemoradiation therapy concluded that an increased dose of radiation improves both local control and survival.9 A better understanding of normal lung tolerability to radiation therapy is needed to optimize radiation dose.
A clinical trial to test the efficacy of high-dose conformal radiation therapy is in progress. Patients with unresectable stage IIIA or IIIB NSCLC are being randomized to concurrent chemoradiation therapy with carboplatin and weekly paclitaxel with either 74 Gy of radiation in 37 fractions over 7.5 weeks, or 60 Gy of radiation in 30 fractions over 6 weeks. Results will be stratified by radiation therapy technique (3D conformal radiation or intensity-modulated radiation therapy). Following an impressive survival rate (median overall survival: 22.7 months) obtained with the addition of cetuximab to the chemoradiation regimen in the phase 2 Radiation Therapy Oncology Group 0324 trial, an amendment to the design further randomized patients in each radiotherapy group to cetuximab or no cetuximab.10 Those randomized to cetuximab will continue on consolidation therapy with carboplatin, paclitaxel, and cetuximab, while the group randomized to no cetuximab will receive consolidation therapy with carboplatin and paclitaxel only.
Another approach in stage III NSCLC is the use of molecular biomarkers to predict response. Tumor typing for specific molecular sensitivities is generally thought to help predict response to systemic chemotherapy, but within the setting of radiotherapy, patients with a mutation of the epidermal growth factor receptor (EGFR) were found to have more radiosensitive tumors and decreased local recurrence rates than those without the EGFR mutation.11,12 Interactions between systemic therapy and radiation may also prove to be important in response to therapy and prognosis.
Figure 1. At median follow-up of 38 months among patients with non–small cell lung cancer, there was no statistically significant difference in median survival between those randomized to immediate concurrent radiotherapy and those who received induction chemotherapy followed by identical chemoradiation (12 months vs 14 months, respectively).Induction chemotherapy followed by chemoradiation was proposed as an alternative to concurrent chemotherapy as a way to potentially improve systemic control in patients with unresectable stage III NSCLC. Induction chemotherapy provided no survival benefit over concurrent chemoradiation alone in a randomized controlled comparison by Vokes et al (Figure 1).13 There was no significant difference in nonhematologic toxicity between the treatment groups, although the incidence of grade 3/4 esophagitis was very high (about 30%) in both arms. The patient selection may have influenced median survival in this trial; approximately 25% of patients enrolled had weight loss in excess of 5%, which has been shown to be a poor prognostic factor.
A three-arm study compared sequential chemotherapy/radiotherapy, induction chemotherapy followed by concurrent chemoradiation, and concurrent chemoradiation followed by consolidation chemotherapy.14 In the sequential and induction arms, paclitaxel and carboplatin were administered for two cycles prior to radiation therapy; in the consolidation arm, the drugs were given following radiation therapy. The median survival was 16.3 months in the consolidation arm, 12.7 months in the induction arm, and 13.0 months in the sequential arm. The induction and consolidation arms were associated with greater toxicity. The incidences of grade 3/4 esophagitis and pulmonary toxicity were highest in the consolidation arm (28% and 16%, respectively). Although the study was not powered for direct comparison of the three treatment arms, the prolonged median survival for concurrent treatment followed by consolidation chemotherapy adds support to the argument that providing the definitive treatment up front followed by systemically active doses of chemotherapy is the preferred therapeutic approach in stage III NSCLC.
The Southwest Oncology Group (SWOG) study 9504 conducted in patients with stage IIIB NSCLC adds to the evidence of a benefit with consolidation chemotherapy after definitive chemoradiation.15 In this trial, consolidation with docetaxel following concurrent cisplatin-etoposide and radiotherapy extended median overall survival to 26 months.
Figure 2. The Hoosier Oncology Group found that no survival advantage was conferred by consolidation docetaxel after cisplatin-etoposide (median survival: 21.1 months), over cisplatin-etoposide and concurrent radiation alone (observation arm, median survival: 23.2 months) in patients with stage III inoperable NSCLC.
In the Hoosier Oncology Group (HOG) LUN 01-24 study, consolidation with docetaxel after cisplatin-etoposide did not have a survival advantage over cisplatin-etoposide and concurrent radiation alone, but it was associated with increased toxicity in patients with stage III inoperable NSCLC (Figure 2).16
The dose intensity and delivery of consolidation docetaxel were similar in the SWOG 9504 and the HOG LUN 01-24 studies. Although no difference in median survival was observed between the consolidation and observation arms in HOG LUN 01-24, the median survival for the observation arm in this trial was much higher than the 15 months demonstrated with the same concurrent regimen (cisplatin-etoposide and chest radiotherapy) in the SWOG 9019 trial.17 A difference in stage distribution across the two trials might explain the differences in survival in the observation arms.
LITTLE PROGRESS WITH BIOLOGIC THERAPIES
The improvements observed when combining chemotherapy with radiation therapy in sequence with systemically active doses of third-generation agents have come at a price of increased toxicity, and most patients will still suffer relapse and ultimately die of metastatic disease. A significant proportion of patients will not be fit enough for more aggressive regimens.
The addition of thalidomide as an immunomodulator agent to chemoradiation did not improve overall or progression-free survival; it was also associated with a higher rate of grade 3+ toxicities in patients with stage IIIA/B NSCLC.18
In CALBG 30407, a regimen of pemetrexed disodium and carboplatin together with radiation therapy with or without cetuximab was studied in patients with stage III unresectable NSCLC.19 Median survival was 22.3 months with pemetrexed-carboplatin; the addition of cetuximab conferred no significant benefit, with maintenance beyond 4 cycles being unfeasible in nearly 50% the patients enrolled.
Integrating the vascular endothelial growth factor inhibitor bevacizumab into combined modality therapy was tested in SWOG 0533. The study consisted of 3 treatment arms in which bevacizumab was introduced at different times in the concurrent chemoradiation setting in patients with stage III NSCLC. Accrual into the trial was terminated because of an unacceptable level of toxicity. Despite the risk stratification, restrictive eligibility criteria, and careful bevacizumab deployment, the approach still proved to be unfeasible.
The small-molecule epidermal tyrosine kinase inhibitors gefitinib and erlotinib had demonstrated efficacy as single agents, but the randomized SWOG 0023 trial of maintenance gefitinib after concurrent chemoradiation and consolidation therapy with docetaxel was terminated early when an interim analysis suggested lack of efficacy of maintenance gefitinib.
CONCLUSIONS
Stage III NSCLC is a heterogeneous disease with considerable variations in prognosis and treatment options. The goals of treatment are local control through the use of radiation therapy and chemotherapy and eradication of distant micrometastases through chemotherapy. For patients with good performance status, concurrent chemoradiation is the standard of care.
Phase 3 trials of full-dose chemotherapy, as either induction or consolidation, have not optimized outcomes. Integration of targeted agents is now under investigation. Any future progress will likely rely on molecular selection, which will require accruing a large number of patients into many clinical trials.
The population of patients with stage III non–small cell lung cancer (NSCLC) presents a management challenge for clinicians. The standard of care for locally advanced NSCLC is chemotherapy plus radiation, but the optimal chemoradiation regimen is a work in progress, building upon decades of clinical trial research. Optimal therapy may require patient participation in a current phase 3 clinical trial.
Understanding the background behind the design of phase 3 clinical trials may permit better understanding of optimal chemoradiation. Most recent research has focused on optimization of chemotherapy with less attention paid to radiation dose and technique, the use of targeted agents, and imaging and planning.
A dilemma in the management of stage III NSCLC is how best to combine the correct treatments in the right sequence to achieve simultaneous local, regional, and distant control, as the disease occurs at multiple levels and cure is not possible without local disease control. Another dilemma concerns administration of radiation therapy when the lung, heart, esophagus, or spinal cord may impede delivery of treatment. Additionally, patients may not present with symptoms until an advanced stage of disease, and their performance status is frequently impaired and often influenced by comorbidities such as smoking.
FACTORS RELATED TO PROGNOSIS AND CHOICE OF TREATMENT
Most potentially curable patients with NSCLC present with locally advanced mediastinal disease. Despite improvements in staging procedures and therapy, however, the prognosis of locally advanced NSCLC remains poor with a survival rate of less than 20% at 5 years.
Prognostic indicators
Poor outcomes can be attributed to the heterogeneity of locally advanced stage III NSCLC and the factors that influence this heterogeneity. Within stage IIIA and stage IIIB, subdivisions vary considerably depending on tumor size, tumor location, and nodal involvement. With routine positron emission tomography (PET) and assessment of intracranial dissemination, a significant number of “stage III” patients are identified with advanced-stage disease and upstaged. Revisions in the staging system that define clinically distinct subsets within stage III attempt to bring more coherence to patient subsets (Table).1
Factors that affect treatment choice
Clinical and patient factors can influence the choice of concurrent chemoradiation therapy. Weight loss, performance status, comorbidity, and pulmonary reserve influence survival and patient outcome. Comorbidities are frequently observed in elderly patients and smokers. More than one-half of patients with stage III NSCLC are currently thought to be ineligible for concurrent regimens if inclusion is restricted to patients younger than 75 years and those with fewer than two serious comorbidities. The exact contribution of comorbidity, age, and other clinical parameters to the reported toxicity is unclear.
Tumor biology
The biology of different types of NSCLC can vary considerably (eg, bronchoalveolar vs squamous cell vs adenocarcinoma). Sometimes cancer grows indolently, even with nodal presentations. Molecular profiling to understand this phenomenon is still in its infancy.
CURRENT APPROACHES TO CHEMORADIATION
Treatment of unresectable stage III NSCLC requires control of local disease and distant metastases. Much work has been undertaken to determine the safety and efficacy of sequential chemoradiation (chemotherapy followed by radiation therapy) and concurrent chemoradiation (chemotherapy during radiation therapy).
Sequential chemoradiation
Dillman et al2,3 ushered in an era of combined modality therapy when in 1990 they demonstrated that a 5-week course of induction chemotherapy followed by radiotherapy in stage III NSCLC resulted in improved median survival compared with radiotherapy alone (13.8 months vs 9.7 months) in a randomized trial.
Sause et al4,5 later showed that in “good risk” patients (Karnofsky Performance Status > 70) with surgically unresectable NSCLC, induction chemotherapy followed by radiation therapy produced superior short-term survival compared with hyperfractionated radiation therapy or standard radiation therapy alone.
Concurrent chemoradiation
The next step in the search for optimal sequencing was the study of concurrent chemotherapy and radiation. In phase 3 studies that compared sequential chemoradiation with concurrent chemoradiation, a consistent advantage in overall survival was conferred by concurrent chemoradiation therapy. Even with concurrent chemoradiation, however, survival was still modest (16% and 21% to 5 years in the two largest comparisons), and median survival improved only from 14.5 months with sequential therapy to 17.1 months with concurrent therapy in the largest comparison.6
Further support for concurrent chemoradiation on the end point of overall survival comes from two meta-analyses. A Cochrane meta-analysis demonstrated a significant 14% reduction in the risk of death with concurrent chemoradiation compared with sequential treatment.7 The NSCLC Collaborative Group discovered a significant survival advantage with concurrent chemoradiation compared with sequential treatment (hazard ratio: 0.84) with an absolute benefit of 5.7% at 3 years (3-year survival of 18.1% with sequential chemoradiation vs 23.8% with concurrent chemoradiation).8
Applying the results of clinical trials to appropriate patients offers the best chance to improve outcomes. The heterogeneity of the NSCLC population makes application of therapeutic advances challenging. One must consider that the selection criteria used in clinical trials, including performance status, weight loss, disease stage, and volume of disease have a great bearing on the results achieved.
When toxicity between the two multimodality approaches was compared, the risk of grade 3 or 4 acute esophagitis was found to increase from 4% with sequential chemoradiation therapy to 18% with concurrent treatment, but no difference in acute pulmonary toxicity has been observed.8
Some investigators used lower doses of chemotherapy in the concurrent chemoradiation arms to minimize radiation toxicity. However, the dose intensity in sequential treatment should be maintained so that the advantage of controlling micrometastatic disease is not lost.
These clinical trials highlight that timing of chemoradiation precludes a significant proportion of patients from receiving uninterrupted radiation therapy, either because of toxicity from chemotherapy, leading to a reduction in performance status, or disease progression during sequential chemotherapy.
ATTEMPTS TO IMPROVE RADIOTHERAPY
Methods to improve radiotherapy have centered on evolving radiologic imaging and computer technology, with the objective of enhanced precision of radiation delivery. The routine use of PET in planning radiotherapy allows for dose escalation and control of toxicity.
Radiotherapy dose and outcomes
Three-dimensional (3D) conformal radiation techniques permit the use of higher doses of targeted radiation to spare normal tissue. A meta-analysis of six trials of concurrent chemoradiation therapy concluded that an increased dose of radiation improves both local control and survival.9 A better understanding of normal lung tolerability to radiation therapy is needed to optimize radiation dose.
A clinical trial to test the efficacy of high-dose conformal radiation therapy is in progress. Patients with unresectable stage IIIA or IIIB NSCLC are being randomized to concurrent chemoradiation therapy with carboplatin and weekly paclitaxel with either 74 Gy of radiation in 37 fractions over 7.5 weeks, or 60 Gy of radiation in 30 fractions over 6 weeks. Results will be stratified by radiation therapy technique (3D conformal radiation or intensity-modulated radiation therapy). Following an impressive survival rate (median overall survival: 22.7 months) obtained with the addition of cetuximab to the chemoradiation regimen in the phase 2 Radiation Therapy Oncology Group 0324 trial, an amendment to the design further randomized patients in each radiotherapy group to cetuximab or no cetuximab.10 Those randomized to cetuximab will continue on consolidation therapy with carboplatin, paclitaxel, and cetuximab, while the group randomized to no cetuximab will receive consolidation therapy with carboplatin and paclitaxel only.
Another approach in stage III NSCLC is the use of molecular biomarkers to predict response. Tumor typing for specific molecular sensitivities is generally thought to help predict response to systemic chemotherapy, but within the setting of radiotherapy, patients with a mutation of the epidermal growth factor receptor (EGFR) were found to have more radiosensitive tumors and decreased local recurrence rates than those without the EGFR mutation.11,12 Interactions between systemic therapy and radiation may also prove to be important in response to therapy and prognosis.
Figure 1. At median follow-up of 38 months among patients with non–small cell lung cancer, there was no statistically significant difference in median survival between those randomized to immediate concurrent radiotherapy and those who received induction chemotherapy followed by identical chemoradiation (12 months vs 14 months, respectively).Induction chemotherapy followed by chemoradiation was proposed as an alternative to concurrent chemotherapy as a way to potentially improve systemic control in patients with unresectable stage III NSCLC. Induction chemotherapy provided no survival benefit over concurrent chemoradiation alone in a randomized controlled comparison by Vokes et al (Figure 1).13 There was no significant difference in nonhematologic toxicity between the treatment groups, although the incidence of grade 3/4 esophagitis was very high (about 30%) in both arms. The patient selection may have influenced median survival in this trial; approximately 25% of patients enrolled had weight loss in excess of 5%, which has been shown to be a poor prognostic factor.
A three-arm study compared sequential chemotherapy/radiotherapy, induction chemotherapy followed by concurrent chemoradiation, and concurrent chemoradiation followed by consolidation chemotherapy.14 In the sequential and induction arms, paclitaxel and carboplatin were administered for two cycles prior to radiation therapy; in the consolidation arm, the drugs were given following radiation therapy. The median survival was 16.3 months in the consolidation arm, 12.7 months in the induction arm, and 13.0 months in the sequential arm. The induction and consolidation arms were associated with greater toxicity. The incidences of grade 3/4 esophagitis and pulmonary toxicity were highest in the consolidation arm (28% and 16%, respectively). Although the study was not powered for direct comparison of the three treatment arms, the prolonged median survival for concurrent treatment followed by consolidation chemotherapy adds support to the argument that providing the definitive treatment up front followed by systemically active doses of chemotherapy is the preferred therapeutic approach in stage III NSCLC.
The Southwest Oncology Group (SWOG) study 9504 conducted in patients with stage IIIB NSCLC adds to the evidence of a benefit with consolidation chemotherapy after definitive chemoradiation.15 In this trial, consolidation with docetaxel following concurrent cisplatin-etoposide and radiotherapy extended median overall survival to 26 months.
Figure 2. The Hoosier Oncology Group found that no survival advantage was conferred by consolidation docetaxel after cisplatin-etoposide (median survival: 21.1 months), over cisplatin-etoposide and concurrent radiation alone (observation arm, median survival: 23.2 months) in patients with stage III inoperable NSCLC.
In the Hoosier Oncology Group (HOG) LUN 01-24 study, consolidation with docetaxel after cisplatin-etoposide did not have a survival advantage over cisplatin-etoposide and concurrent radiation alone, but it was associated with increased toxicity in patients with stage III inoperable NSCLC (Figure 2).16
The dose intensity and delivery of consolidation docetaxel were similar in the SWOG 9504 and the HOG LUN 01-24 studies. Although no difference in median survival was observed between the consolidation and observation arms in HOG LUN 01-24, the median survival for the observation arm in this trial was much higher than the 15 months demonstrated with the same concurrent regimen (cisplatin-etoposide and chest radiotherapy) in the SWOG 9019 trial.17 A difference in stage distribution across the two trials might explain the differences in survival in the observation arms.
LITTLE PROGRESS WITH BIOLOGIC THERAPIES
The improvements observed when combining chemotherapy with radiation therapy in sequence with systemically active doses of third-generation agents have come at a price of increased toxicity, and most patients will still suffer relapse and ultimately die of metastatic disease. A significant proportion of patients will not be fit enough for more aggressive regimens.
The addition of thalidomide as an immunomodulator agent to chemoradiation did not improve overall or progression-free survival; it was also associated with a higher rate of grade 3+ toxicities in patients with stage IIIA/B NSCLC.18
In CALBG 30407, a regimen of pemetrexed disodium and carboplatin together with radiation therapy with or without cetuximab was studied in patients with stage III unresectable NSCLC.19 Median survival was 22.3 months with pemetrexed-carboplatin; the addition of cetuximab conferred no significant benefit, with maintenance beyond 4 cycles being unfeasible in nearly 50% the patients enrolled.
Integrating the vascular endothelial growth factor inhibitor bevacizumab into combined modality therapy was tested in SWOG 0533. The study consisted of 3 treatment arms in which bevacizumab was introduced at different times in the concurrent chemoradiation setting in patients with stage III NSCLC. Accrual into the trial was terminated because of an unacceptable level of toxicity. Despite the risk stratification, restrictive eligibility criteria, and careful bevacizumab deployment, the approach still proved to be unfeasible.
The small-molecule epidermal tyrosine kinase inhibitors gefitinib and erlotinib had demonstrated efficacy as single agents, but the randomized SWOG 0023 trial of maintenance gefitinib after concurrent chemoradiation and consolidation therapy with docetaxel was terminated early when an interim analysis suggested lack of efficacy of maintenance gefitinib.
CONCLUSIONS
Stage III NSCLC is a heterogeneous disease with considerable variations in prognosis and treatment options. The goals of treatment are local control through the use of radiation therapy and chemotherapy and eradication of distant micrometastases through chemotherapy. For patients with good performance status, concurrent chemoradiation is the standard of care.
Phase 3 trials of full-dose chemotherapy, as either induction or consolidation, have not optimized outcomes. Integration of targeted agents is now under investigation. Any future progress will likely rely on molecular selection, which will require accruing a large number of patients into many clinical trials.
References
Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A, eds. AJCC Cancer Staging Handbook. 7th ed. New York, NY: Springer; 2010:297–330.
Dillman RO, Seagren SL, Propert KJ, et al. A randomized trial of induction chemotherapy plus high-dose radiation versus radiation alone in stage III non-small-cell lung cancer. N Engl J Med1990; 323:940–945.
Dillman RO, Herndon J, Seagren SL, Eaton WL, Green MR. Improved survival in stage III non-small-cell lung cancer: seven-year follow-up of Cancer and Leukemia Group B (CALGB) 8433 trial. J Natl Cancer Inst1996; 88:1210–1215.
Sause WT, Scott C, Taylor S, et al. Radiation Therapy Oncology Group (RTOG) 88-08 and Eastern Cooperative Oncology Group (ECOG) 4588: preliminary results of a phase III trial in regionally advanced, unresectable non-small-cell lung cancer. J Natl Cancer Inst1995; 87:198–205.
Sause W, Kolesar P, Taylor S, et al. Final results of phase III trial in regionally advanced, unresectable non-small-cell lung cancer*: Radiation Therapy Oncology Group, Eastern Cooperative Oncology Group, and Southwest Oncology Group. Chest2000; 117:358–364.
Bayman NA, Blackhall F, Jain P, et al. Management of unresectable stage III non-small-cell lung cancer with combined-modality therapy: a review of the current literature and recommendations for treatment. Clin Lung Cancer2008; 9:92–101.
Rowell NP, O’Rourke NP. Concurrent chemoradiotherapy in non-small cell lung cancer. Cochrane Database Syst Rev2004; 18:CD002140.
Aupérin A, Le Pechoux C, Rolland E, et al. Meta-analysis of concomitant versus sequential radiochemotheapy in locally advanced non-small-cell lung cancer. J Clin Oncol2010; 28:2181–2190.
Machtay M, Swann S, Komaki R, et al. Higher BED is associated with improved local-regional control and survival for NSCLC treated with chemoradiotherapy [ASTRO abstract]. Int J Radiat Oncol Biol Phys2005; 63( suppl 1):S40.
Blumenschein GR, Paulus R, Curran WJ, et al. A phase II study of cetuximab (C225) in combination with chemoradiation (CRT) in patients (PTS) with stage IIIA/B non-small cell lung cancer (NSCLC): a report of the 2 year and median survival (MS) for the RTOG 0324 trial. J Clin Oncol2008; 26( suppl). Abstract 7516.
Riesterer O, Milas L, Ang KK. Use of molecular biomarkers for predicting the response to radiotherapy with or without chemotherapy. J Clin Oncol2007; 26:4075–4083.
Mak RH, Doran E, Muzikansky A, et al. Thoracic radiation therapy in locally advanced NSCLC patients (pts) with EGFR mutations. J Clin Oncol2010; 28( suppl). Abstract 7016.
Vokes EE, Herndon JE, Kelley MJ, et al. Induction chemotherapy followed by chemoradiotherapy compared with chemoradiotherapy alone for regionally advanced unresectable stage III non-small-cell lung cancer: Cancer and Leukemia Group B. J Clin Oncol2007; 25:1698–1704.
Belani CP, Choy H, Bonomi P, et al. Combined chemoradiotherapy regimens of paclitaxel and carboplatin for locally advanced non-small-cell lung cancer: a randomized phase II locally advanced multi-modality protocol. J Clin Oncol2005; 23:5883–5891.
Gandara DR, Chansky K, Gaspar LE, Albain KS, Lara PN, Crowley J. Long term survival in stage IIIb non-small cell lung cancer (NSCLC) treated with consolidation docetaxel following concurrent chemoradiotherapy (SWOG S9504). J Clin Oncol2005; 23( suppl). Abstract 7059.
Hanna N, Neubauer M, Yiannoutsos C, et al. Phase III study of cisplatin, etoposide, and concurrent chest radiation with or without consolidation docetaxel in patients with inoperable stage III non-small-cell lung cancer: the Hoosier Oncology Group and U.S. Oncology. J Clin Oncol2008; 35:5755–5760.
Albain KS, Crowley JJ, Turrisi AT, et al. Concurrent cisplatin, etoposide, and chest radiotherapy in pathologic stage IIIB non-small-cell lung cancer: a Southwest Oncology Group phase II study, SWOG 9019. J Clin Oncol2002; 20:3454–3460.
Schiller JH, Dahlberg SE, Mehta M, et al. A phase III trial of carboplatin, paclitaxel, and thoracic radiation therapy with or without thalidomide in patients with stage III non-small cell carcinoma of the lung (NSCLC): E3598. J Clin Oncol2009; 27 (suppl). Abstract 7503.
Govindan R, Bogart J, Wang X, et al. Phase II study of pemetrexed, carboplatin, and thoracic radiation with or without cetuximab in patients with locally advanced unresectable non-small cell lung cancer: CALGB 30407. J Clin Oncol2009; 27 (suppl). Abstract 7505.
References
Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A, eds. AJCC Cancer Staging Handbook. 7th ed. New York, NY: Springer; 2010:297–330.
Dillman RO, Seagren SL, Propert KJ, et al. A randomized trial of induction chemotherapy plus high-dose radiation versus radiation alone in stage III non-small-cell lung cancer. N Engl J Med1990; 323:940–945.
Dillman RO, Herndon J, Seagren SL, Eaton WL, Green MR. Improved survival in stage III non-small-cell lung cancer: seven-year follow-up of Cancer and Leukemia Group B (CALGB) 8433 trial. J Natl Cancer Inst1996; 88:1210–1215.
Sause WT, Scott C, Taylor S, et al. Radiation Therapy Oncology Group (RTOG) 88-08 and Eastern Cooperative Oncology Group (ECOG) 4588: preliminary results of a phase III trial in regionally advanced, unresectable non-small-cell lung cancer. J Natl Cancer Inst1995; 87:198–205.
Sause W, Kolesar P, Taylor S, et al. Final results of phase III trial in regionally advanced, unresectable non-small-cell lung cancer*: Radiation Therapy Oncology Group, Eastern Cooperative Oncology Group, and Southwest Oncology Group. Chest2000; 117:358–364.
Bayman NA, Blackhall F, Jain P, et al. Management of unresectable stage III non-small-cell lung cancer with combined-modality therapy: a review of the current literature and recommendations for treatment. Clin Lung Cancer2008; 9:92–101.
Rowell NP, O’Rourke NP. Concurrent chemoradiotherapy in non-small cell lung cancer. Cochrane Database Syst Rev2004; 18:CD002140.
Aupérin A, Le Pechoux C, Rolland E, et al. Meta-analysis of concomitant versus sequential radiochemotheapy in locally advanced non-small-cell lung cancer. J Clin Oncol2010; 28:2181–2190.
Machtay M, Swann S, Komaki R, et al. Higher BED is associated with improved local-regional control and survival for NSCLC treated with chemoradiotherapy [ASTRO abstract]. Int J Radiat Oncol Biol Phys2005; 63( suppl 1):S40.
Blumenschein GR, Paulus R, Curran WJ, et al. A phase II study of cetuximab (C225) in combination with chemoradiation (CRT) in patients (PTS) with stage IIIA/B non-small cell lung cancer (NSCLC): a report of the 2 year and median survival (MS) for the RTOG 0324 trial. J Clin Oncol2008; 26( suppl). Abstract 7516.
Riesterer O, Milas L, Ang KK. Use of molecular biomarkers for predicting the response to radiotherapy with or without chemotherapy. J Clin Oncol2007; 26:4075–4083.
Mak RH, Doran E, Muzikansky A, et al. Thoracic radiation therapy in locally advanced NSCLC patients (pts) with EGFR mutations. J Clin Oncol2010; 28( suppl). Abstract 7016.
Vokes EE, Herndon JE, Kelley MJ, et al. Induction chemotherapy followed by chemoradiotherapy compared with chemoradiotherapy alone for regionally advanced unresectable stage III non-small-cell lung cancer: Cancer and Leukemia Group B. J Clin Oncol2007; 25:1698–1704.
Belani CP, Choy H, Bonomi P, et al. Combined chemoradiotherapy regimens of paclitaxel and carboplatin for locally advanced non-small-cell lung cancer: a randomized phase II locally advanced multi-modality protocol. J Clin Oncol2005; 23:5883–5891.
Gandara DR, Chansky K, Gaspar LE, Albain KS, Lara PN, Crowley J. Long term survival in stage IIIb non-small cell lung cancer (NSCLC) treated with consolidation docetaxel following concurrent chemoradiotherapy (SWOG S9504). J Clin Oncol2005; 23( suppl). Abstract 7059.
Hanna N, Neubauer M, Yiannoutsos C, et al. Phase III study of cisplatin, etoposide, and concurrent chest radiation with or without consolidation docetaxel in patients with inoperable stage III non-small-cell lung cancer: the Hoosier Oncology Group and U.S. Oncology. J Clin Oncol2008; 35:5755–5760.
Albain KS, Crowley JJ, Turrisi AT, et al. Concurrent cisplatin, etoposide, and chest radiotherapy in pathologic stage IIIB non-small-cell lung cancer: a Southwest Oncology Group phase II study, SWOG 9019. J Clin Oncol2002; 20:3454–3460.
Schiller JH, Dahlberg SE, Mehta M, et al. A phase III trial of carboplatin, paclitaxel, and thoracic radiation therapy with or without thalidomide in patients with stage III non-small cell carcinoma of the lung (NSCLC): E3598. J Clin Oncol2009; 27 (suppl). Abstract 7503.
Govindan R, Bogart J, Wang X, et al. Phase II study of pemetrexed, carboplatin, and thoracic radiation with or without cetuximab in patients with locally advanced unresectable non-small cell lung cancer: CALGB 30407. J Clin Oncol2009; 27 (suppl). Abstract 7505.
Although not every patient with locally advanced non–small cell lung cancer (NSCLC) is a surgical candidate, surgery is worth considering for a subpopulation of patients who can benefit. For patients with stage III disease, choosing the optimal treatment is difficult and best done by a team skilled in managing this type of cancer.
Accurate clinical staging is extremely important to optimize treatment and outcome. The most common staging system used is the tumor, node, metastasis (TNM) system, which was revised in 2009. Surgery as a potential option for patients with lung cancer is becoming more accepted for patients with N2 disease but is still controversial for N3 disease. For the most part, surgical candidates are those with N2 or T4N1 disease. This article therefore focuses on staging and the utility of surgery in patients with N2 disease.
NONINVASIVE STAGING
Computed tomography (CT) of the chest and upper abdomen with intravenous contrast, including the liver and adrenal glands, is standard procedure for noninvasive staging of NSCLC. Contrast CT or magnetic resonance imaging of the brain is necessary to rule out brain metastasis in the patient with NSCLC for whom surgery is being considered.
Figure 1. Fused 18F-fluorodeoxyglucose-positron emission tomography is used for staging patients with non–small cell lung cancer. This image shows an N2-node.Fused 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) is being used increasingly for staging patients with NSCLC. Preoperative staging by FDG-PET improves the detection of occult metastatic disease and alters staging (Figure 1). Pieterman et al1 demonstrated that the use of PET for clinical staging resulted in downstaging of 20 patients and upstaging of 42 patients compared with standard approaches (CT, ultrasonography, bone scanning, and needle biopsies) in a series of 102 patients with potentially resectable NSCLC. For mediastinal lymph node staging, the sensitivity and specificity of FDG-PET were 91% and 86%, respectively, compared with 75% and 66%, respectively, with CT.
At Cleveland Clinic, we have found that PET stage and pathologic stage correlate less than 70% of the time, which reflects the high incidence of histoplasmosis and other endemic inflammatory diseases of the mediastinum.
MEDIASTINAL SAMPLING
The staging evaluation includes an assessment of the mediastinal lymph nodes. Nodal sampling of the mediastinum is advised for every patient with potentially resectable NSCLC, even in the absence of an enlarged mediastinal lymph node on CT, because mediastinal lymph node involvement is a negative prognostic indicator; absence of tumor involvement of the mediastinal lymph nodes confers a more favorable prognosis.
Cervical mediastinoscopy was first introduced for lung cancer staging in 1959 and is considered the gold standard in mediastinal staging. The sensitivity and specificity approach 100% in experienced hands. A single-center experience of 2,137 cervical mediastinoscopies revealed a complication rate of 0.6% and death from mediastinoscopy in 0.05%.2 Node stations obtainable with cervical mediastinoscopy are 2R, 4R, 3, 2L, and 4L, and sometimes 10R. These are central mediastinal nodal stations.
De Leyn et al3 demonstrated that even small tumors can have lymph node involvement. Cervical mediastinoscopy was positive in their series in 9.5% of stage T1 tumors, 17.7% of T2, 31.2% of T3, and 33.3% of T4.
ENDOBRONCHIAL ULTRASOUND (EBUS) AND EBUS STAGING
Endobronchial ultrasound involves the use of a bronchoscope with an ultrasound probe mounted on it to evaluate nodal stations for suspicious lesions that require biopsy. Needle aspiration biopsy is performed by advancing a needle housed in a sheath of the endoscope, using ultrasound to identify target nodal tissue and obtain sample tissue for evaluation.
BRAIN IMAGING
Although brain metastases are uncommon, occurring in only 1% to 5% of asymptomatic patients with NSCLC, their identification is paramount when the treatment for stage III NSCLC is potentially high-morbidity surgery.
PHYSIOLOGIC EVALUATION
When the treatment plan potentially includes surgery, a multidisciplinary evaluation is essential and should involve specialists in medical oncology, radiation oncology, pulmonary medicine, thoracic surgery, and pathology.
Because surgery for stage III NSCLC is aggressive, prior physiologic evaluation is necessary to assess operative risk. Pulmonary function evaluation should include spirometry, measurement of arterial blood gas values, diffusion capacity (transfer factor of the lung for carbon monoxide), 6-minute walk test, and cardiopulmonary exercise testing.
Stress testing, whether by nuclear imaging or dobutamine echocardiogram, is also indicated, especially if considering pneumonectomy. A quantitative ventilation-perfusion scan is indicated for a more definitive evaluation of pulmonary function.
RESULTS OBTAINED WITH MULTIMODALITY THERAPY
Southwest Oncology Group 8805
The Southwest Oncology Group (SWOG) study 8805 used a trimodality approach in patients with bulky stage III NSCLC: induction chemoradiation with concurrent cisplatin, etoposide, and radiotherapy (45 Gy) followed by surgical resection.4 The 3-year survival rate with this treatment strategy was 26%. Patients in this trial who were downstaged following induction therapy so that they had node-negative disease at the time of surgery had a superior prognosis, with a 3-year survival rate of 41%. Therefore, a subset of patients with stage III NSCLC stands to benefit from surgery, but identifying this group prior to surgery may not be possible.
Trial of accelerated multimodality therapy
An accelerated multimodality induction regimen given over 12 days was tested in 105 patients with stage IIIa (n = 78) and stage IIIb (n = 27) NSCLC, 97% of whom had mediastinal involvement.5 Seven patients had T4 disease. The induction regimen consisted of a 12-day course of concurrent cisplatin, paclitaxel, and radiotherapy. A 4-day continuous infusion of cisplatin (20 mg/m2/day) and a 24-hour continuous infusion of paclitaxel (175 mg/m2) were administered on day 1. Concurrent accelerated fractionated radiotherapy consisted of twice-daily fractions of 1.5 Gy.
All patients completed induction therapy. Of the 105 patients, 98 were candidates for surgical treatment and 83 underwent curative resections (lobectomy, n = 42; pneumonectomy, n = 36; and bilobectomy, n = 5).
Surgical mortality was 7% and morbidity was 31% (supraventricular arrhythmia, 18%; recurrent laryngeal nerve palsy, 6%; pneumonia or adult respiratory distress syndrome, 3%; bronchopleural fistula, 3%; wound infection, 2%; reoperation for bleeding, 1%).
Figure 2. Pathologic stage is the most powerful predictive factor in patients with resectable non–small cell lung cancer. Survival among patients with pathologic stages 0 to II is superior to those with residual N2 (stage IIIA) disease. Nonresponders (stage IIIB) have the poorest survival.Survival after resection was 70% at 1 year, 42% at 3 years, and 26% at 5 years. As with SWOG 8805, nodal downstaging was associated with improved survival. Patients with disease that was downstaged to pathologic stage 0 to II had a 5-year survival that approached 50%, whereas patients with persistent stage IIIb disease had a 2-year survival of just 18% (Figure 2). Patients with postresection N0 to N1 status had a 5-year survival of 55%, which declined to approximately 31% with N2 status. Few patients with N3 status survived to 3 years.
Profiles of patients with favorable and unfavorable prognoses were developed. A younger patient with adenocarcinoma whose disease was downstaged with induction therapy had a favorable prognosis, whereas an older patient with squamous carcinoma that did not respond to treatment and continued in pathologic stage IIIb had an unfavorable prognosis.
SURVIVAL DATA FAVOR SURGERY
An accurate head-to-head comparison of chemoradiation with or without surgery in patients with resectable NSCLC is difficult because patients selected for surgery must meet performance status criteria, whereas an evaluation of performance status is not mandated for patients treated with definitive chemoradiation alone. The quality of postoperative care and the management of postoperative complications also differ from institution to institution.
A controlled trial in which patients with stage IIIa NSCLC were randomized to chemoradiation with or without surgical resection was performed by Albain et al.6 The induction regimen consisted of 2 cycles of cisplatin and etoposide plus radiotherapy (45 Gy). At 5 years, overall survival was 27% in patients who underwent resection and 20% in those who continued radiotherapy without resection, a difference that did not achieve statistical significance. Progression-free survival was superior in the group assigned to surgery compared with those not undergoing resection (median: 12.8 months vs 10.5 months).
A Surveillance Epidemiology and End Results registry of more than 48,000 patients with stage III NSCLC revealed significantly better overall survival in those who received neoadjuvant radiotherapy plus surgery compared with radiation therapy alone, postoperative radiation therapy, and surgery alone.7
CLEVELAND CLINIC EXPERIENCE WITH ACCELERATED PROTOCOL
At Cleveland Clinic, the current protocol for stage IIIa and IIIb NSCLC is an accelerated multimodality regimen consisting of paclitaxel, 50 mg/m2 twice weekly for 3 weeks; carboplatin (target area under the concentration vs time curve dosing) twice weekly for 3 weeks; and daily erlotinib (phase 1 dose escalation protocol) with concurrent radiotherapy, 1.5 Gy twice daily, as induction therapy, followed by a preoperative evaluation and surgery if local control is achieved with induction treatment.
This protocol has been used in 30 patients with stage IIIa disease (median age: 61 years) with no operative mortality (62% lobectomy, 38% pneumonectomy) and a median length of stay of 6.2 days. Forty percent of patients had their disease downstaged following induction therapy. Three-year survival is approximately 60% and, at 5 years, survival is still 55%.
CONCLUSION
Multimodality therapy for NSCLC is effective and achieves favorable survival. Pathologic downstaging is an important predictor for survival but patients with residual N2 disease still have meaningful survival with resection.
A team approach to evaluation and treatment among medical oncology, radiation oncology, pulmonary medicine, and thoracic surgery is critical to successful outcome.
References
Pieterman RM, van Putten JWG, Meuzelaar JL, et al. Preoperative staging of non-small-cell lung cancer with positron-emission tomography. N Engl J Med2000; 343:254–261.
Hammoud Z, Anderson RC, Meyers BF, et al. The current role of mediastinoscopy in the evaluation of thoracic disease. J Thorac Cardiovasc Surg1999; 118:894–899.
De Leyn P, Vansteenkiste J, Cuypers P, et al. Role of cervical mediastinoscopy in staging of non-small cell lung cancer without enlarged mediastinal lymph nodes on CT scan. Eur J Cardiothor Surg1997; 12:706–712.
Albain KS, Rusch VW, Crowley JJ, et al. Concurrent cisplatin/etoposide plus chest radiotherapy followed by surgery for stages IIIA (N2) and IIIB non-small-cell lung cancer: mature results of Southwest Oncology Group phase II study 8805. J Clin Oncol1995; 13:1880–1892.
De Camp MM, Rice TW, Adelstein DJ, et al. Value of accelerated multimodality therapy in stage IIIA and IIIB non–small cell lung cancer. J Thor Cardiovasc Surg2003; 126:17–27.
Albain KS, Swann RS, Rusch VW, et al. Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled trial. Lancet2009; 374:379–386.
Koshy M, Goloubeva O, Suntharalingam M. Impact of neoadjuvant radiation on survival in stage III non-small-cell lung cancer. Int J Radiat Oncol Biol Phys2011; 79:1388–1394.
David P. Mason, MD Department of Thoracic and Cardiovascular Surgery, Transplantation Center, Cleveland Clinic, Cleveland, OH
Correspondence: David P. Mason, MD, Department of Thoracic and Cardiovascular Surgery, Cleveland Clinic, 9500 Euclid Avenue, J4-1, Cleveland, OH 44195; masond2@ccf.org
Dr. Mason reported that he has no financial relationships that pose a potential conflict of interest with this article.
This article was developed from an audio transcript of Dr. Mason’s presentation at the “Advances in Lung Cancer Evaluation and Management” symposium held in Cleveland, Ohio, on April 30, 2011. The transcript was formatted and edited by Cleveland Clinic Journal of Medicine staff for clarity and conciseness and was then reviewed, revised, and approved by Dr. Mason.
David P. Mason, MD Department of Thoracic and Cardiovascular Surgery, Transplantation Center, Cleveland Clinic, Cleveland, OH
Correspondence: David P. Mason, MD, Department of Thoracic and Cardiovascular Surgery, Cleveland Clinic, 9500 Euclid Avenue, J4-1, Cleveland, OH 44195; masond2@ccf.org
Dr. Mason reported that he has no financial relationships that pose a potential conflict of interest with this article.
This article was developed from an audio transcript of Dr. Mason’s presentation at the “Advances in Lung Cancer Evaluation and Management” symposium held in Cleveland, Ohio, on April 30, 2011. The transcript was formatted and edited by Cleveland Clinic Journal of Medicine staff for clarity and conciseness and was then reviewed, revised, and approved by Dr. Mason.
Author and Disclosure Information
David P. Mason, MD Department of Thoracic and Cardiovascular Surgery, Transplantation Center, Cleveland Clinic, Cleveland, OH
Correspondence: David P. Mason, MD, Department of Thoracic and Cardiovascular Surgery, Cleveland Clinic, 9500 Euclid Avenue, J4-1, Cleveland, OH 44195; masond2@ccf.org
Dr. Mason reported that he has no financial relationships that pose a potential conflict of interest with this article.
This article was developed from an audio transcript of Dr. Mason’s presentation at the “Advances in Lung Cancer Evaluation and Management” symposium held in Cleveland, Ohio, on April 30, 2011. The transcript was formatted and edited by Cleveland Clinic Journal of Medicine staff for clarity and conciseness and was then reviewed, revised, and approved by Dr. Mason.
Although not every patient with locally advanced non–small cell lung cancer (NSCLC) is a surgical candidate, surgery is worth considering for a subpopulation of patients who can benefit. For patients with stage III disease, choosing the optimal treatment is difficult and best done by a team skilled in managing this type of cancer.
Accurate clinical staging is extremely important to optimize treatment and outcome. The most common staging system used is the tumor, node, metastasis (TNM) system, which was revised in 2009. Surgery as a potential option for patients with lung cancer is becoming more accepted for patients with N2 disease but is still controversial for N3 disease. For the most part, surgical candidates are those with N2 or T4N1 disease. This article therefore focuses on staging and the utility of surgery in patients with N2 disease.
NONINVASIVE STAGING
Computed tomography (CT) of the chest and upper abdomen with intravenous contrast, including the liver and adrenal glands, is standard procedure for noninvasive staging of NSCLC. Contrast CT or magnetic resonance imaging of the brain is necessary to rule out brain metastasis in the patient with NSCLC for whom surgery is being considered.
Figure 1. Fused 18F-fluorodeoxyglucose-positron emission tomography is used for staging patients with non–small cell lung cancer. This image shows an N2-node.Fused 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) is being used increasingly for staging patients with NSCLC. Preoperative staging by FDG-PET improves the detection of occult metastatic disease and alters staging (Figure 1). Pieterman et al1 demonstrated that the use of PET for clinical staging resulted in downstaging of 20 patients and upstaging of 42 patients compared with standard approaches (CT, ultrasonography, bone scanning, and needle biopsies) in a series of 102 patients with potentially resectable NSCLC. For mediastinal lymph node staging, the sensitivity and specificity of FDG-PET were 91% and 86%, respectively, compared with 75% and 66%, respectively, with CT.
At Cleveland Clinic, we have found that PET stage and pathologic stage correlate less than 70% of the time, which reflects the high incidence of histoplasmosis and other endemic inflammatory diseases of the mediastinum.
MEDIASTINAL SAMPLING
The staging evaluation includes an assessment of the mediastinal lymph nodes. Nodal sampling of the mediastinum is advised for every patient with potentially resectable NSCLC, even in the absence of an enlarged mediastinal lymph node on CT, because mediastinal lymph node involvement is a negative prognostic indicator; absence of tumor involvement of the mediastinal lymph nodes confers a more favorable prognosis.
Cervical mediastinoscopy was first introduced for lung cancer staging in 1959 and is considered the gold standard in mediastinal staging. The sensitivity and specificity approach 100% in experienced hands. A single-center experience of 2,137 cervical mediastinoscopies revealed a complication rate of 0.6% and death from mediastinoscopy in 0.05%.2 Node stations obtainable with cervical mediastinoscopy are 2R, 4R, 3, 2L, and 4L, and sometimes 10R. These are central mediastinal nodal stations.
De Leyn et al3 demonstrated that even small tumors can have lymph node involvement. Cervical mediastinoscopy was positive in their series in 9.5% of stage T1 tumors, 17.7% of T2, 31.2% of T3, and 33.3% of T4.
ENDOBRONCHIAL ULTRASOUND (EBUS) AND EBUS STAGING
Endobronchial ultrasound involves the use of a bronchoscope with an ultrasound probe mounted on it to evaluate nodal stations for suspicious lesions that require biopsy. Needle aspiration biopsy is performed by advancing a needle housed in a sheath of the endoscope, using ultrasound to identify target nodal tissue and obtain sample tissue for evaluation.
BRAIN IMAGING
Although brain metastases are uncommon, occurring in only 1% to 5% of asymptomatic patients with NSCLC, their identification is paramount when the treatment for stage III NSCLC is potentially high-morbidity surgery.
PHYSIOLOGIC EVALUATION
When the treatment plan potentially includes surgery, a multidisciplinary evaluation is essential and should involve specialists in medical oncology, radiation oncology, pulmonary medicine, thoracic surgery, and pathology.
Because surgery for stage III NSCLC is aggressive, prior physiologic evaluation is necessary to assess operative risk. Pulmonary function evaluation should include spirometry, measurement of arterial blood gas values, diffusion capacity (transfer factor of the lung for carbon monoxide), 6-minute walk test, and cardiopulmonary exercise testing.
Stress testing, whether by nuclear imaging or dobutamine echocardiogram, is also indicated, especially if considering pneumonectomy. A quantitative ventilation-perfusion scan is indicated for a more definitive evaluation of pulmonary function.
RESULTS OBTAINED WITH MULTIMODALITY THERAPY
Southwest Oncology Group 8805
The Southwest Oncology Group (SWOG) study 8805 used a trimodality approach in patients with bulky stage III NSCLC: induction chemoradiation with concurrent cisplatin, etoposide, and radiotherapy (45 Gy) followed by surgical resection.4 The 3-year survival rate with this treatment strategy was 26%. Patients in this trial who were downstaged following induction therapy so that they had node-negative disease at the time of surgery had a superior prognosis, with a 3-year survival rate of 41%. Therefore, a subset of patients with stage III NSCLC stands to benefit from surgery, but identifying this group prior to surgery may not be possible.
Trial of accelerated multimodality therapy
An accelerated multimodality induction regimen given over 12 days was tested in 105 patients with stage IIIa (n = 78) and stage IIIb (n = 27) NSCLC, 97% of whom had mediastinal involvement.5 Seven patients had T4 disease. The induction regimen consisted of a 12-day course of concurrent cisplatin, paclitaxel, and radiotherapy. A 4-day continuous infusion of cisplatin (20 mg/m2/day) and a 24-hour continuous infusion of paclitaxel (175 mg/m2) were administered on day 1. Concurrent accelerated fractionated radiotherapy consisted of twice-daily fractions of 1.5 Gy.
All patients completed induction therapy. Of the 105 patients, 98 were candidates for surgical treatment and 83 underwent curative resections (lobectomy, n = 42; pneumonectomy, n = 36; and bilobectomy, n = 5).
Surgical mortality was 7% and morbidity was 31% (supraventricular arrhythmia, 18%; recurrent laryngeal nerve palsy, 6%; pneumonia or adult respiratory distress syndrome, 3%; bronchopleural fistula, 3%; wound infection, 2%; reoperation for bleeding, 1%).
Figure 2. Pathologic stage is the most powerful predictive factor in patients with resectable non–small cell lung cancer. Survival among patients with pathologic stages 0 to II is superior to those with residual N2 (stage IIIA) disease. Nonresponders (stage IIIB) have the poorest survival.Survival after resection was 70% at 1 year, 42% at 3 years, and 26% at 5 years. As with SWOG 8805, nodal downstaging was associated with improved survival. Patients with disease that was downstaged to pathologic stage 0 to II had a 5-year survival that approached 50%, whereas patients with persistent stage IIIb disease had a 2-year survival of just 18% (Figure 2). Patients with postresection N0 to N1 status had a 5-year survival of 55%, which declined to approximately 31% with N2 status. Few patients with N3 status survived to 3 years.
Profiles of patients with favorable and unfavorable prognoses were developed. A younger patient with adenocarcinoma whose disease was downstaged with induction therapy had a favorable prognosis, whereas an older patient with squamous carcinoma that did not respond to treatment and continued in pathologic stage IIIb had an unfavorable prognosis.
SURVIVAL DATA FAVOR SURGERY
An accurate head-to-head comparison of chemoradiation with or without surgery in patients with resectable NSCLC is difficult because patients selected for surgery must meet performance status criteria, whereas an evaluation of performance status is not mandated for patients treated with definitive chemoradiation alone. The quality of postoperative care and the management of postoperative complications also differ from institution to institution.
A controlled trial in which patients with stage IIIa NSCLC were randomized to chemoradiation with or without surgical resection was performed by Albain et al.6 The induction regimen consisted of 2 cycles of cisplatin and etoposide plus radiotherapy (45 Gy). At 5 years, overall survival was 27% in patients who underwent resection and 20% in those who continued radiotherapy without resection, a difference that did not achieve statistical significance. Progression-free survival was superior in the group assigned to surgery compared with those not undergoing resection (median: 12.8 months vs 10.5 months).
A Surveillance Epidemiology and End Results registry of more than 48,000 patients with stage III NSCLC revealed significantly better overall survival in those who received neoadjuvant radiotherapy plus surgery compared with radiation therapy alone, postoperative radiation therapy, and surgery alone.7
CLEVELAND CLINIC EXPERIENCE WITH ACCELERATED PROTOCOL
At Cleveland Clinic, the current protocol for stage IIIa and IIIb NSCLC is an accelerated multimodality regimen consisting of paclitaxel, 50 mg/m2 twice weekly for 3 weeks; carboplatin (target area under the concentration vs time curve dosing) twice weekly for 3 weeks; and daily erlotinib (phase 1 dose escalation protocol) with concurrent radiotherapy, 1.5 Gy twice daily, as induction therapy, followed by a preoperative evaluation and surgery if local control is achieved with induction treatment.
This protocol has been used in 30 patients with stage IIIa disease (median age: 61 years) with no operative mortality (62% lobectomy, 38% pneumonectomy) and a median length of stay of 6.2 days. Forty percent of patients had their disease downstaged following induction therapy. Three-year survival is approximately 60% and, at 5 years, survival is still 55%.
CONCLUSION
Multimodality therapy for NSCLC is effective and achieves favorable survival. Pathologic downstaging is an important predictor for survival but patients with residual N2 disease still have meaningful survival with resection.
A team approach to evaluation and treatment among medical oncology, radiation oncology, pulmonary medicine, and thoracic surgery is critical to successful outcome.
Although not every patient with locally advanced non–small cell lung cancer (NSCLC) is a surgical candidate, surgery is worth considering for a subpopulation of patients who can benefit. For patients with stage III disease, choosing the optimal treatment is difficult and best done by a team skilled in managing this type of cancer.
Accurate clinical staging is extremely important to optimize treatment and outcome. The most common staging system used is the tumor, node, metastasis (TNM) system, which was revised in 2009. Surgery as a potential option for patients with lung cancer is becoming more accepted for patients with N2 disease but is still controversial for N3 disease. For the most part, surgical candidates are those with N2 or T4N1 disease. This article therefore focuses on staging and the utility of surgery in patients with N2 disease.
NONINVASIVE STAGING
Computed tomography (CT) of the chest and upper abdomen with intravenous contrast, including the liver and adrenal glands, is standard procedure for noninvasive staging of NSCLC. Contrast CT or magnetic resonance imaging of the brain is necessary to rule out brain metastasis in the patient with NSCLC for whom surgery is being considered.
Figure 1. Fused 18F-fluorodeoxyglucose-positron emission tomography is used for staging patients with non–small cell lung cancer. This image shows an N2-node.Fused 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) is being used increasingly for staging patients with NSCLC. Preoperative staging by FDG-PET improves the detection of occult metastatic disease and alters staging (Figure 1). Pieterman et al1 demonstrated that the use of PET for clinical staging resulted in downstaging of 20 patients and upstaging of 42 patients compared with standard approaches (CT, ultrasonography, bone scanning, and needle biopsies) in a series of 102 patients with potentially resectable NSCLC. For mediastinal lymph node staging, the sensitivity and specificity of FDG-PET were 91% and 86%, respectively, compared with 75% and 66%, respectively, with CT.
At Cleveland Clinic, we have found that PET stage and pathologic stage correlate less than 70% of the time, which reflects the high incidence of histoplasmosis and other endemic inflammatory diseases of the mediastinum.
MEDIASTINAL SAMPLING
The staging evaluation includes an assessment of the mediastinal lymph nodes. Nodal sampling of the mediastinum is advised for every patient with potentially resectable NSCLC, even in the absence of an enlarged mediastinal lymph node on CT, because mediastinal lymph node involvement is a negative prognostic indicator; absence of tumor involvement of the mediastinal lymph nodes confers a more favorable prognosis.
Cervical mediastinoscopy was first introduced for lung cancer staging in 1959 and is considered the gold standard in mediastinal staging. The sensitivity and specificity approach 100% in experienced hands. A single-center experience of 2,137 cervical mediastinoscopies revealed a complication rate of 0.6% and death from mediastinoscopy in 0.05%.2 Node stations obtainable with cervical mediastinoscopy are 2R, 4R, 3, 2L, and 4L, and sometimes 10R. These are central mediastinal nodal stations.
De Leyn et al3 demonstrated that even small tumors can have lymph node involvement. Cervical mediastinoscopy was positive in their series in 9.5% of stage T1 tumors, 17.7% of T2, 31.2% of T3, and 33.3% of T4.
ENDOBRONCHIAL ULTRASOUND (EBUS) AND EBUS STAGING
Endobronchial ultrasound involves the use of a bronchoscope with an ultrasound probe mounted on it to evaluate nodal stations for suspicious lesions that require biopsy. Needle aspiration biopsy is performed by advancing a needle housed in a sheath of the endoscope, using ultrasound to identify target nodal tissue and obtain sample tissue for evaluation.
BRAIN IMAGING
Although brain metastases are uncommon, occurring in only 1% to 5% of asymptomatic patients with NSCLC, their identification is paramount when the treatment for stage III NSCLC is potentially high-morbidity surgery.
PHYSIOLOGIC EVALUATION
When the treatment plan potentially includes surgery, a multidisciplinary evaluation is essential and should involve specialists in medical oncology, radiation oncology, pulmonary medicine, thoracic surgery, and pathology.
Because surgery for stage III NSCLC is aggressive, prior physiologic evaluation is necessary to assess operative risk. Pulmonary function evaluation should include spirometry, measurement of arterial blood gas values, diffusion capacity (transfer factor of the lung for carbon monoxide), 6-minute walk test, and cardiopulmonary exercise testing.
Stress testing, whether by nuclear imaging or dobutamine echocardiogram, is also indicated, especially if considering pneumonectomy. A quantitative ventilation-perfusion scan is indicated for a more definitive evaluation of pulmonary function.
RESULTS OBTAINED WITH MULTIMODALITY THERAPY
Southwest Oncology Group 8805
The Southwest Oncology Group (SWOG) study 8805 used a trimodality approach in patients with bulky stage III NSCLC: induction chemoradiation with concurrent cisplatin, etoposide, and radiotherapy (45 Gy) followed by surgical resection.4 The 3-year survival rate with this treatment strategy was 26%. Patients in this trial who were downstaged following induction therapy so that they had node-negative disease at the time of surgery had a superior prognosis, with a 3-year survival rate of 41%. Therefore, a subset of patients with stage III NSCLC stands to benefit from surgery, but identifying this group prior to surgery may not be possible.
Trial of accelerated multimodality therapy
An accelerated multimodality induction regimen given over 12 days was tested in 105 patients with stage IIIa (n = 78) and stage IIIb (n = 27) NSCLC, 97% of whom had mediastinal involvement.5 Seven patients had T4 disease. The induction regimen consisted of a 12-day course of concurrent cisplatin, paclitaxel, and radiotherapy. A 4-day continuous infusion of cisplatin (20 mg/m2/day) and a 24-hour continuous infusion of paclitaxel (175 mg/m2) were administered on day 1. Concurrent accelerated fractionated radiotherapy consisted of twice-daily fractions of 1.5 Gy.
All patients completed induction therapy. Of the 105 patients, 98 were candidates for surgical treatment and 83 underwent curative resections (lobectomy, n = 42; pneumonectomy, n = 36; and bilobectomy, n = 5).
Surgical mortality was 7% and morbidity was 31% (supraventricular arrhythmia, 18%; recurrent laryngeal nerve palsy, 6%; pneumonia or adult respiratory distress syndrome, 3%; bronchopleural fistula, 3%; wound infection, 2%; reoperation for bleeding, 1%).
Figure 2. Pathologic stage is the most powerful predictive factor in patients with resectable non–small cell lung cancer. Survival among patients with pathologic stages 0 to II is superior to those with residual N2 (stage IIIA) disease. Nonresponders (stage IIIB) have the poorest survival.Survival after resection was 70% at 1 year, 42% at 3 years, and 26% at 5 years. As with SWOG 8805, nodal downstaging was associated with improved survival. Patients with disease that was downstaged to pathologic stage 0 to II had a 5-year survival that approached 50%, whereas patients with persistent stage IIIb disease had a 2-year survival of just 18% (Figure 2). Patients with postresection N0 to N1 status had a 5-year survival of 55%, which declined to approximately 31% with N2 status. Few patients with N3 status survived to 3 years.
Profiles of patients with favorable and unfavorable prognoses were developed. A younger patient with adenocarcinoma whose disease was downstaged with induction therapy had a favorable prognosis, whereas an older patient with squamous carcinoma that did not respond to treatment and continued in pathologic stage IIIb had an unfavorable prognosis.
SURVIVAL DATA FAVOR SURGERY
An accurate head-to-head comparison of chemoradiation with or without surgery in patients with resectable NSCLC is difficult because patients selected for surgery must meet performance status criteria, whereas an evaluation of performance status is not mandated for patients treated with definitive chemoradiation alone. The quality of postoperative care and the management of postoperative complications also differ from institution to institution.
A controlled trial in which patients with stage IIIa NSCLC were randomized to chemoradiation with or without surgical resection was performed by Albain et al.6 The induction regimen consisted of 2 cycles of cisplatin and etoposide plus radiotherapy (45 Gy). At 5 years, overall survival was 27% in patients who underwent resection and 20% in those who continued radiotherapy without resection, a difference that did not achieve statistical significance. Progression-free survival was superior in the group assigned to surgery compared with those not undergoing resection (median: 12.8 months vs 10.5 months).
A Surveillance Epidemiology and End Results registry of more than 48,000 patients with stage III NSCLC revealed significantly better overall survival in those who received neoadjuvant radiotherapy plus surgery compared with radiation therapy alone, postoperative radiation therapy, and surgery alone.7
CLEVELAND CLINIC EXPERIENCE WITH ACCELERATED PROTOCOL
At Cleveland Clinic, the current protocol for stage IIIa and IIIb NSCLC is an accelerated multimodality regimen consisting of paclitaxel, 50 mg/m2 twice weekly for 3 weeks; carboplatin (target area under the concentration vs time curve dosing) twice weekly for 3 weeks; and daily erlotinib (phase 1 dose escalation protocol) with concurrent radiotherapy, 1.5 Gy twice daily, as induction therapy, followed by a preoperative evaluation and surgery if local control is achieved with induction treatment.
This protocol has been used in 30 patients with stage IIIa disease (median age: 61 years) with no operative mortality (62% lobectomy, 38% pneumonectomy) and a median length of stay of 6.2 days. Forty percent of patients had their disease downstaged following induction therapy. Three-year survival is approximately 60% and, at 5 years, survival is still 55%.
CONCLUSION
Multimodality therapy for NSCLC is effective and achieves favorable survival. Pathologic downstaging is an important predictor for survival but patients with residual N2 disease still have meaningful survival with resection.
A team approach to evaluation and treatment among medical oncology, radiation oncology, pulmonary medicine, and thoracic surgery is critical to successful outcome.
References
Pieterman RM, van Putten JWG, Meuzelaar JL, et al. Preoperative staging of non-small-cell lung cancer with positron-emission tomography. N Engl J Med2000; 343:254–261.
Hammoud Z, Anderson RC, Meyers BF, et al. The current role of mediastinoscopy in the evaluation of thoracic disease. J Thorac Cardiovasc Surg1999; 118:894–899.
De Leyn P, Vansteenkiste J, Cuypers P, et al. Role of cervical mediastinoscopy in staging of non-small cell lung cancer without enlarged mediastinal lymph nodes on CT scan. Eur J Cardiothor Surg1997; 12:706–712.
Albain KS, Rusch VW, Crowley JJ, et al. Concurrent cisplatin/etoposide plus chest radiotherapy followed by surgery for stages IIIA (N2) and IIIB non-small-cell lung cancer: mature results of Southwest Oncology Group phase II study 8805. J Clin Oncol1995; 13:1880–1892.
De Camp MM, Rice TW, Adelstein DJ, et al. Value of accelerated multimodality therapy in stage IIIA and IIIB non–small cell lung cancer. J Thor Cardiovasc Surg2003; 126:17–27.
Albain KS, Swann RS, Rusch VW, et al. Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled trial. Lancet2009; 374:379–386.
Koshy M, Goloubeva O, Suntharalingam M. Impact of neoadjuvant radiation on survival in stage III non-small-cell lung cancer. Int J Radiat Oncol Biol Phys2011; 79:1388–1394.
References
Pieterman RM, van Putten JWG, Meuzelaar JL, et al. Preoperative staging of non-small-cell lung cancer with positron-emission tomography. N Engl J Med2000; 343:254–261.
Hammoud Z, Anderson RC, Meyers BF, et al. The current role of mediastinoscopy in the evaluation of thoracic disease. J Thorac Cardiovasc Surg1999; 118:894–899.
De Leyn P, Vansteenkiste J, Cuypers P, et al. Role of cervical mediastinoscopy in staging of non-small cell lung cancer without enlarged mediastinal lymph nodes on CT scan. Eur J Cardiothor Surg1997; 12:706–712.
Albain KS, Rusch VW, Crowley JJ, et al. Concurrent cisplatin/etoposide plus chest radiotherapy followed by surgery for stages IIIA (N2) and IIIB non-small-cell lung cancer: mature results of Southwest Oncology Group phase II study 8805. J Clin Oncol1995; 13:1880–1892.
De Camp MM, Rice TW, Adelstein DJ, et al. Value of accelerated multimodality therapy in stage IIIA and IIIB non–small cell lung cancer. J Thor Cardiovasc Surg2003; 126:17–27.
Albain KS, Swann RS, Rusch VW, et al. Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled trial. Lancet2009; 374:379–386.
Koshy M, Goloubeva O, Suntharalingam M. Impact of neoadjuvant radiation on survival in stage III non-small-cell lung cancer. Int J Radiat Oncol Biol Phys2011; 79:1388–1394.
Reprinted with permission from The New England Journal of Medicine (Patz EF, et al. Screening for lung cancer. N Engl J Med 2000; 343:1627–1633). Copyright © 2000 Massachusetts Medical Society. All rights reserved.
Reprinted with permission from The New England Journal of Medicine (Patz EF, et al. Screening for lung cancer. N Engl J Med 2000; 343:1627–1633). Copyright © 2000 Massachusetts Medical Society. All rights reserved.
