Hospital Physician: Hematology/Oncology

Introduction

Over the past several decades, while the incidence of breast cancer has increased, breast cancer mortality has decreased. This decrease is likely due to both early detection and advances in systemic therapy. However, with more widespread use of screening mammography, there are increasing concerns about potential overdiagnosis of cancer.¹ One key challenge is that breast cancer is a heterogeneous disease. Improved tools for determining breast cancer biology can help physicians individualize treatments. Patients with low-risk cancers can be approached with less aggressive treatments, thus preventing unnecessary toxicities, while those with higher-risk cancers remain treated appropriately with more aggressive therapies.

Traditionally, adjuvant chemotherapy was recommended based on tumor features such as stage (tumor size, regional nodal involvement), grade, expression of hormone receptors (estrogen receptor [ER] and progesterone receptor [PR]) and human epidermal growth factor receptor-2 (HER2), and patient features (age, menopausal status). However, this approach is not accurate enough to guide individualized treatment approaches, which are based on the risk for recurrence and the reduction in this risk that can be achieved with various systemic treatments. In particular, women with low-risk hormone receptor (HR)–positive, HER2-negative breast cancers could be spared the toxicities of cytotoxic chemotherapies without compromising the prognosis.

Beyond chemotherapy, endocrine therapies also have risks, especially when given over extended periods of time. Recently, extended endocrine therapy has been shown to prevent late recurrences of HR-positive breast cancers. In the National Cancer Institute of Canada Clinical Trials Group’s MA.17R study, extended endocrine therapy with letrozole for a total of 10 years (beyond 5 years of an aromatase inhibitor [AI]) decreased the risk for breast cancer recurrence or the occurrence of contralateral breast cancer by 34%.² However, the overall survival was similar between the 2 groups and the disease-free survival benefits were not confirmed in other studies.^3–5 Identifying the subgroup of patients who benefit from this extended AI therapy is important in the era of personalized medicine. Several tumor genomic assays have been developed to provide additional prognostic and predictive information with the goal of individualizing adjuvant therapies for breast cancer. Although assays are also being evaluated in HER2-positive and triple-negative breast cancer, this review will focus on HR-positive, HER2-negative breast cancer.

Tests for Guiding Adjuvant Chemotherapy Decisions

Case Study

Initial Presentation

A 54-year-old postmenopausal woman with no significant past medical history presents with an abnormal screening mammogram, which shows a focal asymmetry in the 10 o’clock position at middle depth of the left breast. Further work-up with a diagnostic mammogram and ultrasound of the left breast shows a suspicious hypoechoic solid mass with irregular margins measuring 17 mm. The patient undergoes an ultrasound-guided core needle biopsy of the suspicious mass, the results of which are consistent with an invasive ductal carcinoma, Nottingham grade 2, ER strongly positive (95%), PR weakly positive (5%), HER2-negative, and Ki-67 of 15%. She undergoes a left partial mastectomy and sentinel lymph node biopsy, with final pathology demonstrating a single focus of invasive ductal carcinoma, measuring 2.2 cm in greatest dimension with no evidence of lymphovascular invasion. Margins are clear and 2 sentinel lymph nodes are negative for metastatic disease (final pathologic stage IIA, pT2 pN0 cM0). She is referred to medical oncology to discuss adjuvant systemic therapy.

• Can additional testing be used to determine prognosis and guide systemic therapy recommendations for early-stage HR-positive/HER2-negative breast cancer?

After a diagnosis of early-stage breast cancer, the key clinical question faced by the patient and medical oncologist is: what is the individual’s risk for a metastatic breast cancer recurrence and thus the risk for death due to breast cancer? Once the risk for recurrence is established, systemic adjuvant chemotherapy, endocrine therapy, and/or HER2-directed therapy are considered based on the receptor status (ER/PR and HER2) to reduce this risk. HR-positive, HER2-negative breast cancer is the most common type of breast cancer. Although adjuvant endocrine therapy has significantly reduced the risk for recurrence and improved survival for patients with HR-positive breast cancer,⁶ the role of adjuvant chemotherapy for this subset of breast cancer remains unclear. Prior to genomic testing, the recommendation for adjuvant chemotherapy for HR-positive/HER2-negative tumors was primarily based on patient age and tumor stage and grade. However, chemotherapy overtreatment remained a concern given the potential short- and long-term risks of chemotherapy. Further studies into HR-positive/HER2-negative tumors have shown that these tumors can be divided into 2 main subtypes, luminal A and luminal B.⁷ These subtypes represent unique biology and differ in terms of prognosis and response to endocrine therapy and chemotherapy. Luminal A tumors are strongly endocrine responsive and have a good prognosis, while luminal B tumors are less endocrine responsive and are associated with a poorer prognosis; the addition of adjuvant chemotherapy is often considered for luminal B tumors.⁸ Several tests, including tumor genomic assays, are now available to help with delineating the tumor subtype and aid in decision-making regarding adjuvant chemotherapy for HR-positive/HER2-negative breast cancers.

 

Ki-67 Assays, Including IHC4 and PEPI

Proliferation is a hallmark of cancer cells.⁹ Ki-67, a nuclear nonhistone protein whose expression varies in intensity throughout the cell cycle, has been used as a measurement of tumor cell proliferation.¹⁰ Two large meta-analyses have demonstrated that high Ki-67 expression in breast tumors is independently associated with worse disease-free and overall survival rates.^11,12 Ki-67 expression has also been used to classify HR-positive tumors as luminal A or B. After classifying tumor subtypes based on intrinsic gene expression profiling, Cheang and colleagues determined that a Ki-67 cut point of 13.25% differentiated luminal A and B tumors.¹³ However, the ideal cut point for Ki-67 remains unclear, as the sensitivity and specificity in this study was 77% and 78%, respectively. Others have combined Ki-67 with standard ER, PR, and HER2 testing. This immunohistochemical 4 (IHC4) score, which weighs each of these variables, was validated in postmenopausal patients from the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial who had ER-positive tumors and did not receive chemotherapy.¹⁴ The prognostic information from the IHC4 was similar to that seen with the 21-gene recurrence score (Oncotype DX), which is discussed later in this article. The key challenge with Ki-67 testing currently is the lack of a validated test methodology and intra-observer variability in interpreting the Ki-67 results.¹⁵ Recent series have suggested that Ki-67 be considered as a continuous marker rather than a set cut point.¹⁶ These issues continue to impact the clinical utility of Ki-67 for decision-making for adjuvant chemotherapy.

Ki-67 and the preoperative endocrine prognostic index (PEPI) score have been explored in the neoadjuvant setting to separate postmenopausal women with endocrine-sensitive versus intrinsically resistant disease and identify patients at risk for recurrent disease.¹⁷ The on-treatment levels of Ki-67 in response to endocrine therapy have been shown to be more prognostic than baseline values, and a decrease in Ki-67 as early as 2 weeks after initiation of neoadjuvant endocrine therapy is associated with endocrine-sensitive tumors and improved outcome. The PEPI score was developed through retrospective analysis of the P024 trial¹⁸ to evaluate the relationship between post-neoadjuvant endocrine therapy tumor characteristics and risk for early relapse. The score was subsequently validated in an independent data set from the IMPACT (Immediate Preoperative Anastrozole, Tamoxifen, or Combined with Tamoxifen) trial.¹⁹ Patients with low pathological stage (0 or 1) and a favorable biomarker profile (PEPI score 0) at surgery had the best prognosis in the absence of chemotherapy. On the other hand, higher pathological stage at surgery and a poor biomarker profile with loss of ER positivity or persistently elevated Ki-67 (PEPI score of 3) identified de novo endocrine-resistant tumors that are higher risk for early relapse.²⁰ The ongoing Alliance A011106 ALTERNATE trial (ALTernate approaches for clinical stage II or III Estrogen Receptor positive breast cancer NeoAdjuvant TrEatment in postmenopausal women, NCT01953588) is a phase 3 study to prospectively test this hypothesis.

21-Gene Recurrence Score (Onco type DX Assay)

The 21-gene Oncotype DX assay is conducted on paraffin-embedded tumor tissue and measures the expression of 16 cancer related genes and 5 reference genes using quantitative polymerase chain reaction (PCR). The genes included in this assay are mainly related to proliferation (including Ki-67), invasion, and HER2 or estrogen signaling.²¹ Originally, the 21-gene recurrence score assay was analyzed as a prognostic biomarker tool in a prospective-retrospective biomarker substudy of the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14 clinical trial in which patients with node-negative, ER-positive tumors were randomly assigned to receive tamoxifen or placebo without chemotherapy.²² Using the standard reported values of low risk (< 18), intermediate risk (18–30), or high risk (≥ 31) for recurrence, among the tamoxifen-treated patients, cancers with a high-risk recurrence score had a significantly worse rate of distant recurrence and overall survival.²¹ Inferior breast cancer survival in cancers with a high recurrence score was also confirmed in other series of endocrine-treated patients with node-negative and node-positive disease.^23–25

The predictive utility of the 21-gene recurrence score for endocrine therapy has also been evaluated. A comparison of the placebo- and tamoxifen-treated patients from the NSABP B-14 trial demonstrated that the 21-gene recurrence score predicted benefit from tamoxifen in cancers with low- or intermediate-risk recurrence scores.²⁶ However, there was no benefit from the use of tamoxifen over placebo in cancers with high-risk recurrence scores. To date, this intriguing data has not been prospectively confirmed, and thus the 21-gene recurrence score is not used to avoid endocrine therapy.

 

The 21-gene recurrence score is primarily used by oncologists to aid in decision-making regarding adjuvant chemotherapy in patients with node-negative and node-positive (with up to 3 positive lymph nodes), HR-positive/HER2-negative breast cancers. The predictive utility of the 21-gene recurrence score for adjuvant chemotherapy was initially tested using tumor samples from the NSABP B-20 study. This study initially compared adjuvant tamoxifen alone with tamoxifen plus chemotherapy in patients with node-negative, HR-positive tumors. The prospective-retrospective biomarker analysis showed that the patients with high-risk 21-gene recurrence scores benefited from the addition of chemotherapy, whereas those with low or intermediate risk did not have an improved freedom from distant recurrence with chemotherapy.²⁷ Similarly, an analysis from the prospective phase 3 Southwest Oncology Group (SWOG) 8814 trial comparing tamoxifen to tamoxifen with chemotherapy showed that for node-positive tumors, chemotherapy benefit was only seen in those with high 21-gene recurrence scores.²⁴

Prospective studies are now starting to report results regarding the predictive role of the 21-gene recurrence score. The TAILORx (Trial Assigning Individualized Options for Treatment) trial includes women with node-negative, HR-positive/HER2-negative tumors measuring 0.6 to 5 cm. All patients were treated with standard-of-care endocrine therapy for at least 5 years. Chemotherapy was determined based on the 21-gene recurrence score results on the primary tumor. The 21-gene recurrence score cutoffs were changed to low (0–10), intermediate (11–25), and high (≥ 26). Patients with scores of 26 or higher were treated with chemotherapy, and those with intermediate scores were randomly assigned to chemotherapy or no chemotherapy; results from this cohort are still pending. However, excellent breast cancer outcomes with endocrine therapy alone were reported from the 1626 (15.9% of total cohort) prospectively followed patients with low recurrence score tumors. The 5-year invasive disease-free survival was 93.8%, with overall survival of 98%.²⁸ Given that 5 years is appropriate follow-up to see any chemotherapy benefit, this data supports the recommendation for no chemotherapy in this cohort of patients with very low 21-gene recurrence scores.

The RxPONDER (Rx for Positive Node, Endocrine Responsive Breast Cancer) trial is evaluating women with 1 to 3 node-positive, HR-positive, HER2-negative tumors. In this trial, patients with 21-gene recurrence scores of 0 to 25 were assigned to adjuvant chemotherapy or none. Those with scores of 26 or higher were assigned to chemotherapy. All patients received standard adjuvant endocrine therapy. This study has completed accrual and results are pending. Of note, TAILORx and RxPONDER did not investigate the potential lack of benefit of endocrine therapy in cancers with high recurrence scores. Furthermore, despite data suggesting that chemotherapy may not even benefit women with 4 or more nodes involved but who have a low recurrence score,²⁴ due to the lack of prospective data in this cohort and the quite high risk for distant recurrence, chemotherapy continues to be the standard of care for these patients.

PAM50 (Breast Cancer Prognostic Gene Signature)

Using microarray and quantitative reverse transcriptase PCR (RT-PCR) on formalin-fixed paraffin-embedded (FFPE) tissues, the Breast Cancer Prognostic Gene Signature (PAM50) assay was initially developed to identify intrinsic breast cancer subtypes, including luminal A, luminal B, HER2-enriched, and basal-like.^7,29 Based on the prediction analysis of microarray (PAM) method, the assay measures the expression levels of 50 genes, provides a risk category (low, intermediate, and high), and generates a numerical risk of recurrence score (ROR). The intrinsic subtype and ROR have been shown to add significant prognostic value to the clinicopathological characteristics of tumors. Clinical validity of PAM50 was evaluated in postmenopausal women with HR-positive early-stage breast cancer treated in the prospective ATAC and ABCSG-8 (Austrian Breast and Colorectal Cancer Study Group 8) trials.^30,31 In 1017 patients with ER-positive breast cancer treated with anastrozole or tamoxifen in the ATAC trial, ROR added significant prognostic information beyond the clinical treatment score (integrated prognostic information from nodal status, tumor size, histopathologic grade, age, and anastrozole or tamoxifen treatment) in all patients. Also, compared with the 21-gene recurrence score, ROR provided more prognostic information in ER-positive, node-negative disease and better differentiation of intermediate- and higher-risk groups. Fewer patients were categorized as intermediate risk by ROR and more as high risk, which could reduce the uncertainty in the estimate of clinical benefit from chemotherapy.³⁰ The clinical utility of PAM50 as a prognostic model was also validated in 1478 postmenopausal women with ER-positive early-stage breast cancer enrolled in the ABCSG-8 trial. In this study, ROR assigned 47% of patients with node-negative disease to the low-risk category. In this low-risk group, the 10-year metastasis risk was less than 3.5%, indicating lack of benefit from additional chemotherapy.³¹ A key limitation of the PAM50 is the lack of any prospective studies with this assay.

PAM50 has been designed to be carried out in any qualified pathology laboratory. Moreover, the ROR score provides additional prognostic information about risk of late recurrence, which will be discussed in the next section.

 

70-Gene Breast Cancer Recurrence Assay (MammaPrint)

MammaPrint is a 70-gene assay that was initially developed using an unsupervised, hierarchical clustering algorithm on whole-genome expression arrays with early-stage breast cancer. Among 295 consecutive patients who had MammaPrint testing, those classified with a good-prognosis tumor signature (n = 115) had an excellent 10-year survival rate (94.5%) compared to those with a poor-prognosis signature (54.5%), and the signature remained prognostic upon multivariate analysis.³² Subsequently, a pooled analysis comparing outcomes by MammaPrint score in patients with node-negative or 1 to 3 node-positive breast cancers treated as per discretion of their medical team with either adjuvant chemotherapy plus endocrine therapy or endocrine therapy alone reported that only those patients with a high-risk score benefited from chemotherapy.³³ Recently, a prospective phase 3 study (MINDACT [Microarray In Node negative Disease may Avoid ChemoTherapy]) evaluating the utility of MammaPrint for adjuvant chemotherapy decision-making reported results.³⁴ In this study, 6693 women with early-stage breast cancer were assessed by clinical risk and genomic risk using MammaPrint. Those with low clinical and genomic risk did not receive chemotherapy, while those with high clinical and genomic risk all received chemotherapy. The primary goal of the study was to assess whether forgoing chemotherapy would be associated with a low rate of recurrence in those patients with a low-risk prognostic MammaPrint signature but high clinical risk. A total of 1550 patients (23.2%) were in the discordant group, and the majority of these patients had HR-positive disease (98.1%). Without chemotherapy, the rate of survival without distant metastasis at 5 years in this group was 94.7% (95% confidence interval [CI] 92.5% to 96.2%), which met the primary endpoint. Of note, initially, MammaPrint was only available for fresh tissue analysis, but recent advances in RNA processing now allow for this analysis on FFPE tissue.³⁵

Summary

These genomic and biomarker assays can identify different subsets of HR-positive breast cancers, including those patients who have tumors with an excellent prognosis with endocrine therapies alone. Thus, we now have the tools to help avoid the toxicities of chemotherapy in many women with early-stage breast cancer.

A summary of the genomic tests available is shown in Table 1.^{21,24,25,30–32,36–40}

 

 

Tests for Assessing Risk for Late Recurrence

Case Continued

The patient undergoes 21-gene recurrence score testing, which shows a low recurrence score of 10, estimating the 10-year risk of distant recurrence to be approximately 7% with 5 years of tamoxifen. Chemotherapy is not recommended. The patient completes adjuvant whole breast radiation therapy, and then, based on data supporting AIs over tamoxifen in postmenopausal women, she is started on anastrozole.⁴¹ She initially experiences mild side effects from treatment, including fatigue, arthralgia, and vaginal dryness, but her symptoms are able to be managed. As she approaches 5 years of adjuvant endocrine therapy with anastrozole, she is struggling with rotator cuff injury and is anxious about recurrence, but has no evidence of recurrent cancer. Her bone density scan in the beginning of her fourth year of therapy shows a decrease in bone mineral density, with the lowest T score of –1.5 at the left femoral neck, consistent with osteopenia. She has been treated with calcium and vitamin D supplements.

• How long should this patient continue treatment with anastrozole?

The risk for recurrence is highest during the first 5 years after diagnosis for all patients with early breast cancer.⁴² Although HR-positive breast cancers have a better prognosis than HR-negative disease, the pattern of recurrence is different between the 2 groups, and it is estimated that approximately half of the recurrences among patients with HR-positive early breast cancer occur after the first 5 years from diagnosis. Annualized hazard of recurrence in HR-positive breast cancer has been shown to remain elevated and fairly stable beyond 10 years, even for those with low tumor burden and node-negative disease.⁴³ Prospective trials showed that for women with HR-positive early breast cancer, 5 years of adjuvant tamoxifen could substantially reduce recurrence rates and improve survival, and this became the standard of care.⁴⁴ AIs are considered the standard of care for adjuvant endocrine therapy in most postmenopausal women, as they result in a significantly lower recurrence rate compared with tamoxifen, either as initial adjuvant therapy or sequentially following 2 to 3 years of tamoxifen.⁴⁵

 

Due to the risk for later recurrences with HR-positive breast cancer, more patients and oncologists are considering extended endocrine therapy. This is based on results from the ATLAS (Adjuvant Tamoxifen: Longer Against Shorter) and aTTOM (Adjuvant Tamoxifen–To Offer More?) studies, both of which showed that women with HR-positive breast cancer who continued tamoxifen for 10 years had a lower late recurrence rate and a lower breast cancer mortality rate compared with those who stopped at 5 years.^46,47 Furthermore, the NCIC MA.17 trial evaluated extended endocrine therapy in postmenopausal women with 5 years of letrozole following 5 years of tamoxifen. Letrozole was shown to improve both disease-free and distant disease-free survival. The overall survival benefit was limited to patients with node-positive disease.⁴⁸ A summary of studies of extended endocrine therapy for HR-positive breast cancers is shown in Table 2.^2,3,46–49

However, extending AI therapy from 5 years to 10 years is not clearly beneficial. In the MA.17R trial, although longer AI therapy resulted in significantly better disease-free survival (95% versus 91%, hazard ratio 0.66, P = 0.01), this was primarily due to a lower incidence of contralateral breast cancer in those taking the AI compared with placebo. The distant recurrence risks were similar and low (4.4% versus 5.5%), and there was no overall survival difference.² Also, the NSABP B-42 study, which was presented at the 2016 San Antonio Breast Cancer Symposium, did not meet its predefined endpoint for benefit from extending adjuvant AI therapy with letrozole beyond 5 years.³ Thus, the absolute benefit from extended endocrine therapy has been modest across these studies. Although endocrine therapy is considered relatively safe and well tolerated, side effects can be significant and even associated with morbidity. Ideally, extended endocrine therapy should be offered to the subset of patients who would benefit the most. Several genomic diagnostic assays, including the EndoPredict test, PAM50, and the Breast Cancer Index (BCI) tests, specifically assess the risk for late recurrence in HR-positive cancers.

PAM50

Studies suggest that the ROR score also has value in predicting late recurrences. Analysis of data in patients enrolled in the ABCSG-8 trial showed that ROR could identify patients with endocrine-sensitive disease who are at low risk for late relapse and could be spared from unwanted toxicities of extended endocrine therapies. In 1246 ABCSG-8 patients between years 5 and 15, the PAM50 ROR demonstrated an absolute risk of distant recurrence of 2.4% in the low-risk group, as compared with 17.5% in the high-risk group.⁵⁰ Also, a combined analysis of patients from both the ATAC and ABCSG-8 trials demonstrated the utility of ROR in identifying this subgroup of patients with low risk for late relapse.⁵¹

EndoPredict

EndoPredict is another quantitative RT-PCR–based assay which uses FFPE tissues to calculate a risk score based on 8 cancer-related and 3 reference genes. The score is combined with clinicopathological factors including tumor size and nodal status to make a comprehensive risk score (EPclin). EPclin is used to dichotomize patients into EndoPredict low- and high-risk groups. EndoPredict has been validated in 2 cohorts of patients enrolled in separate randomized studies, ABCSG-6 and ABCSG-8. EP provided prognostic information beyond clinicopathological variables to predict distant recurrence in patients with HR-positive/HER2-negative early breast cancer.³⁷ More important, EndoPredict has been shown to predict early (years 0–5) versus late (> 5 years after diagnosis) recurrences and identify a low-risk subset of patients who would not be expected to benefit from further treatment beyond 5 years of endocrine therapy.⁵² Recently, EndoPredict and EPclin were compared with the 21-gene (Oncotype DX) recurrence score in a patient population from the TransATAC study. Both EndoPredict and EPclin provided more prognostic information compared to the 21-gene recurrence score and identified early and late relapse events.⁵³ EndoPredict is the first multigene expression assay that could be routinely performed in decentralized molecular pathological laboratories with a short turnaround time.⁵⁴

Breast Cancer Index

The BCI is a RT-PCR–based gene expression assay that consists of 2 gene expression biomarkers: molecular grade index (MGI) and HOXB13/IL17BR (H/I). The BCI was developed as a prognostic test to assess risk for breast cancer recurrence using a cohort of ER-positive patients (n = 588) treated with adjuvant tamoxifen versus observation from the prospective randomized Stockholm trial.³⁸ In this blinded retrospective study, H/I and MGI were measured and a continuous risk model (BCI) was developed in the tamoxifen-treated group. More than 50% of the patients in this group were classified as having a low risk of recurrence. The rate of distant recurrence or death in this low-risk group at 10 years was less than 3%. The performance of the BCI model was then tested in the untreated arm of the Stockholm trial. In the untreated arm, BCI classified 53%, 27%, and 20% of patients as low, intermediate, and high risk, respectively. The rate of distant metastasis at 10 years in these risk groups was 8.3% (95% CI 4.7% to 14.4%), 22.9% (95% CI 14.5% to 35.2%), and 28.5% (95% CI 17.9% to 43.6%), respectively, and the rate of breast cancer–specific mortality was 5.1% (95% CI 1.3% to 8.7%), 19.8% (95% CI 10.0% to 28.6%), and 28.8% (95% CI 15.3% to 40.2%).³⁸

 

The prognostic and predictive values of the BCI have been validated in other large, randomized studies and in patients with both node-negative and node-positive disease.^39,55 The predictive value of the endocrine-response biomarker, the H/I ratio, has been demonstrated in randomized studies. In the MA.17 trial, a high H/I ratio was associated with increased risk for late recurrence in the absence of letrozole. However, extended endocrine therapy with letrozole in patients with high H/I ratios predicted benefit from therapy and decreased the probability of late disease recurrence.⁵⁶ BCI was also compared to IHC4 and the 21-gene recurrence score in the TransATAC study and was the only test to show prognostic significance for both early (0–5 years) and late (5–10 year) recurrence.⁴⁰

The impact of the BCI results on physicians’ recommendations for extended endocrine therapy was assessed by a prospective study. This study showed that the test result had a significant effect on both physician treatment recommendation and patient satisfaction. BCI testing resulted in a change in physician recommendations for extended endocrine therapy, with an overall decrease in recommendations for extended endocrine therapy from 74% to 54%. Knowledge of the test result also led to improved patient satisfaction and decreased anxiety.⁵⁷

Summary

Due to the risk for late recurrence, extended endocrine therapy is being recommended for many patients with HR-positive breast cancers. Multiple genomic assays are being developed to better understand an individual’s risk for late recurrence and the potential for benefit from extended endocrine therapies. However, none of the assays has been validated in prospective randomized studies. Further validation is needed prior to routine use of these assays.

Case Continued

A BCI test is done and the result shows 4.3% BCI low-risk category in years 5–10, which is consistent with a low likelihood of benefit from extended endocrine therapy. After discussing the results of the BCI test in the context of no survival benefit from extending AIs beyond 5 years, both the patient and her oncologist feel comfortable with discontinuing endocrine therapy at the end of 5 years.

Conclusion

Reduction in breast cancer mortality is mainly the result of improved systemic treatments. With advances in breast cancer screening tools in recent years, the rate of cancer detection has increased. This has raised concerns regarding overdiagnosis. To prevent unwanted toxicities associated with overtreatment, better treatment decision tools are needed. Several genomic assays are currently available and widely used to provide prognostic and predictive information and aid in decisions regarding appropriate use of adjuvant chemotherapy in HR-positive/HER2-negative early-stage breast cancer. Ongoing studies are refining the cutoffs for these assays and expanding the applicability to node-positive breast cancers. Furthermore, with several studies now showing benefit from the use of extended endocrine therapy, some of these assays may be able to identify the subset of patients who are at increased risk for late recurrence and who might benefit from extended endocrine therapy. Advances in molecular testing has enabled clinicians to offer more personalized treatments to their patients, improve patients’ compliance, and decrease anxiety and conflict associated with management decisions. Although small numbers of patients with HER2-positive and triple-negative breast cancers were also included in some of these studies, use of genomic assays in this subset of patients is very limited and currently not recommended.

Introduction

Over the past several decades, while the incidence of breast cancer has increased, breast cancer mortality has decreased. This decrease is likely due to both early detection and advances in systemic therapy. However, with more widespread use of screening mammography, there are increasing concerns about potential overdiagnosis of cancer.¹ One key challenge is that breast cancer is a heterogeneous disease. Improved tools for determining breast cancer biology can help physicians individualize treatments. Patients with low-risk cancers can be approached with less aggressive treatments, thus preventing unnecessary toxicities, while those with higher-risk cancers remain treated appropriately with more aggressive therapies.

Traditionally, adjuvant chemotherapy was recommended based on tumor features such as stage (tumor size, regional nodal involvement), grade, expression of hormone receptors (estrogen receptor [ER] and progesterone receptor [PR]) and human epidermal growth factor receptor-2 (HER2), and patient features (age, menopausal status). However, this approach is not accurate enough to guide individualized treatment approaches, which are based on the risk for recurrence and the reduction in this risk that can be achieved with various systemic treatments. In particular, women with low-risk hormone receptor (HR)–positive, HER2-negative breast cancers could be spared the toxicities of cytotoxic chemotherapies without compromising the prognosis.

Beyond chemotherapy, endocrine therapies also have risks, especially when given over extended periods of time. Recently, extended endocrine therapy has been shown to prevent late recurrences of HR-positive breast cancers. In the National Cancer Institute of Canada Clinical Trials Group’s MA.17R study, extended endocrine therapy with letrozole for a total of 10 years (beyond 5 years of an aromatase inhibitor [AI]) decreased the risk for breast cancer recurrence or the occurrence of contralateral breast cancer by 34%.² However, the overall survival was similar between the 2 groups and the disease-free survival benefits were not confirmed in other studies.^3–5 Identifying the subgroup of patients who benefit from this extended AI therapy is important in the era of personalized medicine. Several tumor genomic assays have been developed to provide additional prognostic and predictive information with the goal of individualizing adjuvant therapies for breast cancer. Although assays are also being evaluated in HER2-positive and triple-negative breast cancer, this review will focus on HR-positive, HER2-negative breast cancer.

Tests for Guiding Adjuvant Chemotherapy Decisions

Case Study

Initial Presentation

A 54-year-old postmenopausal woman with no significant past medical history presents with an abnormal screening mammogram, which shows a focal asymmetry in the 10 o’clock position at middle depth of the left breast. Further work-up with a diagnostic mammogram and ultrasound of the left breast shows a suspicious hypoechoic solid mass with irregular margins measuring 17 mm. The patient undergoes an ultrasound-guided core needle biopsy of the suspicious mass, the results of which are consistent with an invasive ductal carcinoma, Nottingham grade 2, ER strongly positive (95%), PR weakly positive (5%), HER2-negative, and Ki-67 of 15%. She undergoes a left partial mastectomy and sentinel lymph node biopsy, with final pathology demonstrating a single focus of invasive ductal carcinoma, measuring 2.2 cm in greatest dimension with no evidence of lymphovascular invasion. Margins are clear and 2 sentinel lymph nodes are negative for metastatic disease (final pathologic stage IIA, pT2 pN0 cM0). She is referred to medical oncology to discuss adjuvant systemic therapy.

• Can additional testing be used to determine prognosis and guide systemic therapy recommendations for early-stage HR-positive/HER2-negative breast cancer?

After a diagnosis of early-stage breast cancer, the key clinical question faced by the patient and medical oncologist is: what is the individual’s risk for a metastatic breast cancer recurrence and thus the risk for death due to breast cancer? Once the risk for recurrence is established, systemic adjuvant chemotherapy, endocrine therapy, and/or HER2-directed therapy are considered based on the receptor status (ER/PR and HER2) to reduce this risk. HR-positive, HER2-negative breast cancer is the most common type of breast cancer. Although adjuvant endocrine therapy has significantly reduced the risk for recurrence and improved survival for patients with HR-positive breast cancer,⁶ the role of adjuvant chemotherapy for this subset of breast cancer remains unclear. Prior to genomic testing, the recommendation for adjuvant chemotherapy for HR-positive/HER2-negative tumors was primarily based on patient age and tumor stage and grade. However, chemotherapy overtreatment remained a concern given the potential short- and long-term risks of chemotherapy. Further studies into HR-positive/HER2-negative tumors have shown that these tumors can be divided into 2 main subtypes, luminal A and luminal B.⁷ These subtypes represent unique biology and differ in terms of prognosis and response to endocrine therapy and chemotherapy. Luminal A tumors are strongly endocrine responsive and have a good prognosis, while luminal B tumors are less endocrine responsive and are associated with a poorer prognosis; the addition of adjuvant chemotherapy is often considered for luminal B tumors.⁸ Several tests, including tumor genomic assays, are now available to help with delineating the tumor subtype and aid in decision-making regarding adjuvant chemotherapy for HR-positive/HER2-negative breast cancers.

 

Ki-67 Assays, Including IHC4 and PEPI

Proliferation is a hallmark of cancer cells.⁹ Ki-67, a nuclear nonhistone protein whose expression varies in intensity throughout the cell cycle, has been used as a measurement of tumor cell proliferation.¹⁰ Two large meta-analyses have demonstrated that high Ki-67 expression in breast tumors is independently associated with worse disease-free and overall survival rates.^11,12 Ki-67 expression has also been used to classify HR-positive tumors as luminal A or B. After classifying tumor subtypes based on intrinsic gene expression profiling, Cheang and colleagues determined that a Ki-67 cut point of 13.25% differentiated luminal A and B tumors.¹³ However, the ideal cut point for Ki-67 remains unclear, as the sensitivity and specificity in this study was 77% and 78%, respectively. Others have combined Ki-67 with standard ER, PR, and HER2 testing. This immunohistochemical 4 (IHC4) score, which weighs each of these variables, was validated in postmenopausal patients from the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial who had ER-positive tumors and did not receive chemotherapy.¹⁴ The prognostic information from the IHC4 was similar to that seen with the 21-gene recurrence score (Oncotype DX), which is discussed later in this article. The key challenge with Ki-67 testing currently is the lack of a validated test methodology and intra-observer variability in interpreting the Ki-67 results.¹⁵ Recent series have suggested that Ki-67 be considered as a continuous marker rather than a set cut point.¹⁶ These issues continue to impact the clinical utility of Ki-67 for decision-making for adjuvant chemotherapy.

Ki-67 and the preoperative endocrine prognostic index (PEPI) score have been explored in the neoadjuvant setting to separate postmenopausal women with endocrine-sensitive versus intrinsically resistant disease and identify patients at risk for recurrent disease.¹⁷ The on-treatment levels of Ki-67 in response to endocrine therapy have been shown to be more prognostic than baseline values, and a decrease in Ki-67 as early as 2 weeks after initiation of neoadjuvant endocrine therapy is associated with endocrine-sensitive tumors and improved outcome. The PEPI score was developed through retrospective analysis of the P024 trial¹⁸ to evaluate the relationship between post-neoadjuvant endocrine therapy tumor characteristics and risk for early relapse. The score was subsequently validated in an independent data set from the IMPACT (Immediate Preoperative Anastrozole, Tamoxifen, or Combined with Tamoxifen) trial.¹⁹ Patients with low pathological stage (0 or 1) and a favorable biomarker profile (PEPI score 0) at surgery had the best prognosis in the absence of chemotherapy. On the other hand, higher pathological stage at surgery and a poor biomarker profile with loss of ER positivity or persistently elevated Ki-67 (PEPI score of 3) identified de novo endocrine-resistant tumors that are higher risk for early relapse.²⁰ The ongoing Alliance A011106 ALTERNATE trial (ALTernate approaches for clinical stage II or III Estrogen Receptor positive breast cancer NeoAdjuvant TrEatment in postmenopausal women, NCT01953588) is a phase 3 study to prospectively test this hypothesis.

21-Gene Recurrence Score (Onco type DX Assay)

The 21-gene Oncotype DX assay is conducted on paraffin-embedded tumor tissue and measures the expression of 16 cancer related genes and 5 reference genes using quantitative polymerase chain reaction (PCR). The genes included in this assay are mainly related to proliferation (including Ki-67), invasion, and HER2 or estrogen signaling.²¹ Originally, the 21-gene recurrence score assay was analyzed as a prognostic biomarker tool in a prospective-retrospective biomarker substudy of the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14 clinical trial in which patients with node-negative, ER-positive tumors were randomly assigned to receive tamoxifen or placebo without chemotherapy.²² Using the standard reported values of low risk (< 18), intermediate risk (18–30), or high risk (≥ 31) for recurrence, among the tamoxifen-treated patients, cancers with a high-risk recurrence score had a significantly worse rate of distant recurrence and overall survival.²¹ Inferior breast cancer survival in cancers with a high recurrence score was also confirmed in other series of endocrine-treated patients with node-negative and node-positive disease.^23–25

The predictive utility of the 21-gene recurrence score for endocrine therapy has also been evaluated. A comparison of the placebo- and tamoxifen-treated patients from the NSABP B-14 trial demonstrated that the 21-gene recurrence score predicted benefit from tamoxifen in cancers with low- or intermediate-risk recurrence scores.²⁶ However, there was no benefit from the use of tamoxifen over placebo in cancers with high-risk recurrence scores. To date, this intriguing data has not been prospectively confirmed, and thus the 21-gene recurrence score is not used to avoid endocrine therapy.

 

The 21-gene recurrence score is primarily used by oncologists to aid in decision-making regarding adjuvant chemotherapy in patients with node-negative and node-positive (with up to 3 positive lymph nodes), HR-positive/HER2-negative breast cancers. The predictive utility of the 21-gene recurrence score for adjuvant chemotherapy was initially tested using tumor samples from the NSABP B-20 study. This study initially compared adjuvant tamoxifen alone with tamoxifen plus chemotherapy in patients with node-negative, HR-positive tumors. The prospective-retrospective biomarker analysis showed that the patients with high-risk 21-gene recurrence scores benefited from the addition of chemotherapy, whereas those with low or intermediate risk did not have an improved freedom from distant recurrence with chemotherapy.²⁷ Similarly, an analysis from the prospective phase 3 Southwest Oncology Group (SWOG) 8814 trial comparing tamoxifen to tamoxifen with chemotherapy showed that for node-positive tumors, chemotherapy benefit was only seen in those with high 21-gene recurrence scores.²⁴

Prospective studies are now starting to report results regarding the predictive role of the 21-gene recurrence score. The TAILORx (Trial Assigning Individualized Options for Treatment) trial includes women with node-negative, HR-positive/HER2-negative tumors measuring 0.6 to 5 cm. All patients were treated with standard-of-care endocrine therapy for at least 5 years. Chemotherapy was determined based on the 21-gene recurrence score results on the primary tumor. The 21-gene recurrence score cutoffs were changed to low (0–10), intermediate (11–25), and high (≥ 26). Patients with scores of 26 or higher were treated with chemotherapy, and those with intermediate scores were randomly assigned to chemotherapy or no chemotherapy; results from this cohort are still pending. However, excellent breast cancer outcomes with endocrine therapy alone were reported from the 1626 (15.9% of total cohort) prospectively followed patients with low recurrence score tumors. The 5-year invasive disease-free survival was 93.8%, with overall survival of 98%.²⁸ Given that 5 years is appropriate follow-up to see any chemotherapy benefit, this data supports the recommendation for no chemotherapy in this cohort of patients with very low 21-gene recurrence scores.

The RxPONDER (Rx for Positive Node, Endocrine Responsive Breast Cancer) trial is evaluating women with 1 to 3 node-positive, HR-positive, HER2-negative tumors. In this trial, patients with 21-gene recurrence scores of 0 to 25 were assigned to adjuvant chemotherapy or none. Those with scores of 26 or higher were assigned to chemotherapy. All patients received standard adjuvant endocrine therapy. This study has completed accrual and results are pending. Of note, TAILORx and RxPONDER did not investigate the potential lack of benefit of endocrine therapy in cancers with high recurrence scores. Furthermore, despite data suggesting that chemotherapy may not even benefit women with 4 or more nodes involved but who have a low recurrence score,²⁴ due to the lack of prospective data in this cohort and the quite high risk for distant recurrence, chemotherapy continues to be the standard of care for these patients.

PAM50 (Breast Cancer Prognostic Gene Signature)

Using microarray and quantitative reverse transcriptase PCR (RT-PCR) on formalin-fixed paraffin-embedded (FFPE) tissues, the Breast Cancer Prognostic Gene Signature (PAM50) assay was initially developed to identify intrinsic breast cancer subtypes, including luminal A, luminal B, HER2-enriched, and basal-like.^7,29 Based on the prediction analysis of microarray (PAM) method, the assay measures the expression levels of 50 genes, provides a risk category (low, intermediate, and high), and generates a numerical risk of recurrence score (ROR). The intrinsic subtype and ROR have been shown to add significant prognostic value to the clinicopathological characteristics of tumors. Clinical validity of PAM50 was evaluated in postmenopausal women with HR-positive early-stage breast cancer treated in the prospective ATAC and ABCSG-8 (Austrian Breast and Colorectal Cancer Study Group 8) trials.^30,31 In 1017 patients with ER-positive breast cancer treated with anastrozole or tamoxifen in the ATAC trial, ROR added significant prognostic information beyond the clinical treatment score (integrated prognostic information from nodal status, tumor size, histopathologic grade, age, and anastrozole or tamoxifen treatment) in all patients. Also, compared with the 21-gene recurrence score, ROR provided more prognostic information in ER-positive, node-negative disease and better differentiation of intermediate- and higher-risk groups. Fewer patients were categorized as intermediate risk by ROR and more as high risk, which could reduce the uncertainty in the estimate of clinical benefit from chemotherapy.³⁰ The clinical utility of PAM50 as a prognostic model was also validated in 1478 postmenopausal women with ER-positive early-stage breast cancer enrolled in the ABCSG-8 trial. In this study, ROR assigned 47% of patients with node-negative disease to the low-risk category. In this low-risk group, the 10-year metastasis risk was less than 3.5%, indicating lack of benefit from additional chemotherapy.³¹ A key limitation of the PAM50 is the lack of any prospective studies with this assay.

PAM50 has been designed to be carried out in any qualified pathology laboratory. Moreover, the ROR score provides additional prognostic information about risk of late recurrence, which will be discussed in the next section.

 

70-Gene Breast Cancer Recurrence Assay (MammaPrint)

MammaPrint is a 70-gene assay that was initially developed using an unsupervised, hierarchical clustering algorithm on whole-genome expression arrays with early-stage breast cancer. Among 295 consecutive patients who had MammaPrint testing, those classified with a good-prognosis tumor signature (n = 115) had an excellent 10-year survival rate (94.5%) compared to those with a poor-prognosis signature (54.5%), and the signature remained prognostic upon multivariate analysis.³² Subsequently, a pooled analysis comparing outcomes by MammaPrint score in patients with node-negative or 1 to 3 node-positive breast cancers treated as per discretion of their medical team with either adjuvant chemotherapy plus endocrine therapy or endocrine therapy alone reported that only those patients with a high-risk score benefited from chemotherapy.³³ Recently, a prospective phase 3 study (MINDACT [Microarray In Node negative Disease may Avoid ChemoTherapy]) evaluating the utility of MammaPrint for adjuvant chemotherapy decision-making reported results.³⁴ In this study, 6693 women with early-stage breast cancer were assessed by clinical risk and genomic risk using MammaPrint. Those with low clinical and genomic risk did not receive chemotherapy, while those with high clinical and genomic risk all received chemotherapy. The primary goal of the study was to assess whether forgoing chemotherapy would be associated with a low rate of recurrence in those patients with a low-risk prognostic MammaPrint signature but high clinical risk. A total of 1550 patients (23.2%) were in the discordant group, and the majority of these patients had HR-positive disease (98.1%). Without chemotherapy, the rate of survival without distant metastasis at 5 years in this group was 94.7% (95% confidence interval [CI] 92.5% to 96.2%), which met the primary endpoint. Of note, initially, MammaPrint was only available for fresh tissue analysis, but recent advances in RNA processing now allow for this analysis on FFPE tissue.³⁵

Summary

These genomic and biomarker assays can identify different subsets of HR-positive breast cancers, including those patients who have tumors with an excellent prognosis with endocrine therapies alone. Thus, we now have the tools to help avoid the toxicities of chemotherapy in many women with early-stage breast cancer.

A summary of the genomic tests available is shown in Table 1.^{21,24,25,30–32,36–40}

 

 

Tests for Assessing Risk for Late Recurrence

Case Continued

The patient undergoes 21-gene recurrence score testing, which shows a low recurrence score of 10, estimating the 10-year risk of distant recurrence to be approximately 7% with 5 years of tamoxifen. Chemotherapy is not recommended. The patient completes adjuvant whole breast radiation therapy, and then, based on data supporting AIs over tamoxifen in postmenopausal women, she is started on anastrozole.⁴¹ She initially experiences mild side effects from treatment, including fatigue, arthralgia, and vaginal dryness, but her symptoms are able to be managed. As she approaches 5 years of adjuvant endocrine therapy with anastrozole, she is struggling with rotator cuff injury and is anxious about recurrence, but has no evidence of recurrent cancer. Her bone density scan in the beginning of her fourth year of therapy shows a decrease in bone mineral density, with the lowest T score of –1.5 at the left femoral neck, consistent with osteopenia. She has been treated with calcium and vitamin D supplements.

• How long should this patient continue treatment with anastrozole?

The risk for recurrence is highest during the first 5 years after diagnosis for all patients with early breast cancer.⁴² Although HR-positive breast cancers have a better prognosis than HR-negative disease, the pattern of recurrence is different between the 2 groups, and it is estimated that approximately half of the recurrences among patients with HR-positive early breast cancer occur after the first 5 years from diagnosis. Annualized hazard of recurrence in HR-positive breast cancer has been shown to remain elevated and fairly stable beyond 10 years, even for those with low tumor burden and node-negative disease.⁴³ Prospective trials showed that for women with HR-positive early breast cancer, 5 years of adjuvant tamoxifen could substantially reduce recurrence rates and improve survival, and this became the standard of care.⁴⁴ AIs are considered the standard of care for adjuvant endocrine therapy in most postmenopausal women, as they result in a significantly lower recurrence rate compared with tamoxifen, either as initial adjuvant therapy or sequentially following 2 to 3 years of tamoxifen.⁴⁵

 

Due to the risk for later recurrences with HR-positive breast cancer, more patients and oncologists are considering extended endocrine therapy. This is based on results from the ATLAS (Adjuvant Tamoxifen: Longer Against Shorter) and aTTOM (Adjuvant Tamoxifen–To Offer More?) studies, both of which showed that women with HR-positive breast cancer who continued tamoxifen for 10 years had a lower late recurrence rate and a lower breast cancer mortality rate compared with those who stopped at 5 years.^46,47 Furthermore, the NCIC MA.17 trial evaluated extended endocrine therapy in postmenopausal women with 5 years of letrozole following 5 years of tamoxifen. Letrozole was shown to improve both disease-free and distant disease-free survival. The overall survival benefit was limited to patients with node-positive disease.⁴⁸ A summary of studies of extended endocrine therapy for HR-positive breast cancers is shown in Table 2.^2,3,46–49

However, extending AI therapy from 5 years to 10 years is not clearly beneficial. In the MA.17R trial, although longer AI therapy resulted in significantly better disease-free survival (95% versus 91%, hazard ratio 0.66, P = 0.01), this was primarily due to a lower incidence of contralateral breast cancer in those taking the AI compared with placebo. The distant recurrence risks were similar and low (4.4% versus 5.5%), and there was no overall survival difference.² Also, the NSABP B-42 study, which was presented at the 2016 San Antonio Breast Cancer Symposium, did not meet its predefined endpoint for benefit from extending adjuvant AI therapy with letrozole beyond 5 years.³ Thus, the absolute benefit from extended endocrine therapy has been modest across these studies. Although endocrine therapy is considered relatively safe and well tolerated, side effects can be significant and even associated with morbidity. Ideally, extended endocrine therapy should be offered to the subset of patients who would benefit the most. Several genomic diagnostic assays, including the EndoPredict test, PAM50, and the Breast Cancer Index (BCI) tests, specifically assess the risk for late recurrence in HR-positive cancers.

PAM50

Studies suggest that the ROR score also has value in predicting late recurrences. Analysis of data in patients enrolled in the ABCSG-8 trial showed that ROR could identify patients with endocrine-sensitive disease who are at low risk for late relapse and could be spared from unwanted toxicities of extended endocrine therapies. In 1246 ABCSG-8 patients between years 5 and 15, the PAM50 ROR demonstrated an absolute risk of distant recurrence of 2.4% in the low-risk group, as compared with 17.5% in the high-risk group.⁵⁰ Also, a combined analysis of patients from both the ATAC and ABCSG-8 trials demonstrated the utility of ROR in identifying this subgroup of patients with low risk for late relapse.⁵¹

EndoPredict

EndoPredict is another quantitative RT-PCR–based assay which uses FFPE tissues to calculate a risk score based on 8 cancer-related and 3 reference genes. The score is combined with clinicopathological factors including tumor size and nodal status to make a comprehensive risk score (EPclin). EPclin is used to dichotomize patients into EndoPredict low- and high-risk groups. EndoPredict has been validated in 2 cohorts of patients enrolled in separate randomized studies, ABCSG-6 and ABCSG-8. EP provided prognostic information beyond clinicopathological variables to predict distant recurrence in patients with HR-positive/HER2-negative early breast cancer.³⁷ More important, EndoPredict has been shown to predict early (years 0–5) versus late (> 5 years after diagnosis) recurrences and identify a low-risk subset of patients who would not be expected to benefit from further treatment beyond 5 years of endocrine therapy.⁵² Recently, EndoPredict and EPclin were compared with the 21-gene (Oncotype DX) recurrence score in a patient population from the TransATAC study. Both EndoPredict and EPclin provided more prognostic information compared to the 21-gene recurrence score and identified early and late relapse events.⁵³ EndoPredict is the first multigene expression assay that could be routinely performed in decentralized molecular pathological laboratories with a short turnaround time.⁵⁴

Breast Cancer Index

The BCI is a RT-PCR–based gene expression assay that consists of 2 gene expression biomarkers: molecular grade index (MGI) and HOXB13/IL17BR (H/I). The BCI was developed as a prognostic test to assess risk for breast cancer recurrence using a cohort of ER-positive patients (n = 588) treated with adjuvant tamoxifen versus observation from the prospective randomized Stockholm trial.³⁸ In this blinded retrospective study, H/I and MGI were measured and a continuous risk model (BCI) was developed in the tamoxifen-treated group. More than 50% of the patients in this group were classified as having a low risk of recurrence. The rate of distant recurrence or death in this low-risk group at 10 years was less than 3%. The performance of the BCI model was then tested in the untreated arm of the Stockholm trial. In the untreated arm, BCI classified 53%, 27%, and 20% of patients as low, intermediate, and high risk, respectively. The rate of distant metastasis at 10 years in these risk groups was 8.3% (95% CI 4.7% to 14.4%), 22.9% (95% CI 14.5% to 35.2%), and 28.5% (95% CI 17.9% to 43.6%), respectively, and the rate of breast cancer–specific mortality was 5.1% (95% CI 1.3% to 8.7%), 19.8% (95% CI 10.0% to 28.6%), and 28.8% (95% CI 15.3% to 40.2%).³⁸

 

The prognostic and predictive values of the BCI have been validated in other large, randomized studies and in patients with both node-negative and node-positive disease.^39,55 The predictive value of the endocrine-response biomarker, the H/I ratio, has been demonstrated in randomized studies. In the MA.17 trial, a high H/I ratio was associated with increased risk for late recurrence in the absence of letrozole. However, extended endocrine therapy with letrozole in patients with high H/I ratios predicted benefit from therapy and decreased the probability of late disease recurrence.⁵⁶ BCI was also compared to IHC4 and the 21-gene recurrence score in the TransATAC study and was the only test to show prognostic significance for both early (0–5 years) and late (5–10 year) recurrence.⁴⁰

The impact of the BCI results on physicians’ recommendations for extended endocrine therapy was assessed by a prospective study. This study showed that the test result had a significant effect on both physician treatment recommendation and patient satisfaction. BCI testing resulted in a change in physician recommendations for extended endocrine therapy, with an overall decrease in recommendations for extended endocrine therapy from 74% to 54%. Knowledge of the test result also led to improved patient satisfaction and decreased anxiety.⁵⁷

Summary

Due to the risk for late recurrence, extended endocrine therapy is being recommended for many patients with HR-positive breast cancers. Multiple genomic assays are being developed to better understand an individual’s risk for late recurrence and the potential for benefit from extended endocrine therapies. However, none of the assays has been validated in prospective randomized studies. Further validation is needed prior to routine use of these assays.

Case Continued

A BCI test is done and the result shows 4.3% BCI low-risk category in years 5–10, which is consistent with a low likelihood of benefit from extended endocrine therapy. After discussing the results of the BCI test in the context of no survival benefit from extending AIs beyond 5 years, both the patient and her oncologist feel comfortable with discontinuing endocrine therapy at the end of 5 years.

Conclusion

Reduction in breast cancer mortality is mainly the result of improved systemic treatments. With advances in breast cancer screening tools in recent years, the rate of cancer detection has increased. This has raised concerns regarding overdiagnosis. To prevent unwanted toxicities associated with overtreatment, better treatment decision tools are needed. Several genomic assays are currently available and widely used to provide prognostic and predictive information and aid in decisions regarding appropriate use of adjuvant chemotherapy in HR-positive/HER2-negative early-stage breast cancer. Ongoing studies are refining the cutoffs for these assays and expanding the applicability to node-positive breast cancers. Furthermore, with several studies now showing benefit from the use of extended endocrine therapy, some of these assays may be able to identify the subset of patients who are at increased risk for late recurrence and who might benefit from extended endocrine therapy. Advances in molecular testing has enabled clinicians to offer more personalized treatments to their patients, improve patients’ compliance, and decrease anxiety and conflict associated with management decisions. Although small numbers of patients with HER2-positive and triple-negative breast cancers were also included in some of these studies, use of genomic assays in this subset of patients is very limited and currently not recommended.

Introduction

Over the past several decades, while the incidence of breast cancer has increased, breast cancer mortality has decreased. This decrease is likely due to both early detection and advances in systemic therapy. However, with more widespread use of screening mammography, there are increasing concerns about potential overdiagnosis of cancer.¹ One key challenge is that breast cancer is a heterogeneous disease. Improved tools for determining breast cancer biology can help physicians individualize treatments. Patients with low-risk cancers can be approached with less aggressive treatments, thus preventing unnecessary toxicities, while those with higher-risk cancers remain treated appropriately with more aggressive therapies.

Traditionally, adjuvant chemotherapy was recommended based on tumor features such as stage (tumor size, regional nodal involvement), grade, expression of hormone receptors (estrogen receptor [ER] and progesterone receptor [PR]) and human epidermal growth factor receptor-2 (HER2), and patient features (age, menopausal status). However, this approach is not accurate enough to guide individualized treatment approaches, which are based on the risk for recurrence and the reduction in this risk that can be achieved with various systemic treatments. In particular, women with low-risk hormone receptor (HR)–positive, HER2-negative breast cancers could be spared the toxicities of cytotoxic chemotherapies without compromising the prognosis.

Beyond chemotherapy, endocrine therapies also have risks, especially when given over extended periods of time. Recently, extended endocrine therapy has been shown to prevent late recurrences of HR-positive breast cancers. In the National Cancer Institute of Canada Clinical Trials Group’s MA.17R study, extended endocrine therapy with letrozole for a total of 10 years (beyond 5 years of an aromatase inhibitor [AI]) decreased the risk for breast cancer recurrence or the occurrence of contralateral breast cancer by 34%.² However, the overall survival was similar between the 2 groups and the disease-free survival benefits were not confirmed in other studies.^3–5 Identifying the subgroup of patients who benefit from this extended AI therapy is important in the era of personalized medicine. Several tumor genomic assays have been developed to provide additional prognostic and predictive information with the goal of individualizing adjuvant therapies for breast cancer. Although assays are also being evaluated in HER2-positive and triple-negative breast cancer, this review will focus on HR-positive, HER2-negative breast cancer.

Tests for Guiding Adjuvant Chemotherapy Decisions

Case Study

Initial Presentation

A 54-year-old postmenopausal woman with no significant past medical history presents with an abnormal screening mammogram, which shows a focal asymmetry in the 10 o’clock position at middle depth of the left breast. Further work-up with a diagnostic mammogram and ultrasound of the left breast shows a suspicious hypoechoic solid mass with irregular margins measuring 17 mm. The patient undergoes an ultrasound-guided core needle biopsy of the suspicious mass, the results of which are consistent with an invasive ductal carcinoma, Nottingham grade 2, ER strongly positive (95%), PR weakly positive (5%), HER2-negative, and Ki-67 of 15%. She undergoes a left partial mastectomy and sentinel lymph node biopsy, with final pathology demonstrating a single focus of invasive ductal carcinoma, measuring 2.2 cm in greatest dimension with no evidence of lymphovascular invasion. Margins are clear and 2 sentinel lymph nodes are negative for metastatic disease (final pathologic stage IIA, pT2 pN0 cM0). She is referred to medical oncology to discuss adjuvant systemic therapy.

• Can additional testing be used to determine prognosis and guide systemic therapy recommendations for early-stage HR-positive/HER2-negative breast cancer?

After a diagnosis of early-stage breast cancer, the key clinical question faced by the patient and medical oncologist is: what is the individual’s risk for a metastatic breast cancer recurrence and thus the risk for death due to breast cancer? Once the risk for recurrence is established, systemic adjuvant chemotherapy, endocrine therapy, and/or HER2-directed therapy are considered based on the receptor status (ER/PR and HER2) to reduce this risk. HR-positive, HER2-negative breast cancer is the most common type of breast cancer. Although adjuvant endocrine therapy has significantly reduced the risk for recurrence and improved survival for patients with HR-positive breast cancer,⁶ the role of adjuvant chemotherapy for this subset of breast cancer remains unclear. Prior to genomic testing, the recommendation for adjuvant chemotherapy for HR-positive/HER2-negative tumors was primarily based on patient age and tumor stage and grade. However, chemotherapy overtreatment remained a concern given the potential short- and long-term risks of chemotherapy. Further studies into HR-positive/HER2-negative tumors have shown that these tumors can be divided into 2 main subtypes, luminal A and luminal B.⁷ These subtypes represent unique biology and differ in terms of prognosis and response to endocrine therapy and chemotherapy. Luminal A tumors are strongly endocrine responsive and have a good prognosis, while luminal B tumors are less endocrine responsive and are associated with a poorer prognosis; the addition of adjuvant chemotherapy is often considered for luminal B tumors.⁸ Several tests, including tumor genomic assays, are now available to help with delineating the tumor subtype and aid in decision-making regarding adjuvant chemotherapy for HR-positive/HER2-negative breast cancers.

 

Ki-67 Assays, Including IHC4 and PEPI

Proliferation is a hallmark of cancer cells.⁹ Ki-67, a nuclear nonhistone protein whose expression varies in intensity throughout the cell cycle, has been used as a measurement of tumor cell proliferation.¹⁰ Two large meta-analyses have demonstrated that high Ki-67 expression in breast tumors is independently associated with worse disease-free and overall survival rates.^11,12 Ki-67 expression has also been used to classify HR-positive tumors as luminal A or B. After classifying tumor subtypes based on intrinsic gene expression profiling, Cheang and colleagues determined that a Ki-67 cut point of 13.25% differentiated luminal A and B tumors.¹³ However, the ideal cut point for Ki-67 remains unclear, as the sensitivity and specificity in this study was 77% and 78%, respectively. Others have combined Ki-67 with standard ER, PR, and HER2 testing. This immunohistochemical 4 (IHC4) score, which weighs each of these variables, was validated in postmenopausal patients from the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial who had ER-positive tumors and did not receive chemotherapy.¹⁴ The prognostic information from the IHC4 was similar to that seen with the 21-gene recurrence score (Oncotype DX), which is discussed later in this article. The key challenge with Ki-67 testing currently is the lack of a validated test methodology and intra-observer variability in interpreting the Ki-67 results.¹⁵ Recent series have suggested that Ki-67 be considered as a continuous marker rather than a set cut point.¹⁶ These issues continue to impact the clinical utility of Ki-67 for decision-making for adjuvant chemotherapy.

Ki-67 and the preoperative endocrine prognostic index (PEPI) score have been explored in the neoadjuvant setting to separate postmenopausal women with endocrine-sensitive versus intrinsically resistant disease and identify patients at risk for recurrent disease.¹⁷ The on-treatment levels of Ki-67 in response to endocrine therapy have been shown to be more prognostic than baseline values, and a decrease in Ki-67 as early as 2 weeks after initiation of neoadjuvant endocrine therapy is associated with endocrine-sensitive tumors and improved outcome. The PEPI score was developed through retrospective analysis of the P024 trial¹⁸ to evaluate the relationship between post-neoadjuvant endocrine therapy tumor characteristics and risk for early relapse. The score was subsequently validated in an independent data set from the IMPACT (Immediate Preoperative Anastrozole, Tamoxifen, or Combined with Tamoxifen) trial.¹⁹ Patients with low pathological stage (0 or 1) and a favorable biomarker profile (PEPI score 0) at surgery had the best prognosis in the absence of chemotherapy. On the other hand, higher pathological stage at surgery and a poor biomarker profile with loss of ER positivity or persistently elevated Ki-67 (PEPI score of 3) identified de novo endocrine-resistant tumors that are higher risk for early relapse.²⁰ The ongoing Alliance A011106 ALTERNATE trial (ALTernate approaches for clinical stage II or III Estrogen Receptor positive breast cancer NeoAdjuvant TrEatment in postmenopausal women, NCT01953588) is a phase 3 study to prospectively test this hypothesis.

21-Gene Recurrence Score (Onco type DX Assay)

The 21-gene Oncotype DX assay is conducted on paraffin-embedded tumor tissue and measures the expression of 16 cancer related genes and 5 reference genes using quantitative polymerase chain reaction (PCR). The genes included in this assay are mainly related to proliferation (including Ki-67), invasion, and HER2 or estrogen signaling.²¹ Originally, the 21-gene recurrence score assay was analyzed as a prognostic biomarker tool in a prospective-retrospective biomarker substudy of the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14 clinical trial in which patients with node-negative, ER-positive tumors were randomly assigned to receive tamoxifen or placebo without chemotherapy.²² Using the standard reported values of low risk (< 18), intermediate risk (18–30), or high risk (≥ 31) for recurrence, among the tamoxifen-treated patients, cancers with a high-risk recurrence score had a significantly worse rate of distant recurrence and overall survival.²¹ Inferior breast cancer survival in cancers with a high recurrence score was also confirmed in other series of endocrine-treated patients with node-negative and node-positive disease.^23–25

The predictive utility of the 21-gene recurrence score for endocrine therapy has also been evaluated. A comparison of the placebo- and tamoxifen-treated patients from the NSABP B-14 trial demonstrated that the 21-gene recurrence score predicted benefit from tamoxifen in cancers with low- or intermediate-risk recurrence scores.²⁶ However, there was no benefit from the use of tamoxifen over placebo in cancers with high-risk recurrence scores. To date, this intriguing data has not been prospectively confirmed, and thus the 21-gene recurrence score is not used to avoid endocrine therapy.

 

The 21-gene recurrence score is primarily used by oncologists to aid in decision-making regarding adjuvant chemotherapy in patients with node-negative and node-positive (with up to 3 positive lymph nodes), HR-positive/HER2-negative breast cancers. The predictive utility of the 21-gene recurrence score for adjuvant chemotherapy was initially tested using tumor samples from the NSABP B-20 study. This study initially compared adjuvant tamoxifen alone with tamoxifen plus chemotherapy in patients with node-negative, HR-positive tumors. The prospective-retrospective biomarker analysis showed that the patients with high-risk 21-gene recurrence scores benefited from the addition of chemotherapy, whereas those with low or intermediate risk did not have an improved freedom from distant recurrence with chemotherapy.²⁷ Similarly, an analysis from the prospective phase 3 Southwest Oncology Group (SWOG) 8814 trial comparing tamoxifen to tamoxifen with chemotherapy showed that for node-positive tumors, chemotherapy benefit was only seen in those with high 21-gene recurrence scores.²⁴

Prospective studies are now starting to report results regarding the predictive role of the 21-gene recurrence score. The TAILORx (Trial Assigning Individualized Options for Treatment) trial includes women with node-negative, HR-positive/HER2-negative tumors measuring 0.6 to 5 cm. All patients were treated with standard-of-care endocrine therapy for at least 5 years. Chemotherapy was determined based on the 21-gene recurrence score results on the primary tumor. The 21-gene recurrence score cutoffs were changed to low (0–10), intermediate (11–25), and high (≥ 26). Patients with scores of 26 or higher were treated with chemotherapy, and those with intermediate scores were randomly assigned to chemotherapy or no chemotherapy; results from this cohort are still pending. However, excellent breast cancer outcomes with endocrine therapy alone were reported from the 1626 (15.9% of total cohort) prospectively followed patients with low recurrence score tumors. The 5-year invasive disease-free survival was 93.8%, with overall survival of 98%.²⁸ Given that 5 years is appropriate follow-up to see any chemotherapy benefit, this data supports the recommendation for no chemotherapy in this cohort of patients with very low 21-gene recurrence scores.

The RxPONDER (Rx for Positive Node, Endocrine Responsive Breast Cancer) trial is evaluating women with 1 to 3 node-positive, HR-positive, HER2-negative tumors. In this trial, patients with 21-gene recurrence scores of 0 to 25 were assigned to adjuvant chemotherapy or none. Those with scores of 26 or higher were assigned to chemotherapy. All patients received standard adjuvant endocrine therapy. This study has completed accrual and results are pending. Of note, TAILORx and RxPONDER did not investigate the potential lack of benefit of endocrine therapy in cancers with high recurrence scores. Furthermore, despite data suggesting that chemotherapy may not even benefit women with 4 or more nodes involved but who have a low recurrence score,²⁴ due to the lack of prospective data in this cohort and the quite high risk for distant recurrence, chemotherapy continues to be the standard of care for these patients.

PAM50 (Breast Cancer Prognostic Gene Signature)

Using microarray and quantitative reverse transcriptase PCR (RT-PCR) on formalin-fixed paraffin-embedded (FFPE) tissues, the Breast Cancer Prognostic Gene Signature (PAM50) assay was initially developed to identify intrinsic breast cancer subtypes, including luminal A, luminal B, HER2-enriched, and basal-like.^7,29 Based on the prediction analysis of microarray (PAM) method, the assay measures the expression levels of 50 genes, provides a risk category (low, intermediate, and high), and generates a numerical risk of recurrence score (ROR). The intrinsic subtype and ROR have been shown to add significant prognostic value to the clinicopathological characteristics of tumors. Clinical validity of PAM50 was evaluated in postmenopausal women with HR-positive early-stage breast cancer treated in the prospective ATAC and ABCSG-8 (Austrian Breast and Colorectal Cancer Study Group 8) trials.^30,31 In 1017 patients with ER-positive breast cancer treated with anastrozole or tamoxifen in the ATAC trial, ROR added significant prognostic information beyond the clinical treatment score (integrated prognostic information from nodal status, tumor size, histopathologic grade, age, and anastrozole or tamoxifen treatment) in all patients. Also, compared with the 21-gene recurrence score, ROR provided more prognostic information in ER-positive, node-negative disease and better differentiation of intermediate- and higher-risk groups. Fewer patients were categorized as intermediate risk by ROR and more as high risk, which could reduce the uncertainty in the estimate of clinical benefit from chemotherapy.³⁰ The clinical utility of PAM50 as a prognostic model was also validated in 1478 postmenopausal women with ER-positive early-stage breast cancer enrolled in the ABCSG-8 trial. In this study, ROR assigned 47% of patients with node-negative disease to the low-risk category. In this low-risk group, the 10-year metastasis risk was less than 3.5%, indicating lack of benefit from additional chemotherapy.³¹ A key limitation of the PAM50 is the lack of any prospective studies with this assay.

PAM50 has been designed to be carried out in any qualified pathology laboratory. Moreover, the ROR score provides additional prognostic information about risk of late recurrence, which will be discussed in the next section.

 

70-Gene Breast Cancer Recurrence Assay (MammaPrint)

MammaPrint is a 70-gene assay that was initially developed using an unsupervised, hierarchical clustering algorithm on whole-genome expression arrays with early-stage breast cancer. Among 295 consecutive patients who had MammaPrint testing, those classified with a good-prognosis tumor signature (n = 115) had an excellent 10-year survival rate (94.5%) compared to those with a poor-prognosis signature (54.5%), and the signature remained prognostic upon multivariate analysis.³² Subsequently, a pooled analysis comparing outcomes by MammaPrint score in patients with node-negative or 1 to 3 node-positive breast cancers treated as per discretion of their medical team with either adjuvant chemotherapy plus endocrine therapy or endocrine therapy alone reported that only those patients with a high-risk score benefited from chemotherapy.³³ Recently, a prospective phase 3 study (MINDACT [Microarray In Node negative Disease may Avoid ChemoTherapy]) evaluating the utility of MammaPrint for adjuvant chemotherapy decision-making reported results.³⁴ In this study, 6693 women with early-stage breast cancer were assessed by clinical risk and genomic risk using MammaPrint. Those with low clinical and genomic risk did not receive chemotherapy, while those with high clinical and genomic risk all received chemotherapy. The primary goal of the study was to assess whether forgoing chemotherapy would be associated with a low rate of recurrence in those patients with a low-risk prognostic MammaPrint signature but high clinical risk. A total of 1550 patients (23.2%) were in the discordant group, and the majority of these patients had HR-positive disease (98.1%). Without chemotherapy, the rate of survival without distant metastasis at 5 years in this group was 94.7% (95% confidence interval [CI] 92.5% to 96.2%), which met the primary endpoint. Of note, initially, MammaPrint was only available for fresh tissue analysis, but recent advances in RNA processing now allow for this analysis on FFPE tissue.³⁵

Summary

These genomic and biomarker assays can identify different subsets of HR-positive breast cancers, including those patients who have tumors with an excellent prognosis with endocrine therapies alone. Thus, we now have the tools to help avoid the toxicities of chemotherapy in many women with early-stage breast cancer.

A summary of the genomic tests available is shown in Table 1.^{21,24,25,30–32,36–40}

 

 

Tests for Assessing Risk for Late Recurrence

Case Continued

The patient undergoes 21-gene recurrence score testing, which shows a low recurrence score of 10, estimating the 10-year risk of distant recurrence to be approximately 7% with 5 years of tamoxifen. Chemotherapy is not recommended. The patient completes adjuvant whole breast radiation therapy, and then, based on data supporting AIs over tamoxifen in postmenopausal women, she is started on anastrozole.⁴¹ She initially experiences mild side effects from treatment, including fatigue, arthralgia, and vaginal dryness, but her symptoms are able to be managed. As she approaches 5 years of adjuvant endocrine therapy with anastrozole, she is struggling with rotator cuff injury and is anxious about recurrence, but has no evidence of recurrent cancer. Her bone density scan in the beginning of her fourth year of therapy shows a decrease in bone mineral density, with the lowest T score of –1.5 at the left femoral neck, consistent with osteopenia. She has been treated with calcium and vitamin D supplements.

• How long should this patient continue treatment with anastrozole?

The risk for recurrence is highest during the first 5 years after diagnosis for all patients with early breast cancer.⁴² Although HR-positive breast cancers have a better prognosis than HR-negative disease, the pattern of recurrence is different between the 2 groups, and it is estimated that approximately half of the recurrences among patients with HR-positive early breast cancer occur after the first 5 years from diagnosis. Annualized hazard of recurrence in HR-positive breast cancer has been shown to remain elevated and fairly stable beyond 10 years, even for those with low tumor burden and node-negative disease.⁴³ Prospective trials showed that for women with HR-positive early breast cancer, 5 years of adjuvant tamoxifen could substantially reduce recurrence rates and improve survival, and this became the standard of care.⁴⁴ AIs are considered the standard of care for adjuvant endocrine therapy in most postmenopausal women, as they result in a significantly lower recurrence rate compared with tamoxifen, either as initial adjuvant therapy or sequentially following 2 to 3 years of tamoxifen.⁴⁵

 

Due to the risk for later recurrences with HR-positive breast cancer, more patients and oncologists are considering extended endocrine therapy. This is based on results from the ATLAS (Adjuvant Tamoxifen: Longer Against Shorter) and aTTOM (Adjuvant Tamoxifen–To Offer More?) studies, both of which showed that women with HR-positive breast cancer who continued tamoxifen for 10 years had a lower late recurrence rate and a lower breast cancer mortality rate compared with those who stopped at 5 years.^46,47 Furthermore, the NCIC MA.17 trial evaluated extended endocrine therapy in postmenopausal women with 5 years of letrozole following 5 years of tamoxifen. Letrozole was shown to improve both disease-free and distant disease-free survival. The overall survival benefit was limited to patients with node-positive disease.⁴⁸ A summary of studies of extended endocrine therapy for HR-positive breast cancers is shown in Table 2.^2,3,46–49

However, extending AI therapy from 5 years to 10 years is not clearly beneficial. In the MA.17R trial, although longer AI therapy resulted in significantly better disease-free survival (95% versus 91%, hazard ratio 0.66, P = 0.01), this was primarily due to a lower incidence of contralateral breast cancer in those taking the AI compared with placebo. The distant recurrence risks were similar and low (4.4% versus 5.5%), and there was no overall survival difference.² Also, the NSABP B-42 study, which was presented at the 2016 San Antonio Breast Cancer Symposium, did not meet its predefined endpoint for benefit from extending adjuvant AI therapy with letrozole beyond 5 years.³ Thus, the absolute benefit from extended endocrine therapy has been modest across these studies. Although endocrine therapy is considered relatively safe and well tolerated, side effects can be significant and even associated with morbidity. Ideally, extended endocrine therapy should be offered to the subset of patients who would benefit the most. Several genomic diagnostic assays, including the EndoPredict test, PAM50, and the Breast Cancer Index (BCI) tests, specifically assess the risk for late recurrence in HR-positive cancers.

PAM50

Studies suggest that the ROR score also has value in predicting late recurrences. Analysis of data in patients enrolled in the ABCSG-8 trial showed that ROR could identify patients with endocrine-sensitive disease who are at low risk for late relapse and could be spared from unwanted toxicities of extended endocrine therapies. In 1246 ABCSG-8 patients between years 5 and 15, the PAM50 ROR demonstrated an absolute risk of distant recurrence of 2.4% in the low-risk group, as compared with 17.5% in the high-risk group.⁵⁰ Also, a combined analysis of patients from both the ATAC and ABCSG-8 trials demonstrated the utility of ROR in identifying this subgroup of patients with low risk for late relapse.⁵¹

EndoPredict

EndoPredict is another quantitative RT-PCR–based assay which uses FFPE tissues to calculate a risk score based on 8 cancer-related and 3 reference genes. The score is combined with clinicopathological factors including tumor size and nodal status to make a comprehensive risk score (EPclin). EPclin is used to dichotomize patients into EndoPredict low- and high-risk groups. EndoPredict has been validated in 2 cohorts of patients enrolled in separate randomized studies, ABCSG-6 and ABCSG-8. EP provided prognostic information beyond clinicopathological variables to predict distant recurrence in patients with HR-positive/HER2-negative early breast cancer.³⁷ More important, EndoPredict has been shown to predict early (years 0–5) versus late (> 5 years after diagnosis) recurrences and identify a low-risk subset of patients who would not be expected to benefit from further treatment beyond 5 years of endocrine therapy.⁵² Recently, EndoPredict and EPclin were compared with the 21-gene (Oncotype DX) recurrence score in a patient population from the TransATAC study. Both EndoPredict and EPclin provided more prognostic information compared to the 21-gene recurrence score and identified early and late relapse events.⁵³ EndoPredict is the first multigene expression assay that could be routinely performed in decentralized molecular pathological laboratories with a short turnaround time.⁵⁴

Breast Cancer Index

The BCI is a RT-PCR–based gene expression assay that consists of 2 gene expression biomarkers: molecular grade index (MGI) and HOXB13/IL17BR (H/I). The BCI was developed as a prognostic test to assess risk for breast cancer recurrence using a cohort of ER-positive patients (n = 588) treated with adjuvant tamoxifen versus observation from the prospective randomized Stockholm trial.³⁸ In this blinded retrospective study, H/I and MGI were measured and a continuous risk model (BCI) was developed in the tamoxifen-treated group. More than 50% of the patients in this group were classified as having a low risk of recurrence. The rate of distant recurrence or death in this low-risk group at 10 years was less than 3%. The performance of the BCI model was then tested in the untreated arm of the Stockholm trial. In the untreated arm, BCI classified 53%, 27%, and 20% of patients as low, intermediate, and high risk, respectively. The rate of distant metastasis at 10 years in these risk groups was 8.3% (95% CI 4.7% to 14.4%), 22.9% (95% CI 14.5% to 35.2%), and 28.5% (95% CI 17.9% to 43.6%), respectively, and the rate of breast cancer–specific mortality was 5.1% (95% CI 1.3% to 8.7%), 19.8% (95% CI 10.0% to 28.6%), and 28.8% (95% CI 15.3% to 40.2%).³⁸

 

The prognostic and predictive values of the BCI have been validated in other large, randomized studies and in patients with both node-negative and node-positive disease.^39,55 The predictive value of the endocrine-response biomarker, the H/I ratio, has been demonstrated in randomized studies. In the MA.17 trial, a high H/I ratio was associated with increased risk for late recurrence in the absence of letrozole. However, extended endocrine therapy with letrozole in patients with high H/I ratios predicted benefit from therapy and decreased the probability of late disease recurrence.⁵⁶ BCI was also compared to IHC4 and the 21-gene recurrence score in the TransATAC study and was the only test to show prognostic significance for both early (0–5 years) and late (5–10 year) recurrence.⁴⁰

The impact of the BCI results on physicians’ recommendations for extended endocrine therapy was assessed by a prospective study. This study showed that the test result had a significant effect on both physician treatment recommendation and patient satisfaction. BCI testing resulted in a change in physician recommendations for extended endocrine therapy, with an overall decrease in recommendations for extended endocrine therapy from 74% to 54%. Knowledge of the test result also led to improved patient satisfaction and decreased anxiety.⁵⁷

Summary

Due to the risk for late recurrence, extended endocrine therapy is being recommended for many patients with HR-positive breast cancers. Multiple genomic assays are being developed to better understand an individual’s risk for late recurrence and the potential for benefit from extended endocrine therapies. However, none of the assays has been validated in prospective randomized studies. Further validation is needed prior to routine use of these assays.

Case Continued

A BCI test is done and the result shows 4.3% BCI low-risk category in years 5–10, which is consistent with a low likelihood of benefit from extended endocrine therapy. After discussing the results of the BCI test in the context of no survival benefit from extending AIs beyond 5 years, both the patient and her oncologist feel comfortable with discontinuing endocrine therapy at the end of 5 years.

Conclusion

Reduction in breast cancer mortality is mainly the result of improved systemic treatments. With advances in breast cancer screening tools in recent years, the rate of cancer detection has increased. This has raised concerns regarding overdiagnosis. To prevent unwanted toxicities associated with overtreatment, better treatment decision tools are needed. Several genomic assays are currently available and widely used to provide prognostic and predictive information and aid in decisions regarding appropriate use of adjuvant chemotherapy in HR-positive/HER2-negative early-stage breast cancer. Ongoing studies are refining the cutoffs for these assays and expanding the applicability to node-positive breast cancers. Furthermore, with several studies now showing benefit from the use of extended endocrine therapy, some of these assays may be able to identify the subset of patients who are at increased risk for late recurrence and who might benefit from extended endocrine therapy. Advances in molecular testing has enabled clinicians to offer more personalized treatments to their patients, improve patients’ compliance, and decrease anxiety and conflict associated with management decisions. Although small numbers of patients with HER2-positive and triple-negative breast cancers were also included in some of these studies, use of genomic assays in this subset of patients is very limited and currently not recommended.

INTRODUCTION

Hodgkin lymphoma, previously known as Hodgkin’s disease, is a B-cell lymphoproliferative disease characterized by a unique set of pathologic and epidemiologic features. The disease is characterized by the presence of multinucleate giant cells called Hodgkin Reed-Sternberg (HRS) cells.¹ Hodgkin lymphoma is unique compared to other B-cell lymphomas because of the relative rarity of the malignant cells within affected tissues. The HRS cells, which usually account for only 0.1% to 10% of the cells, induce accumulation of nonmalignant lymphocytes, macrophages, granulocytes, eosinophils, plasma cells, and histiocytes, which then constitute the majority of tumor cellularity.² Although the disease was first described by Sir Thomas Hodgkin in 1832, in part because of this unique histopathology, it was not until the 1990s that it was conclusively demonstrated that HRS cells are in fact monoclonal germinal center–derived B cells.

Due to the development of highly effective therapies for Hodgkin lymphoma, cure is a reasonable goal for most patients. Because of the high cure rate, late complications of therapy must be considered when selecting treatment. This article reviews the clinical features and treatment options for advanced stage and relapsed/refractory Hodgkin lymphoma. A previously published article reviewed the epidemiology, etiology/pathogenesis, pathologic classification, initial workup, and staging evaluation of Hodgkin lymphoma, as well as the prognostic stratification and treatment of patients with early-stage Hodgkin lymphoma.³ 

PRESENTATION, INITIAL EVALUATION, AND PROGNOSIS

Overall, classical Hodgkin lymphoma (cHL) usually presents with asymptomatic mediastinal or cervical lymphadenopathy. At least 50% of patients will have stage I or II disease.⁴ A mediastinal mass is seen in most patients with nodular sclerosis cHL, at times showing the characteristics of bulky (> 10 cm) disease. Constitutional, or B, symptoms (fever, night sweats, and weight loss) are present in approximately 25% of all patients with cHL, but 50% of advanced stage patients. Between 10% and 15% of patients will have extranodal disease, most commonly involving lung, bone, and liver. Lymphocyte-predominant Hodgkin lymphoma (LPHL) is a rare histological subtype of Hodgkin lymphoma that is differentiated from cHL by distinct clinicopathological features. The clinical course and treatment approach for LPHL are dependent upon the stage of disease. The clinicopathological features of LPHL are discussed in the early-stage Hodgkin lymphoma article.³

For the purposes of prognosis and selection of treatment, Hodgkin lymphoma is commonly classified as early stage favorable, early stage unfavorable, and advanced stage. For advanced stage Hodgkin lymphoma patients, prognosis can be defined using a tool commonly referred to as the International Prognostic Score (IPS). This index consists of 7 factors: male gender, age 45 years or older, stage IV disease, hemoglobin < 10.5 g/dL, white blood cell (WBC) count > 15,000/μL, lymphopenia (absolute lymphocyte count < 600 cells/μL or lymphocytes < 8% of WBC count), and serum albumin < 4 g/dL.⁵ In the original study by Hasenclever et al,⁵ the 5-year freedom from progression (FFP) ranged from 42% to 84% and the 5-year overall survival (OS) ranged from 56% to 90%, depending on the number of factors present. This scoring system, however, was developed using a patient population treated prior to 1992. Using a more recently treated patient population, the British Columbia Cancer Agency (BCCA) found that the IPS is still valid for prognostication, but outcomes have improved across all IPS groups, with 5-year FFP now ranging from 62% to 88% and 5-year OS ranging from 67% to 98%.⁶ This improvement is likely a reflection of improved therapy and supportive care. Table 1 shows the PFS and OS within each IPS group, comparing the data from the German Hodgkin Study Group (GHSG) and BCCA group.^5,6

 A closer evaluation of the 7 IPS variables was performed using data from patients enrolled in the Eastern Cooperative Oncology Group (ECOG) 2496 trial.⁷ This analysis revealed that, though the original IPS remained prognostic, its prognostic range has narrowed. Age and stage of disease remained significant for FFP, while age, stage of disease, and hemoglobin level remained significant for OS. An alternative prognostic index, the IPS-3, was constructed using age, stage, and hemoglobin levels. IPS-3, which identifies 4 risk groups, performed as a better tool for risk prediction for both FFP and OS, suggesting that it may provide a simpler and more accurate risk assessment than the IPS in advanced HL.⁷

High expression of CD68 is associated with adverse outcomes, whereas high FOXP3 and CD20 expression on tumor cells are predictors of superior outcomes.⁸ A recent study found that CD68 expression was associated with OS. Five-year OS was 88% in those with less than 25% CD68 expression, versus 63% in those with greater than 25% CD68 expression.⁹

Roemer and colleagues evaluated 108 newly diagnosed cHL biopsy specimens and found that almost all cHL patients had concordant alteration of PD-L1 (programmed death ligand-1) and PD-L2 loci, with a spectrum of 9p24.1 alterations ranging from low level polysomy to near uniform 9p24.1 amplification. PD-L1/PD-L2 copy number alterations are therefore a defining pathobiological feature of cHL.¹⁰ PFS was significantly shorter for patients with 9p24.1 amplification, and those patients were likely to have advanced disease suggesting that 9p24.1 amplification is associated with less favorable prognosis.¹⁰ This may change with the increasing use of PD-1 inhibitors in the treatment of cHL.

High baseline metabolic tumor volume and total lesion glycolysis have also been associated with adverse outcomes in cHL. While not routinely assessed in practice currently, these tools may ultimately be used to assess prognosis and guide therapy in clinical practice.¹¹

 

ADVANCED STAGE HODGKIN LYMPHOMA

FRONTLINE THERAPY

First-line Chemotherapy 

Chemotherapy plays an essential role in the treatment of advanced stage Hodgkin lymphoma. In the 1960s, the MOPP regimen (nitrogen mustard, vincristine, procarbazine, prednisone) was developed, with a 10-year OS of 50% and a progression-free survival (PFS) of 52% reported in advanced stage patients. The complete remission (CR) rate was 81%, and 36% of patients who achieved CR relapsed later.¹² This chemotherapy regimen is associated with a significant rate of myelosuppression and infertility as well as long-term risk of secondary myelodysplasia and acute leukemias.^13,14 This led to the development of newer regimens such as ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine).¹⁵ In a randomized trial, ABVD showed improved failure-free survival (FFS) over MOPP (61% versus 50% at 5 years) but similar OS (66%–73%).¹⁶ In light of these findings, and considering the lower rate of infertility and myelotoxicity, ABVD became the standard of care for advanced stage cHL in the United States.

The Stanford V regimen was developed in an attempt to further minimize toxicity.¹⁷ Stanford V is a condensed, 12-week chemotherapy regimen that includes mechlorethamine, doxorubicin, vinblastine, etoposide, prednisone, vincristine, and bleomycin, followed by involved-field radiation therapy (IFRT). Subsequent trials compared the Stanford V and ABVD regimens and showed similar OS, freedom from treatment failure (FFTF), and response rates.^18,19 The ABVD regimen was noted to have higher pulmonary toxicity, while other toxicities such as lymphopenia and neuropathy were higher with the Stanford V regimen. In addition, Stanford V requires patients to receive radiation therapy (RT) to original sites of disease larger than 5 cm in size and contiguous sites. 

Another regimen which has been studied extensively for advanced stage Hodgkin lymphoma, and is considered a standard of care in some parts of the world, is escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone). In the HD9 study (n = 1196), the GHSG evaluated BEACOPP, escalated BEACOPP, and COPP/ABVD in advanced stage Hodgkin lymphoma.²⁰ All arms of the study included 30 Gy RT to sites of bulky disease or residual disease. This study showed improved OS and FFTF with escalated BEACOPP, but at the cost of higher rates of toxicity. At 10 years, FFTF was 64%, 70%, and 82% with OS rates of 75%, 80%, and 86% for COPP/ABVD, baseline BEACOPP, and escalated BEACOPP, respectively (P < 0.001). The rate of secondary acute leukemia 10 years after treatment was 0.4% for COPP/ABVD, 1.5% for BEACOPP, and 3.0% for escalated BEACOPP. However, 3 subsequent randomized trials did not confirm a survival benefit with escalated BEACOPP relative to ABVD. In the HD 2000 trial (n = 295)²¹ and in a trial by Viviani and colleagues (n = 331),²² an improvement in OS was not demonstrated in favor of escalated BEACOPP. These studies also confirmed a higher rate of toxicities as well as secondary malignancies associated with the escalated BEACOPP regimen. In the EORTC20012 Intergroup trial (n = 549), 8 cycles of ABVD was compared with 4 cycles of escalated BEACOPP followed by 4 cycles of baseline BEACOPP, without radiation, in patients with clinical stage III or IV Hodgkin lymphoma with IPS score ≥ 3. Both regimens resulted in statistically similar FFS (63.7% in ABVD × 8 versus 69.3% in BEACOPP 4+4) and OS (86.7% in ABVD × 8 vs 90.3% in BEACOPP 4+4).²³

In the United States, ABVD (6–8 cycles) is commonly used, although escalated BEACOPP (particularly for patients with an IPS of 4 or higher) and Stanford V are considered appropriate as well.²⁴ In the North American Intergroup study comparing ABVD to Stanford V, and in the trial by Viviani et al, ABVD was associated with a 5- to 7-year FFS of 73% to 79% and OS of 84% to 92%.^19,22 Given these excellent results, as well as the potential to cure patients with second-line therapy consisting of autologous hematopoietic cell transplantation (auto-HCT), the general consensus among most U.S. hematologists and oncologists is that ABVD remains the treatment of choice, and that the improved FFS/PFS with escalated BEACOPP is not outweighed by the additional toxicity associated with the regimen. There may, however, be a role for escalated BEACOPP in select patients who have a suboptimal response to ABVD as defined by interim positron emission tomography (iPET) scan (see below).

Brentuximab vedotin is an anti-CD30 antibody-drug conjugate (ADC) consisting of an anti-CD30 antibody linked to monomethyl auristatin E (MMAE), a potent antitubulin agent. CD30 is highly expressed on HRS cells and also in anaplastic large cell lymphoma. Upon binding to CD30, the ADC/CD30 complex is then internalized and directed to the lysosome, where the ADC is proteolytically cleaved, releasing MMAE from the antibody. MMAE then disrupts microtubule networks within the cell, leading to G2/M cycle arrest and apoptosis. CD30 is consistently expressed on HRS cells. In addition to being studied in the relapsed/refractory setting (described below), brentuximab has been studied in the first-line setting. In a phase 1 trial, brentuximab combined with ABVD was associated with increased pulmonary toxicity, while brentuximab + AVD had no significant pulmonary toxicity, with an excellent CR rate (96%), suggesting that substituting brentuximab for bleomycin may be an effective strategy. In addition to possibly being more efficacious, this strategy would also have the benefit of eliminating the risk of bleomycin pulmonary toxicity.²⁵ Based on this data, a large international phase 3 study (the ECHELON-1 trial) comparing ABVD versus brentuximab + AVD in advanced stage cHL patients was recently completed. This study enrolled 1334 patients, and preliminary results were recently announced. With a median follow-up of 24 months, the brentuximab + AVD arm had a 4.9% absolute improvement in PFS relative to the ABVD arm (82.1% versus 77.2%). The brentuximab + AVD arm had an increased incidence of febrile neutropenia, managed with growth factors and peripheral neuropathy requiring dose adjustments, whereas the ABVD arm had an increased rate and severity of pulmonary toxicity.²⁶ Further follow-up will be required to determine whether this will translate into a survival benefit. See Table 2 for a summary of recent large randomized prospective phase 3 trials in advanced stage Hodgkin lymphoma. 

 

Alternative Regimens in Older Patients

Patients older than 60 years of age often have poor tolerance for ABVD and especially escalated BEACOPP. This results in increased treatment-related mortality and reduced overall dose intensity, with higher relapse rates and poor OS. In an attempt to improve on the results of treatment of elderly patients with Hodgkin lymphoma, alternative regimens have been explored. One example is PVAG (prednisone, vinblastine, doxorubicin, gemcitabine). With this regimen, the 3-year OS was 66% and PFS was 58%. One patient out of 59 died from treatment-related toxicity, which is much improved over the historical figures for elderly patients with Hodgkin lymphoma.²⁷ Another commonly used approach in practice is to simply omit bleomycin from ABVD. In the early-stage setting (GHSG HD-13 trial), this regimen (referred to as AVD) led to 89.6% PFS at 5 years, compared to 93.5% with ABVD.²⁸ It therefore stands to reason that this should be a reasonable option in older or more frail advanced stage cHL patients as well.

Brentuximab has been evaluated as a single-agent therapy for first-line therapy of elderly patients with Hodgkin lymphoma. In a phase 2 study, 27 patients (63% with advanced stage disease) were treated, with a 92% overall response rate and 73% CR rate. However the median duration of remission was disappointing at only 9.1 months.²⁹ Based on this data, single-agent brentuximab appears to be a reasonable and well tolerated option for frail or elderly patients, although with the caveat that long-term disease control is relatively uncommon.

RESPONSE-ADAPTED FRONTLINE THERAPY USING INTERIM PET SCAN

In recent years, response-adapted treatment approaches have been extensively researched in cHL using iPET. The goal is to reduce toxicity by minimizing therapy in those who achieve negative iPET and/or to intensify treatment for patients with suboptimal response on iPET. Gallamini et al evaluated the prognostic role of an early iPET scan in advanced Hodgkin lymphoma patients (n = 190) treated with ABVD. This study found that patients with positive iPET had a 2-year PFS of 12.8% versus 95.0% in patients with negative iPET. This result was highly statistically significant (P < 0.0001). This study also showed that PET-2 (iPET after 2 cycles of ABVD) superseded the prognostic value of the IPS at diagnosis.³⁰ As a result, numerous subsequent studies have been pursued using iPET for risk-adapted treatment in cHL.

A critical element to the conduct of iPET risk-adapted treatment for cHL is the interpretation of the iPET. In hopes of standardizing iPET interpretation in clinical trials, a scoring system called the Deauville score was developed. The Deauville score ranges from 1 to 5 (Table 3).

 For risk-adapted trials in cHL, a Deauville score of 1 to 3 is generally considered a negative iPET, whereas a score of 4 or 5 is considered a positive iPET.^31,32

The SWOG (Southwest Oncology Group) S0816 trial (n = 358) evaluated iPET-adapted treatment after 2 cycles of ABVD in stage III or IV Hodgkin lymphoma patients. Patients with positive iPET (Deauville score 4 to 5; n = 60) received escalated BEACOPP for 6 cycles, whereas iPET-negative (Deauville score 1 to 3; n = 271) patients continued to receive 4 more cycles of ABVD. The 2-year PFS was 64% for iPET-positive patients.³³ This PFS was much higher than the expected 15% to 30% from prior studies such as Gallamini et al,³⁰ suggesting that the treatment intensification may have been of benefit.

In the HD0801 study (n = 519), newly diagnosed advanced Hodgkin lymphoma patients with positive iPET after 2 cycles of ABVD (n = 103) received early ifosfamide-containing salvage therapy followed by high-dose therapy with autologous stem cell rescue. The 2-year PFS was 76% for PET-2–positive patients, comparable with PET-2–negative patients who had PFS of 81%.³⁴ Again, this result for iPET-positive patients was much better than expected based on the historical control from Gallamini et al, suggesting that the treatment intensification may have been beneficial. It should be emphasized, however, that neither HD0801 nor S0816 were randomized prospective trials; rather, all iPET-positive patients were assigned to an intensified treatment approach.

In the HD18 trial (n = 1100), patients with advanced stage cHL started therapy with escalated BEACOPP and underwent an iPET after 2 cycles. For those with a positive iPET, rituximab was added to escalated BEACOPP in the experimental arm (n = 220) for cycles 3 through 8. The control group (n = 220) continued to receive 6 more cycles of escalated BEACOPP. In the 2 groups, the 3-year PFS was similar (91.4% in escalated BEACOPP, 93% in rituximab + escalated BEACOPP), suggesting no significant benefit with addition of rituximab.³⁵ This study also calls into question whether iPET provides useful information for patients receiving intensive therapy such as escalated BEACOPP, and indicates that the historical control data for iPET-positive patients from Gallamini et al may not be consistently reproduced in other prospective trials. As a result, nonrandomized trials that implement an iPET risk-adapted approach should be interpreted with caution. See Table 4 for a summary of recent trials in advanced stage Hodgkin lymphoma using iPET scan to guide therapy. 

 

RADIATION THERAPY IN FRONTLINE TREATMENT

In patients with advanced stage Hodgkin lymphoma, IFRT to initial bulky sites of disease may be incorporated into frontline therapy to improve local control. However, whether this provides a survival benefit and which patients benefit most from consolidative RT remain unclear.

The European Organization for Research and Treatment of Cancer (EORTC) completed a randomized study in advanced stage Hodgkin lymphoma patients who achieved complete or partial remission after MOPP-ABV.³⁶ Patients in CR were randomly assigned to receive no further treatment versus IFRT (24 Gy to all initially involved nodal areas and 16 to 24 Gy to all initially involved extranodal sites). Patients in partial remission (PR) were treated with 30 Gy to nodal areas and 18 to 24 Gy to extranodal sites. Among the CR patients, the 5-year event-free survival (EFS) was 79% to 84% and did not differ for those who received radiation versus those who did not. Five-year OS was 85% to 91% and also did not differ between the 2 groups. However, among the patients in PR after chemotherapy, the 5-year EFS was 79% and the 5-year OS was 87%, which is better than expected for PR patients, indicating a possible benefit to RT in patients with a partial response after chemotherapy. In the GHSG HD12 trial, patients with advanced stage Hodgkin lymphoma who had a residual lesion by computed tomography (CT) (but not analyzed by PET) had a very subtle improvement in FFTF (90% versus 87%) in favor of consolidation with IFRT, but again no survival benefit was seen.³⁷

The EORTC and HD12 studies described above utilized CT scan for assigning remission status following chemotherapy, and it is now well known that many patients with residual masses (by CT) after chemotherapy may in fact be cured, as such residual radiographic abnormalities may simply be composed of fibrosis. PET scan is more accurate than CT in identifying patients who truly have residual active disease following chemotherapy. As a result, the EORTC study discussed above and the GHSG HD12 trial are of limited relevance in the modern era, in which patients routinely undergo PET scan at the end of therapy. Restricting IFRT to sites that remain PET-positive after completing chemotherapy may be a reasonable strategy that would allow for the avoidance of RT in many patients, and may obviate the need for aggressive second-line therapy (eg, high-dose therapy and autologous hematopoietic cell transplant [auto-HCT]). This approach was taken in the GHSG HD15 trial (n = 2182) in which advanced stage patients were treated with 3 variations on the BEACOPP regimen (8 cycles of escalated BEACOPP, 6 cycles of escalated BEACOPP, or 8 cycles of baseline BEACOPP, randomized in a 1:1:1 ratio). Patients with a residual mass of 2.5 cm or greater on CT scan then underwent a PET scan; if the lesion was PET positive, it was treated with 30 Gy of IFRT. This overall strategy was very effective, with 5-year FFTF rates of 84.4%, 89.3%, and 85.4%, respectively. The OS rates were 91.9%, 95.3%, and 94.5%, respectively. For patients with lesions that remained PET positive after chemotherapy, the PFS rate was 86.2% at 48 months, whereas patients in PR with persistent mass ≥ 2.5 cm but with negative PET had a PFS of 92.6%, similar to that of patients in CR.³⁸ With this approach of BEACOPP followed by PET-guided radiation, the proportion of patients receiving RT was reduced from 71% (in the HD9 study) to only 11% in the HD15 study,³⁸ with no apparent loss in overall efficacy when comparing the results of the 2 studies.

UPFRONT STEM CELL TRANSPLANTATION 

To further improve outcomes of patients with advanced Hodgkin lymphoma with high-risk disease, high-dose therapy with auto-HCT has been explored as part of frontline therapy. While this has been shown to be feasible in such patients,³⁹ randomized trials have not shown a clear benefit in terms of FFS or OS with upfront auto-HCT. ^40,41 Therefore, auto-HCT is not considered a standard component of frontline therapy for cHL patients who achieve CR by PET/CT scan.

RELAPSED AND REFRACTORY HODGKIN LYMPHOMA 

Depending on the stage, risk factors, and frontline regimen utilized, between 5% and 40% of patients with Hodgkin lymphoma can be expected to experience either primary induction failure or a relapse after attaining remission with frontline therapy.³ Primary refractory Hodgkin lymphoma, which occurs in up to 5% to 10% of patients, is defined as progression or no response during induction treatment or within 90 days of completing treatment. In cases where remission status is in question, an updated tissue biopsy is recommended. Biopsy is also recommended in cases in which new sites of disease have appeared or if relapse has occurred after a durable period of remission. Restaging is recommended at the time of relapse. 

 

For younger patients with relapsed/refractory Hodgkin lymphoma, the standard of care in most cases is second-line (or salvage) chemotherapy followed by high-dose therapy and auto-HCT. For patients not felt to be candidates for auto-HCT, options include conventional second-line chemotherapy alone, salvage radiotherapy, novel agents such as brentuximab or immune checkpoint inhibitors, and/or participation in clinical trials. 

CONVENTIONAL MULTI-AGENT CHEMOTHERAPY REGIMENS

Numerous conventional regimens have been shown in phase 2 studies to be active in relapsed and refractory Hodgkin lymphoma. These include platinum-based regimens, gemcitabine-based regimens, and alkylator-based regimens. No randomized trials in Hodgkin lymphoma have been conducted comparing these regimens. In general, regimens are chosen based on the patient’s age, performance status, comorbidities, and whether auto-HCT is being considered. 

In the United States, platinum-based regimens such as ICE (ifosfamide, carboplatin, etoposide),⁴² DHAP (dexamethasone, cisplatin, high-dose cytarabine),⁴³ ESHAP (etoposide, methylprednisolone, high-dose cytarabine, cisplatin),⁴⁴ GDP (gemcitabine, cisplatin, dexamethasone),⁴⁵ and GCD (gemcitabine, carboplatin, dexamethasone)⁴⁶ are all considered appropriate second-line therapy options for patients being considered for auto-HCT, due to their high response rates and because autologous hematopoietic stem cell collection remains feasible after these regimens. Response rates range from 60% to 88%, with CR rates between 17% and 41%, and toxic death rates generally well below 5%.

Other gemcitabine-based regimens such as IGEV (ifosfamide, gemcitabine, vinorelbine) and GVD (gemcitabine, vinorelbine, liposomal doxorubicin) are also effective.^47,48 GVD is an excellent choice since it is a generally well-tolerated outpatient regimen with a 60% response rate even in heavily pretreated patients.⁴⁸ Stem cell collection remains feasible after both IGEV and GVD as well. ABVD can produce CR in approximately 20% to 50% of patients initially treated with MOPP.^49–51 In practice, however, most patients today with relapsed or refractory Hodgkin lymphoma have already received ABVD as part of their first-line therapy, and retreatment with ABVD is not a good option because it would be associated with prohibitively high cumulative doses of doxorubicin. 

These multi-agent chemotherapy regimens may not be tolerated well in patients over age 65 to 70 years or those with significant underlying comorbidities. In recent years, bendamustine has emerged as one of the most active conventional agents for cHL, with overall response rates of 53% to 58% in heavily pre-treated patients.^52,53 Bendamustine can generally be tolerated even in elderly patients as well.

Some centers, particularly in Europe, investigated aggressive salvage regimens such as mini-BEAM (carmustine, etoposide, cytarabine, melphalan)⁵⁴ or dexa-BEAM (BEAM plus dexamethasone).⁵⁵ These regimens, however, are associated with significant hematologic toxicity and high (2%–5%) treatment-related mortality. As a result, these are rarely used in the United States.

For patients who have progressed after (or are not candidates for) platinum- and/or gemcitabine-based therapy, older alkylator-based regimens such as MOPP, C-MOPP, or ChlVPP (chlorambucil, vinblastine, procarbazine, prednisone) can be considered.^56–58 However, these regimens are associated with significant bone marrow suppression, and autologous hematopoietic stem cell collection may no longer be feasible after such regimens. Therefore, these regimens should only be given to patients not felt to be auto-HCT candidates, or patients for whom autologous hematopoietic stem cell collection has already been completed. Weekly vinblastine or single-agent gemcitabine are palliative chemotherapy options, with response rates in the 60% to 80% range. Patients can sometimes be maintained on such low-intensity palliative regimens for 6 to 12 months or longer.^59,60

BRENTUXIMAB VEDOTIN

Several trials are evaluating incorporation of brentuximab into second-line therapy in transplant-eligible patients. These approaches have used brentuximab prior to, concurrent with, or following platinum-based chemotherapy.⁶¹ While there is currently no consensus on the optimal way to incorporate brentuximab into salvage therapy, it is possible that the use of brentuximab or other novel agents in salvage therapy may allow for avoidance of conventional chemotherapy in some patients. In addition, this may translate into more patients proceeding to auto-HCT in a PET negative state. PET negativity prior to auto-HCT is a powerful predictor of long-term remission after auto-HCT, so any intervention that increases the rate of PET negativity prior to auto-HCT would be expected to improve outcomes with auto-HCT.^62–65

For patients not being considered for autoHCT, or those for whom platinum-based salvage therapy was ineffective, single-agent brentuximab is an excellent option. In 2 phase 2 studies, an overall response rate (ORR) of 60% to 75% (including a CR rate of 22%–34%) was seen in relapsed and refractory Hodgkin lymphoma patients.⁶⁶ The US Food and Drug Administration (FDA) approved brentuximab vedotin in August 2011 for treatment of relapsed and refractory Hodgkin lymphoma, after a failed auto-HCT, or in patients who are not auto-HCT candidates and who have received at least 2 prior chemotherapy regimens. With more extended follow-up, it has become clear that a proportion of patients who achieve CR to brentuximab may maintain remission long-term—58% at 3 years and 38% at 5 years.⁶⁷ These patients may in fact be cured, in many cases without having undergone allogeneic HCT (allo-HCT) after brentuximab.

 

PD-1 (IMMUNE CHECKPOINT) INHIBITORS

As discussed earlier, PD-L1/PD-L2 copy number alterations represent a disease-defining feature of cHL. Alterations in chromosome 9p24.1 increase the expression of PD-1 ligands PD-L1 and PD-L2. Nivolumab and pembrolizumab are PD-1-blocking antibodies, which have recently been FDA approved for relapsed and refractory cHL. In a study with 23 patients, with 78% of them relapsing after auto-HCT and 78% relapsing after brentuximab, nivolumab produced an objective response in 87% of the patients, with 17% achieving CR and 70% achieving PR. The rate of PFS was 86% at 24 weeks.⁶⁸ Pembrolizumab, another PD-1 antagonist, was also tested in relapsed and refractory Hodgkin lymphoma. In the KEYNOTE-087 study (n = 210), pembrolizumab produced an ORR of 64% to 70% in 3 different cohorts of relapsed and refractory cHL patients. Overall CR rate was 22%.⁶⁹ In general, these agents are well tolerated, although patients must be monitored closely for

inflammatory/autoimmune-type toxicities including skin rash, diarrhea/colitis, transaminitis, endocrine abnormalities, and pneumonitis. Prompt recognition and initiation of corticosteroids is essential in managing these toxicities. Of note, PD-1 inhibitors should be given very cautiously to patients with a prior history of allo-HCT, since 30% to 55% of such patients will experience acute graft-versus-host disease (GVHD) in this setting. In 2 retrospective studies, the response rate was very high at 77% to 95%; however, 10% to 26% of all patients treated with PD-1 inhibitors post-allo-HCT died from GVHD induced by PD-1 inhibition.^70,71 These risks and benefits therefore need to be carefully weighed in the post-allo-HCT setting. In another recent study, the outcomes were reported for 39 patients who underwent allo-HCT after prior therapy with a PD-1 inhibitor. Three patients (7.7%) developed lethal acute GVHD, suggesting there may be an increased risk of GVHD in patients undergoing allo-HCT after prior PD-1 inhibitor therapy.⁷²

AUTOLOGOUS STEM CELL TRANSPLANTATION 

Several studies have shown an improved disease-free survival (DFS) or FFS in patients with relapsed cHL treated by auto-HCT as compared to those receiving conventional chemotherapy alone.^55,73,74 Overall, for relapsed disease, one can expect an approximately 50% to 60% chance for DFS at 5 years post-transplant. In a retrospective, matched-pair analysis, FFP was 62% for auto-HCT patients, compared to 32% for conventional chemotherapy patients. OS, however, was similar for the 2 groups (47%–54%). Patients failing induction therapy or relapsing within 1 year were seen to benefit the most from auto-HCT, including an OS benefit.⁷⁴

A European prospective randomized trial was conducted comparing conventional salvage therapy to auto-HCT. In this study, 161 patients with relapsed Hodgkin lymphoma were treated with 2 cycles of dexa-BEAM. Those with chemo-sensitive disease were then randomized to either 2 more cycles of dexa-BEAM or high-dose BEAM with auto-HCT. Auto-HCT was associated with an approximately 55% FFTF at 3 years, versus 34% with conventional chemotherapy alone.⁵⁵ This benefit again was most apparent for patients relapsing within 1 year of completion of primary therapy, although an OS benefit was not seen with auto-HCT. For patients with late relapse (>1 year after completion of primary therapy), auto-HCT was associated with an approximately 75% FFTF at 3 years, versus 50% with chemotherapy alone. One other small randomized trial of auto-HCT in relapsed and refractory Hodgkin lymphoma also showed an improved 3-year EFS in favor of auto-HCT (53% versus 10%), again with no difference in OS.⁷³ 

The lack of OS benefit seen in these studies suggests that auto-HCT at first or second relapse provides comparable outcomes. Auto-HCT offers the benefit of avoiding the long-term toxicities associated with multiple salvage regimens and the anxiety associated with multiple relapses. In addition, the treatment-related mortality with auto-HCT is now in the 1% to 2% range in younger patients, at centers that perform the procedure routinely. For all of these reasons, auto-HCT is commonly recommended by physicians for Hodgkin lymphoma patients in first or second relapse. In most cases, transplant is favored in first relapse, since waiting until second relapse may be associated with a lower chance of achieving CR and difficulty collecting sufficient hematopoietic stem cells. For patients with early relapse or primary refractory disease, an even stronger case can be made for auto-HCT as the best option to achieve sustained control of the disease. For patients with late relapse, conventional salvage therapy alone may be a reasonable option, particularly in older or frail patients, or those with significant comorbid conditions. 

The optimal conditioning regimen for autoHCT for relapsed and refractory Hodgkin lymphoma remains undefined. No randomized trials have been performed comparing conditioning regimens for relapsed and refractory Hodgkin lymphoma. One retrospective study compared 92 patients with Hodgkin lymphoma who underwent auto-HCT using a total-body irradiation (TBI) regimen versus a chemotherapy-alone regimen. No difference in 5-year OS or EFS was seen.⁷⁵ Given the lack of benefit seen with TBI, along with reports of increased rates of secondary malignancies and myelodysplasia with TBI,⁷⁶ chemotherapy-alone conditioning regimens are most widely employed. For example, in the United States, either the BEAM or CBV (cyclophosphamide, carmustine, etoposide) regimens are used in over 80% of cases.⁷⁷ This practice was justified in a Center for International Blood and Marrow Transplant Research (CIBMTR) retrospective study comparing outcomes by conditioning regimens, in which no regimen performed better than BEAM or CBV.⁷⁸

IFRT is often given as an adjunctive therapy to sites of initial and/or relapsed disease following auto-HCT. Although a relatively common practice, whether this truly enhances outcomes beyond that obtained with auto-HCT alone is unclear. Two retrospective studies have shown some benefit in terms of improvement in OS at 3 to 5 years in the group that received IFRT (70%–73% versus 40%–56%).^79,80 Given the retrospective nature and small size of these studies, a prospective study would be needed to properly define the potential role for IFRT following auto-HCT in relapsed/refractory Hodgkin lymphoma. Another retrospective study (n = 73) that evaluated peri-transplant IFRT in Hodgkin lymphoma patients receiving auto transplant found no improvement in survival for patients who received peri-transplant IFRT. This study, however, did show a survival benefit in the subgroup of patients with limited stage disease.⁸¹

 

Prognostic Factors Associated with Outcome with Auto-HCT

The factor most consistently associated with improved outcome for patients with relapsed and refractory Hodgkin lymphoma who undergo auto-HCT is the disease status at transplant.^63,77 Those in a second CR, versus a chemo-sensitive relapse (but not CR), versus a chemo-refractory relapse have DFS rates of 60% to 70%, 30% to 40%, and 10% to 20%, respectively.⁶³ The duration between remission and relapse also has important prognostic significance. Late relapse (> 1 year after completion of frontline therapy) is associated with better outcomes as compared to early relapse.⁵⁵ Other factors with prognostic significance at relapse include anemia, time to relapse and clinical stage, B symptoms, extranodal disease, number of prior chemotherapy regimens, and performance status.^42,82 The prognostic impact of pretransplant disease status has been confirmed by studies using functional imaging (eg, FDG-PET or gallium scans). In a report by Moskowitz et al, patients with negative functional imaging following second-line therapy had a 77% EFS post-auto-HCT versus 33% in those whose functional imaging remained positive.⁶² Very similar findings have been reported by other groups.^63–65

Post-Auto-HCT Brentuximab Maintenance

In the multicenter, randomized, double-blinded phase 3 AETHERA trial (n = 329), brentuximab (n = 165) was compared with placebo (n = 164) in patients with unfavorable risk relapsed or primary refractory cHL who had undergone autologous transplant. Eligible patients had at least 1 of the following risk factors for progression after auto-HCT: primary refractory Hodgkin lymphoma (failure to achieve complete remission), relapsed Hodgkin lymphoma with an initial remission duration of less than 12 months, or extranodal involvement at the start of pre-transplantation salvage chemotherapy. Patients were required to have CR, PR, or stable disease after pretransplant salvage chemotherapy with adequate kidney, liver, and bone marrow function. Patients who previously received brentuximab were excluded. Patients received 16 cycles of brentuximab or placebo once every 3 weeks starting 30 to 45 days after transplant. The PFS was significantly improved in the brentuximab group when compared to the placebo group (hazard ratio 0.57; P = 0.0013) after a median observation time of 30 months. Median PFS was 42.9 months in the brentuximab group versus 24.1 months in the placebo group; estimated 2-year PFS rates were 63% in the brentuximab group and 51% in the placebo group. OS was not significantly different between the study groups (~85%), presumably due to the fact that patients in the control group who relapsed likely went on to receive brentuximab as a subsequent therapy.⁸³

PRIMARY REFRACTORY HODGKIN LYMPHOMA 

Patients with primary refractory Hodgkin lymphoma have a poor outcome. Salvage therapy using conventional chemotherapy and/or RT results in long-term DFS in 10% or fewer of such patients.^13,84 Given these poor outcomes with conventional salvage therapy, auto-HCT is considered to be the standard of care for this subset of patients. The GHSG retrospectively analyzed the prognostic factors and outcomes of patients with primary refractory Hodgkin lymphoma. The 5-year freedom-from-second-failure and the 5-year OS were reported to be 31% and 43%, respectively, for those patients treated with auto-HCT. Patients with poor functional status at time of transplant, age greater than 50 years, and failure to attain a temporary remission had a 0% 5-year OS, as compared to 55% in patients without any of these risk factors.⁸⁵ A large retrospective European study showed that patients with chemo-resistant disease who underwent transplant had a 19% survival at 5 years.⁶³ Hence, even patients with primary refractory Hodgkin lymphoma have some chance of achieving long-term survival following auto-HCT. 

SALVAGE RADIOTHERAPY

The GHSG performed a retrospective analysis of the efficacy of salvage RT in patients with refractory or first-relapsed Hodgkin lymphoma. Five-year FFTF and OS rates were 28% and 51%, respectively. Patients with a limited-stage relapse and without B symptoms were more likely to benefit from salvage RT.⁸⁶ Campbell et al reported on 81 patients undergoing salvage RT for persistent or recurrent Hodgkin lymphoma after chemotherapy. The 10-year FFTF and OS rates were 33% and 46%, respectively.⁸⁷ Similarly, Wirth et al reported a 5-year FFS of 26% and 5-year OS of 57%. These figures were 36% and 75%, respectively, in patients whose relapse was limited to supradiaphragmatic nodal sites without B symptoms.⁸⁸ RT therefore may be a useful strategy for a subset of patients who relapse following chemotherapy, particularly those with a limited-stage relapse, without B symptoms, and those with relapsed disease after a CR, as opposed to those with a partial response or lack of response to the prior chemotherapy regimen. 

INVESTIGATIONAL AGENTS AND NOVEL COMBINATIONS

Several biological therapies are emerging as options for the treatment of refractory or relapsed disease. These therapies consist of monoclonal antibodies and ADCs that target cell surface antigens, or small molecules that inhibit key intracellular pathways within neoplastic cells. 

 

Rituximab

Rituximab is a chimeric anti-CD20 monoclonal antibody used widely in B-cell non-Hodgkin lymphomas. The CD20 molecule is typically highly expressed in nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL). Two studies (one in relapsed patients, the other in a mixture of relapsed and previously untreated patients) showed significant activity of rituximab in relapsed NLPHL, with ORRs ranging from 94% to 100%, CR rates ranging from 41% to 53%, and median duration of remission in the 10- to 33-month range.^89,90 In cHL, CD20 is expressed in HRS cells in 20% to 30% of cases. In such cases, single-agent rituximab has also shown activity. There is also evidence that rituximab may be effective even in cases in which the HRS cells are CD20-negative, presumably by virtue of depleting reactive B lymphocytes from the microenvironment, which may enhance anti-tumor immunity, or by eliminating a putative CD20-expressing Hodgkin lymphoma stem cell.^91,92

Lenalidomide

Lenalidomide is an immunomodulatory drug that has multiple modes of action, including direct induction of apoptosis in tumor cells, antiangiogenic effects, and the activation of immune cells, such as natural killer cells and T cells. Lenalidomide has been shown to modify many features of the microenvironment of HRS cells and has demonstrated activity in other B-cell neoplasms. As a result, lenalidomide has been evaluated in relapsed and refractory Hodgkin lymphoma patients. A multicenter phase 2 study by Fehniger et al included 35 patients, 87% of whom had previously undergone HCT and 55% of whom were refractory to the last therapy.⁹³ All patients were given lenalidomide 25 mg/day from days 1 to 21 of a 28-day cycle until disease progression. One patient was noted to achieve CR, 6 achieved PR, and 5 had stable disease lasting more than 6 months, for an ORR of 19% and a “cytostatic overall response rate” of 33%. The median duration of CR/partial remission was 6 months, with the median time-to-treatment failure in responders (including those with stable disease > 6 months) being 15 months. Similarly, in another study, Böll et al evaluated 12 patients across 4 German centers with relapsed or refractory disease who were treated with oral lenalidomide for 21 days in a 28-day cycle. No radiological evidence of disease progression after 2 cycles of lenalidomide was seen in any of the enrolled patients. ORR was noted to be 50%, with 6 patients with stable disease and 5 patients achieving PR after 2 cycles.⁹⁴

Novel Brentuximab Combination Therapies

Brentuximab plus bendamustine. The combination of brentuximab and bendamustine was tested as an outpatient regimen in a phase 1/2 study (n = 55) in primary refractory Hodgkin lymphoma or after first relapse. The CR rate of the combination was 74%, with an overall objective response (CR + PR) of 93%. The CR rates were 64% and 84%, respectively, for refractory and relapsed patients. The PFS at 12 months was 80%, establishing this combination therapy as an effective salvage regimen with durable response.⁹⁵

Brentuximab plus nivolumab. Preliminary results have recently been presented from 2 studies^96,97 evaluating the combination of brentuximab and nivolumab. While this combination would still be considered investigational, these studies showed very encouraging ORRs of 90% to 100% and a CR rate of 62% to 66%. Longer follow-up is needed to determine whether these responses are durable and to document the toxicity profile of this combination.

Mammalian Target of Rapamycin Inhibitors

Two mammalian target of rapamycin (mTOR) inhibitors, everolimus and temsirolimus, are currently available in the United States. While neither drug currently has FDA approval for Hodgkin lymphoma, everolimus was evaluated in a phase 2 trial in a heavily pretreated group of relapsed/refractory patients. An ORR of 47% was seen, with a median time to progression of 7.2 months.⁹⁸

ALLOGENEIC STEM CELL TRANSPLANTATION 

Historically, patients who relapse after having an auto-HCT generally had a poor outcome, with a median survival of 2 to 3 years after failure of auto-HCT.⁹⁹ These patients may be offered palliative chemotherapy (see above), treatment with novel agents (see above), or enrollment in a clinical trial. Select patients may benefit from a second hematopoietic stem cell transplant, most commonly an allo-HCT. However, rare patients with late relapse after auto-HCT may be considered for a second auto-HCT, with a minority of such patients achieving a durable remission after the second auto-HCT.^100,101 Because relapse or progressive disease occurs most commonly in the first several months following auto-HCT, patients are more often considered for allo-HCT than a second auto-HCT. In addition, a second auto-HCT may not be feasible due to impaired bone marrow reserve and/or concerns for development of secondary myelodysplasia or acute myeloid leukemia.

 

Several studies have evaluated allo-HCT in relapsed/ refractory Hodgkin lymphoma. Early studies evaluating myeloablative allo-HCT for Hodgkin lymphoma showed excessive treatment-related mortality (up to 50%) and disappointingly low rates of long-term survival (< 25%).^102,103 This was likely related to the fact that, in that era, most of the patients with Hodgkin lymphoma evaluated for allo-HCT were heavily pretreated and therefore at a higher risk for toxicity as well as lymphoma progression. 

More recently, several studies have focused on the use of reduced-intensity conditioning (RIC) allo-HCT for relapsed and refractory Hodgkin lymphoma. This approach relies more on a “graft-versus-lymphoma” effect, the existence of which has been debated in Hodgkin lymphoma. Three single-center studies of RIC allo-HCT in patients with multiply recurrent Hodgkin lymphoma showed improved rates of treatment-related mortality (8%–16%) but still relatively low rates of long-term PFS (23%–39% at 2 to 4 years).^104–106 Interestingly, in one of these studies the outcomes were more favorable for patients who underwent haploidentical (versus matched sibling or matched unrelated donor) transplants.¹⁰⁵

Two large registry studies have also reported on the outcomes of RIC allo-HCT in patients with relapsed and refractory Hodgkin lymphoma.^107,108 These studies also confirmed a modest improvement in outcomes compared with those seen historically with myeloablative transplants. Treatment-related mortality at 1 to 2 years was 23% to 33%, depending on whether a matched sibling donor versus an unrelated donor was used. However, long-term PFS (18%–20% at 2 to 5 years) and OS (28%–37% at 2 to 5 years) remained poor, primarily due to high rates of progressive lymphoma post-transplant. In both of these studies, patients were heavily pretreated (84%–96% had received 3 or more prior lines of chemotherapy, and 62%–89% received a prior auto-HCT), with 47% to 55% of patients chemo-resistant prior to transplant. Of note, both of these registry studies reflect patients who underwent transplant prior to the widespread use of brentuximab and PD-1 inhibitors.

Based on the single-center and registry data above, a prospective multicenter European phase 2 trial was conducted to evaluate the benefit of RIC allo-HCT in Hodgkin lymphoma.¹⁰⁹ Ninety-two patients (86% with prior auto-HCT, 90% with 3 or more prior lines of therapy) were enrolled and given salvage therapy. Those who had stable disease or better following salvage therapy remained on protocol (n = 78) and underwent RIC with fludarabine and melphalan, followed by allo-HCT (70% with matched sibling donors). Treatment-related mortality was 15% at 1 year. Relapse or progression occurred in 49% at 2 years (35% if chemo-sensitive prior to transplant). Chronic GVHD was associated with a decreased rate of relapse, supporting the existence of a graft-versus-lymphoma effect in Hodgkin lymphoma. Unfortunately, PFS among all allografted patients was still relatively poor (24% at 4 years). However, among patients in CR prior to allo-HCT, a 50% PFS was seen at 4 years. Therefore, even in a prospective multicenter study, RIC allo-HCT offered significant benefit with manageable toxicity in relapsed and refractory Hodgkin lymphoma patients with chemo-sensitive disease. 

These studies suggest that outcomes with allo-HCT would improve further if implemented earlier in the course of disease and/or with a lower burden of disease at transplant. It has therefore been suggested that allo-HCT should be considered soon after failure of auto-HCT is documented. In a retrospective study by Sarina et al, 185 Hodgkin lymphoma patients who relapsed following auto-HCT were then immediately considered for reduced-intensity allo-HCT.¹¹⁰ Of these, 122 had a donor identified, and 104 (85%) actually underwent allo-HCT. These 104 patients were then compared to the other 81 patients who either had no donor identified or had a donor but did not receive the planned allo-HCT. Two-year PFS and OS were superior in the patients undergoing allo-HCT (39% versus 14% and 66% versus 42%, respectively, P < 0.001), with a median follow-up of 4 years. The presence of chronic GVHD again was associated with improved PFS and OS. Disease status prior to transplant remained highly predictive of PFS and OS by multivariate analysis. Two other smaller retrospective studies similarly found a survival benefit associated with allo-HCT compared with patients who underwent conventional salvage therapies alone.^111,112 These studies, although subject to the usual limitations of retrospective analyses, suggest that the results with reduced-intensity allo-HCT are in fact enhanced if applied earlier in the disease course, and are superior to those with conventional therapy alone. 

Currently, the exact role of allo-HSCT, including the optimal timing and optimal donor source (matched sibling versus haploidentical sibling versus matched unrelated donor), remain undefined for relapsed and refractory Hodgkin lymphoma. As discussed earlier, brentuximab is highly active in relapsed Hodgkin lymphoma patients, with a subset of patients still in CR at 5 years.⁶⁷ For such patients, avoiding the risks of allo-HCT is a desirable goal.

 

For those who relapse or progress after auto-HCT, a reasonable strategy therefore is to treat initially with brentuximab, unless the patient is already known to have responded poorly to brentuximab, or already has significant neuropathy. Those who achieve a CR to brentuximab are then observed. A subset of those patients will remain in remission at 5 years without further therapy. For those who relapse, or who achieve less than a CR to brentuximab, additional treatment (with brentuximab re-treatment being one option) followed by a reduced-intensity allo-HCT is a reasonable consideration. This approach has the theoretical advantages of (1) avoiding the risk of allo-HCT in the subset potentially cured by brentuximab, (2) getting patients to allo-HCT with fewer comorbidities (due to a lower total exposure to conventional chemotherapy pre-transplant), and (3) applying allo-HCT in the setting of sensitive disease/lower disease burden (due to the high efficacy of brentuximab). The results of a small study suggest that brentuximab may in fact be a very effective “bridge” to allotransplant. Chen et al¹¹³ reported on 18 patients with relapsed/refractory Hodgkin lymphoma (17 of whom had previously undergone auto-HCT) who were treated on brentuximab vedotin clinical trials. The data were retrospectively evaluated to determine the efficacy and safety of subsequent reduced-intensity allo-HCT. Remarkably, at 1 year the OS was 100%, PFS was 92%, and nonrelapse mortality was 0% with a median follow-up of 14 months. Hence, brentuximab is safe for use prior to reduced-intensity allo-HCT in heavily pre-treated patients and appears to be associated with very favorable post-transplant outcomes, particularly in comparison to older studies of allo-HCT in the era prior to brentuximab.

SUMMARY

Currently, cure is possible for the majority of patients diagnosed with advanced stage Hodgkin lymphoma. The challenge to the clinician is to provide curative treatment with the lowest risk of serious toxicities. Which regimen will best provide this balance of risk and benefit needs to be assessed based on the relapse risk, age, frailty, and comorbidity profile for an individual patient. For many patients with relapsed or refractory Hodgkin lymphoma, cure remains possible using approaches based on hematopoietic stem cell transplantation, RT, and/or brentuximab. In addition, there are now numerous conventional chemotherapy agents, RT strategies, and exciting newer agents such as PD-1 inhibitors, that can provide significant clinical benefit even when cure is not feasible.

INTRODUCTION

Hodgkin lymphoma, previously known as Hodgkin’s disease, is a B-cell lymphoproliferative disease characterized by a unique set of pathologic and epidemiologic features. The disease is characterized by the presence of multinucleate giant cells called Hodgkin Reed-Sternberg (HRS) cells.¹ Hodgkin lymphoma is unique compared to other B-cell lymphomas because of the relative rarity of the malignant cells within affected tissues. The HRS cells, which usually account for only 0.1% to 10% of the cells, induce accumulation of nonmalignant lymphocytes, macrophages, granulocytes, eosinophils, plasma cells, and histiocytes, which then constitute the majority of tumor cellularity.² Although the disease was first described by Sir Thomas Hodgkin in 1832, in part because of this unique histopathology, it was not until the 1990s that it was conclusively demonstrated that HRS cells are in fact monoclonal germinal center–derived B cells.

Due to the development of highly effective therapies for Hodgkin lymphoma, cure is a reasonable goal for most patients. Because of the high cure rate, late complications of therapy must be considered when selecting treatment. This article reviews the clinical features and treatment options for advanced stage and relapsed/refractory Hodgkin lymphoma. A previously published article reviewed the epidemiology, etiology/pathogenesis, pathologic classification, initial workup, and staging evaluation of Hodgkin lymphoma, as well as the prognostic stratification and treatment of patients with early-stage Hodgkin lymphoma.³ 

PRESENTATION, INITIAL EVALUATION, AND PROGNOSIS

Overall, classical Hodgkin lymphoma (cHL) usually presents with asymptomatic mediastinal or cervical lymphadenopathy. At least 50% of patients will have stage I or II disease.⁴ A mediastinal mass is seen in most patients with nodular sclerosis cHL, at times showing the characteristics of bulky (> 10 cm) disease. Constitutional, or B, symptoms (fever, night sweats, and weight loss) are present in approximately 25% of all patients with cHL, but 50% of advanced stage patients. Between 10% and 15% of patients will have extranodal disease, most commonly involving lung, bone, and liver. Lymphocyte-predominant Hodgkin lymphoma (LPHL) is a rare histological subtype of Hodgkin lymphoma that is differentiated from cHL by distinct clinicopathological features. The clinical course and treatment approach for LPHL are dependent upon the stage of disease. The clinicopathological features of LPHL are discussed in the early-stage Hodgkin lymphoma article.³

For the purposes of prognosis and selection of treatment, Hodgkin lymphoma is commonly classified as early stage favorable, early stage unfavorable, and advanced stage. For advanced stage Hodgkin lymphoma patients, prognosis can be defined using a tool commonly referred to as the International Prognostic Score (IPS). This index consists of 7 factors: male gender, age 45 years or older, stage IV disease, hemoglobin < 10.5 g/dL, white blood cell (WBC) count > 15,000/μL, lymphopenia (absolute lymphocyte count < 600 cells/μL or lymphocytes < 8% of WBC count), and serum albumin < 4 g/dL.⁵ In the original study by Hasenclever et al,⁵ the 5-year freedom from progression (FFP) ranged from 42% to 84% and the 5-year overall survival (OS) ranged from 56% to 90%, depending on the number of factors present. This scoring system, however, was developed using a patient population treated prior to 1992. Using a more recently treated patient population, the British Columbia Cancer Agency (BCCA) found that the IPS is still valid for prognostication, but outcomes have improved across all IPS groups, with 5-year FFP now ranging from 62% to 88% and 5-year OS ranging from 67% to 98%.⁶ This improvement is likely a reflection of improved therapy and supportive care. Table 1 shows the PFS and OS within each IPS group, comparing the data from the German Hodgkin Study Group (GHSG) and BCCA group.^5,6

 A closer evaluation of the 7 IPS variables was performed using data from patients enrolled in the Eastern Cooperative Oncology Group (ECOG) 2496 trial.⁷ This analysis revealed that, though the original IPS remained prognostic, its prognostic range has narrowed. Age and stage of disease remained significant for FFP, while age, stage of disease, and hemoglobin level remained significant for OS. An alternative prognostic index, the IPS-3, was constructed using age, stage, and hemoglobin levels. IPS-3, which identifies 4 risk groups, performed as a better tool for risk prediction for both FFP and OS, suggesting that it may provide a simpler and more accurate risk assessment than the IPS in advanced HL.⁷

High expression of CD68 is associated with adverse outcomes, whereas high FOXP3 and CD20 expression on tumor cells are predictors of superior outcomes.⁸ A recent study found that CD68 expression was associated with OS. Five-year OS was 88% in those with less than 25% CD68 expression, versus 63% in those with greater than 25% CD68 expression.⁹

Roemer and colleagues evaluated 108 newly diagnosed cHL biopsy specimens and found that almost all cHL patients had concordant alteration of PD-L1 (programmed death ligand-1) and PD-L2 loci, with a spectrum of 9p24.1 alterations ranging from low level polysomy to near uniform 9p24.1 amplification. PD-L1/PD-L2 copy number alterations are therefore a defining pathobiological feature of cHL.¹⁰ PFS was significantly shorter for patients with 9p24.1 amplification, and those patients were likely to have advanced disease suggesting that 9p24.1 amplification is associated with less favorable prognosis.¹⁰ This may change with the increasing use of PD-1 inhibitors in the treatment of cHL.

High baseline metabolic tumor volume and total lesion glycolysis have also been associated with adverse outcomes in cHL. While not routinely assessed in practice currently, these tools may ultimately be used to assess prognosis and guide therapy in clinical practice.¹¹

 

ADVANCED STAGE HODGKIN LYMPHOMA

FRONTLINE THERAPY

First-line Chemotherapy 

Chemotherapy plays an essential role in the treatment of advanced stage Hodgkin lymphoma. In the 1960s, the MOPP regimen (nitrogen mustard, vincristine, procarbazine, prednisone) was developed, with a 10-year OS of 50% and a progression-free survival (PFS) of 52% reported in advanced stage patients. The complete remission (CR) rate was 81%, and 36% of patients who achieved CR relapsed later.¹² This chemotherapy regimen is associated with a significant rate of myelosuppression and infertility as well as long-term risk of secondary myelodysplasia and acute leukemias.^13,14 This led to the development of newer regimens such as ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine).¹⁵ In a randomized trial, ABVD showed improved failure-free survival (FFS) over MOPP (61% versus 50% at 5 years) but similar OS (66%–73%).¹⁶ In light of these findings, and considering the lower rate of infertility and myelotoxicity, ABVD became the standard of care for advanced stage cHL in the United States.

The Stanford V regimen was developed in an attempt to further minimize toxicity.¹⁷ Stanford V is a condensed, 12-week chemotherapy regimen that includes mechlorethamine, doxorubicin, vinblastine, etoposide, prednisone, vincristine, and bleomycin, followed by involved-field radiation therapy (IFRT). Subsequent trials compared the Stanford V and ABVD regimens and showed similar OS, freedom from treatment failure (FFTF), and response rates.^18,19 The ABVD regimen was noted to have higher pulmonary toxicity, while other toxicities such as lymphopenia and neuropathy were higher with the Stanford V regimen. In addition, Stanford V requires patients to receive radiation therapy (RT) to original sites of disease larger than 5 cm in size and contiguous sites. 

Another regimen which has been studied extensively for advanced stage Hodgkin lymphoma, and is considered a standard of care in some parts of the world, is escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone). In the HD9 study (n = 1196), the GHSG evaluated BEACOPP, escalated BEACOPP, and COPP/ABVD in advanced stage Hodgkin lymphoma.²⁰ All arms of the study included 30 Gy RT to sites of bulky disease or residual disease. This study showed improved OS and FFTF with escalated BEACOPP, but at the cost of higher rates of toxicity. At 10 years, FFTF was 64%, 70%, and 82% with OS rates of 75%, 80%, and 86% for COPP/ABVD, baseline BEACOPP, and escalated BEACOPP, respectively (P < 0.001). The rate of secondary acute leukemia 10 years after treatment was 0.4% for COPP/ABVD, 1.5% for BEACOPP, and 3.0% for escalated BEACOPP. However, 3 subsequent randomized trials did not confirm a survival benefit with escalated BEACOPP relative to ABVD. In the HD 2000 trial (n = 295)²¹ and in a trial by Viviani and colleagues (n = 331),²² an improvement in OS was not demonstrated in favor of escalated BEACOPP. These studies also confirmed a higher rate of toxicities as well as secondary malignancies associated with the escalated BEACOPP regimen. In the EORTC20012 Intergroup trial (n = 549), 8 cycles of ABVD was compared with 4 cycles of escalated BEACOPP followed by 4 cycles of baseline BEACOPP, without radiation, in patients with clinical stage III or IV Hodgkin lymphoma with IPS score ≥ 3. Both regimens resulted in statistically similar FFS (63.7% in ABVD × 8 versus 69.3% in BEACOPP 4+4) and OS (86.7% in ABVD × 8 vs 90.3% in BEACOPP 4+4).²³

In the United States, ABVD (6–8 cycles) is commonly used, although escalated BEACOPP (particularly for patients with an IPS of 4 or higher) and Stanford V are considered appropriate as well.²⁴ In the North American Intergroup study comparing ABVD to Stanford V, and in the trial by Viviani et al, ABVD was associated with a 5- to 7-year FFS of 73% to 79% and OS of 84% to 92%.^19,22 Given these excellent results, as well as the potential to cure patients with second-line therapy consisting of autologous hematopoietic cell transplantation (auto-HCT), the general consensus among most U.S. hematologists and oncologists is that ABVD remains the treatment of choice, and that the improved FFS/PFS with escalated BEACOPP is not outweighed by the additional toxicity associated with the regimen. There may, however, be a role for escalated BEACOPP in select patients who have a suboptimal response to ABVD as defined by interim positron emission tomography (iPET) scan (see below).

Brentuximab vedotin is an anti-CD30 antibody-drug conjugate (ADC) consisting of an anti-CD30 antibody linked to monomethyl auristatin E (MMAE), a potent antitubulin agent. CD30 is highly expressed on HRS cells and also in anaplastic large cell lymphoma. Upon binding to CD30, the ADC/CD30 complex is then internalized and directed to the lysosome, where the ADC is proteolytically cleaved, releasing MMAE from the antibody. MMAE then disrupts microtubule networks within the cell, leading to G2/M cycle arrest and apoptosis. CD30 is consistently expressed on HRS cells. In addition to being studied in the relapsed/refractory setting (described below), brentuximab has been studied in the first-line setting. In a phase 1 trial, brentuximab combined with ABVD was associated with increased pulmonary toxicity, while brentuximab + AVD had no significant pulmonary toxicity, with an excellent CR rate (96%), suggesting that substituting brentuximab for bleomycin may be an effective strategy. In addition to possibly being more efficacious, this strategy would also have the benefit of eliminating the risk of bleomycin pulmonary toxicity.²⁵ Based on this data, a large international phase 3 study (the ECHELON-1 trial) comparing ABVD versus brentuximab + AVD in advanced stage cHL patients was recently completed. This study enrolled 1334 patients, and preliminary results were recently announced. With a median follow-up of 24 months, the brentuximab + AVD arm had a 4.9% absolute improvement in PFS relative to the ABVD arm (82.1% versus 77.2%). The brentuximab + AVD arm had an increased incidence of febrile neutropenia, managed with growth factors and peripheral neuropathy requiring dose adjustments, whereas the ABVD arm had an increased rate and severity of pulmonary toxicity.²⁶ Further follow-up will be required to determine whether this will translate into a survival benefit. See Table 2 for a summary of recent large randomized prospective phase 3 trials in advanced stage Hodgkin lymphoma. 

 

Alternative Regimens in Older Patients

Patients older than 60 years of age often have poor tolerance for ABVD and especially escalated BEACOPP. This results in increased treatment-related mortality and reduced overall dose intensity, with higher relapse rates and poor OS. In an attempt to improve on the results of treatment of elderly patients with Hodgkin lymphoma, alternative regimens have been explored. One example is PVAG (prednisone, vinblastine, doxorubicin, gemcitabine). With this regimen, the 3-year OS was 66% and PFS was 58%. One patient out of 59 died from treatment-related toxicity, which is much improved over the historical figures for elderly patients with Hodgkin lymphoma.²⁷ Another commonly used approach in practice is to simply omit bleomycin from ABVD. In the early-stage setting (GHSG HD-13 trial), this regimen (referred to as AVD) led to 89.6% PFS at 5 years, compared to 93.5% with ABVD.²⁸ It therefore stands to reason that this should be a reasonable option in older or more frail advanced stage cHL patients as well.

Brentuximab has been evaluated as a single-agent therapy for first-line therapy of elderly patients with Hodgkin lymphoma. In a phase 2 study, 27 patients (63% with advanced stage disease) were treated, with a 92% overall response rate and 73% CR rate. However the median duration of remission was disappointing at only 9.1 months.²⁹ Based on this data, single-agent brentuximab appears to be a reasonable and well tolerated option for frail or elderly patients, although with the caveat that long-term disease control is relatively uncommon.

RESPONSE-ADAPTED FRONTLINE THERAPY USING INTERIM PET SCAN

In recent years, response-adapted treatment approaches have been extensively researched in cHL using iPET. The goal is to reduce toxicity by minimizing therapy in those who achieve negative iPET and/or to intensify treatment for patients with suboptimal response on iPET. Gallamini et al evaluated the prognostic role of an early iPET scan in advanced Hodgkin lymphoma patients (n = 190) treated with ABVD. This study found that patients with positive iPET had a 2-year PFS of 12.8% versus 95.0% in patients with negative iPET. This result was highly statistically significant (P < 0.0001). This study also showed that PET-2 (iPET after 2 cycles of ABVD) superseded the prognostic value of the IPS at diagnosis.³⁰ As a result, numerous subsequent studies have been pursued using iPET for risk-adapted treatment in cHL.

A critical element to the conduct of iPET risk-adapted treatment for cHL is the interpretation of the iPET. In hopes of standardizing iPET interpretation in clinical trials, a scoring system called the Deauville score was developed. The Deauville score ranges from 1 to 5 (Table 3).

 For risk-adapted trials in cHL, a Deauville score of 1 to 3 is generally considered a negative iPET, whereas a score of 4 or 5 is considered a positive iPET.^31,32

The SWOG (Southwest Oncology Group) S0816 trial (n = 358) evaluated iPET-adapted treatment after 2 cycles of ABVD in stage III or IV Hodgkin lymphoma patients. Patients with positive iPET (Deauville score 4 to 5; n = 60) received escalated BEACOPP for 6 cycles, whereas iPET-negative (Deauville score 1 to 3; n = 271) patients continued to receive 4 more cycles of ABVD. The 2-year PFS was 64% for iPET-positive patients.³³ This PFS was much higher than the expected 15% to 30% from prior studies such as Gallamini et al,³⁰ suggesting that the treatment intensification may have been of benefit.

In the HD0801 study (n = 519), newly diagnosed advanced Hodgkin lymphoma patients with positive iPET after 2 cycles of ABVD (n = 103) received early ifosfamide-containing salvage therapy followed by high-dose therapy with autologous stem cell rescue. The 2-year PFS was 76% for PET-2–positive patients, comparable with PET-2–negative patients who had PFS of 81%.³⁴ Again, this result for iPET-positive patients was much better than expected based on the historical control from Gallamini et al, suggesting that the treatment intensification may have been beneficial. It should be emphasized, however, that neither HD0801 nor S0816 were randomized prospective trials; rather, all iPET-positive patients were assigned to an intensified treatment approach.

In the HD18 trial (n = 1100), patients with advanced stage cHL started therapy with escalated BEACOPP and underwent an iPET after 2 cycles. For those with a positive iPET, rituximab was added to escalated BEACOPP in the experimental arm (n = 220) for cycles 3 through 8. The control group (n = 220) continued to receive 6 more cycles of escalated BEACOPP. In the 2 groups, the 3-year PFS was similar (91.4% in escalated BEACOPP, 93% in rituximab + escalated BEACOPP), suggesting no significant benefit with addition of rituximab.³⁵ This study also calls into question whether iPET provides useful information for patients receiving intensive therapy such as escalated BEACOPP, and indicates that the historical control data for iPET-positive patients from Gallamini et al may not be consistently reproduced in other prospective trials. As a result, nonrandomized trials that implement an iPET risk-adapted approach should be interpreted with caution. See Table 4 for a summary of recent trials in advanced stage Hodgkin lymphoma using iPET scan to guide therapy. 

 

RADIATION THERAPY IN FRONTLINE TREATMENT

In patients with advanced stage Hodgkin lymphoma, IFRT to initial bulky sites of disease may be incorporated into frontline therapy to improve local control. However, whether this provides a survival benefit and which patients benefit most from consolidative RT remain unclear.

The European Organization for Research and Treatment of Cancer (EORTC) completed a randomized study in advanced stage Hodgkin lymphoma patients who achieved complete or partial remission after MOPP-ABV.³⁶ Patients in CR were randomly assigned to receive no further treatment versus IFRT (24 Gy to all initially involved nodal areas and 16 to 24 Gy to all initially involved extranodal sites). Patients in partial remission (PR) were treated with 30 Gy to nodal areas and 18 to 24 Gy to extranodal sites. Among the CR patients, the 5-year event-free survival (EFS) was 79% to 84% and did not differ for those who received radiation versus those who did not. Five-year OS was 85% to 91% and also did not differ between the 2 groups. However, among the patients in PR after chemotherapy, the 5-year EFS was 79% and the 5-year OS was 87%, which is better than expected for PR patients, indicating a possible benefit to RT in patients with a partial response after chemotherapy. In the GHSG HD12 trial, patients with advanced stage Hodgkin lymphoma who had a residual lesion by computed tomography (CT) (but not analyzed by PET) had a very subtle improvement in FFTF (90% versus 87%) in favor of consolidation with IFRT, but again no survival benefit was seen.³⁷

The EORTC and HD12 studies described above utilized CT scan for assigning remission status following chemotherapy, and it is now well known that many patients with residual masses (by CT) after chemotherapy may in fact be cured, as such residual radiographic abnormalities may simply be composed of fibrosis. PET scan is more accurate than CT in identifying patients who truly have residual active disease following chemotherapy. As a result, the EORTC study discussed above and the GHSG HD12 trial are of limited relevance in the modern era, in which patients routinely undergo PET scan at the end of therapy. Restricting IFRT to sites that remain PET-positive after completing chemotherapy may be a reasonable strategy that would allow for the avoidance of RT in many patients, and may obviate the need for aggressive second-line therapy (eg, high-dose therapy and autologous hematopoietic cell transplant [auto-HCT]). This approach was taken in the GHSG HD15 trial (n = 2182) in which advanced stage patients were treated with 3 variations on the BEACOPP regimen (8 cycles of escalated BEACOPP, 6 cycles of escalated BEACOPP, or 8 cycles of baseline BEACOPP, randomized in a 1:1:1 ratio). Patients with a residual mass of 2.5 cm or greater on CT scan then underwent a PET scan; if the lesion was PET positive, it was treated with 30 Gy of IFRT. This overall strategy was very effective, with 5-year FFTF rates of 84.4%, 89.3%, and 85.4%, respectively. The OS rates were 91.9%, 95.3%, and 94.5%, respectively. For patients with lesions that remained PET positive after chemotherapy, the PFS rate was 86.2% at 48 months, whereas patients in PR with persistent mass ≥ 2.5 cm but with negative PET had a PFS of 92.6%, similar to that of patients in CR.³⁸ With this approach of BEACOPP followed by PET-guided radiation, the proportion of patients receiving RT was reduced from 71% (in the HD9 study) to only 11% in the HD15 study,³⁸ with no apparent loss in overall efficacy when comparing the results of the 2 studies.

UPFRONT STEM CELL TRANSPLANTATION 

To further improve outcomes of patients with advanced Hodgkin lymphoma with high-risk disease, high-dose therapy with auto-HCT has been explored as part of frontline therapy. While this has been shown to be feasible in such patients,³⁹ randomized trials have not shown a clear benefit in terms of FFS or OS with upfront auto-HCT. ^40,41 Therefore, auto-HCT is not considered a standard component of frontline therapy for cHL patients who achieve CR by PET/CT scan.

RELAPSED AND REFRACTORY HODGKIN LYMPHOMA 

Depending on the stage, risk factors, and frontline regimen utilized, between 5% and 40% of patients with Hodgkin lymphoma can be expected to experience either primary induction failure or a relapse after attaining remission with frontline therapy.³ Primary refractory Hodgkin lymphoma, which occurs in up to 5% to 10% of patients, is defined as progression or no response during induction treatment or within 90 days of completing treatment. In cases where remission status is in question, an updated tissue biopsy is recommended. Biopsy is also recommended in cases in which new sites of disease have appeared or if relapse has occurred after a durable period of remission. Restaging is recommended at the time of relapse. 

 

For younger patients with relapsed/refractory Hodgkin lymphoma, the standard of care in most cases is second-line (or salvage) chemotherapy followed by high-dose therapy and auto-HCT. For patients not felt to be candidates for auto-HCT, options include conventional second-line chemotherapy alone, salvage radiotherapy, novel agents such as brentuximab or immune checkpoint inhibitors, and/or participation in clinical trials. 

CONVENTIONAL MULTI-AGENT CHEMOTHERAPY REGIMENS

Numerous conventional regimens have been shown in phase 2 studies to be active in relapsed and refractory Hodgkin lymphoma. These include platinum-based regimens, gemcitabine-based regimens, and alkylator-based regimens. No randomized trials in Hodgkin lymphoma have been conducted comparing these regimens. In general, regimens are chosen based on the patient’s age, performance status, comorbidities, and whether auto-HCT is being considered. 

In the United States, platinum-based regimens such as ICE (ifosfamide, carboplatin, etoposide),⁴² DHAP (dexamethasone, cisplatin, high-dose cytarabine),⁴³ ESHAP (etoposide, methylprednisolone, high-dose cytarabine, cisplatin),⁴⁴ GDP (gemcitabine, cisplatin, dexamethasone),⁴⁵ and GCD (gemcitabine, carboplatin, dexamethasone)⁴⁶ are all considered appropriate second-line therapy options for patients being considered for auto-HCT, due to their high response rates and because autologous hematopoietic stem cell collection remains feasible after these regimens. Response rates range from 60% to 88%, with CR rates between 17% and 41%, and toxic death rates generally well below 5%.

Other gemcitabine-based regimens such as IGEV (ifosfamide, gemcitabine, vinorelbine) and GVD (gemcitabine, vinorelbine, liposomal doxorubicin) are also effective.^47,48 GVD is an excellent choice since it is a generally well-tolerated outpatient regimen with a 60% response rate even in heavily pretreated patients.⁴⁸ Stem cell collection remains feasible after both IGEV and GVD as well. ABVD can produce CR in approximately 20% to 50% of patients initially treated with MOPP.^49–51 In practice, however, most patients today with relapsed or refractory Hodgkin lymphoma have already received ABVD as part of their first-line therapy, and retreatment with ABVD is not a good option because it would be associated with prohibitively high cumulative doses of doxorubicin. 

These multi-agent chemotherapy regimens may not be tolerated well in patients over age 65 to 70 years or those with significant underlying comorbidities. In recent years, bendamustine has emerged as one of the most active conventional agents for cHL, with overall response rates of 53% to 58% in heavily pre-treated patients.^52,53 Bendamustine can generally be tolerated even in elderly patients as well.

Some centers, particularly in Europe, investigated aggressive salvage regimens such as mini-BEAM (carmustine, etoposide, cytarabine, melphalan)⁵⁴ or dexa-BEAM (BEAM plus dexamethasone).⁵⁵ These regimens, however, are associated with significant hematologic toxicity and high (2%–5%) treatment-related mortality. As a result, these are rarely used in the United States.

For patients who have progressed after (or are not candidates for) platinum- and/or gemcitabine-based therapy, older alkylator-based regimens such as MOPP, C-MOPP, or ChlVPP (chlorambucil, vinblastine, procarbazine, prednisone) can be considered.^56–58 However, these regimens are associated with significant bone marrow suppression, and autologous hematopoietic stem cell collection may no longer be feasible after such regimens. Therefore, these regimens should only be given to patients not felt to be auto-HCT candidates, or patients for whom autologous hematopoietic stem cell collection has already been completed. Weekly vinblastine or single-agent gemcitabine are palliative chemotherapy options, with response rates in the 60% to 80% range. Patients can sometimes be maintained on such low-intensity palliative regimens for 6 to 12 months or longer.^59,60

BRENTUXIMAB VEDOTIN

Several trials are evaluating incorporation of brentuximab into second-line therapy in transplant-eligible patients. These approaches have used brentuximab prior to, concurrent with, or following platinum-based chemotherapy.⁶¹ While there is currently no consensus on the optimal way to incorporate brentuximab into salvage therapy, it is possible that the use of brentuximab or other novel agents in salvage therapy may allow for avoidance of conventional chemotherapy in some patients. In addition, this may translate into more patients proceeding to auto-HCT in a PET negative state. PET negativity prior to auto-HCT is a powerful predictor of long-term remission after auto-HCT, so any intervention that increases the rate of PET negativity prior to auto-HCT would be expected to improve outcomes with auto-HCT.^62–65

For patients not being considered for autoHCT, or those for whom platinum-based salvage therapy was ineffective, single-agent brentuximab is an excellent option. In 2 phase 2 studies, an overall response rate (ORR) of 60% to 75% (including a CR rate of 22%–34%) was seen in relapsed and refractory Hodgkin lymphoma patients.⁶⁶ The US Food and Drug Administration (FDA) approved brentuximab vedotin in August 2011 for treatment of relapsed and refractory Hodgkin lymphoma, after a failed auto-HCT, or in patients who are not auto-HCT candidates and who have received at least 2 prior chemotherapy regimens. With more extended follow-up, it has become clear that a proportion of patients who achieve CR to brentuximab may maintain remission long-term—58% at 3 years and 38% at 5 years.⁶⁷ These patients may in fact be cured, in many cases without having undergone allogeneic HCT (allo-HCT) after brentuximab.

 

PD-1 (IMMUNE CHECKPOINT) INHIBITORS

As discussed earlier, PD-L1/PD-L2 copy number alterations represent a disease-defining feature of cHL. Alterations in chromosome 9p24.1 increase the expression of PD-1 ligands PD-L1 and PD-L2. Nivolumab and pembrolizumab are PD-1-blocking antibodies, which have recently been FDA approved for relapsed and refractory cHL. In a study with 23 patients, with 78% of them relapsing after auto-HCT and 78% relapsing after brentuximab, nivolumab produced an objective response in 87% of the patients, with 17% achieving CR and 70% achieving PR. The rate of PFS was 86% at 24 weeks.⁶⁸ Pembrolizumab, another PD-1 antagonist, was also tested in relapsed and refractory Hodgkin lymphoma. In the KEYNOTE-087 study (n = 210), pembrolizumab produced an ORR of 64% to 70% in 3 different cohorts of relapsed and refractory cHL patients. Overall CR rate was 22%.⁶⁹ In general, these agents are well tolerated, although patients must be monitored closely for

inflammatory/autoimmune-type toxicities including skin rash, diarrhea/colitis, transaminitis, endocrine abnormalities, and pneumonitis. Prompt recognition and initiation of corticosteroids is essential in managing these toxicities. Of note, PD-1 inhibitors should be given very cautiously to patients with a prior history of allo-HCT, since 30% to 55% of such patients will experience acute graft-versus-host disease (GVHD) in this setting. In 2 retrospective studies, the response rate was very high at 77% to 95%; however, 10% to 26% of all patients treated with PD-1 inhibitors post-allo-HCT died from GVHD induced by PD-1 inhibition.^70,71 These risks and benefits therefore need to be carefully weighed in the post-allo-HCT setting. In another recent study, the outcomes were reported for 39 patients who underwent allo-HCT after prior therapy with a PD-1 inhibitor. Three patients (7.7%) developed lethal acute GVHD, suggesting there may be an increased risk of GVHD in patients undergoing allo-HCT after prior PD-1 inhibitor therapy.⁷²

AUTOLOGOUS STEM CELL TRANSPLANTATION 

Several studies have shown an improved disease-free survival (DFS) or FFS in patients with relapsed cHL treated by auto-HCT as compared to those receiving conventional chemotherapy alone.^55,73,74 Overall, for relapsed disease, one can expect an approximately 50% to 60% chance for DFS at 5 years post-transplant. In a retrospective, matched-pair analysis, FFP was 62% for auto-HCT patients, compared to 32% for conventional chemotherapy patients. OS, however, was similar for the 2 groups (47%–54%). Patients failing induction therapy or relapsing within 1 year were seen to benefit the most from auto-HCT, including an OS benefit.⁷⁴

A European prospective randomized trial was conducted comparing conventional salvage therapy to auto-HCT. In this study, 161 patients with relapsed Hodgkin lymphoma were treated with 2 cycles of dexa-BEAM. Those with chemo-sensitive disease were then randomized to either 2 more cycles of dexa-BEAM or high-dose BEAM with auto-HCT. Auto-HCT was associated with an approximately 55% FFTF at 3 years, versus 34% with conventional chemotherapy alone.⁵⁵ This benefit again was most apparent for patients relapsing within 1 year of completion of primary therapy, although an OS benefit was not seen with auto-HCT. For patients with late relapse (>1 year after completion of primary therapy), auto-HCT was associated with an approximately 75% FFTF at 3 years, versus 50% with chemotherapy alone. One other small randomized trial of auto-HCT in relapsed and refractory Hodgkin lymphoma also showed an improved 3-year EFS in favor of auto-HCT (53% versus 10%), again with no difference in OS.⁷³ 

The lack of OS benefit seen in these studies suggests that auto-HCT at first or second relapse provides comparable outcomes. Auto-HCT offers the benefit of avoiding the long-term toxicities associated with multiple salvage regimens and the anxiety associated with multiple relapses. In addition, the treatment-related mortality with auto-HCT is now in the 1% to 2% range in younger patients, at centers that perform the procedure routinely. For all of these reasons, auto-HCT is commonly recommended by physicians for Hodgkin lymphoma patients in first or second relapse. In most cases, transplant is favored in first relapse, since waiting until second relapse may be associated with a lower chance of achieving CR and difficulty collecting sufficient hematopoietic stem cells. For patients with early relapse or primary refractory disease, an even stronger case can be made for auto-HCT as the best option to achieve sustained control of the disease. For patients with late relapse, conventional salvage therapy alone may be a reasonable option, particularly in older or frail patients, or those with significant comorbid conditions. 

The optimal conditioning regimen for autoHCT for relapsed and refractory Hodgkin lymphoma remains undefined. No randomized trials have been performed comparing conditioning regimens for relapsed and refractory Hodgkin lymphoma. One retrospective study compared 92 patients with Hodgkin lymphoma who underwent auto-HCT using a total-body irradiation (TBI) regimen versus a chemotherapy-alone regimen. No difference in 5-year OS or EFS was seen.⁷⁵ Given the lack of benefit seen with TBI, along with reports of increased rates of secondary malignancies and myelodysplasia with TBI,⁷⁶ chemotherapy-alone conditioning regimens are most widely employed. For example, in the United States, either the BEAM or CBV (cyclophosphamide, carmustine, etoposide) regimens are used in over 80% of cases.⁷⁷ This practice was justified in a Center for International Blood and Marrow Transplant Research (CIBMTR) retrospective study comparing outcomes by conditioning regimens, in which no regimen performed better than BEAM or CBV.⁷⁸

IFRT is often given as an adjunctive therapy to sites of initial and/or relapsed disease following auto-HCT. Although a relatively common practice, whether this truly enhances outcomes beyond that obtained with auto-HCT alone is unclear. Two retrospective studies have shown some benefit in terms of improvement in OS at 3 to 5 years in the group that received IFRT (70%–73% versus 40%–56%).^79,80 Given the retrospective nature and small size of these studies, a prospective study would be needed to properly define the potential role for IFRT following auto-HCT in relapsed/refractory Hodgkin lymphoma. Another retrospective study (n = 73) that evaluated peri-transplant IFRT in Hodgkin lymphoma patients receiving auto transplant found no improvement in survival for patients who received peri-transplant IFRT. This study, however, did show a survival benefit in the subgroup of patients with limited stage disease.⁸¹

 

Prognostic Factors Associated with Outcome with Auto-HCT

The factor most consistently associated with improved outcome for patients with relapsed and refractory Hodgkin lymphoma who undergo auto-HCT is the disease status at transplant.^63,77 Those in a second CR, versus a chemo-sensitive relapse (but not CR), versus a chemo-refractory relapse have DFS rates of 60% to 70%, 30% to 40%, and 10% to 20%, respectively.⁶³ The duration between remission and relapse also has important prognostic significance. Late relapse (> 1 year after completion of frontline therapy) is associated with better outcomes as compared to early relapse.⁵⁵ Other factors with prognostic significance at relapse include anemia, time to relapse and clinical stage, B symptoms, extranodal disease, number of prior chemotherapy regimens, and performance status.^42,82 The prognostic impact of pretransplant disease status has been confirmed by studies using functional imaging (eg, FDG-PET or gallium scans). In a report by Moskowitz et al, patients with negative functional imaging following second-line therapy had a 77% EFS post-auto-HCT versus 33% in those whose functional imaging remained positive.⁶² Very similar findings have been reported by other groups.^63–65

Post-Auto-HCT Brentuximab Maintenance

In the multicenter, randomized, double-blinded phase 3 AETHERA trial (n = 329), brentuximab (n = 165) was compared with placebo (n = 164) in patients with unfavorable risk relapsed or primary refractory cHL who had undergone autologous transplant. Eligible patients had at least 1 of the following risk factors for progression after auto-HCT: primary refractory Hodgkin lymphoma (failure to achieve complete remission), relapsed Hodgkin lymphoma with an initial remission duration of less than 12 months, or extranodal involvement at the start of pre-transplantation salvage chemotherapy. Patients were required to have CR, PR, or stable disease after pretransplant salvage chemotherapy with adequate kidney, liver, and bone marrow function. Patients who previously received brentuximab were excluded. Patients received 16 cycles of brentuximab or placebo once every 3 weeks starting 30 to 45 days after transplant. The PFS was significantly improved in the brentuximab group when compared to the placebo group (hazard ratio 0.57; P = 0.0013) after a median observation time of 30 months. Median PFS was 42.9 months in the brentuximab group versus 24.1 months in the placebo group; estimated 2-year PFS rates were 63% in the brentuximab group and 51% in the placebo group. OS was not significantly different between the study groups (~85%), presumably due to the fact that patients in the control group who relapsed likely went on to receive brentuximab as a subsequent therapy.⁸³

PRIMARY REFRACTORY HODGKIN LYMPHOMA 

Patients with primary refractory Hodgkin lymphoma have a poor outcome. Salvage therapy using conventional chemotherapy and/or RT results in long-term DFS in 10% or fewer of such patients.^13,84 Given these poor outcomes with conventional salvage therapy, auto-HCT is considered to be the standard of care for this subset of patients. The GHSG retrospectively analyzed the prognostic factors and outcomes of patients with primary refractory Hodgkin lymphoma. The 5-year freedom-from-second-failure and the 5-year OS were reported to be 31% and 43%, respectively, for those patients treated with auto-HCT. Patients with poor functional status at time of transplant, age greater than 50 years, and failure to attain a temporary remission had a 0% 5-year OS, as compared to 55% in patients without any of these risk factors.⁸⁵ A large retrospective European study showed that patients with chemo-resistant disease who underwent transplant had a 19% survival at 5 years.⁶³ Hence, even patients with primary refractory Hodgkin lymphoma have some chance of achieving long-term survival following auto-HCT. 

SALVAGE RADIOTHERAPY

The GHSG performed a retrospective analysis of the efficacy of salvage RT in patients with refractory or first-relapsed Hodgkin lymphoma. Five-year FFTF and OS rates were 28% and 51%, respectively. Patients with a limited-stage relapse and without B symptoms were more likely to benefit from salvage RT.⁸⁶ Campbell et al reported on 81 patients undergoing salvage RT for persistent or recurrent Hodgkin lymphoma after chemotherapy. The 10-year FFTF and OS rates were 33% and 46%, respectively.⁸⁷ Similarly, Wirth et al reported a 5-year FFS of 26% and 5-year OS of 57%. These figures were 36% and 75%, respectively, in patients whose relapse was limited to supradiaphragmatic nodal sites without B symptoms.⁸⁸ RT therefore may be a useful strategy for a subset of patients who relapse following chemotherapy, particularly those with a limited-stage relapse, without B symptoms, and those with relapsed disease after a CR, as opposed to those with a partial response or lack of response to the prior chemotherapy regimen. 

INVESTIGATIONAL AGENTS AND NOVEL COMBINATIONS

Several biological therapies are emerging as options for the treatment of refractory or relapsed disease. These therapies consist of monoclonal antibodies and ADCs that target cell surface antigens, or small molecules that inhibit key intracellular pathways within neoplastic cells. 

 

Rituximab

Rituximab is a chimeric anti-CD20 monoclonal antibody used widely in B-cell non-Hodgkin lymphomas. The CD20 molecule is typically highly expressed in nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL). Two studies (one in relapsed patients, the other in a mixture of relapsed and previously untreated patients) showed significant activity of rituximab in relapsed NLPHL, with ORRs ranging from 94% to 100%, CR rates ranging from 41% to 53%, and median duration of remission in the 10- to 33-month range.^89,90 In cHL, CD20 is expressed in HRS cells in 20% to 30% of cases. In such cases, single-agent rituximab has also shown activity. There is also evidence that rituximab may be effective even in cases in which the HRS cells are CD20-negative, presumably by virtue of depleting reactive B lymphocytes from the microenvironment, which may enhance anti-tumor immunity, or by eliminating a putative CD20-expressing Hodgkin lymphoma stem cell.^91,92

Lenalidomide

Lenalidomide is an immunomodulatory drug that has multiple modes of action, including direct induction of apoptosis in tumor cells, antiangiogenic effects, and the activation of immune cells, such as natural killer cells and T cells. Lenalidomide has been shown to modify many features of the microenvironment of HRS cells and has demonstrated activity in other B-cell neoplasms. As a result, lenalidomide has been evaluated in relapsed and refractory Hodgkin lymphoma patients. A multicenter phase 2 study by Fehniger et al included 35 patients, 87% of whom had previously undergone HCT and 55% of whom were refractory to the last therapy.⁹³ All patients were given lenalidomide 25 mg/day from days 1 to 21 of a 28-day cycle until disease progression. One patient was noted to achieve CR, 6 achieved PR, and 5 had stable disease lasting more than 6 months, for an ORR of 19% and a “cytostatic overall response rate” of 33%. The median duration of CR/partial remission was 6 months, with the median time-to-treatment failure in responders (including those with stable disease > 6 months) being 15 months. Similarly, in another study, Böll et al evaluated 12 patients across 4 German centers with relapsed or refractory disease who were treated with oral lenalidomide for 21 days in a 28-day cycle. No radiological evidence of disease progression after 2 cycles of lenalidomide was seen in any of the enrolled patients. ORR was noted to be 50%, with 6 patients with stable disease and 5 patients achieving PR after 2 cycles.⁹⁴

Novel Brentuximab Combination Therapies

Brentuximab plus bendamustine. The combination of brentuximab and bendamustine was tested as an outpatient regimen in a phase 1/2 study (n = 55) in primary refractory Hodgkin lymphoma or after first relapse. The CR rate of the combination was 74%, with an overall objective response (CR + PR) of 93%. The CR rates were 64% and 84%, respectively, for refractory and relapsed patients. The PFS at 12 months was 80%, establishing this combination therapy as an effective salvage regimen with durable response.⁹⁵

Brentuximab plus nivolumab. Preliminary results have recently been presented from 2 studies^96,97 evaluating the combination of brentuximab and nivolumab. While this combination would still be considered investigational, these studies showed very encouraging ORRs of 90% to 100% and a CR rate of 62% to 66%. Longer follow-up is needed to determine whether these responses are durable and to document the toxicity profile of this combination.

Mammalian Target of Rapamycin Inhibitors

Two mammalian target of rapamycin (mTOR) inhibitors, everolimus and temsirolimus, are currently available in the United States. While neither drug currently has FDA approval for Hodgkin lymphoma, everolimus was evaluated in a phase 2 trial in a heavily pretreated group of relapsed/refractory patients. An ORR of 47% was seen, with a median time to progression of 7.2 months.⁹⁸

ALLOGENEIC STEM CELL TRANSPLANTATION 

Historically, patients who relapse after having an auto-HCT generally had a poor outcome, with a median survival of 2 to 3 years after failure of auto-HCT.⁹⁹ These patients may be offered palliative chemotherapy (see above), treatment with novel agents (see above), or enrollment in a clinical trial. Select patients may benefit from a second hematopoietic stem cell transplant, most commonly an allo-HCT. However, rare patients with late relapse after auto-HCT may be considered for a second auto-HCT, with a minority of such patients achieving a durable remission after the second auto-HCT.^100,101 Because relapse or progressive disease occurs most commonly in the first several months following auto-HCT, patients are more often considered for allo-HCT than a second auto-HCT. In addition, a second auto-HCT may not be feasible due to impaired bone marrow reserve and/or concerns for development of secondary myelodysplasia or acute myeloid leukemia.

 

Several studies have evaluated allo-HCT in relapsed/ refractory Hodgkin lymphoma. Early studies evaluating myeloablative allo-HCT for Hodgkin lymphoma showed excessive treatment-related mortality (up to 50%) and disappointingly low rates of long-term survival (< 25%).^102,103 This was likely related to the fact that, in that era, most of the patients with Hodgkin lymphoma evaluated for allo-HCT were heavily pretreated and therefore at a higher risk for toxicity as well as lymphoma progression. 

More recently, several studies have focused on the use of reduced-intensity conditioning (RIC) allo-HCT for relapsed and refractory Hodgkin lymphoma. This approach relies more on a “graft-versus-lymphoma” effect, the existence of which has been debated in Hodgkin lymphoma. Three single-center studies of RIC allo-HCT in patients with multiply recurrent Hodgkin lymphoma showed improved rates of treatment-related mortality (8%–16%) but still relatively low rates of long-term PFS (23%–39% at 2 to 4 years).^104–106 Interestingly, in one of these studies the outcomes were more favorable for patients who underwent haploidentical (versus matched sibling or matched unrelated donor) transplants.¹⁰⁵

Two large registry studies have also reported on the outcomes of RIC allo-HCT in patients with relapsed and refractory Hodgkin lymphoma.^107,108 These studies also confirmed a modest improvement in outcomes compared with those seen historically with myeloablative transplants. Treatment-related mortality at 1 to 2 years was 23% to 33%, depending on whether a matched sibling donor versus an unrelated donor was used. However, long-term PFS (18%–20% at 2 to 5 years) and OS (28%–37% at 2 to 5 years) remained poor, primarily due to high rates of progressive lymphoma post-transplant. In both of these studies, patients were heavily pretreated (84%–96% had received 3 or more prior lines of chemotherapy, and 62%–89% received a prior auto-HCT), with 47% to 55% of patients chemo-resistant prior to transplant. Of note, both of these registry studies reflect patients who underwent transplant prior to the widespread use of brentuximab and PD-1 inhibitors.

Based on the single-center and registry data above, a prospective multicenter European phase 2 trial was conducted to evaluate the benefit of RIC allo-HCT in Hodgkin lymphoma.¹⁰⁹ Ninety-two patients (86% with prior auto-HCT, 90% with 3 or more prior lines of therapy) were enrolled and given salvage therapy. Those who had stable disease or better following salvage therapy remained on protocol (n = 78) and underwent RIC with fludarabine and melphalan, followed by allo-HCT (70% with matched sibling donors). Treatment-related mortality was 15% at 1 year. Relapse or progression occurred in 49% at 2 years (35% if chemo-sensitive prior to transplant). Chronic GVHD was associated with a decreased rate of relapse, supporting the existence of a graft-versus-lymphoma effect in Hodgkin lymphoma. Unfortunately, PFS among all allografted patients was still relatively poor (24% at 4 years). However, among patients in CR prior to allo-HCT, a 50% PFS was seen at 4 years. Therefore, even in a prospective multicenter study, RIC allo-HCT offered significant benefit with manageable toxicity in relapsed and refractory Hodgkin lymphoma patients with chemo-sensitive disease. 

These studies suggest that outcomes with allo-HCT would improve further if implemented earlier in the course of disease and/or with a lower burden of disease at transplant. It has therefore been suggested that allo-HCT should be considered soon after failure of auto-HCT is documented. In a retrospective study by Sarina et al, 185 Hodgkin lymphoma patients who relapsed following auto-HCT were then immediately considered for reduced-intensity allo-HCT.¹¹⁰ Of these, 122 had a donor identified, and 104 (85%) actually underwent allo-HCT. These 104 patients were then compared to the other 81 patients who either had no donor identified or had a donor but did not receive the planned allo-HCT. Two-year PFS and OS were superior in the patients undergoing allo-HCT (39% versus 14% and 66% versus 42%, respectively, P < 0.001), with a median follow-up of 4 years. The presence of chronic GVHD again was associated with improved PFS and OS. Disease status prior to transplant remained highly predictive of PFS and OS by multivariate analysis. Two other smaller retrospective studies similarly found a survival benefit associated with allo-HCT compared with patients who underwent conventional salvage therapies alone.^111,112 These studies, although subject to the usual limitations of retrospective analyses, suggest that the results with reduced-intensity allo-HCT are in fact enhanced if applied earlier in the disease course, and are superior to those with conventional therapy alone. 

Currently, the exact role of allo-HSCT, including the optimal timing and optimal donor source (matched sibling versus haploidentical sibling versus matched unrelated donor), remain undefined for relapsed and refractory Hodgkin lymphoma. As discussed earlier, brentuximab is highly active in relapsed Hodgkin lymphoma patients, with a subset of patients still in CR at 5 years.⁶⁷ For such patients, avoiding the risks of allo-HCT is a desirable goal.

 

For those who relapse or progress after auto-HCT, a reasonable strategy therefore is to treat initially with brentuximab, unless the patient is already known to have responded poorly to brentuximab, or already has significant neuropathy. Those who achieve a CR to brentuximab are then observed. A subset of those patients will remain in remission at 5 years without further therapy. For those who relapse, or who achieve less than a CR to brentuximab, additional treatment (with brentuximab re-treatment being one option) followed by a reduced-intensity allo-HCT is a reasonable consideration. This approach has the theoretical advantages of (1) avoiding the risk of allo-HCT in the subset potentially cured by brentuximab, (2) getting patients to allo-HCT with fewer comorbidities (due to a lower total exposure to conventional chemotherapy pre-transplant), and (3) applying allo-HCT in the setting of sensitive disease/lower disease burden (due to the high efficacy of brentuximab). The results of a small study suggest that brentuximab may in fact be a very effective “bridge” to allotransplant. Chen et al¹¹³ reported on 18 patients with relapsed/refractory Hodgkin lymphoma (17 of whom had previously undergone auto-HCT) who were treated on brentuximab vedotin clinical trials. The data were retrospectively evaluated to determine the efficacy and safety of subsequent reduced-intensity allo-HCT. Remarkably, at 1 year the OS was 100%, PFS was 92%, and nonrelapse mortality was 0% with a median follow-up of 14 months. Hence, brentuximab is safe for use prior to reduced-intensity allo-HCT in heavily pre-treated patients and appears to be associated with very favorable post-transplant outcomes, particularly in comparison to older studies of allo-HCT in the era prior to brentuximab.

SUMMARY

Currently, cure is possible for the majority of patients diagnosed with advanced stage Hodgkin lymphoma. The challenge to the clinician is to provide curative treatment with the lowest risk of serious toxicities. Which regimen will best provide this balance of risk and benefit needs to be assessed based on the relapse risk, age, frailty, and comorbidity profile for an individual patient. For many patients with relapsed or refractory Hodgkin lymphoma, cure remains possible using approaches based on hematopoietic stem cell transplantation, RT, and/or brentuximab. In addition, there are now numerous conventional chemotherapy agents, RT strategies, and exciting newer agents such as PD-1 inhibitors, that can provide significant clinical benefit even when cure is not feasible.

INTRODUCTION

Hodgkin lymphoma, previously known as Hodgkin’s disease, is a B-cell lymphoproliferative disease characterized by a unique set of pathologic and epidemiologic features. The disease is characterized by the presence of multinucleate giant cells called Hodgkin Reed-Sternberg (HRS) cells.¹ Hodgkin lymphoma is unique compared to other B-cell lymphomas because of the relative rarity of the malignant cells within affected tissues. The HRS cells, which usually account for only 0.1% to 10% of the cells, induce accumulation of nonmalignant lymphocytes, macrophages, granulocytes, eosinophils, plasma cells, and histiocytes, which then constitute the majority of tumor cellularity.² Although the disease was first described by Sir Thomas Hodgkin in 1832, in part because of this unique histopathology, it was not until the 1990s that it was conclusively demonstrated that HRS cells are in fact monoclonal germinal center–derived B cells.

Due to the development of highly effective therapies for Hodgkin lymphoma, cure is a reasonable goal for most patients. Because of the high cure rate, late complications of therapy must be considered when selecting treatment. This article reviews the clinical features and treatment options for advanced stage and relapsed/refractory Hodgkin lymphoma. A previously published article reviewed the epidemiology, etiology/pathogenesis, pathologic classification, initial workup, and staging evaluation of Hodgkin lymphoma, as well as the prognostic stratification and treatment of patients with early-stage Hodgkin lymphoma.³ 

PRESENTATION, INITIAL EVALUATION, AND PROGNOSIS

Overall, classical Hodgkin lymphoma (cHL) usually presents with asymptomatic mediastinal or cervical lymphadenopathy. At least 50% of patients will have stage I or II disease.⁴ A mediastinal mass is seen in most patients with nodular sclerosis cHL, at times showing the characteristics of bulky (> 10 cm) disease. Constitutional, or B, symptoms (fever, night sweats, and weight loss) are present in approximately 25% of all patients with cHL, but 50% of advanced stage patients. Between 10% and 15% of patients will have extranodal disease, most commonly involving lung, bone, and liver. Lymphocyte-predominant Hodgkin lymphoma (LPHL) is a rare histological subtype of Hodgkin lymphoma that is differentiated from cHL by distinct clinicopathological features. The clinical course and treatment approach for LPHL are dependent upon the stage of disease. The clinicopathological features of LPHL are discussed in the early-stage Hodgkin lymphoma article.³

For the purposes of prognosis and selection of treatment, Hodgkin lymphoma is commonly classified as early stage favorable, early stage unfavorable, and advanced stage. For advanced stage Hodgkin lymphoma patients, prognosis can be defined using a tool commonly referred to as the International Prognostic Score (IPS). This index consists of 7 factors: male gender, age 45 years or older, stage IV disease, hemoglobin < 10.5 g/dL, white blood cell (WBC) count > 15,000/μL, lymphopenia (absolute lymphocyte count < 600 cells/μL or lymphocytes < 8% of WBC count), and serum albumin < 4 g/dL.⁵ In the original study by Hasenclever et al,⁵ the 5-year freedom from progression (FFP) ranged from 42% to 84% and the 5-year overall survival (OS) ranged from 56% to 90%, depending on the number of factors present. This scoring system, however, was developed using a patient population treated prior to 1992. Using a more recently treated patient population, the British Columbia Cancer Agency (BCCA) found that the IPS is still valid for prognostication, but outcomes have improved across all IPS groups, with 5-year FFP now ranging from 62% to 88% and 5-year OS ranging from 67% to 98%.⁶ This improvement is likely a reflection of improved therapy and supportive care. Table 1 shows the PFS and OS within each IPS group, comparing the data from the German Hodgkin Study Group (GHSG) and BCCA group.^5,6

 A closer evaluation of the 7 IPS variables was performed using data from patients enrolled in the Eastern Cooperative Oncology Group (ECOG) 2496 trial.⁷ This analysis revealed that, though the original IPS remained prognostic, its prognostic range has narrowed. Age and stage of disease remained significant for FFP, while age, stage of disease, and hemoglobin level remained significant for OS. An alternative prognostic index, the IPS-3, was constructed using age, stage, and hemoglobin levels. IPS-3, which identifies 4 risk groups, performed as a better tool for risk prediction for both FFP and OS, suggesting that it may provide a simpler and more accurate risk assessment than the IPS in advanced HL.⁷

High expression of CD68 is associated with adverse outcomes, whereas high FOXP3 and CD20 expression on tumor cells are predictors of superior outcomes.⁸ A recent study found that CD68 expression was associated with OS. Five-year OS was 88% in those with less than 25% CD68 expression, versus 63% in those with greater than 25% CD68 expression.⁹

Roemer and colleagues evaluated 108 newly diagnosed cHL biopsy specimens and found that almost all cHL patients had concordant alteration of PD-L1 (programmed death ligand-1) and PD-L2 loci, with a spectrum of 9p24.1 alterations ranging from low level polysomy to near uniform 9p24.1 amplification. PD-L1/PD-L2 copy number alterations are therefore a defining pathobiological feature of cHL.¹⁰ PFS was significantly shorter for patients with 9p24.1 amplification, and those patients were likely to have advanced disease suggesting that 9p24.1 amplification is associated with less favorable prognosis.¹⁰ This may change with the increasing use of PD-1 inhibitors in the treatment of cHL.

High baseline metabolic tumor volume and total lesion glycolysis have also been associated with adverse outcomes in cHL. While not routinely assessed in practice currently, these tools may ultimately be used to assess prognosis and guide therapy in clinical practice.¹¹

 

ADVANCED STAGE HODGKIN LYMPHOMA

FRONTLINE THERAPY

First-line Chemotherapy 

Chemotherapy plays an essential role in the treatment of advanced stage Hodgkin lymphoma. In the 1960s, the MOPP regimen (nitrogen mustard, vincristine, procarbazine, prednisone) was developed, with a 10-year OS of 50% and a progression-free survival (PFS) of 52% reported in advanced stage patients. The complete remission (CR) rate was 81%, and 36% of patients who achieved CR relapsed later.¹² This chemotherapy regimen is associated with a significant rate of myelosuppression and infertility as well as long-term risk of secondary myelodysplasia and acute leukemias.^13,14 This led to the development of newer regimens such as ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine).¹⁵ In a randomized trial, ABVD showed improved failure-free survival (FFS) over MOPP (61% versus 50% at 5 years) but similar OS (66%–73%).¹⁶ In light of these findings, and considering the lower rate of infertility and myelotoxicity, ABVD became the standard of care for advanced stage cHL in the United States.

The Stanford V regimen was developed in an attempt to further minimize toxicity.¹⁷ Stanford V is a condensed, 12-week chemotherapy regimen that includes mechlorethamine, doxorubicin, vinblastine, etoposide, prednisone, vincristine, and bleomycin, followed by involved-field radiation therapy (IFRT). Subsequent trials compared the Stanford V and ABVD regimens and showed similar OS, freedom from treatment failure (FFTF), and response rates.^18,19 The ABVD regimen was noted to have higher pulmonary toxicity, while other toxicities such as lymphopenia and neuropathy were higher with the Stanford V regimen. In addition, Stanford V requires patients to receive radiation therapy (RT) to original sites of disease larger than 5 cm in size and contiguous sites. 

Another regimen which has been studied extensively for advanced stage Hodgkin lymphoma, and is considered a standard of care in some parts of the world, is escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone). In the HD9 study (n = 1196), the GHSG evaluated BEACOPP, escalated BEACOPP, and COPP/ABVD in advanced stage Hodgkin lymphoma.²⁰ All arms of the study included 30 Gy RT to sites of bulky disease or residual disease. This study showed improved OS and FFTF with escalated BEACOPP, but at the cost of higher rates of toxicity. At 10 years, FFTF was 64%, 70%, and 82% with OS rates of 75%, 80%, and 86% for COPP/ABVD, baseline BEACOPP, and escalated BEACOPP, respectively (P < 0.001). The rate of secondary acute leukemia 10 years after treatment was 0.4% for COPP/ABVD, 1.5% for BEACOPP, and 3.0% for escalated BEACOPP. However, 3 subsequent randomized trials did not confirm a survival benefit with escalated BEACOPP relative to ABVD. In the HD 2000 trial (n = 295)²¹ and in a trial by Viviani and colleagues (n = 331),²² an improvement in OS was not demonstrated in favor of escalated BEACOPP. These studies also confirmed a higher rate of toxicities as well as secondary malignancies associated with the escalated BEACOPP regimen. In the EORTC20012 Intergroup trial (n = 549), 8 cycles of ABVD was compared with 4 cycles of escalated BEACOPP followed by 4 cycles of baseline BEACOPP, without radiation, in patients with clinical stage III or IV Hodgkin lymphoma with IPS score ≥ 3. Both regimens resulted in statistically similar FFS (63.7% in ABVD × 8 versus 69.3% in BEACOPP 4+4) and OS (86.7% in ABVD × 8 vs 90.3% in BEACOPP 4+4).²³

In the United States, ABVD (6–8 cycles) is commonly used, although escalated BEACOPP (particularly for patients with an IPS of 4 or higher) and Stanford V are considered appropriate as well.²⁴ In the North American Intergroup study comparing ABVD to Stanford V, and in the trial by Viviani et al, ABVD was associated with a 5- to 7-year FFS of 73% to 79% and OS of 84% to 92%.^19,22 Given these excellent results, as well as the potential to cure patients with second-line therapy consisting of autologous hematopoietic cell transplantation (auto-HCT), the general consensus among most U.S. hematologists and oncologists is that ABVD remains the treatment of choice, and that the improved FFS/PFS with escalated BEACOPP is not outweighed by the additional toxicity associated with the regimen. There may, however, be a role for escalated BEACOPP in select patients who have a suboptimal response to ABVD as defined by interim positron emission tomography (iPET) scan (see below).

Brentuximab vedotin is an anti-CD30 antibody-drug conjugate (ADC) consisting of an anti-CD30 antibody linked to monomethyl auristatin E (MMAE), a potent antitubulin agent. CD30 is highly expressed on HRS cells and also in anaplastic large cell lymphoma. Upon binding to CD30, the ADC/CD30 complex is then internalized and directed to the lysosome, where the ADC is proteolytically cleaved, releasing MMAE from the antibody. MMAE then disrupts microtubule networks within the cell, leading to G2/M cycle arrest and apoptosis. CD30 is consistently expressed on HRS cells. In addition to being studied in the relapsed/refractory setting (described below), brentuximab has been studied in the first-line setting. In a phase 1 trial, brentuximab combined with ABVD was associated with increased pulmonary toxicity, while brentuximab + AVD had no significant pulmonary toxicity, with an excellent CR rate (96%), suggesting that substituting brentuximab for bleomycin may be an effective strategy. In addition to possibly being more efficacious, this strategy would also have the benefit of eliminating the risk of bleomycin pulmonary toxicity.²⁵ Based on this data, a large international phase 3 study (the ECHELON-1 trial) comparing ABVD versus brentuximab + AVD in advanced stage cHL patients was recently completed. This study enrolled 1334 patients, and preliminary results were recently announced. With a median follow-up of 24 months, the brentuximab + AVD arm had a 4.9% absolute improvement in PFS relative to the ABVD arm (82.1% versus 77.2%). The brentuximab + AVD arm had an increased incidence of febrile neutropenia, managed with growth factors and peripheral neuropathy requiring dose adjustments, whereas the ABVD arm had an increased rate and severity of pulmonary toxicity.²⁶ Further follow-up will be required to determine whether this will translate into a survival benefit. See Table 2 for a summary of recent large randomized prospective phase 3 trials in advanced stage Hodgkin lymphoma. 

 

Alternative Regimens in Older Patients

Patients older than 60 years of age often have poor tolerance for ABVD and especially escalated BEACOPP. This results in increased treatment-related mortality and reduced overall dose intensity, with higher relapse rates and poor OS. In an attempt to improve on the results of treatment of elderly patients with Hodgkin lymphoma, alternative regimens have been explored. One example is PVAG (prednisone, vinblastine, doxorubicin, gemcitabine). With this regimen, the 3-year OS was 66% and PFS was 58%. One patient out of 59 died from treatment-related toxicity, which is much improved over the historical figures for elderly patients with Hodgkin lymphoma.²⁷ Another commonly used approach in practice is to simply omit bleomycin from ABVD. In the early-stage setting (GHSG HD-13 trial), this regimen (referred to as AVD) led to 89.6% PFS at 5 years, compared to 93.5% with ABVD.²⁸ It therefore stands to reason that this should be a reasonable option in older or more frail advanced stage cHL patients as well.

Brentuximab has been evaluated as a single-agent therapy for first-line therapy of elderly patients with Hodgkin lymphoma. In a phase 2 study, 27 patients (63% with advanced stage disease) were treated, with a 92% overall response rate and 73% CR rate. However the median duration of remission was disappointing at only 9.1 months.²⁹ Based on this data, single-agent brentuximab appears to be a reasonable and well tolerated option for frail or elderly patients, although with the caveat that long-term disease control is relatively uncommon.

RESPONSE-ADAPTED FRONTLINE THERAPY USING INTERIM PET SCAN

In recent years, response-adapted treatment approaches have been extensively researched in cHL using iPET. The goal is to reduce toxicity by minimizing therapy in those who achieve negative iPET and/or to intensify treatment for patients with suboptimal response on iPET. Gallamini et al evaluated the prognostic role of an early iPET scan in advanced Hodgkin lymphoma patients (n = 190) treated with ABVD. This study found that patients with positive iPET had a 2-year PFS of 12.8% versus 95.0% in patients with negative iPET. This result was highly statistically significant (P < 0.0001). This study also showed that PET-2 (iPET after 2 cycles of ABVD) superseded the prognostic value of the IPS at diagnosis.³⁰ As a result, numerous subsequent studies have been pursued using iPET for risk-adapted treatment in cHL.

A critical element to the conduct of iPET risk-adapted treatment for cHL is the interpretation of the iPET. In hopes of standardizing iPET interpretation in clinical trials, a scoring system called the Deauville score was developed. The Deauville score ranges from 1 to 5 (Table 3).

 For risk-adapted trials in cHL, a Deauville score of 1 to 3 is generally considered a negative iPET, whereas a score of 4 or 5 is considered a positive iPET.^31,32

The SWOG (Southwest Oncology Group) S0816 trial (n = 358) evaluated iPET-adapted treatment after 2 cycles of ABVD in stage III or IV Hodgkin lymphoma patients. Patients with positive iPET (Deauville score 4 to 5; n = 60) received escalated BEACOPP for 6 cycles, whereas iPET-negative (Deauville score 1 to 3; n = 271) patients continued to receive 4 more cycles of ABVD. The 2-year PFS was 64% for iPET-positive patients.³³ This PFS was much higher than the expected 15% to 30% from prior studies such as Gallamini et al,³⁰ suggesting that the treatment intensification may have been of benefit.

In the HD0801 study (n = 519), newly diagnosed advanced Hodgkin lymphoma patients with positive iPET after 2 cycles of ABVD (n = 103) received early ifosfamide-containing salvage therapy followed by high-dose therapy with autologous stem cell rescue. The 2-year PFS was 76% for PET-2–positive patients, comparable with PET-2–negative patients who had PFS of 81%.³⁴ Again, this result for iPET-positive patients was much better than expected based on the historical control from Gallamini et al, suggesting that the treatment intensification may have been beneficial. It should be emphasized, however, that neither HD0801 nor S0816 were randomized prospective trials; rather, all iPET-positive patients were assigned to an intensified treatment approach.

In the HD18 trial (n = 1100), patients with advanced stage cHL started therapy with escalated BEACOPP and underwent an iPET after 2 cycles. For those with a positive iPET, rituximab was added to escalated BEACOPP in the experimental arm (n = 220) for cycles 3 through 8. The control group (n = 220) continued to receive 6 more cycles of escalated BEACOPP. In the 2 groups, the 3-year PFS was similar (91.4% in escalated BEACOPP, 93% in rituximab + escalated BEACOPP), suggesting no significant benefit with addition of rituximab.³⁵ This study also calls into question whether iPET provides useful information for patients receiving intensive therapy such as escalated BEACOPP, and indicates that the historical control data for iPET-positive patients from Gallamini et al may not be consistently reproduced in other prospective trials. As a result, nonrandomized trials that implement an iPET risk-adapted approach should be interpreted with caution. See Table 4 for a summary of recent trials in advanced stage Hodgkin lymphoma using iPET scan to guide therapy. 

 

RADIATION THERAPY IN FRONTLINE TREATMENT

In patients with advanced stage Hodgkin lymphoma, IFRT to initial bulky sites of disease may be incorporated into frontline therapy to improve local control. However, whether this provides a survival benefit and which patients benefit most from consolidative RT remain unclear.

The European Organization for Research and Treatment of Cancer (EORTC) completed a randomized study in advanced stage Hodgkin lymphoma patients who achieved complete or partial remission after MOPP-ABV.³⁶ Patients in CR were randomly assigned to receive no further treatment versus IFRT (24 Gy to all initially involved nodal areas and 16 to 24 Gy to all initially involved extranodal sites). Patients in partial remission (PR) were treated with 30 Gy to nodal areas and 18 to 24 Gy to extranodal sites. Among the CR patients, the 5-year event-free survival (EFS) was 79% to 84% and did not differ for those who received radiation versus those who did not. Five-year OS was 85% to 91% and also did not differ between the 2 groups. However, among the patients in PR after chemotherapy, the 5-year EFS was 79% and the 5-year OS was 87%, which is better than expected for PR patients, indicating a possible benefit to RT in patients with a partial response after chemotherapy. In the GHSG HD12 trial, patients with advanced stage Hodgkin lymphoma who had a residual lesion by computed tomography (CT) (but not analyzed by PET) had a very subtle improvement in FFTF (90% versus 87%) in favor of consolidation with IFRT, but again no survival benefit was seen.³⁷

The EORTC and HD12 studies described above utilized CT scan for assigning remission status following chemotherapy, and it is now well known that many patients with residual masses (by CT) after chemotherapy may in fact be cured, as such residual radiographic abnormalities may simply be composed of fibrosis. PET scan is more accurate than CT in identifying patients who truly have residual active disease following chemotherapy. As a result, the EORTC study discussed above and the GHSG HD12 trial are of limited relevance in the modern era, in which patients routinely undergo PET scan at the end of therapy. Restricting IFRT to sites that remain PET-positive after completing chemotherapy may be a reasonable strategy that would allow for the avoidance of RT in many patients, and may obviate the need for aggressive second-line therapy (eg, high-dose therapy and autologous hematopoietic cell transplant [auto-HCT]). This approach was taken in the GHSG HD15 trial (n = 2182) in which advanced stage patients were treated with 3 variations on the BEACOPP regimen (8 cycles of escalated BEACOPP, 6 cycles of escalated BEACOPP, or 8 cycles of baseline BEACOPP, randomized in a 1:1:1 ratio). Patients with a residual mass of 2.5 cm or greater on CT scan then underwent a PET scan; if the lesion was PET positive, it was treated with 30 Gy of IFRT. This overall strategy was very effective, with 5-year FFTF rates of 84.4%, 89.3%, and 85.4%, respectively. The OS rates were 91.9%, 95.3%, and 94.5%, respectively. For patients with lesions that remained PET positive after chemotherapy, the PFS rate was 86.2% at 48 months, whereas patients in PR with persistent mass ≥ 2.5 cm but with negative PET had a PFS of 92.6%, similar to that of patients in CR.³⁸ With this approach of BEACOPP followed by PET-guided radiation, the proportion of patients receiving RT was reduced from 71% (in the HD9 study) to only 11% in the HD15 study,³⁸ with no apparent loss in overall efficacy when comparing the results of the 2 studies.

UPFRONT STEM CELL TRANSPLANTATION 

To further improve outcomes of patients with advanced Hodgkin lymphoma with high-risk disease, high-dose therapy with auto-HCT has been explored as part of frontline therapy. While this has been shown to be feasible in such patients,³⁹ randomized trials have not shown a clear benefit in terms of FFS or OS with upfront auto-HCT. ^40,41 Therefore, auto-HCT is not considered a standard component of frontline therapy for cHL patients who achieve CR by PET/CT scan.

RELAPSED AND REFRACTORY HODGKIN LYMPHOMA 

Depending on the stage, risk factors, and frontline regimen utilized, between 5% and 40% of patients with Hodgkin lymphoma can be expected to experience either primary induction failure or a relapse after attaining remission with frontline therapy.³ Primary refractory Hodgkin lymphoma, which occurs in up to 5% to 10% of patients, is defined as progression or no response during induction treatment or within 90 days of completing treatment. In cases where remission status is in question, an updated tissue biopsy is recommended. Biopsy is also recommended in cases in which new sites of disease have appeared or if relapse has occurred after a durable period of remission. Restaging is recommended at the time of relapse. 

 

For younger patients with relapsed/refractory Hodgkin lymphoma, the standard of care in most cases is second-line (or salvage) chemotherapy followed by high-dose therapy and auto-HCT. For patients not felt to be candidates for auto-HCT, options include conventional second-line chemotherapy alone, salvage radiotherapy, novel agents such as brentuximab or immune checkpoint inhibitors, and/or participation in clinical trials. 

CONVENTIONAL MULTI-AGENT CHEMOTHERAPY REGIMENS

Numerous conventional regimens have been shown in phase 2 studies to be active in relapsed and refractory Hodgkin lymphoma. These include platinum-based regimens, gemcitabine-based regimens, and alkylator-based regimens. No randomized trials in Hodgkin lymphoma have been conducted comparing these regimens. In general, regimens are chosen based on the patient’s age, performance status, comorbidities, and whether auto-HCT is being considered. 

In the United States, platinum-based regimens such as ICE (ifosfamide, carboplatin, etoposide),⁴² DHAP (dexamethasone, cisplatin, high-dose cytarabine),⁴³ ESHAP (etoposide, methylprednisolone, high-dose cytarabine, cisplatin),⁴⁴ GDP (gemcitabine, cisplatin, dexamethasone),⁴⁵ and GCD (gemcitabine, carboplatin, dexamethasone)⁴⁶ are all considered appropriate second-line therapy options for patients being considered for auto-HCT, due to their high response rates and because autologous hematopoietic stem cell collection remains feasible after these regimens. Response rates range from 60% to 88%, with CR rates between 17% and 41%, and toxic death rates generally well below 5%.

Other gemcitabine-based regimens such as IGEV (ifosfamide, gemcitabine, vinorelbine) and GVD (gemcitabine, vinorelbine, liposomal doxorubicin) are also effective.^47,48 GVD is an excellent choice since it is a generally well-tolerated outpatient regimen with a 60% response rate even in heavily pretreated patients.⁴⁸ Stem cell collection remains feasible after both IGEV and GVD as well. ABVD can produce CR in approximately 20% to 50% of patients initially treated with MOPP.^49–51 In practice, however, most patients today with relapsed or refractory Hodgkin lymphoma have already received ABVD as part of their first-line therapy, and retreatment with ABVD is not a good option because it would be associated with prohibitively high cumulative doses of doxorubicin. 

These multi-agent chemotherapy regimens may not be tolerated well in patients over age 65 to 70 years or those with significant underlying comorbidities. In recent years, bendamustine has emerged as one of the most active conventional agents for cHL, with overall response rates of 53% to 58% in heavily pre-treated patients.^52,53 Bendamustine can generally be tolerated even in elderly patients as well.

Some centers, particularly in Europe, investigated aggressive salvage regimens such as mini-BEAM (carmustine, etoposide, cytarabine, melphalan)⁵⁴ or dexa-BEAM (BEAM plus dexamethasone).⁵⁵ These regimens, however, are associated with significant hematologic toxicity and high (2%–5%) treatment-related mortality. As a result, these are rarely used in the United States.

For patients who have progressed after (or are not candidates for) platinum- and/or gemcitabine-based therapy, older alkylator-based regimens such as MOPP, C-MOPP, or ChlVPP (chlorambucil, vinblastine, procarbazine, prednisone) can be considered.^56–58 However, these regimens are associated with significant bone marrow suppression, and autologous hematopoietic stem cell collection may no longer be feasible after such regimens. Therefore, these regimens should only be given to patients not felt to be auto-HCT candidates, or patients for whom autologous hematopoietic stem cell collection has already been completed. Weekly vinblastine or single-agent gemcitabine are palliative chemotherapy options, with response rates in the 60% to 80% range. Patients can sometimes be maintained on such low-intensity palliative regimens for 6 to 12 months or longer.^59,60

BRENTUXIMAB VEDOTIN

Several trials are evaluating incorporation of brentuximab into second-line therapy in transplant-eligible patients. These approaches have used brentuximab prior to, concurrent with, or following platinum-based chemotherapy.⁶¹ While there is currently no consensus on the optimal way to incorporate brentuximab into salvage therapy, it is possible that the use of brentuximab or other novel agents in salvage therapy may allow for avoidance of conventional chemotherapy in some patients. In addition, this may translate into more patients proceeding to auto-HCT in a PET negative state. PET negativity prior to auto-HCT is a powerful predictor of long-term remission after auto-HCT, so any intervention that increases the rate of PET negativity prior to auto-HCT would be expected to improve outcomes with auto-HCT.^62–65

For patients not being considered for autoHCT, or those for whom platinum-based salvage therapy was ineffective, single-agent brentuximab is an excellent option. In 2 phase 2 studies, an overall response rate (ORR) of 60% to 75% (including a CR rate of 22%–34%) was seen in relapsed and refractory Hodgkin lymphoma patients.⁶⁶ The US Food and Drug Administration (FDA) approved brentuximab vedotin in August 2011 for treatment of relapsed and refractory Hodgkin lymphoma, after a failed auto-HCT, or in patients who are not auto-HCT candidates and who have received at least 2 prior chemotherapy regimens. With more extended follow-up, it has become clear that a proportion of patients who achieve CR to brentuximab may maintain remission long-term—58% at 3 years and 38% at 5 years.⁶⁷ These patients may in fact be cured, in many cases without having undergone allogeneic HCT (allo-HCT) after brentuximab.

 

PD-1 (IMMUNE CHECKPOINT) INHIBITORS

As discussed earlier, PD-L1/PD-L2 copy number alterations represent a disease-defining feature of cHL. Alterations in chromosome 9p24.1 increase the expression of PD-1 ligands PD-L1 and PD-L2. Nivolumab and pembrolizumab are PD-1-blocking antibodies, which have recently been FDA approved for relapsed and refractory cHL. In a study with 23 patients, with 78% of them relapsing after auto-HCT and 78% relapsing after brentuximab, nivolumab produced an objective response in 87% of the patients, with 17% achieving CR and 70% achieving PR. The rate of PFS was 86% at 24 weeks.⁶⁸ Pembrolizumab, another PD-1 antagonist, was also tested in relapsed and refractory Hodgkin lymphoma. In the KEYNOTE-087 study (n = 210), pembrolizumab produced an ORR of 64% to 70% in 3 different cohorts of relapsed and refractory cHL patients. Overall CR rate was 22%.⁶⁹ In general, these agents are well tolerated, although patients must be monitored closely for

inflammatory/autoimmune-type toxicities including skin rash, diarrhea/colitis, transaminitis, endocrine abnormalities, and pneumonitis. Prompt recognition and initiation of corticosteroids is essential in managing these toxicities. Of note, PD-1 inhibitors should be given very cautiously to patients with a prior history of allo-HCT, since 30% to 55% of such patients will experience acute graft-versus-host disease (GVHD) in this setting. In 2 retrospective studies, the response rate was very high at 77% to 95%; however, 10% to 26% of all patients treated with PD-1 inhibitors post-allo-HCT died from GVHD induced by PD-1 inhibition.^70,71 These risks and benefits therefore need to be carefully weighed in the post-allo-HCT setting. In another recent study, the outcomes were reported for 39 patients who underwent allo-HCT after prior therapy with a PD-1 inhibitor. Three patients (7.7%) developed lethal acute GVHD, suggesting there may be an increased risk of GVHD in patients undergoing allo-HCT after prior PD-1 inhibitor therapy.⁷²

AUTOLOGOUS STEM CELL TRANSPLANTATION 

Several studies have shown an improved disease-free survival (DFS) or FFS in patients with relapsed cHL treated by auto-HCT as compared to those receiving conventional chemotherapy alone.^55,73,74 Overall, for relapsed disease, one can expect an approximately 50% to 60% chance for DFS at 5 years post-transplant. In a retrospective, matched-pair analysis, FFP was 62% for auto-HCT patients, compared to 32% for conventional chemotherapy patients. OS, however, was similar for the 2 groups (47%–54%). Patients failing induction therapy or relapsing within 1 year were seen to benefit the most from auto-HCT, including an OS benefit.⁷⁴

A European prospective randomized trial was conducted comparing conventional salvage therapy to auto-HCT. In this study, 161 patients with relapsed Hodgkin lymphoma were treated with 2 cycles of dexa-BEAM. Those with chemo-sensitive disease were then randomized to either 2 more cycles of dexa-BEAM or high-dose BEAM with auto-HCT. Auto-HCT was associated with an approximately 55% FFTF at 3 years, versus 34% with conventional chemotherapy alone.⁵⁵ This benefit again was most apparent for patients relapsing within 1 year of completion of primary therapy, although an OS benefit was not seen with auto-HCT. For patients with late relapse (>1 year after completion of primary therapy), auto-HCT was associated with an approximately 75% FFTF at 3 years, versus 50% with chemotherapy alone. One other small randomized trial of auto-HCT in relapsed and refractory Hodgkin lymphoma also showed an improved 3-year EFS in favor of auto-HCT (53% versus 10%), again with no difference in OS.⁷³ 

The lack of OS benefit seen in these studies suggests that auto-HCT at first or second relapse provides comparable outcomes. Auto-HCT offers the benefit of avoiding the long-term toxicities associated with multiple salvage regimens and the anxiety associated with multiple relapses. In addition, the treatment-related mortality with auto-HCT is now in the 1% to 2% range in younger patients, at centers that perform the procedure routinely. For all of these reasons, auto-HCT is commonly recommended by physicians for Hodgkin lymphoma patients in first or second relapse. In most cases, transplant is favored in first relapse, since waiting until second relapse may be associated with a lower chance of achieving CR and difficulty collecting sufficient hematopoietic stem cells. For patients with early relapse or primary refractory disease, an even stronger case can be made for auto-HCT as the best option to achieve sustained control of the disease. For patients with late relapse, conventional salvage therapy alone may be a reasonable option, particularly in older or frail patients, or those with significant comorbid conditions. 

The optimal conditioning regimen for autoHCT for relapsed and refractory Hodgkin lymphoma remains undefined. No randomized trials have been performed comparing conditioning regimens for relapsed and refractory Hodgkin lymphoma. One retrospective study compared 92 patients with Hodgkin lymphoma who underwent auto-HCT using a total-body irradiation (TBI) regimen versus a chemotherapy-alone regimen. No difference in 5-year OS or EFS was seen.⁷⁵ Given the lack of benefit seen with TBI, along with reports of increased rates of secondary malignancies and myelodysplasia with TBI,⁷⁶ chemotherapy-alone conditioning regimens are most widely employed. For example, in the United States, either the BEAM or CBV (cyclophosphamide, carmustine, etoposide) regimens are used in over 80% of cases.⁷⁷ This practice was justified in a Center for International Blood and Marrow Transplant Research (CIBMTR) retrospective study comparing outcomes by conditioning regimens, in which no regimen performed better than BEAM or CBV.⁷⁸

IFRT is often given as an adjunctive therapy to sites of initial and/or relapsed disease following auto-HCT. Although a relatively common practice, whether this truly enhances outcomes beyond that obtained with auto-HCT alone is unclear. Two retrospective studies have shown some benefit in terms of improvement in OS at 3 to 5 years in the group that received IFRT (70%–73% versus 40%–56%).^79,80 Given the retrospective nature and small size of these studies, a prospective study would be needed to properly define the potential role for IFRT following auto-HCT in relapsed/refractory Hodgkin lymphoma. Another retrospective study (n = 73) that evaluated peri-transplant IFRT in Hodgkin lymphoma patients receiving auto transplant found no improvement in survival for patients who received peri-transplant IFRT. This study, however, did show a survival benefit in the subgroup of patients with limited stage disease.⁸¹

 

Prognostic Factors Associated with Outcome with Auto-HCT

The factor most consistently associated with improved outcome for patients with relapsed and refractory Hodgkin lymphoma who undergo auto-HCT is the disease status at transplant.^63,77 Those in a second CR, versus a chemo-sensitive relapse (but not CR), versus a chemo-refractory relapse have DFS rates of 60% to 70%, 30% to 40%, and 10% to 20%, respectively.⁶³ The duration between remission and relapse also has important prognostic significance. Late relapse (> 1 year after completion of frontline therapy) is associated with better outcomes as compared to early relapse.⁵⁵ Other factors with prognostic significance at relapse include anemia, time to relapse and clinical stage, B symptoms, extranodal disease, number of prior chemotherapy regimens, and performance status.^42,82 The prognostic impact of pretransplant disease status has been confirmed by studies using functional imaging (eg, FDG-PET or gallium scans). In a report by Moskowitz et al, patients with negative functional imaging following second-line therapy had a 77% EFS post-auto-HCT versus 33% in those whose functional imaging remained positive.⁶² Very similar findings have been reported by other groups.^63–65

Post-Auto-HCT Brentuximab Maintenance

In the multicenter, randomized, double-blinded phase 3 AETHERA trial (n = 329), brentuximab (n = 165) was compared with placebo (n = 164) in patients with unfavorable risk relapsed or primary refractory cHL who had undergone autologous transplant. Eligible patients had at least 1 of the following risk factors for progression after auto-HCT: primary refractory Hodgkin lymphoma (failure to achieve complete remission), relapsed Hodgkin lymphoma with an initial remission duration of less than 12 months, or extranodal involvement at the start of pre-transplantation salvage chemotherapy. Patients were required to have CR, PR, or stable disease after pretransplant salvage chemotherapy with adequate kidney, liver, and bone marrow function. Patients who previously received brentuximab were excluded. Patients received 16 cycles of brentuximab or placebo once every 3 weeks starting 30 to 45 days after transplant. The PFS was significantly improved in the brentuximab group when compared to the placebo group (hazard ratio 0.57; P = 0.0013) after a median observation time of 30 months. Median PFS was 42.9 months in the brentuximab group versus 24.1 months in the placebo group; estimated 2-year PFS rates were 63% in the brentuximab group and 51% in the placebo group. OS was not significantly different between the study groups (~85%), presumably due to the fact that patients in the control group who relapsed likely went on to receive brentuximab as a subsequent therapy.⁸³

PRIMARY REFRACTORY HODGKIN LYMPHOMA 

Patients with primary refractory Hodgkin lymphoma have a poor outcome. Salvage therapy using conventional chemotherapy and/or RT results in long-term DFS in 10% or fewer of such patients.^13,84 Given these poor outcomes with conventional salvage therapy, auto-HCT is considered to be the standard of care for this subset of patients. The GHSG retrospectively analyzed the prognostic factors and outcomes of patients with primary refractory Hodgkin lymphoma. The 5-year freedom-from-second-failure and the 5-year OS were reported to be 31% and 43%, respectively, for those patients treated with auto-HCT. Patients with poor functional status at time of transplant, age greater than 50 years, and failure to attain a temporary remission had a 0% 5-year OS, as compared to 55% in patients without any of these risk factors.⁸⁵ A large retrospective European study showed that patients with chemo-resistant disease who underwent transplant had a 19% survival at 5 years.⁶³ Hence, even patients with primary refractory Hodgkin lymphoma have some chance of achieving long-term survival following auto-HCT. 

SALVAGE RADIOTHERAPY

The GHSG performed a retrospective analysis of the efficacy of salvage RT in patients with refractory or first-relapsed Hodgkin lymphoma. Five-year FFTF and OS rates were 28% and 51%, respectively. Patients with a limited-stage relapse and without B symptoms were more likely to benefit from salvage RT.⁸⁶ Campbell et al reported on 81 patients undergoing salvage RT for persistent or recurrent Hodgkin lymphoma after chemotherapy. The 10-year FFTF and OS rates were 33% and 46%, respectively.⁸⁷ Similarly, Wirth et al reported a 5-year FFS of 26% and 5-year OS of 57%. These figures were 36% and 75%, respectively, in patients whose relapse was limited to supradiaphragmatic nodal sites without B symptoms.⁸⁸ RT therefore may be a useful strategy for a subset of patients who relapse following chemotherapy, particularly those with a limited-stage relapse, without B symptoms, and those with relapsed disease after a CR, as opposed to those with a partial response or lack of response to the prior chemotherapy regimen. 

INVESTIGATIONAL AGENTS AND NOVEL COMBINATIONS

Several biological therapies are emerging as options for the treatment of refractory or relapsed disease. These therapies consist of monoclonal antibodies and ADCs that target cell surface antigens, or small molecules that inhibit key intracellular pathways within neoplastic cells. 

 

Rituximab

Rituximab is a chimeric anti-CD20 monoclonal antibody used widely in B-cell non-Hodgkin lymphomas. The CD20 molecule is typically highly expressed in nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL). Two studies (one in relapsed patients, the other in a mixture of relapsed and previously untreated patients) showed significant activity of rituximab in relapsed NLPHL, with ORRs ranging from 94% to 100%, CR rates ranging from 41% to 53%, and median duration of remission in the 10- to 33-month range.^89,90 In cHL, CD20 is expressed in HRS cells in 20% to 30% of cases. In such cases, single-agent rituximab has also shown activity. There is also evidence that rituximab may be effective even in cases in which the HRS cells are CD20-negative, presumably by virtue of depleting reactive B lymphocytes from the microenvironment, which may enhance anti-tumor immunity, or by eliminating a putative CD20-expressing Hodgkin lymphoma stem cell.^91,92

Lenalidomide

Lenalidomide is an immunomodulatory drug that has multiple modes of action, including direct induction of apoptosis in tumor cells, antiangiogenic effects, and the activation of immune cells, such as natural killer cells and T cells. Lenalidomide has been shown to modify many features of the microenvironment of HRS cells and has demonstrated activity in other B-cell neoplasms. As a result, lenalidomide has been evaluated in relapsed and refractory Hodgkin lymphoma patients. A multicenter phase 2 study by Fehniger et al included 35 patients, 87% of whom had previously undergone HCT and 55% of whom were refractory to the last therapy.⁹³ All patients were given lenalidomide 25 mg/day from days 1 to 21 of a 28-day cycle until disease progression. One patient was noted to achieve CR, 6 achieved PR, and 5 had stable disease lasting more than 6 months, for an ORR of 19% and a “cytostatic overall response rate” of 33%. The median duration of CR/partial remission was 6 months, with the median time-to-treatment failure in responders (including those with stable disease > 6 months) being 15 months. Similarly, in another study, Böll et al evaluated 12 patients across 4 German centers with relapsed or refractory disease who were treated with oral lenalidomide for 21 days in a 28-day cycle. No radiological evidence of disease progression after 2 cycles of lenalidomide was seen in any of the enrolled patients. ORR was noted to be 50%, with 6 patients with stable disease and 5 patients achieving PR after 2 cycles.⁹⁴

Novel Brentuximab Combination Therapies

Brentuximab plus bendamustine. The combination of brentuximab and bendamustine was tested as an outpatient regimen in a phase 1/2 study (n = 55) in primary refractory Hodgkin lymphoma or after first relapse. The CR rate of the combination was 74%, with an overall objective response (CR + PR) of 93%. The CR rates were 64% and 84%, respectively, for refractory and relapsed patients. The PFS at 12 months was 80%, establishing this combination therapy as an effective salvage regimen with durable response.⁹⁵

Brentuximab plus nivolumab. Preliminary results have recently been presented from 2 studies^96,97 evaluating the combination of brentuximab and nivolumab. While this combination would still be considered investigational, these studies showed very encouraging ORRs of 90% to 100% and a CR rate of 62% to 66%. Longer follow-up is needed to determine whether these responses are durable and to document the toxicity profile of this combination.

Mammalian Target of Rapamycin Inhibitors

Two mammalian target of rapamycin (mTOR) inhibitors, everolimus and temsirolimus, are currently available in the United States. While neither drug currently has FDA approval for Hodgkin lymphoma, everolimus was evaluated in a phase 2 trial in a heavily pretreated group of relapsed/refractory patients. An ORR of 47% was seen, with a median time to progression of 7.2 months.⁹⁸

ALLOGENEIC STEM CELL TRANSPLANTATION 

Historically, patients who relapse after having an auto-HCT generally had a poor outcome, with a median survival of 2 to 3 years after failure of auto-HCT.⁹⁹ These patients may be offered palliative chemotherapy (see above), treatment with novel agents (see above), or enrollment in a clinical trial. Select patients may benefit from a second hematopoietic stem cell transplant, most commonly an allo-HCT. However, rare patients with late relapse after auto-HCT may be considered for a second auto-HCT, with a minority of such patients achieving a durable remission after the second auto-HCT.^100,101 Because relapse or progressive disease occurs most commonly in the first several months following auto-HCT, patients are more often considered for allo-HCT than a second auto-HCT. In addition, a second auto-HCT may not be feasible due to impaired bone marrow reserve and/or concerns for development of secondary myelodysplasia or acute myeloid leukemia.

 

Several studies have evaluated allo-HCT in relapsed/ refractory Hodgkin lymphoma. Early studies evaluating myeloablative allo-HCT for Hodgkin lymphoma showed excessive treatment-related mortality (up to 50%) and disappointingly low rates of long-term survival (< 25%).^102,103 This was likely related to the fact that, in that era, most of the patients with Hodgkin lymphoma evaluated for allo-HCT were heavily pretreated and therefore at a higher risk for toxicity as well as lymphoma progression. 

More recently, several studies have focused on the use of reduced-intensity conditioning (RIC) allo-HCT for relapsed and refractory Hodgkin lymphoma. This approach relies more on a “graft-versus-lymphoma” effect, the existence of which has been debated in Hodgkin lymphoma. Three single-center studies of RIC allo-HCT in patients with multiply recurrent Hodgkin lymphoma showed improved rates of treatment-related mortality (8%–16%) but still relatively low rates of long-term PFS (23%–39% at 2 to 4 years).^104–106 Interestingly, in one of these studies the outcomes were more favorable for patients who underwent haploidentical (versus matched sibling or matched unrelated donor) transplants.¹⁰⁵

Two large registry studies have also reported on the outcomes of RIC allo-HCT in patients with relapsed and refractory Hodgkin lymphoma.^107,108 These studies also confirmed a modest improvement in outcomes compared with those seen historically with myeloablative transplants. Treatment-related mortality at 1 to 2 years was 23% to 33%, depending on whether a matched sibling donor versus an unrelated donor was used. However, long-term PFS (18%–20% at 2 to 5 years) and OS (28%–37% at 2 to 5 years) remained poor, primarily due to high rates of progressive lymphoma post-transplant. In both of these studies, patients were heavily pretreated (84%–96% had received 3 or more prior lines of chemotherapy, and 62%–89% received a prior auto-HCT), with 47% to 55% of patients chemo-resistant prior to transplant. Of note, both of these registry studies reflect patients who underwent transplant prior to the widespread use of brentuximab and PD-1 inhibitors.

Based on the single-center and registry data above, a prospective multicenter European phase 2 trial was conducted to evaluate the benefit of RIC allo-HCT in Hodgkin lymphoma.¹⁰⁹ Ninety-two patients (86% with prior auto-HCT, 90% with 3 or more prior lines of therapy) were enrolled and given salvage therapy. Those who had stable disease or better following salvage therapy remained on protocol (n = 78) and underwent RIC with fludarabine and melphalan, followed by allo-HCT (70% with matched sibling donors). Treatment-related mortality was 15% at 1 year. Relapse or progression occurred in 49% at 2 years (35% if chemo-sensitive prior to transplant). Chronic GVHD was associated with a decreased rate of relapse, supporting the existence of a graft-versus-lymphoma effect in Hodgkin lymphoma. Unfortunately, PFS among all allografted patients was still relatively poor (24% at 4 years). However, among patients in CR prior to allo-HCT, a 50% PFS was seen at 4 years. Therefore, even in a prospective multicenter study, RIC allo-HCT offered significant benefit with manageable toxicity in relapsed and refractory Hodgkin lymphoma patients with chemo-sensitive disease. 

These studies suggest that outcomes with allo-HCT would improve further if implemented earlier in the course of disease and/or with a lower burden of disease at transplant. It has therefore been suggested that allo-HCT should be considered soon after failure of auto-HCT is documented. In a retrospective study by Sarina et al, 185 Hodgkin lymphoma patients who relapsed following auto-HCT were then immediately considered for reduced-intensity allo-HCT.¹¹⁰ Of these, 122 had a donor identified, and 104 (85%) actually underwent allo-HCT. These 104 patients were then compared to the other 81 patients who either had no donor identified or had a donor but did not receive the planned allo-HCT. Two-year PFS and OS were superior in the patients undergoing allo-HCT (39% versus 14% and 66% versus 42%, respectively, P < 0.001), with a median follow-up of 4 years. The presence of chronic GVHD again was associated with improved PFS and OS. Disease status prior to transplant remained highly predictive of PFS and OS by multivariate analysis. Two other smaller retrospective studies similarly found a survival benefit associated with allo-HCT compared with patients who underwent conventional salvage therapies alone.^111,112 These studies, although subject to the usual limitations of retrospective analyses, suggest that the results with reduced-intensity allo-HCT are in fact enhanced if applied earlier in the disease course, and are superior to those with conventional therapy alone. 

Currently, the exact role of allo-HSCT, including the optimal timing and optimal donor source (matched sibling versus haploidentical sibling versus matched unrelated donor), remain undefined for relapsed and refractory Hodgkin lymphoma. As discussed earlier, brentuximab is highly active in relapsed Hodgkin lymphoma patients, with a subset of patients still in CR at 5 years.⁶⁷ For such patients, avoiding the risks of allo-HCT is a desirable goal.

 

For those who relapse or progress after auto-HCT, a reasonable strategy therefore is to treat initially with brentuximab, unless the patient is already known to have responded poorly to brentuximab, or already has significant neuropathy. Those who achieve a CR to brentuximab are then observed. A subset of those patients will remain in remission at 5 years without further therapy. For those who relapse, or who achieve less than a CR to brentuximab, additional treatment (with brentuximab re-treatment being one option) followed by a reduced-intensity allo-HCT is a reasonable consideration. This approach has the theoretical advantages of (1) avoiding the risk of allo-HCT in the subset potentially cured by brentuximab, (2) getting patients to allo-HCT with fewer comorbidities (due to a lower total exposure to conventional chemotherapy pre-transplant), and (3) applying allo-HCT in the setting of sensitive disease/lower disease burden (due to the high efficacy of brentuximab). The results of a small study suggest that brentuximab may in fact be a very effective “bridge” to allotransplant. Chen et al¹¹³ reported on 18 patients with relapsed/refractory Hodgkin lymphoma (17 of whom had previously undergone auto-HCT) who were treated on brentuximab vedotin clinical trials. The data were retrospectively evaluated to determine the efficacy and safety of subsequent reduced-intensity allo-HCT. Remarkably, at 1 year the OS was 100%, PFS was 92%, and nonrelapse mortality was 0% with a median follow-up of 14 months. Hence, brentuximab is safe for use prior to reduced-intensity allo-HCT in heavily pre-treated patients and appears to be associated with very favorable post-transplant outcomes, particularly in comparison to older studies of allo-HCT in the era prior to brentuximab.

SUMMARY

Currently, cure is possible for the majority of patients diagnosed with advanced stage Hodgkin lymphoma. The challenge to the clinician is to provide curative treatment with the lowest risk of serious toxicities. Which regimen will best provide this balance of risk and benefit needs to be assessed based on the relapse risk, age, frailty, and comorbidity profile for an individual patient. For many patients with relapsed or refractory Hodgkin lymphoma, cure remains possible using approaches based on hematopoietic stem cell transplantation, RT, and/or brentuximab. In addition, there are now numerous conventional chemotherapy agents, RT strategies, and exciting newer agents such as PD-1 inhibitors, that can provide significant clinical benefit even when cure is not feasible.

 

INTRODUCTION

In the normal person, the process of coagulation is finely controlled at many levels to ensure the appropriate amount of hemostasis at the appropriate location. Broadly defined, disseminated intravascular coagulation (DIC) is the name given to any process that disrupts this fine tuning, leading to unregulated coagulation. Defined this way, DIC may be found in a variety of patients with a variety of disease states, and can present with a spectrum of findings ranging from asymptomatic abnormal laboratory results to florid bleeding or thrombosis. It is important to remember that DIC is always a consequence of an underlying pathological process and not a disease in and of itself. This article first reviews concepts common to all forms of DIC, and then reviews the more common disease states that lead to DIC.

PATHOGENESIS

At the most basic level, DIC is the clinical manifestation of inappropriate thrombin activation.^1–5 Inappropriate thrombin activation can be due to underlying conditions such as sepsis and obstetric disasters. The activation of thrombin leads to (1) conversion of fibrinogen to fibrin, (2) activation of platelets (and their consumption), (3) activation of factors V and VIII, (4) activation of protein C (and degradation of factors Va and VIIIa), (5) activation of endothelial cells, and (6) activation of fibrinolysis (Table 1). 

Thus, with excessive activation of thrombin one can see the following processes:

1. Conversion of fibrinogen to fibrin, which leads to the formation of fibrin monomers and excessive thrombus formation. These thrombi are rapidly dissolved by excessive fibrinolysis in most patients. In certain clinical situations, especially cancer, excessive thrombosis will occur. In patients with cancer, this is most often a deep venous thrombosis. Rare patients, especially those with pancreatic cancer, may have severe DIC with multiple arterial and venous thromboses. Nonbacterial thrombotic endocarditis can also be seen in these patients, leading to widespread embolic complications.

2. Activation of platelets and their consumption. Thrombin is the most potent physiologic activator of platelets, so in DIC there is increased activation of platelets. These activated platelets are consumed, resulting in thrombocytopenia. Platelet dysfunction is also present. Platelets that have been activated and have released their contents but still circulate are known as “exhausted” platelets; these cells can no longer function to support coagulation. The fibrin degradation products (FDP) in DIC can also bind to GP IIb/IIIa and inhibit further platelet aggregation.

3. Activation of factors V, VIII, XI, and XIII. Activation of these factors can promote thrombosis, but they are then rapidly cleared by antithrombin (XI) or activated protein C (V and VIII) or by binding to the fibrin clot (XIII). This can lead to depletion of all the prothrombotic clotting factors and antithrombin, which in turn can lead to both thrombosis and bleeding.

4. Activation of protein C further promotes degradation of factors Va and VIIIa, enhances fibrinolysis, and decreases protein C levels.

5. Activation of endothelial cells, especially in the skin, may lead to thrombosis, and in certain patients, especially those with meningococcemia, purpura fulminans. Endothelial damage will down-regulate thrombomodulin, preventing activation of protein C and leading to further reductions in levels of activated protein C.⁵6. Activation of fibrinolysis leads to the breakdown of fibrin monomers, formation of fibrin thrombi, and increased circulating fibrinogen. In most patients with DIC, the fibrinolytic response is brisk.⁶ This is why most patients with DIC present with bleeding and prolonged clotting times.

PATTERNS OF DIC

The clinical manifestations of DIC in a given patient depend on the balance of thrombin activation and secondary fibrinolysis plus the patient’s ability to compensate for the DIC. Patients with DIC can present in 1 of 4 patterns:^1–3

1. Asymptomatic. Patients can present with laboratory evidence of DIC but no bleeding or thrombosis. This is often seen in patients with sepsis or cancer. However, with further progression of the underlying disease, these patients can rapidly become symptomatic.

2. Bleeding. The bleeding is due to a combination of factor depletion, platelet dysfunction, thrombocytopenia, and excessive fibrinolysis.¹ These patients may present with diffuse bleeding from multiple sites (eg, intravenous sites, areas of instrumentation).

3. Thrombosis. Despite the general activation of the coagulation process, thrombosis is unusual in most patients with acute DIC. The exceptions include patients with cancer, trauma patients, and certain obstetrical patients. Most often the thrombosis is venous, but arterial thrombosis and nonbacterial thrombotic endocarditis have been reported.⁷

4. Purpura fulminans. This form of DIC is discussed in more detail later (see Specific DIC Syndromes section).

DIAGNOSIS

There is no one test that will diagnose DIC; one must match the test to the clinical situation (Table 2).⁸ 

 

SCREENING TESTS

The prothrombin time-INR and activated thromboplastin time (aPPT) are usually elevated in severe DIC but may be normal or shortened in chronic forms.⁹ One may also see a shortened aPTT in severe acute DIC due to large amounts of activated thrombin and factor X “bypassing” the contact pathway. An aPTT as short as 10 seconds has been seen in acute DIC. The platelet count is usually reduced but may be normal in chronic DIC. Serum fibrinogen and platelets are decreased in acute DIC but again may be in the “normal” range in chronic DIC.¹⁰ The most sensitive screening test for DIC is a fall in the platelet count, with low counts seen in 98% of patients and counts under 50,000 cells/μL in 50%.^9,11 The least specific test is fibrinogen, which tends to fall below normal only in severe acute DIC.⁹

SPECIFIC TESTS

This group of tests allows one to deduce that abnormally high concentrations of thrombin are present.

Ethanol Gel and Protamine Tests

Both of these older tests detected circulating fibrin monomers, whose appearance is an early sign of DIC. Circulating fibrin monomers are seen when thrombin acts on fibrinogen. Usually the monomer polymerizes with the fibrin clot, but when there is excess thrombin these monomers can circulate. Detection of circulating fibrin monomer means there is too much IIa and, ergo, DIC is present.

Fibrin(ogen) Degradation Products

Plasmin acts on the fibrin/fibrinogen molecule to cleave the molecule in specific places. The resulting degradation product levels will be elevated in situations of increased fibrin/fibrinogen destruction (DIC and fibrinolysis). The FDP are typically mildly elevated in renal and liver disease due to reduced clearance.

D-Dimers

When fibrin monomers bind to form a thrombus, factor XIII acts to bind their “D” domains together. This bond is resistant to plasmin and thus this degradation fragment is known as the “D-dimer.” High levels of D-dimer indicate that (1) IIa has acted on fibrinogen to form a fibrin monomer that bonded to another fibrin monomer, and (2) this thrombus was lysed by plasmin. Because D-dimers can be elevated (eg, with exercise, after surgery), an elevated D-dimer needs to be interpreted in the context of the clinical situation.¹¹ Currently, this is the most common specific test for DIC performed.

Other Tests

Several other tests are sometimes helpful in diagnosing DIC.

Thrombin time. This test is performed by adding thrombin to plasma. Thrombin times are elevated in DIC (FDPs interfere with polymerization), in the presence of low fibrinogen levels, in dysfibrinogenemia, and in the presence of heparin (very sensitive).

Reptilase time is the same as thrombin time but is performed with a snake venom that is insensitive to heparin. Reptilase time is elevated in the same conditions as the thrombin time, with the exception of the presence of heparin. Thrombin time and reptilase time are most useful in evaluation of dysfibrinogenemia.

Prothrombin fragment 1.2 (F_1.2). F_1.2 is a small peptide cleaved off when prothrombin is activated to thrombin. Thus, high levels of F_1.2 are found in DIC but can be seen in other thrombotic disorders. This test is still of limited clinical value.

DIC scoring system. A scoring system to both diagnose and quantify DIC has been proposed (Figure).^11,12 

This system is especially helpful for clinical trials. A drawback of the score that keeps it from being implemented for routine clinical use is that it requires the prothrombin time, which is not standardized nor often reported by many clinical laboratories.

Thromboelastography (TEG). This is a point-of-care test that uses whole blood to determine specific coagulation parameters such as R time (time from start of test to clot formation), maximal amplitude (MA, maximum extent of thrombus), and LY30 (MA at 30 minutes, a measure of fibrinolysis).¹³ Studies have shown that TEG can identify DIC by demonstrating a shorter R time (excess thrombin generation) which prolongs as coagulation factors are consumed. The MA is decreased as fibrinogen is consumed and the LY30 shows excess fibrinolysis. TEG has been shown to be of particular value in the management of the complex coagulopathy of trauma.¹⁴

MIMICKERS OF DIC

It is important to recognize coagulation syndromes that are not DIC, especially those that have specific other therapies. The syndromes most frequently encountered are thrombotic thrombocytopenic purpura (TTP) and catastrophic antiphospholipid antibody syndrome (CAPS). One important clue to both of these syndromes is that, unlike DIC, there is no primary disorder (cancer, sepsis) that is driving the coagulation abnormalities.

TTP should be suspected when any patient presents with any combination of thrombo­cytopenia, microangiopathic hemolytic anemia (schistocytes and signs of hemolysis) plus end-organ damage.^15–18 Patients with TTP most often present with intractable seizures, strokes, or sequelae of renal insufficiency. Many patients who present with TTP have been misdiagnosed as having sepsis, “lupus flare,” or vasculitis. The key diagnostic differentiator between TTP and DIC is the lack of activation of coagulation with TTP—fibrinogen is normal and D-dimers are minimally or not elevated. In TTP, lactate dehydrogenase is invariably elevated, often 2 to 3 times normal.¹⁹ The importance of identifying TTP is that untreated TTP is rapidly fatal. Mortality in the pre–plasma exchange era ranged from 95% to 100%. Today plasma exchange therapy is the foundation of TTP treatment and has reduced mortality to less than 20%.^16,20–23Rarely patients with antiphospholipid antibody syndrome can present with fulminant multiorgan system failure.^24–28 CAPS is caused by widespread microthrombi in multiple vascular fields. These patients will develop renal failure, encephalopathy, adult respiratory distress syndrome (often with pulmonary hemorrhage), cardiac failure, dramatic livedo reticularis, and worsening thrombocytopenia. Many of these patients have pre-existing autoimmune disorders and high-titer anticardiolipin antibodies. It appears that the best therapy for these patients is aggressive immunosuppression with steroids plus plasmapheresis, followed by rituximab or, if in the setting of lupus, intravenous cyclophosphamide monthly.^27,29 Early recognition of CAPS can lead to quick therapy and resolution of the multiorgan system failure.

 

GENERAL THERAPY

The best way to treat DIC is to treat the underlying cause that is driving the thrombin generation.^1,2,4,30,31 Fully addressing the underlying cause may not be possible or may take time, and in the meantime it is necessary to disrupt the cycle of thrombosis and/or hemorrhage. In the past, there was concern about using factor replacement due to fears of “feeding the fire,” or perpetuating the cycle of thrombosis. However, these concerns are not supported by evidence, and factors must be replaced if depletion occurs and bleeding ensues.³²

Transfusion therapy of the patient with DIC is guided by the 5 laboratory tests that reflect the basic parameters essential for both hemostasis and blood volume status:^33,34 hematocrit, platelet count, prothrombin time-INR, aPTT, and fibrinogen level. Decisions regarding replacement therapy are based on the results of these laboratory tests and the clinical situation of the patient (Table 3). 

The transfusion threshold for a low hematocrit depends on the stability of the patient. If the hematocrit is below 21% and the patient is bleeding or hemodynamically unstable, packed red cells should be transfused. Stable patients can tolerate lower hematocrits and an aggressive transfusion policy may be detrimental. ^35–37 In DIC, due to both the bleeding and platelet dysfunction, keeping the platelet count higher than 50,000 cells/μL is reasonable.^33,38 The dose of platelets to be transfused should be 6 to 8 platelet concentrates or 1 plateletpheresis unit. In patients with a fibrinogen level less than 150 mg/dL, transfusion of 10 units of cryoprecipitate is expected to increase the plasma fibrinogen level by 150 mg/dL. In patients with an INR greater than 2 and an abnormal aPTT, 2 to 4 units of fresh frozen plasma (FFP) can be given.³¹ For an aPTT greater than 1.5 times normal, 4 units of plasma should be given. Elevation of the aPTT above 1.8 times normal is associated with bleeding in trauma patients.³⁹ Patients with marked abnormalities, such as an aPTT increased 2 times normal, may require aggressive therapy with at least 15 to 30 mL/kg (4–8 units for an average adult) of plasma.⁴⁰

The basic 5 laboratory tests should be repeated after administering the blood products. This allows one to ensure that adequate replacement therapy was given for the coagulation defects. Frequent checks of the coagulation tests also allow rapid identification and treatment of new coagulation defects in a timely fashion. A flow chart of the test and the blood products administered should also be maintained. This is important in acute situations such as trauma or obstetrical bleeding.

In theory, since DIC is the manifestation of exuberant thrombin production, blocking thrombin with heparin should decrease or shut down DIC. However, studies have shown that in most patients heparin administration has led to excessive bleeding. Currently, heparin therapy is reserved for patients who have thrombosis as a component of their DIC.^2,41,42 Given the coagulopathy that is often present, specific heparin levels instead of the aPTT should be used to monitor anticoagulation.^43,44

SPECIFIC DIC SYNDROMES

SEPSIS/INFECTIOUS DISEASE

Any overwhelming infection can lead to DIC.⁴⁵ Classically, it was believed that gram-negative bacteria can lead tissue factor exposure via production of endotoxin, but recent studies indicate that DIC can be seen with any overwhelming infection.^46,47 There are several potential avenues by which infections can lead to DIC. As mentioned, gram-negative bacteria produce endotoxin that can directly lead to tissue factor exposure, resulting in excess thrombin generation. In addition, any infection can lead to expression of inflammatory cytokines that induce tissue-factor expression by endothelium and monocytes. Some viruses and Rickettsia species can directly infect the vascular endothelium, converting it from an antithrombotic to a prothrombotic phenotype.⁴⁸ When fighting infections, neutrophils can extrude their contents, including DNA, to help trap organisms. These neutrophil extracellular traps (NETS) may play an important role in promoting coagulopathy.^49,50 The hypotension produced by sepsis leads to tissue hypoxia, which results in more DIC. The coagulopathy in sepsis can range from subtle abnormalities of testing to purpura fulminans. Thrombocytopenia is worsened by cytokine-induced hemophagocytic syndrome.

As with all forms of DIC, empiric therapy targeting the most likely source of infection and maintaining hemodynamic stability is the key to therapy. As discussed below, heparin and other forms of coagulation replacement appear to be of no benefit in therapy.

PURPURA FULMINANS

DIC in association with necrosis of the skin is seen in primary and secondary purpura fulminans.^51,52 Primary purpura fulminans is most often seen after a viral infection.⁵³ In these patients, the purpura fulminans starts with a painful red area on an extremity that rapidly progresses to a black ischemic area. In many patients, acquired deficiency of protein S is found.^51,54,55 Secondary purpura fulminans is most often associated with meningococcemia infections but can be seen in any patient with overwhelming infection.^56–58 Post-splenectomy sepsis syndrome patients and those with functional hyposplenism due to chronic liver diseases are also at risk.⁵⁹ Patients present with signs of sepsis, and the skin lesions often involve the extremities and may lead to amputations. As opposed to primary purpura fulminans, those with the secondary form will have symmetrical ischemia distally (toes and fingers) that ascends as the process progresses. Rarely, adrenal infarction (Waterhouse-Friderichsen syndrome) occurs, which leads to severe hypotension.⁴⁵

 

Recently, Warkenten has reported on limb gangrene in critically ill patients complicating sepsis or cardiogenic shock.^60,61 These patients have DIC that is complicated by shock liver. Deep venous thrombosis with ischemic gangrene then develops, which can result in tissue loss and even amputation. The pathogenesis is hypothesized to be hepatic dysfunction leading to sudden drops in protein C and S plasma levels, which then leads to thrombophilia with widespread microvascular thrombosis. Therapy for purpura fulminans is controversial. Primary purpura fulminans, especially in those with postvaricella autoimmune protein S deficiency, has responded to plasma infusion titrated to keep the protein S level above 25%.⁵¹ Intravenous immunoglobulin has also been reported to help decrease the anti-protein S antibodies. Heparin has been reported to control the DIC and extent of necrosis.⁶² The starting dose in these patients is 5 to 8 units/kg/hr.²

Sick patients with secondary purpura fulminans have been treated with plasma drips, plasmapheresis, and continuous plasma ultrafiltration.^62–66 Heparin therapy alone has not been shown to improve survival.⁶⁶ Much attention has been given to replacement of natural anticoagulants such as protein C and antithrombin as therapy for purpura fulminans, but unfortunately randomized trials using antithrombin have shown mostly negative results.^{51,55,67–69} Trials using protein C concentrates have shown more promise in controlling the coagulopathy of purpura fulminans, but this is not widely available.^63,70–72 Unfortunately, many patients will need debridement and amputation for their necrotic limbs, with one review showing approximately 66% of patients needing amputations.⁵²

TRAUMA

Currently, the most common cause of acute DIC is trauma. The coagulation defects that occur in trauma patients are complex in origin and still controversial (including if even calling it DIC is appropriate!).^73–76 The most common etiologies are

• Generation of excess activated protein C leading to increased consumption of factor V and VIII and increased fibrinolysis;
• Tissue damage leading to generation of excess thrombin generation;
• Dilution of hemostatic factors by blood or fluid resuscitation; and
• Activation of endothelial cells leading to generation of a prothrombotic surface and shedding of glycocalyx with antithrombotic properties.

Trauma patients are prone to hypothermia, and this can be the major complicating factor in their bleeding.^77,78 Patients may be out “in the field” for a prolonged period of time and be hypothermic on arrival.⁷⁹ Packed red cells are stored at 4°C, and the infusion of 1 unit can lower the body temperature by 0.16°C.⁸⁰ Hypothermia has profound effects on the coagulation system that are associated with clinical bleeding.^77,81,82 Even modest hypothermia can greatly augment bleeding and needs to be treated or prevented.

The initial management of the bleeding trauma patient is administration of red cells and plasma (FFP) in a 1:1 ratio. This has been shown by clinical studies to lessen the risk of exsanguination in the first 24 hours and to be associated with improved clinical outcomes.^83,84 The basic set of coagulation tests should also be obtained to guide product replacement, especially as the bleeding is brought under control. Hypothermia can be prevented by several measures, including transfusing the blood through blood warmers. Devices are available that can warm 1 unit of blood per minute. An increasingly used technique is to perform “damage control” surgery. Patients are initially stabilized with control of damaged vessels and packing of oozing sites.⁸⁵ Then the patient is taken to the intensive care unit to be warmed and have coagulation defects corrected.

For trauma patients at risk of serious bleeding, the use of tranexamic acid reduced all- cause mortality (relative risk 0.91), with death due to bleeding also being reduced (relative risk 0.85).⁸⁶ There was no increase in thrombosis, but benefit was restricted to patients treated within 3 hours of the trauma. The dose of tranexamic acid was a 1-g bolus followed by a 1-g continuous infusion over 8 hours.

PREGNANCY-RELATED DIC SYNDROMES

Acute DIC of Pregnancy

Pregnancy can be associated with the rapid onset of severe DIC in 2 situations, abruption and amniotic fluid embolism.^87,88 The separation of the placenta from the uterine wall creates a space for blood to occupy. Given the richness of the placenta in tissue factor, this leads to activation of coagulation both locally and systemically. Release of blood when this space reaches the vaginal opening can lead to rapid hemorrhage, further augmenting the coagulation abnormalities. Placental insufficiency can lead to fetal demise, which can also worsen the DIC. Management depends on the size of the abruption and the clinical status of both mother and fetus.⁸⁷ For severe bleeding and DIC, blood product support is crucial to allow safe delivery. In pregnancy, the fibrinogen goal needs to be higher—200 mg/dL.⁸⁹ For smaller abruption, close observation with early delivery is indicated.

 

Amniotic fluid embolism is sudden, with the vascular collapse of the woman soon after delivery. Due to the presence of procoagulant rich fluid in the circulatory system, there is often overwhelming DIC. Therapy is directed at both supporting blood volume and correcting hemostatic defects.

HELLP

The acronym HELLP (hemolysis, elevated liver tests, low platelets) describes a variant of preeclampsia.⁹⁰ Classically, HELLP syndrome occurs after 28 weeks of gestation in a patient with preeclampsia, but can occur as early as 22 weeks in patients with antiphospholipid antibody syndrome.^91–93 The preeclampsia need not be severe. The first sign of HELLP is a decrease in the platelet count followed by abnormal liver function tests. Signs of hemolysis are present with abundant schistocytes on the smear and a high lactate dehydrogenase level. HELLP can progress to liver failure, and deaths are also reported due to hepatic rupture. Unlike TTP, fetal involvement is present in the HELLP syndrome, with fetal thrombocytopenia reported in 30% of cases. In severe cases, elevated D-dimers consistent with DIC are also found. Delivery of the child will most often result in cessation of the HELLP syndrome, but refractory cases will require dexamethasone and plasma exchange.⁹⁴ Patients should be closely observed for 1 to 2 days after delivery as the hematologic picture can transiently worsen before improving.⁹⁵

Acute Fatty Liver of Pregnancy

Fatty liver of pregnancy also occurs late in pregnancy and is only associated with preeclampsia in 50% of cases.^96,97 Patients first present with nonspecific symptoms of nausea and vomiting but can progress to fulminant liver failure. Patients develop thrombocytopenia early in the course, but in the later stages can develop DIC and very low fibrinogen levels. Mortality rates without therapy can be as high as 90%. Low blood glucose and high ammonia levels can help distinguish fatty liver from other pregnancy complications.⁹⁸ Treatment consists of prompt delivery of the child and aggressive blood product support.

Retained Dead Fetus Syndrome

Becoming rarer in modern practices, the presence of a dead fetus for many weeks (usually ≥ 5) can result in a chronic DIC state with fibrinogen depletion and coagulopathy. In some women, this is worsened at delivery. In a stable patient, a short trial of heparin prior to planning delivery can control the DIC to allow the coagulopathy to stabilize.

DRUG-INDUCED HEMOLYTIC-DIC SYNDROMES

A severe variant of the drug-induced immune complex hemolysis associated with DIC has been recognized. Rare patients who receive certain second- and third-generation cephalosporins (especially cefotetan and ceftriaxone) have developed this syndrome.^99–104 The clinical syndrome starts 7 to 10 days after the drug is administered. Often the patient has only received the antibiotic for surgical prophylaxis. The patient will develop severe Coombs’-positive hemolysis with hypotension and DIC. The patients are often believed to have sepsis and in the management of the supposed sepsis often are re-exposed to the cephalosporin, resulting in worsening of the clinical picture. The outcome is often fatal due to massive hemolysis and thrombosis.^{101,105–107}

Quinine is associated with a unique syndrome of drug-induced DIC.^108–111 Approximately 24 to 96 hours after quinine exposure, the patient becomes acutely ill with nausea and vomiting. The patient then develops a microangiopathic hemolytic anemia, DIC, and renal failure. Some patients, besides having antiplatelet antibodies, also have antibodies binding to red cells and neutrophils, which may lead to the more severe syndrome. Despite therapy, patients with quinine-induced TTP have a high incidence of chronic renal failure.

Treatment of the drug-induced hemolytic-DIC syndrome is anecdotal. Patients have responded to aggressive therapy, including plasma exchange, dialysis, and prednisone. Early recognition of the hemolytic anemia and the suspicion it is drug related is important for early diagnosis so that the incriminated drug can be discontinued.

CANCER

Cancers, primarily adenocarcinomas, can result in DIC. The classic Trousseau syndrome referred to the association of migratory superficial thrombophlebitis with cancer¹¹² but now refers to cancer associated with thrombotic DIC.^113,114 Highly vascular tumor cells are known to express tissue factor.^114,115 In addition, some tumor cells can express a direct activator of factor X (“cancer procoagulant”). Unlike many DIC states, cancer presents with thrombosis instead of bleeding. This may be due to the inflammatory state which accompanies cancer, or it may be a unique part of the chronic nature of cancer DIC biology that allows time for the body to compensate for loss of coagulation factors. In some patients, thrombosis is the first sign of an underlying cancer, sometimes predating the cancer diagnosis by months.¹¹⁵ Rarely, the DIC can result in nonthrombotic endocarditis with micro-emboli leading to widespread small-vessel thrombosis.¹¹³

 

Since effective antineoplastic therapy is lacking for many tumors associated with Trousseau syndrome, DIC therapy is aimed at suppressing thrombosis. An exception is prostate cancer, where hormonal therapy can markedly decrease the DIC.¹¹⁶ Due to the tumor directly activating coagulation factors, inhibition of active enzymes via heparin has been shown to reduce rates of recurrence compared with warfarin.^114,115 Clinical trials have demonstrated that heparin therapy is associated with a lower thrombosis recurrence rate than warfarin.^117,118 In some patients, the thrombotic process is so vigorous that new thrombosis can be seen within hours of stopping heparin.¹¹²

ACUTE PROMYELOCYTIC LEUKEMIA

There are multiple hemostatic defects in patients with acute promyelocytic leukemia (APL).¹¹⁹ Most, if not all, patients with APL have evidence of DIC at the time of diagnosis. Patients with APL have a higher risk of death during induction therapy as compared with patients with other forms of leukemia, with death most often due to bleeding. Once in remission, APL patients have a higher cure rate than most patients with leukemia. APL is also unique among leukemias in that biologic therapy with retinoic acid or arsenic is effective in inducing remission and cure in most patients. Although effective therapy is available, early death rates due to bleeding have not changed.¹¹⁹

APL patients can present with pancytopenia due to leukemic marrow replacement or with diffuse bleeding due to DIC and thrombocytopenia. Life-threatening bleeding such as intracranial hemorrhage may occur at any time until the leukemia is put into remission. The etiology of the hemostatic defects in APL is complex and is thought to be the result of DIC, fibrinolysis, and the release of prothrombotic extracellular chromatin and other procoagulant enzymes.^119,120 The diagnosis of APL can be straightforward when the leukemic cells are promyelocytes with abundant Auer rods, although some patients have the microgranular form without obvious Auer rods. The precise diagnosis requires molecular methods, including obtaining FISH for detecting the t(15;17) in PML/RARA fusion. Upon diagnosis of APL, one should obtain a complete coagulation profile, including INR, aPTT, fibrinogen, platelet count, and D-dimers. Change in fibrinogen levels tends to be a good marker of progress in treating the coagulation defects.

Therapy of APL involves treating both the leukemia and the coagulopathy. Currently, the standard treatment for APL is trans-retinoic acid (ATRA) in combination with chemotherapy or arsenic.^121,122 This approach will induce remission in more than 90% of patients, and a sizable majority of these patients will be cured of their APL. ATRA therapy will also lead to early correction of the coagulation defects, often within the first week of therapy.¹²³ This is in stark contrast to the chemotherapy era when the coagulation defects would become worse with therapy. Given the marked beneficial effect of ATRA on the coagulopathy of APL and its low toxicity profile, it should be empirically started for any patients suspected of having APL while genetic testing is being performed. Rare reports of massive thrombosis complicating therapy with ATRA exist, but the relationship to either the APL or ATRA is unknown.

Therapy for the coagulation defects consists of aggressive transfusion therapy support and possible use of other pharmacologic agents to control DIC.^124,125 The fibrinogen level should be maintained at over 150 mg/dL and the platelet count at over 50,000 cells/µL.¹²⁶ Controversy still exists over the role of heparin in therapy of APL.¹⁰⁴ Although attractive for its ability to quench thrombin, heparin use can lead to profound bleeding and its use in treating APL has fallen out of favor.

SNAKEBITES

Snake envenomation can lead to direct activation of multiple coagulation enzymes, including factors V, X, thrombin, and protein C, and lead to cleavage of fibrinogen.^127,128 Envenomation can also activate coagulation and damage vascular endothelium. The DIC can be enhanced by widespread tissue necrosis and hypotension. The key to management of snake bites is administration of specific antivenom. The role of prophylactic factor replacement is controversial, but this therapy is indicated if there is clinical bleeding.¹²⁹ One confounder is that some snake venoms, especially rattlesnake, can induce reversible platelet aggregation, which corrects with antivenom.

LOCAL VASCULAR ABNORMALITIES

Abnormal vascular structures, such as vascular tumors, vascular malformations, and aneurysms, can lead to localized areas of thrombin generation that can “spill-over” into the general circulation, leading to DIC. The diagnosis Kasabach-Merritt phenomenon should be reserved for children with vascular tumors such as angioma or hemangioendothelioma.¹³⁰ Therapy depends on the lesion. Embolization to reduce blood flow of vascular malformations can either be definitive therapy or stabilize the patient for surgery. Aneurysms can be repaired by surgery or stenting. Rare patients with aneurysms with significant coagulopathy may require heparin to raise the fibrinogen level before surgery. Kasabach-Merritt disease can respond to steroids or therapy such as vincristine or interferon.¹³⁰ Increasing data shows that use of the mTOR inhibitor sirolimus can shrink these vascular abnormalities leading to lessening of the coagulopathy.¹³¹

 

CONCLUSION

At the most basic level, DIC is the excess activity of thrombin. However, the clinical presentation and therapy can differ greatly depending on the primary cause. Both diagnosis and therapy involve close coordination of laboratory data and clinical assessment.

 

INTRODUCTION

In the normal person, the process of coagulation is finely controlled at many levels to ensure the appropriate amount of hemostasis at the appropriate location. Broadly defined, disseminated intravascular coagulation (DIC) is the name given to any process that disrupts this fine tuning, leading to unregulated coagulation. Defined this way, DIC may be found in a variety of patients with a variety of disease states, and can present with a spectrum of findings ranging from asymptomatic abnormal laboratory results to florid bleeding or thrombosis. It is important to remember that DIC is always a consequence of an underlying pathological process and not a disease in and of itself. This article first reviews concepts common to all forms of DIC, and then reviews the more common disease states that lead to DIC.

PATHOGENESIS

At the most basic level, DIC is the clinical manifestation of inappropriate thrombin activation.^1–5 Inappropriate thrombin activation can be due to underlying conditions such as sepsis and obstetric disasters. The activation of thrombin leads to (1) conversion of fibrinogen to fibrin, (2) activation of platelets (and their consumption), (3) activation of factors V and VIII, (4) activation of protein C (and degradation of factors Va and VIIIa), (5) activation of endothelial cells, and (6) activation of fibrinolysis (Table 1). 

Thus, with excessive activation of thrombin one can see the following processes:

1. Conversion of fibrinogen to fibrin, which leads to the formation of fibrin monomers and excessive thrombus formation. These thrombi are rapidly dissolved by excessive fibrinolysis in most patients. In certain clinical situations, especially cancer, excessive thrombosis will occur. In patients with cancer, this is most often a deep venous thrombosis. Rare patients, especially those with pancreatic cancer, may have severe DIC with multiple arterial and venous thromboses. Nonbacterial thrombotic endocarditis can also be seen in these patients, leading to widespread embolic complications.

2. Activation of platelets and their consumption. Thrombin is the most potent physiologic activator of platelets, so in DIC there is increased activation of platelets. These activated platelets are consumed, resulting in thrombocytopenia. Platelet dysfunction is also present. Platelets that have been activated and have released their contents but still circulate are known as “exhausted” platelets; these cells can no longer function to support coagulation. The fibrin degradation products (FDP) in DIC can also bind to GP IIb/IIIa and inhibit further platelet aggregation.

3. Activation of factors V, VIII, XI, and XIII. Activation of these factors can promote thrombosis, but they are then rapidly cleared by antithrombin (XI) or activated protein C (V and VIII) or by binding to the fibrin clot (XIII). This can lead to depletion of all the prothrombotic clotting factors and antithrombin, which in turn can lead to both thrombosis and bleeding.

4. Activation of protein C further promotes degradation of factors Va and VIIIa, enhances fibrinolysis, and decreases protein C levels.

5. Activation of endothelial cells, especially in the skin, may lead to thrombosis, and in certain patients, especially those with meningococcemia, purpura fulminans. Endothelial damage will down-regulate thrombomodulin, preventing activation of protein C and leading to further reductions in levels of activated protein C.⁵6. Activation of fibrinolysis leads to the breakdown of fibrin monomers, formation of fibrin thrombi, and increased circulating fibrinogen. In most patients with DIC, the fibrinolytic response is brisk.⁶ This is why most patients with DIC present with bleeding and prolonged clotting times.

PATTERNS OF DIC

The clinical manifestations of DIC in a given patient depend on the balance of thrombin activation and secondary fibrinolysis plus the patient’s ability to compensate for the DIC. Patients with DIC can present in 1 of 4 patterns:^1–3

1. Asymptomatic. Patients can present with laboratory evidence of DIC but no bleeding or thrombosis. This is often seen in patients with sepsis or cancer. However, with further progression of the underlying disease, these patients can rapidly become symptomatic.

2. Bleeding. The bleeding is due to a combination of factor depletion, platelet dysfunction, thrombocytopenia, and excessive fibrinolysis.¹ These patients may present with diffuse bleeding from multiple sites (eg, intravenous sites, areas of instrumentation).

3. Thrombosis. Despite the general activation of the coagulation process, thrombosis is unusual in most patients with acute DIC. The exceptions include patients with cancer, trauma patients, and certain obstetrical patients. Most often the thrombosis is venous, but arterial thrombosis and nonbacterial thrombotic endocarditis have been reported.⁷

4. Purpura fulminans. This form of DIC is discussed in more detail later (see Specific DIC Syndromes section).

DIAGNOSIS

There is no one test that will diagnose DIC; one must match the test to the clinical situation (Table 2).⁸ 

 

SCREENING TESTS

The prothrombin time-INR and activated thromboplastin time (aPPT) are usually elevated in severe DIC but may be normal or shortened in chronic forms.⁹ One may also see a shortened aPTT in severe acute DIC due to large amounts of activated thrombin and factor X “bypassing” the contact pathway. An aPTT as short as 10 seconds has been seen in acute DIC. The platelet count is usually reduced but may be normal in chronic DIC. Serum fibrinogen and platelets are decreased in acute DIC but again may be in the “normal” range in chronic DIC.¹⁰ The most sensitive screening test for DIC is a fall in the platelet count, with low counts seen in 98% of patients and counts under 50,000 cells/μL in 50%.^9,11 The least specific test is fibrinogen, which tends to fall below normal only in severe acute DIC.⁹

SPECIFIC TESTS

This group of tests allows one to deduce that abnormally high concentrations of thrombin are present.

Ethanol Gel and Protamine Tests

Both of these older tests detected circulating fibrin monomers, whose appearance is an early sign of DIC. Circulating fibrin monomers are seen when thrombin acts on fibrinogen. Usually the monomer polymerizes with the fibrin clot, but when there is excess thrombin these monomers can circulate. Detection of circulating fibrin monomer means there is too much IIa and, ergo, DIC is present.

Fibrin(ogen) Degradation Products

Plasmin acts on the fibrin/fibrinogen molecule to cleave the molecule in specific places. The resulting degradation product levels will be elevated in situations of increased fibrin/fibrinogen destruction (DIC and fibrinolysis). The FDP are typically mildly elevated in renal and liver disease due to reduced clearance.

D-Dimers

When fibrin monomers bind to form a thrombus, factor XIII acts to bind their “D” domains together. This bond is resistant to plasmin and thus this degradation fragment is known as the “D-dimer.” High levels of D-dimer indicate that (1) IIa has acted on fibrinogen to form a fibrin monomer that bonded to another fibrin monomer, and (2) this thrombus was lysed by plasmin. Because D-dimers can be elevated (eg, with exercise, after surgery), an elevated D-dimer needs to be interpreted in the context of the clinical situation.¹¹ Currently, this is the most common specific test for DIC performed.

Other Tests

Several other tests are sometimes helpful in diagnosing DIC.

Thrombin time. This test is performed by adding thrombin to plasma. Thrombin times are elevated in DIC (FDPs interfere with polymerization), in the presence of low fibrinogen levels, in dysfibrinogenemia, and in the presence of heparin (very sensitive).

Reptilase time is the same as thrombin time but is performed with a snake venom that is insensitive to heparin. Reptilase time is elevated in the same conditions as the thrombin time, with the exception of the presence of heparin. Thrombin time and reptilase time are most useful in evaluation of dysfibrinogenemia.

Prothrombin fragment 1.2 (F_1.2). F_1.2 is a small peptide cleaved off when prothrombin is activated to thrombin. Thus, high levels of F_1.2 are found in DIC but can be seen in other thrombotic disorders. This test is still of limited clinical value.

DIC scoring system. A scoring system to both diagnose and quantify DIC has been proposed (Figure).^11,12 

This system is especially helpful for clinical trials. A drawback of the score that keeps it from being implemented for routine clinical use is that it requires the prothrombin time, which is not standardized nor often reported by many clinical laboratories.

Thromboelastography (TEG). This is a point-of-care test that uses whole blood to determine specific coagulation parameters such as R time (time from start of test to clot formation), maximal amplitude (MA, maximum extent of thrombus), and LY30 (MA at 30 minutes, a measure of fibrinolysis).¹³ Studies have shown that TEG can identify DIC by demonstrating a shorter R time (excess thrombin generation) which prolongs as coagulation factors are consumed. The MA is decreased as fibrinogen is consumed and the LY30 shows excess fibrinolysis. TEG has been shown to be of particular value in the management of the complex coagulopathy of trauma.¹⁴

MIMICKERS OF DIC

It is important to recognize coagulation syndromes that are not DIC, especially those that have specific other therapies. The syndromes most frequently encountered are thrombotic thrombocytopenic purpura (TTP) and catastrophic antiphospholipid antibody syndrome (CAPS). One important clue to both of these syndromes is that, unlike DIC, there is no primary disorder (cancer, sepsis) that is driving the coagulation abnormalities.

TTP should be suspected when any patient presents with any combination of thrombo­cytopenia, microangiopathic hemolytic anemia (schistocytes and signs of hemolysis) plus end-organ damage.^15–18 Patients with TTP most often present with intractable seizures, strokes, or sequelae of renal insufficiency. Many patients who present with TTP have been misdiagnosed as having sepsis, “lupus flare,” or vasculitis. The key diagnostic differentiator between TTP and DIC is the lack of activation of coagulation with TTP—fibrinogen is normal and D-dimers are minimally or not elevated. In TTP, lactate dehydrogenase is invariably elevated, often 2 to 3 times normal.¹⁹ The importance of identifying TTP is that untreated TTP is rapidly fatal. Mortality in the pre–plasma exchange era ranged from 95% to 100%. Today plasma exchange therapy is the foundation of TTP treatment and has reduced mortality to less than 20%.^16,20–23Rarely patients with antiphospholipid antibody syndrome can present with fulminant multiorgan system failure.^24–28 CAPS is caused by widespread microthrombi in multiple vascular fields. These patients will develop renal failure, encephalopathy, adult respiratory distress syndrome (often with pulmonary hemorrhage), cardiac failure, dramatic livedo reticularis, and worsening thrombocytopenia. Many of these patients have pre-existing autoimmune disorders and high-titer anticardiolipin antibodies. It appears that the best therapy for these patients is aggressive immunosuppression with steroids plus plasmapheresis, followed by rituximab or, if in the setting of lupus, intravenous cyclophosphamide monthly.^27,29 Early recognition of CAPS can lead to quick therapy and resolution of the multiorgan system failure.

 

GENERAL THERAPY

The best way to treat DIC is to treat the underlying cause that is driving the thrombin generation.^1,2,4,30,31 Fully addressing the underlying cause may not be possible or may take time, and in the meantime it is necessary to disrupt the cycle of thrombosis and/or hemorrhage. In the past, there was concern about using factor replacement due to fears of “feeding the fire,” or perpetuating the cycle of thrombosis. However, these concerns are not supported by evidence, and factors must be replaced if depletion occurs and bleeding ensues.³²

Transfusion therapy of the patient with DIC is guided by the 5 laboratory tests that reflect the basic parameters essential for both hemostasis and blood volume status:^33,34 hematocrit, platelet count, prothrombin time-INR, aPTT, and fibrinogen level. Decisions regarding replacement therapy are based on the results of these laboratory tests and the clinical situation of the patient (Table 3). 

The transfusion threshold for a low hematocrit depends on the stability of the patient. If the hematocrit is below 21% and the patient is bleeding or hemodynamically unstable, packed red cells should be transfused. Stable patients can tolerate lower hematocrits and an aggressive transfusion policy may be detrimental. ^35–37 In DIC, due to both the bleeding and platelet dysfunction, keeping the platelet count higher than 50,000 cells/μL is reasonable.^33,38 The dose of platelets to be transfused should be 6 to 8 platelet concentrates or 1 plateletpheresis unit. In patients with a fibrinogen level less than 150 mg/dL, transfusion of 10 units of cryoprecipitate is expected to increase the plasma fibrinogen level by 150 mg/dL. In patients with an INR greater than 2 and an abnormal aPTT, 2 to 4 units of fresh frozen plasma (FFP) can be given.³¹ For an aPTT greater than 1.5 times normal, 4 units of plasma should be given. Elevation of the aPTT above 1.8 times normal is associated with bleeding in trauma patients.³⁹ Patients with marked abnormalities, such as an aPTT increased 2 times normal, may require aggressive therapy with at least 15 to 30 mL/kg (4–8 units for an average adult) of plasma.⁴⁰

The basic 5 laboratory tests should be repeated after administering the blood products. This allows one to ensure that adequate replacement therapy was given for the coagulation defects. Frequent checks of the coagulation tests also allow rapid identification and treatment of new coagulation defects in a timely fashion. A flow chart of the test and the blood products administered should also be maintained. This is important in acute situations such as trauma or obstetrical bleeding.

In theory, since DIC is the manifestation of exuberant thrombin production, blocking thrombin with heparin should decrease or shut down DIC. However, studies have shown that in most patients heparin administration has led to excessive bleeding. Currently, heparin therapy is reserved for patients who have thrombosis as a component of their DIC.^2,41,42 Given the coagulopathy that is often present, specific heparin levels instead of the aPTT should be used to monitor anticoagulation.^43,44

SPECIFIC DIC SYNDROMES

SEPSIS/INFECTIOUS DISEASE

Any overwhelming infection can lead to DIC.⁴⁵ Classically, it was believed that gram-negative bacteria can lead tissue factor exposure via production of endotoxin, but recent studies indicate that DIC can be seen with any overwhelming infection.^46,47 There are several potential avenues by which infections can lead to DIC. As mentioned, gram-negative bacteria produce endotoxin that can directly lead to tissue factor exposure, resulting in excess thrombin generation. In addition, any infection can lead to expression of inflammatory cytokines that induce tissue-factor expression by endothelium and monocytes. Some viruses and Rickettsia species can directly infect the vascular endothelium, converting it from an antithrombotic to a prothrombotic phenotype.⁴⁸ When fighting infections, neutrophils can extrude their contents, including DNA, to help trap organisms. These neutrophil extracellular traps (NETS) may play an important role in promoting coagulopathy.^49,50 The hypotension produced by sepsis leads to tissue hypoxia, which results in more DIC. The coagulopathy in sepsis can range from subtle abnormalities of testing to purpura fulminans. Thrombocytopenia is worsened by cytokine-induced hemophagocytic syndrome.

As with all forms of DIC, empiric therapy targeting the most likely source of infection and maintaining hemodynamic stability is the key to therapy. As discussed below, heparin and other forms of coagulation replacement appear to be of no benefit in therapy.

PURPURA FULMINANS

DIC in association with necrosis of the skin is seen in primary and secondary purpura fulminans.^51,52 Primary purpura fulminans is most often seen after a viral infection.⁵³ In these patients, the purpura fulminans starts with a painful red area on an extremity that rapidly progresses to a black ischemic area. In many patients, acquired deficiency of protein S is found.^51,54,55 Secondary purpura fulminans is most often associated with meningococcemia infections but can be seen in any patient with overwhelming infection.^56–58 Post-splenectomy sepsis syndrome patients and those with functional hyposplenism due to chronic liver diseases are also at risk.⁵⁹ Patients present with signs of sepsis, and the skin lesions often involve the extremities and may lead to amputations. As opposed to primary purpura fulminans, those with the secondary form will have symmetrical ischemia distally (toes and fingers) that ascends as the process progresses. Rarely, adrenal infarction (Waterhouse-Friderichsen syndrome) occurs, which leads to severe hypotension.⁴⁵

 

Recently, Warkenten has reported on limb gangrene in critically ill patients complicating sepsis or cardiogenic shock.^60,61 These patients have DIC that is complicated by shock liver. Deep venous thrombosis with ischemic gangrene then develops, which can result in tissue loss and even amputation. The pathogenesis is hypothesized to be hepatic dysfunction leading to sudden drops in protein C and S plasma levels, which then leads to thrombophilia with widespread microvascular thrombosis. Therapy for purpura fulminans is controversial. Primary purpura fulminans, especially in those with postvaricella autoimmune protein S deficiency, has responded to plasma infusion titrated to keep the protein S level above 25%.⁵¹ Intravenous immunoglobulin has also been reported to help decrease the anti-protein S antibodies. Heparin has been reported to control the DIC and extent of necrosis.⁶² The starting dose in these patients is 5 to 8 units/kg/hr.²

Sick patients with secondary purpura fulminans have been treated with plasma drips, plasmapheresis, and continuous plasma ultrafiltration.^62–66 Heparin therapy alone has not been shown to improve survival.⁶⁶ Much attention has been given to replacement of natural anticoagulants such as protein C and antithrombin as therapy for purpura fulminans, but unfortunately randomized trials using antithrombin have shown mostly negative results.^{51,55,67–69} Trials using protein C concentrates have shown more promise in controlling the coagulopathy of purpura fulminans, but this is not widely available.^63,70–72 Unfortunately, many patients will need debridement and amputation for their necrotic limbs, with one review showing approximately 66% of patients needing amputations.⁵²

TRAUMA

Currently, the most common cause of acute DIC is trauma. The coagulation defects that occur in trauma patients are complex in origin and still controversial (including if even calling it DIC is appropriate!).^73–76 The most common etiologies are

• Generation of excess activated protein C leading to increased consumption of factor V and VIII and increased fibrinolysis;
• Tissue damage leading to generation of excess thrombin generation;
• Dilution of hemostatic factors by blood or fluid resuscitation; and
• Activation of endothelial cells leading to generation of a prothrombotic surface and shedding of glycocalyx with antithrombotic properties.

Trauma patients are prone to hypothermia, and this can be the major complicating factor in their bleeding.^77,78 Patients may be out “in the field” for a prolonged period of time and be hypothermic on arrival.⁷⁹ Packed red cells are stored at 4°C, and the infusion of 1 unit can lower the body temperature by 0.16°C.⁸⁰ Hypothermia has profound effects on the coagulation system that are associated with clinical bleeding.^77,81,82 Even modest hypothermia can greatly augment bleeding and needs to be treated or prevented.

The initial management of the bleeding trauma patient is administration of red cells and plasma (FFP) in a 1:1 ratio. This has been shown by clinical studies to lessen the risk of exsanguination in the first 24 hours and to be associated with improved clinical outcomes.^83,84 The basic set of coagulation tests should also be obtained to guide product replacement, especially as the bleeding is brought under control. Hypothermia can be prevented by several measures, including transfusing the blood through blood warmers. Devices are available that can warm 1 unit of blood per minute. An increasingly used technique is to perform “damage control” surgery. Patients are initially stabilized with control of damaged vessels and packing of oozing sites.⁸⁵ Then the patient is taken to the intensive care unit to be warmed and have coagulation defects corrected.

For trauma patients at risk of serious bleeding, the use of tranexamic acid reduced all- cause mortality (relative risk 0.91), with death due to bleeding also being reduced (relative risk 0.85).⁸⁶ There was no increase in thrombosis, but benefit was restricted to patients treated within 3 hours of the trauma. The dose of tranexamic acid was a 1-g bolus followed by a 1-g continuous infusion over 8 hours.

PREGNANCY-RELATED DIC SYNDROMES

Acute DIC of Pregnancy

Pregnancy can be associated with the rapid onset of severe DIC in 2 situations, abruption and amniotic fluid embolism.^87,88 The separation of the placenta from the uterine wall creates a space for blood to occupy. Given the richness of the placenta in tissue factor, this leads to activation of coagulation both locally and systemically. Release of blood when this space reaches the vaginal opening can lead to rapid hemorrhage, further augmenting the coagulation abnormalities. Placental insufficiency can lead to fetal demise, which can also worsen the DIC. Management depends on the size of the abruption and the clinical status of both mother and fetus.⁸⁷ For severe bleeding and DIC, blood product support is crucial to allow safe delivery. In pregnancy, the fibrinogen goal needs to be higher—200 mg/dL.⁸⁹ For smaller abruption, close observation with early delivery is indicated.

 

Amniotic fluid embolism is sudden, with the vascular collapse of the woman soon after delivery. Due to the presence of procoagulant rich fluid in the circulatory system, there is often overwhelming DIC. Therapy is directed at both supporting blood volume and correcting hemostatic defects.

HELLP

The acronym HELLP (hemolysis, elevated liver tests, low platelets) describes a variant of preeclampsia.⁹⁰ Classically, HELLP syndrome occurs after 28 weeks of gestation in a patient with preeclampsia, but can occur as early as 22 weeks in patients with antiphospholipid antibody syndrome.^91–93 The preeclampsia need not be severe. The first sign of HELLP is a decrease in the platelet count followed by abnormal liver function tests. Signs of hemolysis are present with abundant schistocytes on the smear and a high lactate dehydrogenase level. HELLP can progress to liver failure, and deaths are also reported due to hepatic rupture. Unlike TTP, fetal involvement is present in the HELLP syndrome, with fetal thrombocytopenia reported in 30% of cases. In severe cases, elevated D-dimers consistent with DIC are also found. Delivery of the child will most often result in cessation of the HELLP syndrome, but refractory cases will require dexamethasone and plasma exchange.⁹⁴ Patients should be closely observed for 1 to 2 days after delivery as the hematologic picture can transiently worsen before improving.⁹⁵

Acute Fatty Liver of Pregnancy

Fatty liver of pregnancy also occurs late in pregnancy and is only associated with preeclampsia in 50% of cases.^96,97 Patients first present with nonspecific symptoms of nausea and vomiting but can progress to fulminant liver failure. Patients develop thrombocytopenia early in the course, but in the later stages can develop DIC and very low fibrinogen levels. Mortality rates without therapy can be as high as 90%. Low blood glucose and high ammonia levels can help distinguish fatty liver from other pregnancy complications.⁹⁸ Treatment consists of prompt delivery of the child and aggressive blood product support.

Retained Dead Fetus Syndrome

Becoming rarer in modern practices, the presence of a dead fetus for many weeks (usually ≥ 5) can result in a chronic DIC state with fibrinogen depletion and coagulopathy. In some women, this is worsened at delivery. In a stable patient, a short trial of heparin prior to planning delivery can control the DIC to allow the coagulopathy to stabilize.

DRUG-INDUCED HEMOLYTIC-DIC SYNDROMES

A severe variant of the drug-induced immune complex hemolysis associated with DIC has been recognized. Rare patients who receive certain second- and third-generation cephalosporins (especially cefotetan and ceftriaxone) have developed this syndrome.^99–104 The clinical syndrome starts 7 to 10 days after the drug is administered. Often the patient has only received the antibiotic for surgical prophylaxis. The patient will develop severe Coombs’-positive hemolysis with hypotension and DIC. The patients are often believed to have sepsis and in the management of the supposed sepsis often are re-exposed to the cephalosporin, resulting in worsening of the clinical picture. The outcome is often fatal due to massive hemolysis and thrombosis.^{101,105–107}

Quinine is associated with a unique syndrome of drug-induced DIC.^108–111 Approximately 24 to 96 hours after quinine exposure, the patient becomes acutely ill with nausea and vomiting. The patient then develops a microangiopathic hemolytic anemia, DIC, and renal failure. Some patients, besides having antiplatelet antibodies, also have antibodies binding to red cells and neutrophils, which may lead to the more severe syndrome. Despite therapy, patients with quinine-induced TTP have a high incidence of chronic renal failure.

Treatment of the drug-induced hemolytic-DIC syndrome is anecdotal. Patients have responded to aggressive therapy, including plasma exchange, dialysis, and prednisone. Early recognition of the hemolytic anemia and the suspicion it is drug related is important for early diagnosis so that the incriminated drug can be discontinued.

CANCER

Cancers, primarily adenocarcinomas, can result in DIC. The classic Trousseau syndrome referred to the association of migratory superficial thrombophlebitis with cancer¹¹² but now refers to cancer associated with thrombotic DIC.^113,114 Highly vascular tumor cells are known to express tissue factor.^114,115 In addition, some tumor cells can express a direct activator of factor X (“cancer procoagulant”). Unlike many DIC states, cancer presents with thrombosis instead of bleeding. This may be due to the inflammatory state which accompanies cancer, or it may be a unique part of the chronic nature of cancer DIC biology that allows time for the body to compensate for loss of coagulation factors. In some patients, thrombosis is the first sign of an underlying cancer, sometimes predating the cancer diagnosis by months.¹¹⁵ Rarely, the DIC can result in nonthrombotic endocarditis with micro-emboli leading to widespread small-vessel thrombosis.¹¹³

 

Since effective antineoplastic therapy is lacking for many tumors associated with Trousseau syndrome, DIC therapy is aimed at suppressing thrombosis. An exception is prostate cancer, where hormonal therapy can markedly decrease the DIC.¹¹⁶ Due to the tumor directly activating coagulation factors, inhibition of active enzymes via heparin has been shown to reduce rates of recurrence compared with warfarin.^114,115 Clinical trials have demonstrated that heparin therapy is associated with a lower thrombosis recurrence rate than warfarin.^117,118 In some patients, the thrombotic process is so vigorous that new thrombosis can be seen within hours of stopping heparin.¹¹²

ACUTE PROMYELOCYTIC LEUKEMIA

There are multiple hemostatic defects in patients with acute promyelocytic leukemia (APL).¹¹⁹ Most, if not all, patients with APL have evidence of DIC at the time of diagnosis. Patients with APL have a higher risk of death during induction therapy as compared with patients with other forms of leukemia, with death most often due to bleeding. Once in remission, APL patients have a higher cure rate than most patients with leukemia. APL is also unique among leukemias in that biologic therapy with retinoic acid or arsenic is effective in inducing remission and cure in most patients. Although effective therapy is available, early death rates due to bleeding have not changed.¹¹⁹

APL patients can present with pancytopenia due to leukemic marrow replacement or with diffuse bleeding due to DIC and thrombocytopenia. Life-threatening bleeding such as intracranial hemorrhage may occur at any time until the leukemia is put into remission. The etiology of the hemostatic defects in APL is complex and is thought to be the result of DIC, fibrinolysis, and the release of prothrombotic extracellular chromatin and other procoagulant enzymes.^119,120 The diagnosis of APL can be straightforward when the leukemic cells are promyelocytes with abundant Auer rods, although some patients have the microgranular form without obvious Auer rods. The precise diagnosis requires molecular methods, including obtaining FISH for detecting the t(15;17) in PML/RARA fusion. Upon diagnosis of APL, one should obtain a complete coagulation profile, including INR, aPTT, fibrinogen, platelet count, and D-dimers. Change in fibrinogen levels tends to be a good marker of progress in treating the coagulation defects.

Therapy of APL involves treating both the leukemia and the coagulopathy. Currently, the standard treatment for APL is trans-retinoic acid (ATRA) in combination with chemotherapy or arsenic.^121,122 This approach will induce remission in more than 90% of patients, and a sizable majority of these patients will be cured of their APL. ATRA therapy will also lead to early correction of the coagulation defects, often within the first week of therapy.¹²³ This is in stark contrast to the chemotherapy era when the coagulation defects would become worse with therapy. Given the marked beneficial effect of ATRA on the coagulopathy of APL and its low toxicity profile, it should be empirically started for any patients suspected of having APL while genetic testing is being performed. Rare reports of massive thrombosis complicating therapy with ATRA exist, but the relationship to either the APL or ATRA is unknown.

Therapy for the coagulation defects consists of aggressive transfusion therapy support and possible use of other pharmacologic agents to control DIC.^124,125 The fibrinogen level should be maintained at over 150 mg/dL and the platelet count at over 50,000 cells/µL.¹²⁶ Controversy still exists over the role of heparin in therapy of APL.¹⁰⁴ Although attractive for its ability to quench thrombin, heparin use can lead to profound bleeding and its use in treating APL has fallen out of favor.

SNAKEBITES

Snake envenomation can lead to direct activation of multiple coagulation enzymes, including factors V, X, thrombin, and protein C, and lead to cleavage of fibrinogen.^127,128 Envenomation can also activate coagulation and damage vascular endothelium. The DIC can be enhanced by widespread tissue necrosis and hypotension. The key to management of snake bites is administration of specific antivenom. The role of prophylactic factor replacement is controversial, but this therapy is indicated if there is clinical bleeding.¹²⁹ One confounder is that some snake venoms, especially rattlesnake, can induce reversible platelet aggregation, which corrects with antivenom.

LOCAL VASCULAR ABNORMALITIES

Abnormal vascular structures, such as vascular tumors, vascular malformations, and aneurysms, can lead to localized areas of thrombin generation that can “spill-over” into the general circulation, leading to DIC. The diagnosis Kasabach-Merritt phenomenon should be reserved for children with vascular tumors such as angioma or hemangioendothelioma.¹³⁰ Therapy depends on the lesion. Embolization to reduce blood flow of vascular malformations can either be definitive therapy or stabilize the patient for surgery. Aneurysms can be repaired by surgery or stenting. Rare patients with aneurysms with significant coagulopathy may require heparin to raise the fibrinogen level before surgery. Kasabach-Merritt disease can respond to steroids or therapy such as vincristine or interferon.¹³⁰ Increasing data shows that use of the mTOR inhibitor sirolimus can shrink these vascular abnormalities leading to lessening of the coagulopathy.¹³¹

 

CONCLUSION

At the most basic level, DIC is the excess activity of thrombin. However, the clinical presentation and therapy can differ greatly depending on the primary cause. Both diagnosis and therapy involve close coordination of laboratory data and clinical assessment.

 

INTRODUCTION

In the normal person, the process of coagulation is finely controlled at many levels to ensure the appropriate amount of hemostasis at the appropriate location. Broadly defined, disseminated intravascular coagulation (DIC) is the name given to any process that disrupts this fine tuning, leading to unregulated coagulation. Defined this way, DIC may be found in a variety of patients with a variety of disease states, and can present with a spectrum of findings ranging from asymptomatic abnormal laboratory results to florid bleeding or thrombosis. It is important to remember that DIC is always a consequence of an underlying pathological process and not a disease in and of itself. This article first reviews concepts common to all forms of DIC, and then reviews the more common disease states that lead to DIC.

PATHOGENESIS

At the most basic level, DIC is the clinical manifestation of inappropriate thrombin activation.^1–5 Inappropriate thrombin activation can be due to underlying conditions such as sepsis and obstetric disasters. The activation of thrombin leads to (1) conversion of fibrinogen to fibrin, (2) activation of platelets (and their consumption), (3) activation of factors V and VIII, (4) activation of protein C (and degradation of factors Va and VIIIa), (5) activation of endothelial cells, and (6) activation of fibrinolysis (Table 1). 

Thus, with excessive activation of thrombin one can see the following processes:

1. Conversion of fibrinogen to fibrin, which leads to the formation of fibrin monomers and excessive thrombus formation. These thrombi are rapidly dissolved by excessive fibrinolysis in most patients. In certain clinical situations, especially cancer, excessive thrombosis will occur. In patients with cancer, this is most often a deep venous thrombosis. Rare patients, especially those with pancreatic cancer, may have severe DIC with multiple arterial and venous thromboses. Nonbacterial thrombotic endocarditis can also be seen in these patients, leading to widespread embolic complications.

2. Activation of platelets and their consumption. Thrombin is the most potent physiologic activator of platelets, so in DIC there is increased activation of platelets. These activated platelets are consumed, resulting in thrombocytopenia. Platelet dysfunction is also present. Platelets that have been activated and have released their contents but still circulate are known as “exhausted” platelets; these cells can no longer function to support coagulation. The fibrin degradation products (FDP) in DIC can also bind to GP IIb/IIIa and inhibit further platelet aggregation.

3. Activation of factors V, VIII, XI, and XIII. Activation of these factors can promote thrombosis, but they are then rapidly cleared by antithrombin (XI) or activated protein C (V and VIII) or by binding to the fibrin clot (XIII). This can lead to depletion of all the prothrombotic clotting factors and antithrombin, which in turn can lead to both thrombosis and bleeding.

4. Activation of protein C further promotes degradation of factors Va and VIIIa, enhances fibrinolysis, and decreases protein C levels.

5. Activation of endothelial cells, especially in the skin, may lead to thrombosis, and in certain patients, especially those with meningococcemia, purpura fulminans. Endothelial damage will down-regulate thrombomodulin, preventing activation of protein C and leading to further reductions in levels of activated protein C.⁵6. Activation of fibrinolysis leads to the breakdown of fibrin monomers, formation of fibrin thrombi, and increased circulating fibrinogen. In most patients with DIC, the fibrinolytic response is brisk.⁶ This is why most patients with DIC present with bleeding and prolonged clotting times.

PATTERNS OF DIC

The clinical manifestations of DIC in a given patient depend on the balance of thrombin activation and secondary fibrinolysis plus the patient’s ability to compensate for the DIC. Patients with DIC can present in 1 of 4 patterns:^1–3

1. Asymptomatic. Patients can present with laboratory evidence of DIC but no bleeding or thrombosis. This is often seen in patients with sepsis or cancer. However, with further progression of the underlying disease, these patients can rapidly become symptomatic.

2. Bleeding. The bleeding is due to a combination of factor depletion, platelet dysfunction, thrombocytopenia, and excessive fibrinolysis.¹ These patients may present with diffuse bleeding from multiple sites (eg, intravenous sites, areas of instrumentation).

3. Thrombosis. Despite the general activation of the coagulation process, thrombosis is unusual in most patients with acute DIC. The exceptions include patients with cancer, trauma patients, and certain obstetrical patients. Most often the thrombosis is venous, but arterial thrombosis and nonbacterial thrombotic endocarditis have been reported.⁷

4. Purpura fulminans. This form of DIC is discussed in more detail later (see Specific DIC Syndromes section).

DIAGNOSIS

There is no one test that will diagnose DIC; one must match the test to the clinical situation (Table 2).⁸ 

 

SCREENING TESTS

The prothrombin time-INR and activated thromboplastin time (aPPT) are usually elevated in severe DIC but may be normal or shortened in chronic forms.⁹ One may also see a shortened aPTT in severe acute DIC due to large amounts of activated thrombin and factor X “bypassing” the contact pathway. An aPTT as short as 10 seconds has been seen in acute DIC. The platelet count is usually reduced but may be normal in chronic DIC. Serum fibrinogen and platelets are decreased in acute DIC but again may be in the “normal” range in chronic DIC.¹⁰ The most sensitive screening test for DIC is a fall in the platelet count, with low counts seen in 98% of patients and counts under 50,000 cells/μL in 50%.^9,11 The least specific test is fibrinogen, which tends to fall below normal only in severe acute DIC.⁹

SPECIFIC TESTS

This group of tests allows one to deduce that abnormally high concentrations of thrombin are present.

Ethanol Gel and Protamine Tests

Both of these older tests detected circulating fibrin monomers, whose appearance is an early sign of DIC. Circulating fibrin monomers are seen when thrombin acts on fibrinogen. Usually the monomer polymerizes with the fibrin clot, but when there is excess thrombin these monomers can circulate. Detection of circulating fibrin monomer means there is too much IIa and, ergo, DIC is present.

Fibrin(ogen) Degradation Products

Plasmin acts on the fibrin/fibrinogen molecule to cleave the molecule in specific places. The resulting degradation product levels will be elevated in situations of increased fibrin/fibrinogen destruction (DIC and fibrinolysis). The FDP are typically mildly elevated in renal and liver disease due to reduced clearance.

D-Dimers

When fibrin monomers bind to form a thrombus, factor XIII acts to bind their “D” domains together. This bond is resistant to plasmin and thus this degradation fragment is known as the “D-dimer.” High levels of D-dimer indicate that (1) IIa has acted on fibrinogen to form a fibrin monomer that bonded to another fibrin monomer, and (2) this thrombus was lysed by plasmin. Because D-dimers can be elevated (eg, with exercise, after surgery), an elevated D-dimer needs to be interpreted in the context of the clinical situation.¹¹ Currently, this is the most common specific test for DIC performed.

Other Tests

Several other tests are sometimes helpful in diagnosing DIC.

Thrombin time. This test is performed by adding thrombin to plasma. Thrombin times are elevated in DIC (FDPs interfere with polymerization), in the presence of low fibrinogen levels, in dysfibrinogenemia, and in the presence of heparin (very sensitive).

Reptilase time is the same as thrombin time but is performed with a snake venom that is insensitive to heparin. Reptilase time is elevated in the same conditions as the thrombin time, with the exception of the presence of heparin. Thrombin time and reptilase time are most useful in evaluation of dysfibrinogenemia.

Prothrombin fragment 1.2 (F_1.2). F_1.2 is a small peptide cleaved off when prothrombin is activated to thrombin. Thus, high levels of F_1.2 are found in DIC but can be seen in other thrombotic disorders. This test is still of limited clinical value.

DIC scoring system. A scoring system to both diagnose and quantify DIC has been proposed (Figure).^11,12 

This system is especially helpful for clinical trials. A drawback of the score that keeps it from being implemented for routine clinical use is that it requires the prothrombin time, which is not standardized nor often reported by many clinical laboratories.

Thromboelastography (TEG). This is a point-of-care test that uses whole blood to determine specific coagulation parameters such as R time (time from start of test to clot formation), maximal amplitude (MA, maximum extent of thrombus), and LY30 (MA at 30 minutes, a measure of fibrinolysis).¹³ Studies have shown that TEG can identify DIC by demonstrating a shorter R time (excess thrombin generation) which prolongs as coagulation factors are consumed. The MA is decreased as fibrinogen is consumed and the LY30 shows excess fibrinolysis. TEG has been shown to be of particular value in the management of the complex coagulopathy of trauma.¹⁴

MIMICKERS OF DIC

It is important to recognize coagulation syndromes that are not DIC, especially those that have specific other therapies. The syndromes most frequently encountered are thrombotic thrombocytopenic purpura (TTP) and catastrophic antiphospholipid antibody syndrome (CAPS). One important clue to both of these syndromes is that, unlike DIC, there is no primary disorder (cancer, sepsis) that is driving the coagulation abnormalities.

TTP should be suspected when any patient presents with any combination of thrombo­cytopenia, microangiopathic hemolytic anemia (schistocytes and signs of hemolysis) plus end-organ damage.^15–18 Patients with TTP most often present with intractable seizures, strokes, or sequelae of renal insufficiency. Many patients who present with TTP have been misdiagnosed as having sepsis, “lupus flare,” or vasculitis. The key diagnostic differentiator between TTP and DIC is the lack of activation of coagulation with TTP—fibrinogen is normal and D-dimers are minimally or not elevated. In TTP, lactate dehydrogenase is invariably elevated, often 2 to 3 times normal.¹⁹ The importance of identifying TTP is that untreated TTP is rapidly fatal. Mortality in the pre–plasma exchange era ranged from 95% to 100%. Today plasma exchange therapy is the foundation of TTP treatment and has reduced mortality to less than 20%.^16,20–23Rarely patients with antiphospholipid antibody syndrome can present with fulminant multiorgan system failure.^24–28 CAPS is caused by widespread microthrombi in multiple vascular fields. These patients will develop renal failure, encephalopathy, adult respiratory distress syndrome (often with pulmonary hemorrhage), cardiac failure, dramatic livedo reticularis, and worsening thrombocytopenia. Many of these patients have pre-existing autoimmune disorders and high-titer anticardiolipin antibodies. It appears that the best therapy for these patients is aggressive immunosuppression with steroids plus plasmapheresis, followed by rituximab or, if in the setting of lupus, intravenous cyclophosphamide monthly.^27,29 Early recognition of CAPS can lead to quick therapy and resolution of the multiorgan system failure.

 

GENERAL THERAPY

The best way to treat DIC is to treat the underlying cause that is driving the thrombin generation.^1,2,4,30,31 Fully addressing the underlying cause may not be possible or may take time, and in the meantime it is necessary to disrupt the cycle of thrombosis and/or hemorrhage. In the past, there was concern about using factor replacement due to fears of “feeding the fire,” or perpetuating the cycle of thrombosis. However, these concerns are not supported by evidence, and factors must be replaced if depletion occurs and bleeding ensues.³²

Transfusion therapy of the patient with DIC is guided by the 5 laboratory tests that reflect the basic parameters essential for both hemostasis and blood volume status:^33,34 hematocrit, platelet count, prothrombin time-INR, aPTT, and fibrinogen level. Decisions regarding replacement therapy are based on the results of these laboratory tests and the clinical situation of the patient (Table 3). 

The transfusion threshold for a low hematocrit depends on the stability of the patient. If the hematocrit is below 21% and the patient is bleeding or hemodynamically unstable, packed red cells should be transfused. Stable patients can tolerate lower hematocrits and an aggressive transfusion policy may be detrimental. ^35–37 In DIC, due to both the bleeding and platelet dysfunction, keeping the platelet count higher than 50,000 cells/μL is reasonable.^33,38 The dose of platelets to be transfused should be 6 to 8 platelet concentrates or 1 plateletpheresis unit. In patients with a fibrinogen level less than 150 mg/dL, transfusion of 10 units of cryoprecipitate is expected to increase the plasma fibrinogen level by 150 mg/dL. In patients with an INR greater than 2 and an abnormal aPTT, 2 to 4 units of fresh frozen plasma (FFP) can be given.³¹ For an aPTT greater than 1.5 times normal, 4 units of plasma should be given. Elevation of the aPTT above 1.8 times normal is associated with bleeding in trauma patients.³⁹ Patients with marked abnormalities, such as an aPTT increased 2 times normal, may require aggressive therapy with at least 15 to 30 mL/kg (4–8 units for an average adult) of plasma.⁴⁰

The basic 5 laboratory tests should be repeated after administering the blood products. This allows one to ensure that adequate replacement therapy was given for the coagulation defects. Frequent checks of the coagulation tests also allow rapid identification and treatment of new coagulation defects in a timely fashion. A flow chart of the test and the blood products administered should also be maintained. This is important in acute situations such as trauma or obstetrical bleeding.

In theory, since DIC is the manifestation of exuberant thrombin production, blocking thrombin with heparin should decrease or shut down DIC. However, studies have shown that in most patients heparin administration has led to excessive bleeding. Currently, heparin therapy is reserved for patients who have thrombosis as a component of their DIC.^2,41,42 Given the coagulopathy that is often present, specific heparin levels instead of the aPTT should be used to monitor anticoagulation.^43,44

SPECIFIC DIC SYNDROMES

SEPSIS/INFECTIOUS DISEASE

Any overwhelming infection can lead to DIC.⁴⁵ Classically, it was believed that gram-negative bacteria can lead tissue factor exposure via production of endotoxin, but recent studies indicate that DIC can be seen with any overwhelming infection.^46,47 There are several potential avenues by which infections can lead to DIC. As mentioned, gram-negative bacteria produce endotoxin that can directly lead to tissue factor exposure, resulting in excess thrombin generation. In addition, any infection can lead to expression of inflammatory cytokines that induce tissue-factor expression by endothelium and monocytes. Some viruses and Rickettsia species can directly infect the vascular endothelium, converting it from an antithrombotic to a prothrombotic phenotype.⁴⁸ When fighting infections, neutrophils can extrude their contents, including DNA, to help trap organisms. These neutrophil extracellular traps (NETS) may play an important role in promoting coagulopathy.^49,50 The hypotension produced by sepsis leads to tissue hypoxia, which results in more DIC. The coagulopathy in sepsis can range from subtle abnormalities of testing to purpura fulminans. Thrombocytopenia is worsened by cytokine-induced hemophagocytic syndrome.

As with all forms of DIC, empiric therapy targeting the most likely source of infection and maintaining hemodynamic stability is the key to therapy. As discussed below, heparin and other forms of coagulation replacement appear to be of no benefit in therapy.

PURPURA FULMINANS

DIC in association with necrosis of the skin is seen in primary and secondary purpura fulminans.^51,52 Primary purpura fulminans is most often seen after a viral infection.⁵³ In these patients, the purpura fulminans starts with a painful red area on an extremity that rapidly progresses to a black ischemic area. In many patients, acquired deficiency of protein S is found.^51,54,55 Secondary purpura fulminans is most often associated with meningococcemia infections but can be seen in any patient with overwhelming infection.^56–58 Post-splenectomy sepsis syndrome patients and those with functional hyposplenism due to chronic liver diseases are also at risk.⁵⁹ Patients present with signs of sepsis, and the skin lesions often involve the extremities and may lead to amputations. As opposed to primary purpura fulminans, those with the secondary form will have symmetrical ischemia distally (toes and fingers) that ascends as the process progresses. Rarely, adrenal infarction (Waterhouse-Friderichsen syndrome) occurs, which leads to severe hypotension.⁴⁵

 

Recently, Warkenten has reported on limb gangrene in critically ill patients complicating sepsis or cardiogenic shock.^60,61 These patients have DIC that is complicated by shock liver. Deep venous thrombosis with ischemic gangrene then develops, which can result in tissue loss and even amputation. The pathogenesis is hypothesized to be hepatic dysfunction leading to sudden drops in protein C and S plasma levels, which then leads to thrombophilia with widespread microvascular thrombosis. Therapy for purpura fulminans is controversial. Primary purpura fulminans, especially in those with postvaricella autoimmune protein S deficiency, has responded to plasma infusion titrated to keep the protein S level above 25%.⁵¹ Intravenous immunoglobulin has also been reported to help decrease the anti-protein S antibodies. Heparin has been reported to control the DIC and extent of necrosis.⁶² The starting dose in these patients is 5 to 8 units/kg/hr.²

Sick patients with secondary purpura fulminans have been treated with plasma drips, plasmapheresis, and continuous plasma ultrafiltration.^62–66 Heparin therapy alone has not been shown to improve survival.⁶⁶ Much attention has been given to replacement of natural anticoagulants such as protein C and antithrombin as therapy for purpura fulminans, but unfortunately randomized trials using antithrombin have shown mostly negative results.^{51,55,67–69} Trials using protein C concentrates have shown more promise in controlling the coagulopathy of purpura fulminans, but this is not widely available.^63,70–72 Unfortunately, many patients will need debridement and amputation for their necrotic limbs, with one review showing approximately 66% of patients needing amputations.⁵²

TRAUMA

Currently, the most common cause of acute DIC is trauma. The coagulation defects that occur in trauma patients are complex in origin and still controversial (including if even calling it DIC is appropriate!).^73–76 The most common etiologies are

• Generation of excess activated protein C leading to increased consumption of factor V and VIII and increased fibrinolysis;
• Tissue damage leading to generation of excess thrombin generation;
• Dilution of hemostatic factors by blood or fluid resuscitation; and
• Activation of endothelial cells leading to generation of a prothrombotic surface and shedding of glycocalyx with antithrombotic properties.

Trauma patients are prone to hypothermia, and this can be the major complicating factor in their bleeding.^77,78 Patients may be out “in the field” for a prolonged period of time and be hypothermic on arrival.⁷⁹ Packed red cells are stored at 4°C, and the infusion of 1 unit can lower the body temperature by 0.16°C.⁸⁰ Hypothermia has profound effects on the coagulation system that are associated with clinical bleeding.^77,81,82 Even modest hypothermia can greatly augment bleeding and needs to be treated or prevented.

The initial management of the bleeding trauma patient is administration of red cells and plasma (FFP) in a 1:1 ratio. This has been shown by clinical studies to lessen the risk of exsanguination in the first 24 hours and to be associated with improved clinical outcomes.^83,84 The basic set of coagulation tests should also be obtained to guide product replacement, especially as the bleeding is brought under control. Hypothermia can be prevented by several measures, including transfusing the blood through blood warmers. Devices are available that can warm 1 unit of blood per minute. An increasingly used technique is to perform “damage control” surgery. Patients are initially stabilized with control of damaged vessels and packing of oozing sites.⁸⁵ Then the patient is taken to the intensive care unit to be warmed and have coagulation defects corrected.

For trauma patients at risk of serious bleeding, the use of tranexamic acid reduced all- cause mortality (relative risk 0.91), with death due to bleeding also being reduced (relative risk 0.85).⁸⁶ There was no increase in thrombosis, but benefit was restricted to patients treated within 3 hours of the trauma. The dose of tranexamic acid was a 1-g bolus followed by a 1-g continuous infusion over 8 hours.

PREGNANCY-RELATED DIC SYNDROMES

Acute DIC of Pregnancy

Pregnancy can be associated with the rapid onset of severe DIC in 2 situations, abruption and amniotic fluid embolism.^87,88 The separation of the placenta from the uterine wall creates a space for blood to occupy. Given the richness of the placenta in tissue factor, this leads to activation of coagulation both locally and systemically. Release of blood when this space reaches the vaginal opening can lead to rapid hemorrhage, further augmenting the coagulation abnormalities. Placental insufficiency can lead to fetal demise, which can also worsen the DIC. Management depends on the size of the abruption and the clinical status of both mother and fetus.⁸⁷ For severe bleeding and DIC, blood product support is crucial to allow safe delivery. In pregnancy, the fibrinogen goal needs to be higher—200 mg/dL.⁸⁹ For smaller abruption, close observation with early delivery is indicated.

 

Amniotic fluid embolism is sudden, with the vascular collapse of the woman soon after delivery. Due to the presence of procoagulant rich fluid in the circulatory system, there is often overwhelming DIC. Therapy is directed at both supporting blood volume and correcting hemostatic defects.

HELLP

The acronym HELLP (hemolysis, elevated liver tests, low platelets) describes a variant of preeclampsia.⁹⁰ Classically, HELLP syndrome occurs after 28 weeks of gestation in a patient with preeclampsia, but can occur as early as 22 weeks in patients with antiphospholipid antibody syndrome.^91–93 The preeclampsia need not be severe. The first sign of HELLP is a decrease in the platelet count followed by abnormal liver function tests. Signs of hemolysis are present with abundant schistocytes on the smear and a high lactate dehydrogenase level. HELLP can progress to liver failure, and deaths are also reported due to hepatic rupture. Unlike TTP, fetal involvement is present in the HELLP syndrome, with fetal thrombocytopenia reported in 30% of cases. In severe cases, elevated D-dimers consistent with DIC are also found. Delivery of the child will most often result in cessation of the HELLP syndrome, but refractory cases will require dexamethasone and plasma exchange.⁹⁴ Patients should be closely observed for 1 to 2 days after delivery as the hematologic picture can transiently worsen before improving.⁹⁵

Acute Fatty Liver of Pregnancy

Fatty liver of pregnancy also occurs late in pregnancy and is only associated with preeclampsia in 50% of cases.^96,97 Patients first present with nonspecific symptoms of nausea and vomiting but can progress to fulminant liver failure. Patients develop thrombocytopenia early in the course, but in the later stages can develop DIC and very low fibrinogen levels. Mortality rates without therapy can be as high as 90%. Low blood glucose and high ammonia levels can help distinguish fatty liver from other pregnancy complications.⁹⁸ Treatment consists of prompt delivery of the child and aggressive blood product support.

Retained Dead Fetus Syndrome

Becoming rarer in modern practices, the presence of a dead fetus for many weeks (usually ≥ 5) can result in a chronic DIC state with fibrinogen depletion and coagulopathy. In some women, this is worsened at delivery. In a stable patient, a short trial of heparin prior to planning delivery can control the DIC to allow the coagulopathy to stabilize.

DRUG-INDUCED HEMOLYTIC-DIC SYNDROMES

A severe variant of the drug-induced immune complex hemolysis associated with DIC has been recognized. Rare patients who receive certain second- and third-generation cephalosporins (especially cefotetan and ceftriaxone) have developed this syndrome.^99–104 The clinical syndrome starts 7 to 10 days after the drug is administered. Often the patient has only received the antibiotic for surgical prophylaxis. The patient will develop severe Coombs’-positive hemolysis with hypotension and DIC. The patients are often believed to have sepsis and in the management of the supposed sepsis often are re-exposed to the cephalosporin, resulting in worsening of the clinical picture. The outcome is often fatal due to massive hemolysis and thrombosis.^{101,105–107}

Quinine is associated with a unique syndrome of drug-induced DIC.^108–111 Approximately 24 to 96 hours after quinine exposure, the patient becomes acutely ill with nausea and vomiting. The patient then develops a microangiopathic hemolytic anemia, DIC, and renal failure. Some patients, besides having antiplatelet antibodies, also have antibodies binding to red cells and neutrophils, which may lead to the more severe syndrome. Despite therapy, patients with quinine-induced TTP have a high incidence of chronic renal failure.

Treatment of the drug-induced hemolytic-DIC syndrome is anecdotal. Patients have responded to aggressive therapy, including plasma exchange, dialysis, and prednisone. Early recognition of the hemolytic anemia and the suspicion it is drug related is important for early diagnosis so that the incriminated drug can be discontinued.

CANCER

Cancers, primarily adenocarcinomas, can result in DIC. The classic Trousseau syndrome referred to the association of migratory superficial thrombophlebitis with cancer¹¹² but now refers to cancer associated with thrombotic DIC.^113,114 Highly vascular tumor cells are known to express tissue factor.^114,115 In addition, some tumor cells can express a direct activator of factor X (“cancer procoagulant”). Unlike many DIC states, cancer presents with thrombosis instead of bleeding. This may be due to the inflammatory state which accompanies cancer, or it may be a unique part of the chronic nature of cancer DIC biology that allows time for the body to compensate for loss of coagulation factors. In some patients, thrombosis is the first sign of an underlying cancer, sometimes predating the cancer diagnosis by months.¹¹⁵ Rarely, the DIC can result in nonthrombotic endocarditis with micro-emboli leading to widespread small-vessel thrombosis.¹¹³

 

Since effective antineoplastic therapy is lacking for many tumors associated with Trousseau syndrome, DIC therapy is aimed at suppressing thrombosis. An exception is prostate cancer, where hormonal therapy can markedly decrease the DIC.¹¹⁶ Due to the tumor directly activating coagulation factors, inhibition of active enzymes via heparin has been shown to reduce rates of recurrence compared with warfarin.^114,115 Clinical trials have demonstrated that heparin therapy is associated with a lower thrombosis recurrence rate than warfarin.^117,118 In some patients, the thrombotic process is so vigorous that new thrombosis can be seen within hours of stopping heparin.¹¹²

ACUTE PROMYELOCYTIC LEUKEMIA

There are multiple hemostatic defects in patients with acute promyelocytic leukemia (APL).¹¹⁹ Most, if not all, patients with APL have evidence of DIC at the time of diagnosis. Patients with APL have a higher risk of death during induction therapy as compared with patients with other forms of leukemia, with death most often due to bleeding. Once in remission, APL patients have a higher cure rate than most patients with leukemia. APL is also unique among leukemias in that biologic therapy with retinoic acid or arsenic is effective in inducing remission and cure in most patients. Although effective therapy is available, early death rates due to bleeding have not changed.¹¹⁹

APL patients can present with pancytopenia due to leukemic marrow replacement or with diffuse bleeding due to DIC and thrombocytopenia. Life-threatening bleeding such as intracranial hemorrhage may occur at any time until the leukemia is put into remission. The etiology of the hemostatic defects in APL is complex and is thought to be the result of DIC, fibrinolysis, and the release of prothrombotic extracellular chromatin and other procoagulant enzymes.^119,120 The diagnosis of APL can be straightforward when the leukemic cells are promyelocytes with abundant Auer rods, although some patients have the microgranular form without obvious Auer rods. The precise diagnosis requires molecular methods, including obtaining FISH for detecting the t(15;17) in PML/RARA fusion. Upon diagnosis of APL, one should obtain a complete coagulation profile, including INR, aPTT, fibrinogen, platelet count, and D-dimers. Change in fibrinogen levels tends to be a good marker of progress in treating the coagulation defects.

Therapy of APL involves treating both the leukemia and the coagulopathy. Currently, the standard treatment for APL is trans-retinoic acid (ATRA) in combination with chemotherapy or arsenic.^121,122 This approach will induce remission in more than 90% of patients, and a sizable majority of these patients will be cured of their APL. ATRA therapy will also lead to early correction of the coagulation defects, often within the first week of therapy.¹²³ This is in stark contrast to the chemotherapy era when the coagulation defects would become worse with therapy. Given the marked beneficial effect of ATRA on the coagulopathy of APL and its low toxicity profile, it should be empirically started for any patients suspected of having APL while genetic testing is being performed. Rare reports of massive thrombosis complicating therapy with ATRA exist, but the relationship to either the APL or ATRA is unknown.

Therapy for the coagulation defects consists of aggressive transfusion therapy support and possible use of other pharmacologic agents to control DIC.^124,125 The fibrinogen level should be maintained at over 150 mg/dL and the platelet count at over 50,000 cells/µL.¹²⁶ Controversy still exists over the role of heparin in therapy of APL.¹⁰⁴ Although attractive for its ability to quench thrombin, heparin use can lead to profound bleeding and its use in treating APL has fallen out of favor.

SNAKEBITES

Snake envenomation can lead to direct activation of multiple coagulation enzymes, including factors V, X, thrombin, and protein C, and lead to cleavage of fibrinogen.^127,128 Envenomation can also activate coagulation and damage vascular endothelium. The DIC can be enhanced by widespread tissue necrosis and hypotension. The key to management of snake bites is administration of specific antivenom. The role of prophylactic factor replacement is controversial, but this therapy is indicated if there is clinical bleeding.¹²⁹ One confounder is that some snake venoms, especially rattlesnake, can induce reversible platelet aggregation, which corrects with antivenom.

LOCAL VASCULAR ABNORMALITIES

Abnormal vascular structures, such as vascular tumors, vascular malformations, and aneurysms, can lead to localized areas of thrombin generation that can “spill-over” into the general circulation, leading to DIC. The diagnosis Kasabach-Merritt phenomenon should be reserved for children with vascular tumors such as angioma or hemangioendothelioma.¹³⁰ Therapy depends on the lesion. Embolization to reduce blood flow of vascular malformations can either be definitive therapy or stabilize the patient for surgery. Aneurysms can be repaired by surgery or stenting. Rare patients with aneurysms with significant coagulopathy may require heparin to raise the fibrinogen level before surgery. Kasabach-Merritt disease can respond to steroids or therapy such as vincristine or interferon.¹³⁰ Increasing data shows that use of the mTOR inhibitor sirolimus can shrink these vascular abnormalities leading to lessening of the coagulopathy.¹³¹

 

CONCLUSION

At the most basic level, DIC is the excess activity of thrombin. However, the clinical presentation and therapy can differ greatly depending on the primary cause. Both diagnosis and therapy involve close coordination of laboratory data and clinical assessment.

INTRODUCTION

Fatigue is a common distressing effect of cancer.¹ It impairs the quality of life of patients undergoing active cancer treatment and of post-treatment survivors alike. The National Comprehensive Cancer Network (NCCN) defines cancer-related fatigue (CRF) as “a distressing, persistent, subjective sense of physical, emotional and/or cognitive tiredness related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning.”² CRF differs from fatigue reported by individuals without cancer in that CRF is more severe and is not relieved by rest. The prevalence of CRF in cancer patients and survivors is highly variable, with estimates ranging between 25% and 99%.^2,3 The methods used for screening patients for fatigue and the characteristics of the patient groups may account for this variability. In this article, we review evaluation of CRF and approaches to its management.

PATHOPHYSIOLOGY

The specific pathophysiologic mechanism underlying CRF is unknown, making targeted treatment a challenge. The multidimensional and subjective nature of CRF has limited the development of research methodologies to explain this condition. However, research has been done in both human and animal models, and several theories have been proposed to explain the pathophysiology of CRF. While pro-inflammatory cytokines remain the central factor playing a significant role at multiple levels in CRF, there may be a complex interplay of multiple mechanisms contributing to fatigue in an individual patient.

CENTRAL NERVOUS SYSTEM DISTURBANCES

The basal ganglia are known to influence motivation. Lack of motivation and drive may cause failure to complete physical and mental tasks, even with preserved cognitive ability and motor function. In a study of melanoma patients receiving interferon, increased activity of the basal ganglia and the cerebellum resulted in higher fatigue scores.⁴ Increased levels of cytokines may alter blood flow to the cerebellum and lead to the perception of fatigue. In a study of 12 patients and matched controls, when patients were asked to perform sustained elbow flexion until they perceived exhaustion, CRF patients perceived physical exhaustion sooner than controls. In CRF patients in this study, muscle fatigue measured by electromyogram was less than that in healthy individuals at the time of exhaustion, suggesting the role of the central nervous system in CRF.⁵ However, there is not enough evidence at this time to support central nervous system disturbance as the main factor contributing to fatigue in cancer patients.

CIRCADIAN RHYTHM DYSREGULATION

Circadian rhythm is regulated by the suprachiasmatic nucleus in the hypothalamus through cortisol and melatonin. Sleep disturbances occur with disruption of the circadian rhythm. Tumor-related peptides such as epidermal growth factor or alterations in serotonin and cortisol can influence the suprachiasmatic nucleus and the complex signaling pathways.² Positive feedback loops that are activated by cortisol under the influence of cytokines may lead to continuous cytokine production and altered circadian rhythm. Bower et al showed that changes in the cortisol curve influence fatigue in breast cancer survivors.⁶ These patients had a late evening peak in cortisol levels, compared with an early morning peak in individuals without cancer.

INHIBITION OF HYPOTHALAMIC-PITUITARY-ADRENAL AXIS

The hypothalamic–pituitary–adrenal (HPA) axis regulates the release of the stress hormone cortisol. One of several hypotheses advanced to explain the effect of serotonin and the HPA axis on CRF suggests that lower serotonin levels cause decreased activation of 5-hydroxytrytophan 1-a (5-HT1-a) receptors in the hypothalamus, leading to decreased activity of the HPA axis.⁶ Inhibition of the HPA axis may occur with higher levels of serotonin as well.⁷ The 5-HT1-a receptors are also triggered by cytokines. However, the correction of serotonin levels by antidepressants was not shown to improve fatigue.⁸ Inhibition of the HPA axis can also lead to lower testosterone, progesterone, or estrogen levels, which may indirectly contribute to fatigue.²

SKELETAL MUSCLE EFFECT

Chemotherapy- and tumor-related cachexia have a direct effect on the metabolism of skeletal muscles. This effect may lead to impaired adenosine triphosphate (ATP) generation during muscle contraction.⁹ ATP infusion improved muscle strength in 1 trial, but this was not confirmed in another trial.^10,11 Muscle contraction studies showed no differences in the contractile properties of muscles in fatigued patients who failed earlier in motor tasks and healthy controls.¹² This finding suggests that there could be a failure of skeletal muscle activation by the central nervous system or inhibition of skeletal muscle activity. Cytokines and other neurotransmitters activate vagal efferent nerve fibers, which may lead to reflex inhibition in skeletal muscles.^13,14

PRO-INFLAMMATORY CYTOKINES

Tumors or treatment of them may cause tissue injury, which triggers immune cells to release cytokines, signaling the brain to manifest the symptom of fatigue. Inflammatory pathways are influenced by psychological, behavioral, and biological factors, which play a role as risk factors in CRF. Levels of interleukin 6 (IL-6), interleukin-1 receptor antagonist, interleukin-1, and tumor necrosis factor (TNF) have been shown to be elevated in fatigued patients being treated for leukemia and non-Hodgkin lymphoma.¹⁵ IL-6 was also associated with increased fatigue in breast cancer survivors.¹⁶ Similar findings were reported in patients undergoing stem cell transplantation and high-dose chemotherapy.¹⁷ Elevated levels of IL-6 and C-reactive protein were also linked to fatigue in terminally ill cancer patients.^18,19 Furthermore, TNF-α signaling was associated with post-chemotherapy fatigue in breast cancer patients.²⁰ Leukocytes in breast cancer survivors with fatigue also have increased gene expression of pro-inflammatory cytokines, emphasizing the role of cytokines and inflammation in the pathogenesis of CRF.²¹

 

OTHER HYPOTHESES

Several other hypotheses for CRF pathogenesis have been proposed. Activation of latent viruses such as Epstein-Barr virus, lack of social support,²² genetic alterations in the immune pathway,²³ epigenetic changes,²⁴ accumulation of neurotoxic metabolites and depletion of serotonin by indoleamine 2,3-dioxygenase pathway activation,²⁵ elevated vascular endothelial growth factor levels,²⁶ and hypoxia-related organ dysfunction due to anemia or hemoglobin dysfunction¹³ all have been postulated to cause CRF.

EVALUATION AND TREATMENT

Fours steps are involved in the evaluation and treatment of CRF (Figure).

Patients are screened for fatigue as the first step, and those who have fatigue undergo a primary evaluation to assess for potential precipitating causes. The third step is implementation of pharmacologic and nonpharmacologic interventions aimed at alleviating or mitigating fatigue. The fourth step involves reevaluating patients periodically to recognize and manage changes in fatigue levels. A multidisciplinary approach involving nursing, physical therapy, social work, and nutrition is critical in managing fatigue in these patients. Education and counselling of patients and involvement of the family are essential for effective management as well.

SCREENING

Because patients and health care professionals may be unaware of the treatment options available for CRF, patients may not report fatigue levels to their clinicians, and clinicians may not understand the impact of fatigue on their patients’ quality of life. This leads to under-recognition of the problem. The NCCN recommends screening every cancer patient and post-treatment survivor for fatigue.² Patients should be screened at their first visit and then at periodic intervals during and after cancer treatment.

Many scales are available to screen patients for CRF in clinical practice and clinical trials.²⁷ A single item that asks patients to rate their fatigue on a scale from 0 to 10—in which 0 indicates no fatigue, 1 to 3 indicates mild fatigue, 4 to 6 indicates moderate fatigue, 7 to 9 indicates severe fatigue, and 10 indicates the worst fatigue imaginable—is commonly used to screen for CRF.² This scale was adapted from the MD Anderson Symptom Inventory scale and is based on a large nationwide study of cancer patients and survivors.²⁸ The statistically derived cutoff points in this study are consistent with other scales such as the Brief Fatigue Inventory (BFI) and support the cutoff points (4–6 for moderate and ≥ 7 for severe fatigue) used in various fatigue management guidelines. Furthermore, studies of fatigue in cancer patients have revealed a marked decrease in physical function at levels of 7 or higher, suggesting 7 as an optimal cutoff to identify severe fatigue.^29,30 The Visual Analog Scale is another simple-to-use tool that helps in understanding variations in fatigue throughout the course of the day.³¹ The 9-item BFI is often used in clinical trials.²⁹ It measures the severity of fatigue over the previous 24 hours and has been validated in patients who do not speak English.³²

CRF affects not only the somatic domain, but also the cognitive, behavioral, and affective domains; therefore, multidimensional scales have been developed for screening. One such tool is the Multidimensional Fatigue Inventory, which assesses 5 dimensions of fatigue—general fatigue, physical fatigue, reduced motivation, reduced activity, and mental fatigue—and compares the patient’s results with those of individuals without cancer.^33,34 The Functional Assessment of Cancer Therapy for Fatigue (FACT-F) is a 13-item questionnaire that has been used to measure CRF in clinical trials as well as in patients receiving various treatments.³⁵

Although many scales are available, the validity of self-reporting on simple fatigue-rating scales is equal to or better than most complex, lengthy scales.³⁶ Therefore, unidimensional tools such as the numeric rating scale of 0–10 are commonly used in clinical practice. Mild fatigue (0–3) requires periodic reevaluation, and moderate and severe fatigue need further evaluation and management.³⁷

PRIMARY EVALUATION

This phase involves a focused history and physical examination and assessment of concurrent symptoms and contributing factors.

History and Physical Examination

A detailed history of the patient’s malignancy and type of previous and current treatment may help reveal the cause of fatigue. New-onset fatigue or increase in fatigue may be related to the progression of disease in patients with active malignancy or recurrence of cancer in survivors. These patients may require appropriate testing to assess the underlying disease pattern. A detailed review of systems may help identify some of the contributing factors, which are discussed below. A detailed history regarding medications, including over-the-counter drugs, complementary agents, and past and prior cancer therapies, is helpful as medications can contribute to fatigue. For example, opioids may cause drowsiness and fatigue, which could be improved by dose adjustments. A focused history of fatigue should be obtained in all patients with moderate to severe CRF, which includes the onset, pattern, duration, associated or alleviating factors, and interference with functioning, including activities of daily living.³⁷ Physical examination should focus on identifying signs of organ dysfunction and features of substance or alcohol abuse, which may cause poor sleep and fatigue.

 

Assessment of Contributing Factors

The management of fatigue should be multifactorial, with a comprehensive assessment and treatment plan to address all modifiable fatigue etiologies. The Table lists potential contributing factors to fatigue that should be considered when evaluating patients for CRF; several common conditions are discussed below. 

Anemia. Anemia has been correlated with fatigue and quality of life. In a study of 4382 cancer patients receiving chemotherapy, quality-of-life measures using FACT-Anemia scores improved with increased hemoglobin levels.³⁸ Cancer patients may have anemia due to marrow-suppressing effects of chemotherapy and may also have iron deficiency anemia due to blood loss or auto-immune hemolytic anemia. Therefore, a detailed work-up is required to identify the etiology of anemia. Patients with CRF whose anemia is related to chemotherapy or anemia of chronic disease may benefit from red blood cell transfusion or erythropoiesis-stimulating agents (ESAs). ESAs have been studied extensively; however, their use is controversial because of concerns about thromboembolic side effects leading to adverse outcomes.³⁹ Also, ESA therapy is not recommended in patients with hematologic malignancies. ESA use should be restricted to patients with chemotherapy-related anemia with hemoglobin below 10 mg/dL and should be discontinued in 6 to 8 weeks if patients do not respond.⁴⁰ Other patients may benefit from blood transfusions, which were shown to help in patients with hemoglobin levels between 7.5 and 8.5 g/dL.⁴¹

Sleep disturbance. Poor sleep is common in fatigued cancer survivors.⁴² Pro-inflammatory cytokines can disrupt the sleep–wake cycle, causing changes in the HPA axis and neuro­endocrine system, which in turn may lead to increasing fatigue. Heckler et al showed that improvement in nighttime sleep leads to improvement of fatigue.⁴³ Cognitive behavioral therapy and sleep hygiene are important in caring for patients with CRF and poor sleep.⁴⁴ Taking a warm bath and/or drinking a glass of milk before bedtime, avoiding caffeinated drinks, and avoiding frequent napping in the day might help. Some patients may require medications such as benzodiazepines or non-benzodiazepine hypnotics (eg, zolpidem) to promote sleep.⁴⁵ Melatonin agonists are approved for insomnia in the United States, but not in Europe.⁴⁶

Malnutrition. Patients with advanced-stage cancer and with cancers affecting the gastrointestinal tract frequently develop mechanical bowel obstructions, especially at the end of their life, which cause malnutrition. Chemotherapy-related nausea and vomiting may also cause poor oral intake and malnutrition, causing fatigue from muscle weakness. Dehydration and electrolyte imbalances frequently occur as a result of poor oral intake, which might worsen fatigue. In our experience, modifying dietary intake with appropriate caloric exchanges with the help of a nutrition expert has lessened fatigue in some patients. However, terminally ill patients are advised to eat based on their comfort.

Medical comorbidities. Congestive heart failure from anthracycline chemotherapy, hypothyroidism after radiation therapy for head and neck cancers, renal failure, or hepatic failure from chemotherapy may indirectly lead to fatigue. Chemotherapy, opioids, and steroids may cause hypogonadism, which can contribute to fatigue in men.⁴⁷

Assessment of Concurrent Symptoms

Depression is common in cancer patients and coexists with pain, insomnia, fatigue, and anxiety as a symptom cluster.⁴⁸ A symptom cluster is defined as 2 or more concurrent and interrelated symptoms occurring together; treating one of these symptoms without addressing other symptoms is not effective.⁴⁹ Therefore, screening for and management of depression, anxiety, and insomnia play an important role in the management of CRF.

Physical symptoms due to the tumor or to therapy— such as pain, dyspnea, nausea, and decreased physical activity—may also contribute to fatigue both directly and indirectly. Patients with lung cancer may have hypoxemia, which can contribute to dyspnea with activity and a perception of fatigue. Optimal management of pain and other physical symptoms in patients with cancer may significantly alleviate fatigue.⁵⁰

MANAGEMENT

Management of CRF is individualized based on the patient’s clinical status: active cancer treatment, survivor, or end of life. Education and counselling of patients and their caregivers play an important role in CRF. NCCN guidelines recommend focusing on pain control, distress management, energy conservation, physical activity, nutrition, and sleep hygiene.

Nonpharmacologic Interventions

Energy conservation. Energy conservation strategies, in which patients are advised to set priorities and realistic expectations, are highly recommended. Some energy-conserving strategies are to pace oneself, delegate and schedule activities at times of peak energy, postpone nonessential activities, attend to 1 activity at a time, structure daily routines, and maintain a diary to identify their peak energy period and structure activities around that time.^51,52 When patients approach the end of life, increasing fatigue may limit their activity level, and they may depend on caregivers for assistance with activities of daily living, monitoring treatment-related adverse effects, and taking medications, especially elderly patients.⁵³

 

Cognitive behavioral therapy. Cognitive behavioral therapy (CBT) has been shown to improve CRF during active treatment, and the benefits persist for a minimum of 2 years after therapy.⁵⁴ CBT interventions that optimize sleep quality may improve fatigue.⁵⁵ More studies are needed to understand whether referral to a psychologist for formal CBT is required. Randomized clinical trials showed patient fatigue education, learned self-care, coping techniques, and balancing rest and activity benefit patients with CRF.⁵⁶

Exercise. Physical activity is highly encouraged in patients with CRF. Exercise increases muscle protein synthesis, improves cytokine response, and decreases the rate of sarcopenia in healthy populations.⁵⁷ Studies have shown that exercise helps CRF at all phases of the cancer journey, including radiation therapy, chemotherapy, and survivorship.⁵⁸ Some patients may feel less motivated to exercise and may not believe that exercise is possible or could potentially help them. Counselling is needed for such patients.

Older cancer survivors have a decline in their functional capacity and reduced muscle mass. Exercise can improve their cardiorespiratory fitness, muscle strength, and body composition.⁵⁷ Exercise not only helps at the cellular level but also has psychosocial benefits from improved self-esteem. Therefore, exercise may be recommended for younger patients as well as for the older population, who may have comorbidities and less motivation than younger patients.

In a meta-analysis of 56 randomized controlled trials involving 4068 participants, aerobic exercise was found to have beneficial effects on CRF for patients during and after chemotherapy, specifically for patients with solid tumors.⁵⁹ In another meta-analysis of breast and prostate cancer survivors, a combination of aerobic exercise with resistance training (3–6 metabolic equivalents, 60%–80% range of motion) was shown to reduce CRF more than aerobic exercise alone.⁶⁰ This effect was also shown in a randomized controlled trial of 160 patients with stage 0 to III breast cancer undergoing radiation therapy.⁶¹ The control group in this study had a group-based non-exercise intervention/relaxation; therefore, the study showed that the effect of resistance training extends beyond the psychosocial benefits of group-based interventions. The intervention comprised 8 progressive machine-based resistance exercises (3 sets, 8–12 repetitions at 60%–80% of 1 repetition maximum) for 60 minutes twice weekly for 12 weeks. However, fatigue assessment questionnaire scores showed benefits only in the physical fatigue components, but not in the affective and cognitive components.

The American Society of Clinical Oncology’s guidelines for cancer survivors with fatigue recommends 150 minutes of moderate aerobic exercise (eg, fast walking, cycling, or swimming) per week, with 2 or 3 sessions of strength training per week.⁶² An individualized approach to exercise is recommended, as patients’ ability to perform certain types of exercises may be limited by thrombocytopenia, neutropenia, or lytic bone metastasis. Routine use of pre-exercise cardiovascular testing is not recommended but may be considered in high-risk populations, especially patients with risk factors for coronary heart disease and diabetes.⁶³ Patients with comorbidities, substantial deconditioning, functional and anatomic defects, or recent major surgery may benefit from referral to physical therapy.³⁷ Patients near end of life may also benefit from an exercise program, as demonstrated in several studies that showed benefit in CRF and quality of life.^64,65 We recommend that physicians use their best clinical judgement in suggesting the type and intensity of exercise program, as it may not be feasible in some patients.

Mind-body interventions. Mindfulness-based stress reduction (MBSR) has shown promise in breast cancer survivors, who reported immediate improvements in fatigue severity that continued up to 6 weeks after cessation of the training.⁶⁶ Prior studies had similar findings, suggesting that MBSR modestly decreases fatigue and sleep disturbances and has a greater effect on the degree to which symptoms interfere with many facets of life.⁶⁷

Yoga. A study of a yoga intervention showed a benefit in older cancer survivors.⁶⁸ In breast cancer patients undergoing chemotherapy, yoga was shown to benefit both physical and cognitive fatigue.⁶⁹ DVD-based yoga had benefits similar to strengthening exercises in a study of 34 early-stage breast cancer survivors with CRF.⁷⁰ More studies are needed in men and patients and survivors of other cancers, as most studies of yoga were conducted in women with breast cancer.

Tai chi/qigong. Like yoga, tai chi and qigong are practices of meditative movement. These practices use postures or movements with a focus on breath and a meditative state to bring about deep states of relaxation. Qigong is a series of simple, repeated practices including body posture/movement, breath practice, and meditation performed in synchrony. Tai chi easy (TCE) is a simplified set of common, repetitive tai chi movements. In a trial, qigong/TCE was compared with sham qigong, which had physical movements but no breathing or meditative practice. Breast cancer survivors in the qigong/TCE group had improved fatigue scores, and the effect persisted for 3 months.⁷¹ Additional research is needed in this area.

Acupuncture. A randomized controlled trial in breast cancer patients with CRF showed an improvement in the mean general fatigue score (per the Multidimensional Fatigue Inventory) in patients who received acupuncture versus those who did not (−3.11 [95% confidence interval −3.97 to −2.25]; P < 0.001) at 6 weeks. Improvements were seen in both the mental and physical aspects of fatigue.⁷² However, Deng et al noted that true acupuncture was no more effective than sham acupuncture for reducing post-chemotherapy chronic fatigue.⁷³ Presently, there is not sufficient evidence to evaluate the benefits of acupuncture in CRF.

Other modalities. Massage therapy, music therapy, hypnosis, therapeutic touch, biofield therapies, relaxation, and reiki are other therapies for which few studies have been done; of the studies that have been done, the results are mixed, and additional research is needed.⁷⁴ Currently, there are not sufficient data to recommend any of these modalities.

 

Pharmacologic Interventions

Psychostimulants. Methylphenidate and modafinil are psychostimulants or wakefulness-promoting agents. Pilot studies showed benefit from methylphenidate and modafinil in CRF,^75–77 but randomized controlled trials have yielded mixed results. Therefore, in patients with severe fatigue during cancer therapy, the initial management strategy involves evaluation and treatment of medical conditions such as anemia and a trial of nonpharmacological strategies as discussed above. If symptoms persist, then a therapeutic trial of a psychostimulant may be considered per NCCN guidelines for patients undergoing active cancer treatment.³⁷

Methylphenidate directly stimulates adrenergic receptors and indirectly releases dopamine and norepinephrine from presynaptic terminals, which may explain why the drug benefits patients receiving opioid-induced sedation. It is a commonly studied psychostimulant, though its mechanism of action in CRF is unclear. Randomized controlled trials of methylphenidate have resulted in a wide range of findings due to the heterogeneity of study populations and variations in the dosage of methylphenidate. A meta-analysis of 7 studies indicates that methylphenidate benefitted the subgroup of patients with CRF.⁷⁸ Likewise, in an analysis of 5 randomized controlled trials, Minton et al showed a benefit of psychostimulants in fatigue compared with placebo.⁷⁹ However, another study of methylphenidate in patients with CRF showed a benefit only in patients with severe fatigue or advanced disease.⁸⁰ Methylphenidate was found to benefit cancer patients receiving opioid-induced sedation, as methylphenidate promotes wakefulness, though fatigue was not studied specifically.⁸¹ In a trial with 30 hospice patients in which the methylphenidate dose was titrated based on response and adverse effects, Kerr at al found that the drug improved fatigue in a dose-dependent manner.⁸² However, a study in patients with CRF at the University of Texas MD Anderson Cancer Center found no significant difference in BFI scores between patients receiving methylphenidate and those receiving placebo at the end of 2 weeks of treatment.⁸³ Also, other randomized controlled trials in patients undergoing adjuvant chemotherapy for breast cancer⁸⁴ and patients receiving radiation therapy for brain tumors⁸⁵ failed to demonstrate the efficacy of methylphenidate in CRF. It should be used cautiously after ruling out other causes of fatigue. The drug is overall well tolerated and side effects include headache and nausea.

Modafinil is a non-amphetamine psychostimulant that has been approved for the treatment of narcolepsy. In a trial studying the effect of modafinil on patients receiving docetaxel-based chemotherapy for metastatic breast or prostate cancer, there was a modest but not statistically significant improvement in fatigue scores on the MD Anderson Symptom Inventory compared with placebo. Nausea and vomiting were higher in the modafinil arm than in the placebo arm.⁸⁶ Similarly, modafinil was not superior to placebo for CRF in 208 patients with non-squamous cell lung cancer not undergoing chemotherapy or radiation.⁸⁷ A placebo effect was also noted in patients with multiple myeloma⁸⁸ and patients with primary brain tumors.⁸⁹ In a phase 3, multicenter, randomized, placebo-controlled, double-blind clinical trial of modafinil for CRF in 867 patients undergoing chemotherapy, there was a reduction in fatigue only for patients with severe baseline fatigue, with no significant effect on mild to moderate fatigue.⁹⁰ In another recent study, modafinil was shown to reduce depressive symptoms only in patients with severe fatigue (BFI item 3 score ≥ 7).⁹¹ This finding is consistent with previous studies showing benefit in patients with high baseline fatigue, but additional randomized controlled trials are needed to provide clarity. NCCN guidelines do not recommend the use of modafinil to treat CRF.³⁷

Other pharmacologic interventions. Corticosteroids are often used for symptom control in cancer patients. These drugs have anti-inflammatory effects through their modulation of pro-inflammatory cytokines.⁹² In a randomized controlled trial evaluating the efficacy of corticosteroids, patients receiving dexamethasone (4 mg twice daily) experienced significant improvement in their FACT-F scores compared with patients receiving placebo.⁹³ A similar benefit in fatigue was demonstrated in another study of methylprednisolone (32 mg daily) versus placebo.⁹⁴ Despite the benefits of steroids, their adverse effects, such as mood swings, gastritis, hyperglycemia, and immune suppression, limit their long-term use. Therefore, the use of steroids should be restricted to terminally ill fatigued patients with other symptoms such as anorexia, brain metastasis, or pain related to bone metastasis.³⁷

Testosterone replacement has been shown to diminish fatigue in non-cancer patients. Many men with advanced cancer have hypogonadism leading to low serum testosterone, which may cause fatigue. In a small trial in which cancer patients with hypogonadism received intramuscular testosterone every 14 days or placebo, the group receiving testosterone showed improvement in FACT-F scores, but there was no significant difference in FACT-F scores between the 2 groups.⁹⁵

Antidepressants have failed to demonstrate benefit in CRF without depression.⁸ However, if a patient has both fatigue and depression, antidepressants may help.⁹⁶ A selective serotonin receptor inhibitor is recommended as a first-line antidepressant.⁹⁷ Patients with cancer are often receiving multiple medications, and medication interactions should be considered to prevent adverse events such as serotonin syndrome.

 

Complementary and Alternative Supplements

Studies using vitamin supplementation have been inconclusive in patients with CRF.⁷⁴ The use of other dietary supplements has yielded mixed results, and coenzyme Q has shown no benefit for patients with CRF.⁹⁸

The benefit of ginseng was studied in a RCT involving 364 patients with CRF. There was an improvement in Multidimensional Fatigue Symptom Inventory-short form (MFSI-SF) scores at 8 weeks in patients receiving 2000 mg of Wisconsin ginseng compared with patients receiving placebo.⁹⁹ Patients on active treatment had greater improvement as compared to the post-treatment group in this trial. In another study of high-dose panax ginseng (ginseng root) at 800 mg daily for 29 days, patients had improvement of CRF as well as overall quality of life, appetite, and sleep at night. It was also well tolerated with few adverse effects.¹⁰⁰ Interaction with warfarin, calcium channel blockers, antiplatelet agents, thrombolytic agents, imatinib, and other agents may occur; therefore, ginseng must be used with careful monitoring in selected patients. There is not enough evidence at this time to support the routine use of ginseng in CRF.

The seed extract of the guarana plant (Paullinia cupana) traditionally has been used as a stimulant. An improvement in fatigue scores was seen with the use of oral guarana (100 mg daily) at the end of 21 days in breast cancer patients receiving chemotherapy.¹⁰¹ Further studies are needed for these results to be generalized and to understand the adverse effects and interaction profile of guarana.

Reevaluation

Patients who have completed cancer treatment must be monitored for fatigue over the long term, as fatigue may exist beyond the period of active treatment. Many studies have shown fatigue in breast cancer survivors, and fatigue has been demonstrated in survivors of colorectal, lung, and prostate cancers as well as myeloproliferative neoplasms.²⁸ Therefore, it is important to screen patients for fatigue during follow-up visits. There are currently no studies evaluating the long-term treatment of fatigue. In our experience, the timing of follow-up depends on the level of fatigue and interventions prescribed. Once fatigue is stabilized to a level with which the patient is able to cope, the time interval for follow-up may be lengthened. Annual visits may suffice in patients with mild fatigue. Follow-up of patients with moderate to severe fatigue depends on the level of fatigue, the ability to cope, choice of treatment, and presence of contributing factors.

CONCLUSION

CRF is a complex condition that places a significant burden on patients and caregivers, resulting in emotional distress, poor functioning, and suffering. Fatigue can occur before, during, and long after cancer treatment. The approach to CRF begins with screening for and educating patients and their caregivers about the symptoms. Many screening scales are available that may be used to follow patients’ progress over time. The evaluation and management of contributing conditions may help improve fatigue. If the fatigue persists, an individualized approach with a combination of nonpharmacologic and pharmacologic approaches should be considered. More research is needed to understand brain signaling pathways, cytokine changes, and genomic changes in cancer patients with fatigue. Though many hypotheses have been proposed, to date there is no biological marker to assess this condition. Biomarker research needs to be advanced to help to identify patients at risk for fatigue. As cytokines have a major role in CRF, targeted therapy to block cytokine pathways may also be explored in the future.

Acknowledgment: The authors thank Bryan Tutt for providing editorial assistance during the writing of this article.

INTRODUCTION

Fatigue is a common distressing effect of cancer.¹ It impairs the quality of life of patients undergoing active cancer treatment and of post-treatment survivors alike. The National Comprehensive Cancer Network (NCCN) defines cancer-related fatigue (CRF) as “a distressing, persistent, subjective sense of physical, emotional and/or cognitive tiredness related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning.”² CRF differs from fatigue reported by individuals without cancer in that CRF is more severe and is not relieved by rest. The prevalence of CRF in cancer patients and survivors is highly variable, with estimates ranging between 25% and 99%.^2,3 The methods used for screening patients for fatigue and the characteristics of the patient groups may account for this variability. In this article, we review evaluation of CRF and approaches to its management.

PATHOPHYSIOLOGY

The specific pathophysiologic mechanism underlying CRF is unknown, making targeted treatment a challenge. The multidimensional and subjective nature of CRF has limited the development of research methodologies to explain this condition. However, research has been done in both human and animal models, and several theories have been proposed to explain the pathophysiology of CRF. While pro-inflammatory cytokines remain the central factor playing a significant role at multiple levels in CRF, there may be a complex interplay of multiple mechanisms contributing to fatigue in an individual patient.

CENTRAL NERVOUS SYSTEM DISTURBANCES

The basal ganglia are known to influence motivation. Lack of motivation and drive may cause failure to complete physical and mental tasks, even with preserved cognitive ability and motor function. In a study of melanoma patients receiving interferon, increased activity of the basal ganglia and the cerebellum resulted in higher fatigue scores.⁴ Increased levels of cytokines may alter blood flow to the cerebellum and lead to the perception of fatigue. In a study of 12 patients and matched controls, when patients were asked to perform sustained elbow flexion until they perceived exhaustion, CRF patients perceived physical exhaustion sooner than controls. In CRF patients in this study, muscle fatigue measured by electromyogram was less than that in healthy individuals at the time of exhaustion, suggesting the role of the central nervous system in CRF.⁵ However, there is not enough evidence at this time to support central nervous system disturbance as the main factor contributing to fatigue in cancer patients.

CIRCADIAN RHYTHM DYSREGULATION

Circadian rhythm is regulated by the suprachiasmatic nucleus in the hypothalamus through cortisol and melatonin. Sleep disturbances occur with disruption of the circadian rhythm. Tumor-related peptides such as epidermal growth factor or alterations in serotonin and cortisol can influence the suprachiasmatic nucleus and the complex signaling pathways.² Positive feedback loops that are activated by cortisol under the influence of cytokines may lead to continuous cytokine production and altered circadian rhythm. Bower et al showed that changes in the cortisol curve influence fatigue in breast cancer survivors.⁶ These patients had a late evening peak in cortisol levels, compared with an early morning peak in individuals without cancer.

INHIBITION OF HYPOTHALAMIC-PITUITARY-ADRENAL AXIS

The hypothalamic–pituitary–adrenal (HPA) axis regulates the release of the stress hormone cortisol. One of several hypotheses advanced to explain the effect of serotonin and the HPA axis on CRF suggests that lower serotonin levels cause decreased activation of 5-hydroxytrytophan 1-a (5-HT1-a) receptors in the hypothalamus, leading to decreased activity of the HPA axis.⁶ Inhibition of the HPA axis may occur with higher levels of serotonin as well.⁷ The 5-HT1-a receptors are also triggered by cytokines. However, the correction of serotonin levels by antidepressants was not shown to improve fatigue.⁸ Inhibition of the HPA axis can also lead to lower testosterone, progesterone, or estrogen levels, which may indirectly contribute to fatigue.²

SKELETAL MUSCLE EFFECT

Chemotherapy- and tumor-related cachexia have a direct effect on the metabolism of skeletal muscles. This effect may lead to impaired adenosine triphosphate (ATP) generation during muscle contraction.⁹ ATP infusion improved muscle strength in 1 trial, but this was not confirmed in another trial.^10,11 Muscle contraction studies showed no differences in the contractile properties of muscles in fatigued patients who failed earlier in motor tasks and healthy controls.¹² This finding suggests that there could be a failure of skeletal muscle activation by the central nervous system or inhibition of skeletal muscle activity. Cytokines and other neurotransmitters activate vagal efferent nerve fibers, which may lead to reflex inhibition in skeletal muscles.^13,14

PRO-INFLAMMATORY CYTOKINES

Tumors or treatment of them may cause tissue injury, which triggers immune cells to release cytokines, signaling the brain to manifest the symptom of fatigue. Inflammatory pathways are influenced by psychological, behavioral, and biological factors, which play a role as risk factors in CRF. Levels of interleukin 6 (IL-6), interleukin-1 receptor antagonist, interleukin-1, and tumor necrosis factor (TNF) have been shown to be elevated in fatigued patients being treated for leukemia and non-Hodgkin lymphoma.¹⁵ IL-6 was also associated with increased fatigue in breast cancer survivors.¹⁶ Similar findings were reported in patients undergoing stem cell transplantation and high-dose chemotherapy.¹⁷ Elevated levels of IL-6 and C-reactive protein were also linked to fatigue in terminally ill cancer patients.^18,19 Furthermore, TNF-α signaling was associated with post-chemotherapy fatigue in breast cancer patients.²⁰ Leukocytes in breast cancer survivors with fatigue also have increased gene expression of pro-inflammatory cytokines, emphasizing the role of cytokines and inflammation in the pathogenesis of CRF.²¹

 

OTHER HYPOTHESES

Several other hypotheses for CRF pathogenesis have been proposed. Activation of latent viruses such as Epstein-Barr virus, lack of social support,²² genetic alterations in the immune pathway,²³ epigenetic changes,²⁴ accumulation of neurotoxic metabolites and depletion of serotonin by indoleamine 2,3-dioxygenase pathway activation,²⁵ elevated vascular endothelial growth factor levels,²⁶ and hypoxia-related organ dysfunction due to anemia or hemoglobin dysfunction¹³ all have been postulated to cause CRF.

EVALUATION AND TREATMENT

Fours steps are involved in the evaluation and treatment of CRF (Figure).

Patients are screened for fatigue as the first step, and those who have fatigue undergo a primary evaluation to assess for potential precipitating causes. The third step is implementation of pharmacologic and nonpharmacologic interventions aimed at alleviating or mitigating fatigue. The fourth step involves reevaluating patients periodically to recognize and manage changes in fatigue levels. A multidisciplinary approach involving nursing, physical therapy, social work, and nutrition is critical in managing fatigue in these patients. Education and counselling of patients and involvement of the family are essential for effective management as well.

SCREENING

Because patients and health care professionals may be unaware of the treatment options available for CRF, patients may not report fatigue levels to their clinicians, and clinicians may not understand the impact of fatigue on their patients’ quality of life. This leads to under-recognition of the problem. The NCCN recommends screening every cancer patient and post-treatment survivor for fatigue.² Patients should be screened at their first visit and then at periodic intervals during and after cancer treatment.

Many scales are available to screen patients for CRF in clinical practice and clinical trials.²⁷ A single item that asks patients to rate their fatigue on a scale from 0 to 10—in which 0 indicates no fatigue, 1 to 3 indicates mild fatigue, 4 to 6 indicates moderate fatigue, 7 to 9 indicates severe fatigue, and 10 indicates the worst fatigue imaginable—is commonly used to screen for CRF.² This scale was adapted from the MD Anderson Symptom Inventory scale and is based on a large nationwide study of cancer patients and survivors.²⁸ The statistically derived cutoff points in this study are consistent with other scales such as the Brief Fatigue Inventory (BFI) and support the cutoff points (4–6 for moderate and ≥ 7 for severe fatigue) used in various fatigue management guidelines. Furthermore, studies of fatigue in cancer patients have revealed a marked decrease in physical function at levels of 7 or higher, suggesting 7 as an optimal cutoff to identify severe fatigue.^29,30 The Visual Analog Scale is another simple-to-use tool that helps in understanding variations in fatigue throughout the course of the day.³¹ The 9-item BFI is often used in clinical trials.²⁹ It measures the severity of fatigue over the previous 24 hours and has been validated in patients who do not speak English.³²

CRF affects not only the somatic domain, but also the cognitive, behavioral, and affective domains; therefore, multidimensional scales have been developed for screening. One such tool is the Multidimensional Fatigue Inventory, which assesses 5 dimensions of fatigue—general fatigue, physical fatigue, reduced motivation, reduced activity, and mental fatigue—and compares the patient’s results with those of individuals without cancer.^33,34 The Functional Assessment of Cancer Therapy for Fatigue (FACT-F) is a 13-item questionnaire that has been used to measure CRF in clinical trials as well as in patients receiving various treatments.³⁵

Although many scales are available, the validity of self-reporting on simple fatigue-rating scales is equal to or better than most complex, lengthy scales.³⁶ Therefore, unidimensional tools such as the numeric rating scale of 0–10 are commonly used in clinical practice. Mild fatigue (0–3) requires periodic reevaluation, and moderate and severe fatigue need further evaluation and management.³⁷

PRIMARY EVALUATION

This phase involves a focused history and physical examination and assessment of concurrent symptoms and contributing factors.

History and Physical Examination

A detailed history of the patient’s malignancy and type of previous and current treatment may help reveal the cause of fatigue. New-onset fatigue or increase in fatigue may be related to the progression of disease in patients with active malignancy or recurrence of cancer in survivors. These patients may require appropriate testing to assess the underlying disease pattern. A detailed review of systems may help identify some of the contributing factors, which are discussed below. A detailed history regarding medications, including over-the-counter drugs, complementary agents, and past and prior cancer therapies, is helpful as medications can contribute to fatigue. For example, opioids may cause drowsiness and fatigue, which could be improved by dose adjustments. A focused history of fatigue should be obtained in all patients with moderate to severe CRF, which includes the onset, pattern, duration, associated or alleviating factors, and interference with functioning, including activities of daily living.³⁷ Physical examination should focus on identifying signs of organ dysfunction and features of substance or alcohol abuse, which may cause poor sleep and fatigue.

 

Assessment of Contributing Factors

The management of fatigue should be multifactorial, with a comprehensive assessment and treatment plan to address all modifiable fatigue etiologies. The Table lists potential contributing factors to fatigue that should be considered when evaluating patients for CRF; several common conditions are discussed below. 

Anemia. Anemia has been correlated with fatigue and quality of life. In a study of 4382 cancer patients receiving chemotherapy, quality-of-life measures using FACT-Anemia scores improved with increased hemoglobin levels.³⁸ Cancer patients may have anemia due to marrow-suppressing effects of chemotherapy and may also have iron deficiency anemia due to blood loss or auto-immune hemolytic anemia. Therefore, a detailed work-up is required to identify the etiology of anemia. Patients with CRF whose anemia is related to chemotherapy or anemia of chronic disease may benefit from red blood cell transfusion or erythropoiesis-stimulating agents (ESAs). ESAs have been studied extensively; however, their use is controversial because of concerns about thromboembolic side effects leading to adverse outcomes.³⁹ Also, ESA therapy is not recommended in patients with hematologic malignancies. ESA use should be restricted to patients with chemotherapy-related anemia with hemoglobin below 10 mg/dL and should be discontinued in 6 to 8 weeks if patients do not respond.⁴⁰ Other patients may benefit from blood transfusions, which were shown to help in patients with hemoglobin levels between 7.5 and 8.5 g/dL.⁴¹

Sleep disturbance. Poor sleep is common in fatigued cancer survivors.⁴² Pro-inflammatory cytokines can disrupt the sleep–wake cycle, causing changes in the HPA axis and neuro­endocrine system, which in turn may lead to increasing fatigue. Heckler et al showed that improvement in nighttime sleep leads to improvement of fatigue.⁴³ Cognitive behavioral therapy and sleep hygiene are important in caring for patients with CRF and poor sleep.⁴⁴ Taking a warm bath and/or drinking a glass of milk before bedtime, avoiding caffeinated drinks, and avoiding frequent napping in the day might help. Some patients may require medications such as benzodiazepines or non-benzodiazepine hypnotics (eg, zolpidem) to promote sleep.⁴⁵ Melatonin agonists are approved for insomnia in the United States, but not in Europe.⁴⁶

Malnutrition. Patients with advanced-stage cancer and with cancers affecting the gastrointestinal tract frequently develop mechanical bowel obstructions, especially at the end of their life, which cause malnutrition. Chemotherapy-related nausea and vomiting may also cause poor oral intake and malnutrition, causing fatigue from muscle weakness. Dehydration and electrolyte imbalances frequently occur as a result of poor oral intake, which might worsen fatigue. In our experience, modifying dietary intake with appropriate caloric exchanges with the help of a nutrition expert has lessened fatigue in some patients. However, terminally ill patients are advised to eat based on their comfort.

Medical comorbidities. Congestive heart failure from anthracycline chemotherapy, hypothyroidism after radiation therapy for head and neck cancers, renal failure, or hepatic failure from chemotherapy may indirectly lead to fatigue. Chemotherapy, opioids, and steroids may cause hypogonadism, which can contribute to fatigue in men.⁴⁷

Assessment of Concurrent Symptoms

Depression is common in cancer patients and coexists with pain, insomnia, fatigue, and anxiety as a symptom cluster.⁴⁸ A symptom cluster is defined as 2 or more concurrent and interrelated symptoms occurring together; treating one of these symptoms without addressing other symptoms is not effective.⁴⁹ Therefore, screening for and management of depression, anxiety, and insomnia play an important role in the management of CRF.

Physical symptoms due to the tumor or to therapy— such as pain, dyspnea, nausea, and decreased physical activity—may also contribute to fatigue both directly and indirectly. Patients with lung cancer may have hypoxemia, which can contribute to dyspnea with activity and a perception of fatigue. Optimal management of pain and other physical symptoms in patients with cancer may significantly alleviate fatigue.⁵⁰

MANAGEMENT

Management of CRF is individualized based on the patient’s clinical status: active cancer treatment, survivor, or end of life. Education and counselling of patients and their caregivers play an important role in CRF. NCCN guidelines recommend focusing on pain control, distress management, energy conservation, physical activity, nutrition, and sleep hygiene.

Nonpharmacologic Interventions

Energy conservation. Energy conservation strategies, in which patients are advised to set priorities and realistic expectations, are highly recommended. Some energy-conserving strategies are to pace oneself, delegate and schedule activities at times of peak energy, postpone nonessential activities, attend to 1 activity at a time, structure daily routines, and maintain a diary to identify their peak energy period and structure activities around that time.^51,52 When patients approach the end of life, increasing fatigue may limit their activity level, and they may depend on caregivers for assistance with activities of daily living, monitoring treatment-related adverse effects, and taking medications, especially elderly patients.⁵³

 

Cognitive behavioral therapy. Cognitive behavioral therapy (CBT) has been shown to improve CRF during active treatment, and the benefits persist for a minimum of 2 years after therapy.⁵⁴ CBT interventions that optimize sleep quality may improve fatigue.⁵⁵ More studies are needed to understand whether referral to a psychologist for formal CBT is required. Randomized clinical trials showed patient fatigue education, learned self-care, coping techniques, and balancing rest and activity benefit patients with CRF.⁵⁶

Exercise. Physical activity is highly encouraged in patients with CRF. Exercise increases muscle protein synthesis, improves cytokine response, and decreases the rate of sarcopenia in healthy populations.⁵⁷ Studies have shown that exercise helps CRF at all phases of the cancer journey, including radiation therapy, chemotherapy, and survivorship.⁵⁸ Some patients may feel less motivated to exercise and may not believe that exercise is possible or could potentially help them. Counselling is needed for such patients.

Older cancer survivors have a decline in their functional capacity and reduced muscle mass. Exercise can improve their cardiorespiratory fitness, muscle strength, and body composition.⁵⁷ Exercise not only helps at the cellular level but also has psychosocial benefits from improved self-esteem. Therefore, exercise may be recommended for younger patients as well as for the older population, who may have comorbidities and less motivation than younger patients.

In a meta-analysis of 56 randomized controlled trials involving 4068 participants, aerobic exercise was found to have beneficial effects on CRF for patients during and after chemotherapy, specifically for patients with solid tumors.⁵⁹ In another meta-analysis of breast and prostate cancer survivors, a combination of aerobic exercise with resistance training (3–6 metabolic equivalents, 60%–80% range of motion) was shown to reduce CRF more than aerobic exercise alone.⁶⁰ This effect was also shown in a randomized controlled trial of 160 patients with stage 0 to III breast cancer undergoing radiation therapy.⁶¹ The control group in this study had a group-based non-exercise intervention/relaxation; therefore, the study showed that the effect of resistance training extends beyond the psychosocial benefits of group-based interventions. The intervention comprised 8 progressive machine-based resistance exercises (3 sets, 8–12 repetitions at 60%–80% of 1 repetition maximum) for 60 minutes twice weekly for 12 weeks. However, fatigue assessment questionnaire scores showed benefits only in the physical fatigue components, but not in the affective and cognitive components.

The American Society of Clinical Oncology’s guidelines for cancer survivors with fatigue recommends 150 minutes of moderate aerobic exercise (eg, fast walking, cycling, or swimming) per week, with 2 or 3 sessions of strength training per week.⁶² An individualized approach to exercise is recommended, as patients’ ability to perform certain types of exercises may be limited by thrombocytopenia, neutropenia, or lytic bone metastasis. Routine use of pre-exercise cardiovascular testing is not recommended but may be considered in high-risk populations, especially patients with risk factors for coronary heart disease and diabetes.⁶³ Patients with comorbidities, substantial deconditioning, functional and anatomic defects, or recent major surgery may benefit from referral to physical therapy.³⁷ Patients near end of life may also benefit from an exercise program, as demonstrated in several studies that showed benefit in CRF and quality of life.^64,65 We recommend that physicians use their best clinical judgement in suggesting the type and intensity of exercise program, as it may not be feasible in some patients.

Mind-body interventions. Mindfulness-based stress reduction (MBSR) has shown promise in breast cancer survivors, who reported immediate improvements in fatigue severity that continued up to 6 weeks after cessation of the training.⁶⁶ Prior studies had similar findings, suggesting that MBSR modestly decreases fatigue and sleep disturbances and has a greater effect on the degree to which symptoms interfere with many facets of life.⁶⁷

Yoga. A study of a yoga intervention showed a benefit in older cancer survivors.⁶⁸ In breast cancer patients undergoing chemotherapy, yoga was shown to benefit both physical and cognitive fatigue.⁶⁹ DVD-based yoga had benefits similar to strengthening exercises in a study of 34 early-stage breast cancer survivors with CRF.⁷⁰ More studies are needed in men and patients and survivors of other cancers, as most studies of yoga were conducted in women with breast cancer.

Tai chi/qigong. Like yoga, tai chi and qigong are practices of meditative movement. These practices use postures or movements with a focus on breath and a meditative state to bring about deep states of relaxation. Qigong is a series of simple, repeated practices including body posture/movement, breath practice, and meditation performed in synchrony. Tai chi easy (TCE) is a simplified set of common, repetitive tai chi movements. In a trial, qigong/TCE was compared with sham qigong, which had physical movements but no breathing or meditative practice. Breast cancer survivors in the qigong/TCE group had improved fatigue scores, and the effect persisted for 3 months.⁷¹ Additional research is needed in this area.

Acupuncture. A randomized controlled trial in breast cancer patients with CRF showed an improvement in the mean general fatigue score (per the Multidimensional Fatigue Inventory) in patients who received acupuncture versus those who did not (−3.11 [95% confidence interval −3.97 to −2.25]; P < 0.001) at 6 weeks. Improvements were seen in both the mental and physical aspects of fatigue.⁷² However, Deng et al noted that true acupuncture was no more effective than sham acupuncture for reducing post-chemotherapy chronic fatigue.⁷³ Presently, there is not sufficient evidence to evaluate the benefits of acupuncture in CRF.

Other modalities. Massage therapy, music therapy, hypnosis, therapeutic touch, biofield therapies, relaxation, and reiki are other therapies for which few studies have been done; of the studies that have been done, the results are mixed, and additional research is needed.⁷⁴ Currently, there are not sufficient data to recommend any of these modalities.

 

Pharmacologic Interventions

Psychostimulants. Methylphenidate and modafinil are psychostimulants or wakefulness-promoting agents. Pilot studies showed benefit from methylphenidate and modafinil in CRF,^75–77 but randomized controlled trials have yielded mixed results. Therefore, in patients with severe fatigue during cancer therapy, the initial management strategy involves evaluation and treatment of medical conditions such as anemia and a trial of nonpharmacological strategies as discussed above. If symptoms persist, then a therapeutic trial of a psychostimulant may be considered per NCCN guidelines for patients undergoing active cancer treatment.³⁷

Methylphenidate directly stimulates adrenergic receptors and indirectly releases dopamine and norepinephrine from presynaptic terminals, which may explain why the drug benefits patients receiving opioid-induced sedation. It is a commonly studied psychostimulant, though its mechanism of action in CRF is unclear. Randomized controlled trials of methylphenidate have resulted in a wide range of findings due to the heterogeneity of study populations and variations in the dosage of methylphenidate. A meta-analysis of 7 studies indicates that methylphenidate benefitted the subgroup of patients with CRF.⁷⁸ Likewise, in an analysis of 5 randomized controlled trials, Minton et al showed a benefit of psychostimulants in fatigue compared with placebo.⁷⁹ However, another study of methylphenidate in patients with CRF showed a benefit only in patients with severe fatigue or advanced disease.⁸⁰ Methylphenidate was found to benefit cancer patients receiving opioid-induced sedation, as methylphenidate promotes wakefulness, though fatigue was not studied specifically.⁸¹ In a trial with 30 hospice patients in which the methylphenidate dose was titrated based on response and adverse effects, Kerr at al found that the drug improved fatigue in a dose-dependent manner.⁸² However, a study in patients with CRF at the University of Texas MD Anderson Cancer Center found no significant difference in BFI scores between patients receiving methylphenidate and those receiving placebo at the end of 2 weeks of treatment.⁸³ Also, other randomized controlled trials in patients undergoing adjuvant chemotherapy for breast cancer⁸⁴ and patients receiving radiation therapy for brain tumors⁸⁵ failed to demonstrate the efficacy of methylphenidate in CRF. It should be used cautiously after ruling out other causes of fatigue. The drug is overall well tolerated and side effects include headache and nausea.

Modafinil is a non-amphetamine psychostimulant that has been approved for the treatment of narcolepsy. In a trial studying the effect of modafinil on patients receiving docetaxel-based chemotherapy for metastatic breast or prostate cancer, there was a modest but not statistically significant improvement in fatigue scores on the MD Anderson Symptom Inventory compared with placebo. Nausea and vomiting were higher in the modafinil arm than in the placebo arm.⁸⁶ Similarly, modafinil was not superior to placebo for CRF in 208 patients with non-squamous cell lung cancer not undergoing chemotherapy or radiation.⁸⁷ A placebo effect was also noted in patients with multiple myeloma⁸⁸ and patients with primary brain tumors.⁸⁹ In a phase 3, multicenter, randomized, placebo-controlled, double-blind clinical trial of modafinil for CRF in 867 patients undergoing chemotherapy, there was a reduction in fatigue only for patients with severe baseline fatigue, with no significant effect on mild to moderate fatigue.⁹⁰ In another recent study, modafinil was shown to reduce depressive symptoms only in patients with severe fatigue (BFI item 3 score ≥ 7).⁹¹ This finding is consistent with previous studies showing benefit in patients with high baseline fatigue, but additional randomized controlled trials are needed to provide clarity. NCCN guidelines do not recommend the use of modafinil to treat CRF.³⁷

Other pharmacologic interventions. Corticosteroids are often used for symptom control in cancer patients. These drugs have anti-inflammatory effects through their modulation of pro-inflammatory cytokines.⁹² In a randomized controlled trial evaluating the efficacy of corticosteroids, patients receiving dexamethasone (4 mg twice daily) experienced significant improvement in their FACT-F scores compared with patients receiving placebo.⁹³ A similar benefit in fatigue was demonstrated in another study of methylprednisolone (32 mg daily) versus placebo.⁹⁴ Despite the benefits of steroids, their adverse effects, such as mood swings, gastritis, hyperglycemia, and immune suppression, limit their long-term use. Therefore, the use of steroids should be restricted to terminally ill fatigued patients with other symptoms such as anorexia, brain metastasis, or pain related to bone metastasis.³⁷

Testosterone replacement has been shown to diminish fatigue in non-cancer patients. Many men with advanced cancer have hypogonadism leading to low serum testosterone, which may cause fatigue. In a small trial in which cancer patients with hypogonadism received intramuscular testosterone every 14 days or placebo, the group receiving testosterone showed improvement in FACT-F scores, but there was no significant difference in FACT-F scores between the 2 groups.⁹⁵

Antidepressants have failed to demonstrate benefit in CRF without depression.⁸ However, if a patient has both fatigue and depression, antidepressants may help.⁹⁶ A selective serotonin receptor inhibitor is recommended as a first-line antidepressant.⁹⁷ Patients with cancer are often receiving multiple medications, and medication interactions should be considered to prevent adverse events such as serotonin syndrome.

 

Complementary and Alternative Supplements

Studies using vitamin supplementation have been inconclusive in patients with CRF.⁷⁴ The use of other dietary supplements has yielded mixed results, and coenzyme Q has shown no benefit for patients with CRF.⁹⁸

The benefit of ginseng was studied in a RCT involving 364 patients with CRF. There was an improvement in Multidimensional Fatigue Symptom Inventory-short form (MFSI-SF) scores at 8 weeks in patients receiving 2000 mg of Wisconsin ginseng compared with patients receiving placebo.⁹⁹ Patients on active treatment had greater improvement as compared to the post-treatment group in this trial. In another study of high-dose panax ginseng (ginseng root) at 800 mg daily for 29 days, patients had improvement of CRF as well as overall quality of life, appetite, and sleep at night. It was also well tolerated with few adverse effects.¹⁰⁰ Interaction with warfarin, calcium channel blockers, antiplatelet agents, thrombolytic agents, imatinib, and other agents may occur; therefore, ginseng must be used with careful monitoring in selected patients. There is not enough evidence at this time to support the routine use of ginseng in CRF.

The seed extract of the guarana plant (Paullinia cupana) traditionally has been used as a stimulant. An improvement in fatigue scores was seen with the use of oral guarana (100 mg daily) at the end of 21 days in breast cancer patients receiving chemotherapy.¹⁰¹ Further studies are needed for these results to be generalized and to understand the adverse effects and interaction profile of guarana.

Reevaluation

Patients who have completed cancer treatment must be monitored for fatigue over the long term, as fatigue may exist beyond the period of active treatment. Many studies have shown fatigue in breast cancer survivors, and fatigue has been demonstrated in survivors of colorectal, lung, and prostate cancers as well as myeloproliferative neoplasms.²⁸ Therefore, it is important to screen patients for fatigue during follow-up visits. There are currently no studies evaluating the long-term treatment of fatigue. In our experience, the timing of follow-up depends on the level of fatigue and interventions prescribed. Once fatigue is stabilized to a level with which the patient is able to cope, the time interval for follow-up may be lengthened. Annual visits may suffice in patients with mild fatigue. Follow-up of patients with moderate to severe fatigue depends on the level of fatigue, the ability to cope, choice of treatment, and presence of contributing factors.

CONCLUSION

CRF is a complex condition that places a significant burden on patients and caregivers, resulting in emotional distress, poor functioning, and suffering. Fatigue can occur before, during, and long after cancer treatment. The approach to CRF begins with screening for and educating patients and their caregivers about the symptoms. Many screening scales are available that may be used to follow patients’ progress over time. The evaluation and management of contributing conditions may help improve fatigue. If the fatigue persists, an individualized approach with a combination of nonpharmacologic and pharmacologic approaches should be considered. More research is needed to understand brain signaling pathways, cytokine changes, and genomic changes in cancer patients with fatigue. Though many hypotheses have been proposed, to date there is no biological marker to assess this condition. Biomarker research needs to be advanced to help to identify patients at risk for fatigue. As cytokines have a major role in CRF, targeted therapy to block cytokine pathways may also be explored in the future.

Acknowledgment: The authors thank Bryan Tutt for providing editorial assistance during the writing of this article.

INTRODUCTION

Fatigue is a common distressing effect of cancer.¹ It impairs the quality of life of patients undergoing active cancer treatment and of post-treatment survivors alike. The National Comprehensive Cancer Network (NCCN) defines cancer-related fatigue (CRF) as “a distressing, persistent, subjective sense of physical, emotional and/or cognitive tiredness related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning.”² CRF differs from fatigue reported by individuals without cancer in that CRF is more severe and is not relieved by rest. The prevalence of CRF in cancer patients and survivors is highly variable, with estimates ranging between 25% and 99%.^2,3 The methods used for screening patients for fatigue and the characteristics of the patient groups may account for this variability. In this article, we review evaluation of CRF and approaches to its management.

PATHOPHYSIOLOGY

The specific pathophysiologic mechanism underlying CRF is unknown, making targeted treatment a challenge. The multidimensional and subjective nature of CRF has limited the development of research methodologies to explain this condition. However, research has been done in both human and animal models, and several theories have been proposed to explain the pathophysiology of CRF. While pro-inflammatory cytokines remain the central factor playing a significant role at multiple levels in CRF, there may be a complex interplay of multiple mechanisms contributing to fatigue in an individual patient.

CENTRAL NERVOUS SYSTEM DISTURBANCES

The basal ganglia are known to influence motivation. Lack of motivation and drive may cause failure to complete physical and mental tasks, even with preserved cognitive ability and motor function. In a study of melanoma patients receiving interferon, increased activity of the basal ganglia and the cerebellum resulted in higher fatigue scores.⁴ Increased levels of cytokines may alter blood flow to the cerebellum and lead to the perception of fatigue. In a study of 12 patients and matched controls, when patients were asked to perform sustained elbow flexion until they perceived exhaustion, CRF patients perceived physical exhaustion sooner than controls. In CRF patients in this study, muscle fatigue measured by electromyogram was less than that in healthy individuals at the time of exhaustion, suggesting the role of the central nervous system in CRF.⁵ However, there is not enough evidence at this time to support central nervous system disturbance as the main factor contributing to fatigue in cancer patients.

CIRCADIAN RHYTHM DYSREGULATION

Circadian rhythm is regulated by the suprachiasmatic nucleus in the hypothalamus through cortisol and melatonin. Sleep disturbances occur with disruption of the circadian rhythm. Tumor-related peptides such as epidermal growth factor or alterations in serotonin and cortisol can influence the suprachiasmatic nucleus and the complex signaling pathways.² Positive feedback loops that are activated by cortisol under the influence of cytokines may lead to continuous cytokine production and altered circadian rhythm. Bower et al showed that changes in the cortisol curve influence fatigue in breast cancer survivors.⁶ These patients had a late evening peak in cortisol levels, compared with an early morning peak in individuals without cancer.

INHIBITION OF HYPOTHALAMIC-PITUITARY-ADRENAL AXIS

The hypothalamic–pituitary–adrenal (HPA) axis regulates the release of the stress hormone cortisol. One of several hypotheses advanced to explain the effect of serotonin and the HPA axis on CRF suggests that lower serotonin levels cause decreased activation of 5-hydroxytrytophan 1-a (5-HT1-a) receptors in the hypothalamus, leading to decreased activity of the HPA axis.⁶ Inhibition of the HPA axis may occur with higher levels of serotonin as well.⁷ The 5-HT1-a receptors are also triggered by cytokines. However, the correction of serotonin levels by antidepressants was not shown to improve fatigue.⁸ Inhibition of the HPA axis can also lead to lower testosterone, progesterone, or estrogen levels, which may indirectly contribute to fatigue.²

SKELETAL MUSCLE EFFECT

Chemotherapy- and tumor-related cachexia have a direct effect on the metabolism of skeletal muscles. This effect may lead to impaired adenosine triphosphate (ATP) generation during muscle contraction.⁹ ATP infusion improved muscle strength in 1 trial, but this was not confirmed in another trial.^10,11 Muscle contraction studies showed no differences in the contractile properties of muscles in fatigued patients who failed earlier in motor tasks and healthy controls.¹² This finding suggests that there could be a failure of skeletal muscle activation by the central nervous system or inhibition of skeletal muscle activity. Cytokines and other neurotransmitters activate vagal efferent nerve fibers, which may lead to reflex inhibition in skeletal muscles.^13,14

PRO-INFLAMMATORY CYTOKINES

Tumors or treatment of them may cause tissue injury, which triggers immune cells to release cytokines, signaling the brain to manifest the symptom of fatigue. Inflammatory pathways are influenced by psychological, behavioral, and biological factors, which play a role as risk factors in CRF. Levels of interleukin 6 (IL-6), interleukin-1 receptor antagonist, interleukin-1, and tumor necrosis factor (TNF) have been shown to be elevated in fatigued patients being treated for leukemia and non-Hodgkin lymphoma.¹⁵ IL-6 was also associated with increased fatigue in breast cancer survivors.¹⁶ Similar findings were reported in patients undergoing stem cell transplantation and high-dose chemotherapy.¹⁷ Elevated levels of IL-6 and C-reactive protein were also linked to fatigue in terminally ill cancer patients.^18,19 Furthermore, TNF-α signaling was associated with post-chemotherapy fatigue in breast cancer patients.²⁰ Leukocytes in breast cancer survivors with fatigue also have increased gene expression of pro-inflammatory cytokines, emphasizing the role of cytokines and inflammation in the pathogenesis of CRF.²¹

 

OTHER HYPOTHESES

Several other hypotheses for CRF pathogenesis have been proposed. Activation of latent viruses such as Epstein-Barr virus, lack of social support,²² genetic alterations in the immune pathway,²³ epigenetic changes,²⁴ accumulation of neurotoxic metabolites and depletion of serotonin by indoleamine 2,3-dioxygenase pathway activation,²⁵ elevated vascular endothelial growth factor levels,²⁶ and hypoxia-related organ dysfunction due to anemia or hemoglobin dysfunction¹³ all have been postulated to cause CRF.

EVALUATION AND TREATMENT

Fours steps are involved in the evaluation and treatment of CRF (Figure).

Patients are screened for fatigue as the first step, and those who have fatigue undergo a primary evaluation to assess for potential precipitating causes. The third step is implementation of pharmacologic and nonpharmacologic interventions aimed at alleviating or mitigating fatigue. The fourth step involves reevaluating patients periodically to recognize and manage changes in fatigue levels. A multidisciplinary approach involving nursing, physical therapy, social work, and nutrition is critical in managing fatigue in these patients. Education and counselling of patients and involvement of the family are essential for effective management as well.

SCREENING

Because patients and health care professionals may be unaware of the treatment options available for CRF, patients may not report fatigue levels to their clinicians, and clinicians may not understand the impact of fatigue on their patients’ quality of life. This leads to under-recognition of the problem. The NCCN recommends screening every cancer patient and post-treatment survivor for fatigue.² Patients should be screened at their first visit and then at periodic intervals during and after cancer treatment.

Many scales are available to screen patients for CRF in clinical practice and clinical trials.²⁷ A single item that asks patients to rate their fatigue on a scale from 0 to 10—in which 0 indicates no fatigue, 1 to 3 indicates mild fatigue, 4 to 6 indicates moderate fatigue, 7 to 9 indicates severe fatigue, and 10 indicates the worst fatigue imaginable—is commonly used to screen for CRF.² This scale was adapted from the MD Anderson Symptom Inventory scale and is based on a large nationwide study of cancer patients and survivors.²⁸ The statistically derived cutoff points in this study are consistent with other scales such as the Brief Fatigue Inventory (BFI) and support the cutoff points (4–6 for moderate and ≥ 7 for severe fatigue) used in various fatigue management guidelines. Furthermore, studies of fatigue in cancer patients have revealed a marked decrease in physical function at levels of 7 or higher, suggesting 7 as an optimal cutoff to identify severe fatigue.^29,30 The Visual Analog Scale is another simple-to-use tool that helps in understanding variations in fatigue throughout the course of the day.³¹ The 9-item BFI is often used in clinical trials.²⁹ It measures the severity of fatigue over the previous 24 hours and has been validated in patients who do not speak English.³²

CRF affects not only the somatic domain, but also the cognitive, behavioral, and affective domains; therefore, multidimensional scales have been developed for screening. One such tool is the Multidimensional Fatigue Inventory, which assesses 5 dimensions of fatigue—general fatigue, physical fatigue, reduced motivation, reduced activity, and mental fatigue—and compares the patient’s results with those of individuals without cancer.^33,34 The Functional Assessment of Cancer Therapy for Fatigue (FACT-F) is a 13-item questionnaire that has been used to measure CRF in clinical trials as well as in patients receiving various treatments.³⁵

Although many scales are available, the validity of self-reporting on simple fatigue-rating scales is equal to or better than most complex, lengthy scales.³⁶ Therefore, unidimensional tools such as the numeric rating scale of 0–10 are commonly used in clinical practice. Mild fatigue (0–3) requires periodic reevaluation, and moderate and severe fatigue need further evaluation and management.³⁷

PRIMARY EVALUATION

This phase involves a focused history and physical examination and assessment of concurrent symptoms and contributing factors.

History and Physical Examination

A detailed history of the patient’s malignancy and type of previous and current treatment may help reveal the cause of fatigue. New-onset fatigue or increase in fatigue may be related to the progression of disease in patients with active malignancy or recurrence of cancer in survivors. These patients may require appropriate testing to assess the underlying disease pattern. A detailed review of systems may help identify some of the contributing factors, which are discussed below. A detailed history regarding medications, including over-the-counter drugs, complementary agents, and past and prior cancer therapies, is helpful as medications can contribute to fatigue. For example, opioids may cause drowsiness and fatigue, which could be improved by dose adjustments. A focused history of fatigue should be obtained in all patients with moderate to severe CRF, which includes the onset, pattern, duration, associated or alleviating factors, and interference with functioning, including activities of daily living.³⁷ Physical examination should focus on identifying signs of organ dysfunction and features of substance or alcohol abuse, which may cause poor sleep and fatigue.

 

Assessment of Contributing Factors

The management of fatigue should be multifactorial, with a comprehensive assessment and treatment plan to address all modifiable fatigue etiologies. The Table lists potential contributing factors to fatigue that should be considered when evaluating patients for CRF; several common conditions are discussed below. 

Anemia. Anemia has been correlated with fatigue and quality of life. In a study of 4382 cancer patients receiving chemotherapy, quality-of-life measures using FACT-Anemia scores improved with increased hemoglobin levels.³⁸ Cancer patients may have anemia due to marrow-suppressing effects of chemotherapy and may also have iron deficiency anemia due to blood loss or auto-immune hemolytic anemia. Therefore, a detailed work-up is required to identify the etiology of anemia. Patients with CRF whose anemia is related to chemotherapy or anemia of chronic disease may benefit from red blood cell transfusion or erythropoiesis-stimulating agents (ESAs). ESAs have been studied extensively; however, their use is controversial because of concerns about thromboembolic side effects leading to adverse outcomes.³⁹ Also, ESA therapy is not recommended in patients with hematologic malignancies. ESA use should be restricted to patients with chemotherapy-related anemia with hemoglobin below 10 mg/dL and should be discontinued in 6 to 8 weeks if patients do not respond.⁴⁰ Other patients may benefit from blood transfusions, which were shown to help in patients with hemoglobin levels between 7.5 and 8.5 g/dL.⁴¹

Sleep disturbance. Poor sleep is common in fatigued cancer survivors.⁴² Pro-inflammatory cytokines can disrupt the sleep–wake cycle, causing changes in the HPA axis and neuro­endocrine system, which in turn may lead to increasing fatigue. Heckler et al showed that improvement in nighttime sleep leads to improvement of fatigue.⁴³ Cognitive behavioral therapy and sleep hygiene are important in caring for patients with CRF and poor sleep.⁴⁴ Taking a warm bath and/or drinking a glass of milk before bedtime, avoiding caffeinated drinks, and avoiding frequent napping in the day might help. Some patients may require medications such as benzodiazepines or non-benzodiazepine hypnotics (eg, zolpidem) to promote sleep.⁴⁵ Melatonin agonists are approved for insomnia in the United States, but not in Europe.⁴⁶

Malnutrition. Patients with advanced-stage cancer and with cancers affecting the gastrointestinal tract frequently develop mechanical bowel obstructions, especially at the end of their life, which cause malnutrition. Chemotherapy-related nausea and vomiting may also cause poor oral intake and malnutrition, causing fatigue from muscle weakness. Dehydration and electrolyte imbalances frequently occur as a result of poor oral intake, which might worsen fatigue. In our experience, modifying dietary intake with appropriate caloric exchanges with the help of a nutrition expert has lessened fatigue in some patients. However, terminally ill patients are advised to eat based on their comfort.

Medical comorbidities. Congestive heart failure from anthracycline chemotherapy, hypothyroidism after radiation therapy for head and neck cancers, renal failure, or hepatic failure from chemotherapy may indirectly lead to fatigue. Chemotherapy, opioids, and steroids may cause hypogonadism, which can contribute to fatigue in men.⁴⁷

Assessment of Concurrent Symptoms

Depression is common in cancer patients and coexists with pain, insomnia, fatigue, and anxiety as a symptom cluster.⁴⁸ A symptom cluster is defined as 2 or more concurrent and interrelated symptoms occurring together; treating one of these symptoms without addressing other symptoms is not effective.⁴⁹ Therefore, screening for and management of depression, anxiety, and insomnia play an important role in the management of CRF.

Physical symptoms due to the tumor or to therapy— such as pain, dyspnea, nausea, and decreased physical activity—may also contribute to fatigue both directly and indirectly. Patients with lung cancer may have hypoxemia, which can contribute to dyspnea with activity and a perception of fatigue. Optimal management of pain and other physical symptoms in patients with cancer may significantly alleviate fatigue.⁵⁰

MANAGEMENT

Management of CRF is individualized based on the patient’s clinical status: active cancer treatment, survivor, or end of life. Education and counselling of patients and their caregivers play an important role in CRF. NCCN guidelines recommend focusing on pain control, distress management, energy conservation, physical activity, nutrition, and sleep hygiene.

Nonpharmacologic Interventions

Energy conservation. Energy conservation strategies, in which patients are advised to set priorities and realistic expectations, are highly recommended. Some energy-conserving strategies are to pace oneself, delegate and schedule activities at times of peak energy, postpone nonessential activities, attend to 1 activity at a time, structure daily routines, and maintain a diary to identify their peak energy period and structure activities around that time.^51,52 When patients approach the end of life, increasing fatigue may limit their activity level, and they may depend on caregivers for assistance with activities of daily living, monitoring treatment-related adverse effects, and taking medications, especially elderly patients.⁵³

 

Cognitive behavioral therapy. Cognitive behavioral therapy (CBT) has been shown to improve CRF during active treatment, and the benefits persist for a minimum of 2 years after therapy.⁵⁴ CBT interventions that optimize sleep quality may improve fatigue.⁵⁵ More studies are needed to understand whether referral to a psychologist for formal CBT is required. Randomized clinical trials showed patient fatigue education, learned self-care, coping techniques, and balancing rest and activity benefit patients with CRF.⁵⁶

Exercise. Physical activity is highly encouraged in patients with CRF. Exercise increases muscle protein synthesis, improves cytokine response, and decreases the rate of sarcopenia in healthy populations.⁵⁷ Studies have shown that exercise helps CRF at all phases of the cancer journey, including radiation therapy, chemotherapy, and survivorship.⁵⁸ Some patients may feel less motivated to exercise and may not believe that exercise is possible or could potentially help them. Counselling is needed for such patients.

Older cancer survivors have a decline in their functional capacity and reduced muscle mass. Exercise can improve their cardiorespiratory fitness, muscle strength, and body composition.⁵⁷ Exercise not only helps at the cellular level but also has psychosocial benefits from improved self-esteem. Therefore, exercise may be recommended for younger patients as well as for the older population, who may have comorbidities and less motivation than younger patients.

In a meta-analysis of 56 randomized controlled trials involving 4068 participants, aerobic exercise was found to have beneficial effects on CRF for patients during and after chemotherapy, specifically for patients with solid tumors.⁵⁹ In another meta-analysis of breast and prostate cancer survivors, a combination of aerobic exercise with resistance training (3–6 metabolic equivalents, 60%–80% range of motion) was shown to reduce CRF more than aerobic exercise alone.⁶⁰ This effect was also shown in a randomized controlled trial of 160 patients with stage 0 to III breast cancer undergoing radiation therapy.⁶¹ The control group in this study had a group-based non-exercise intervention/relaxation; therefore, the study showed that the effect of resistance training extends beyond the psychosocial benefits of group-based interventions. The intervention comprised 8 progressive machine-based resistance exercises (3 sets, 8–12 repetitions at 60%–80% of 1 repetition maximum) for 60 minutes twice weekly for 12 weeks. However, fatigue assessment questionnaire scores showed benefits only in the physical fatigue components, but not in the affective and cognitive components.

The American Society of Clinical Oncology’s guidelines for cancer survivors with fatigue recommends 150 minutes of moderate aerobic exercise (eg, fast walking, cycling, or swimming) per week, with 2 or 3 sessions of strength training per week.⁶² An individualized approach to exercise is recommended, as patients’ ability to perform certain types of exercises may be limited by thrombocytopenia, neutropenia, or lytic bone metastasis. Routine use of pre-exercise cardiovascular testing is not recommended but may be considered in high-risk populations, especially patients with risk factors for coronary heart disease and diabetes.⁶³ Patients with comorbidities, substantial deconditioning, functional and anatomic defects, or recent major surgery may benefit from referral to physical therapy.³⁷ Patients near end of life may also benefit from an exercise program, as demonstrated in several studies that showed benefit in CRF and quality of life.^64,65 We recommend that physicians use their best clinical judgement in suggesting the type and intensity of exercise program, as it may not be feasible in some patients.

Mind-body interventions. Mindfulness-based stress reduction (MBSR) has shown promise in breast cancer survivors, who reported immediate improvements in fatigue severity that continued up to 6 weeks after cessation of the training.⁶⁶ Prior studies had similar findings, suggesting that MBSR modestly decreases fatigue and sleep disturbances and has a greater effect on the degree to which symptoms interfere with many facets of life.⁶⁷

Yoga. A study of a yoga intervention showed a benefit in older cancer survivors.⁶⁸ In breast cancer patients undergoing chemotherapy, yoga was shown to benefit both physical and cognitive fatigue.⁶⁹ DVD-based yoga had benefits similar to strengthening exercises in a study of 34 early-stage breast cancer survivors with CRF.⁷⁰ More studies are needed in men and patients and survivors of other cancers, as most studies of yoga were conducted in women with breast cancer.

Tai chi/qigong. Like yoga, tai chi and qigong are practices of meditative movement. These practices use postures or movements with a focus on breath and a meditative state to bring about deep states of relaxation. Qigong is a series of simple, repeated practices including body posture/movement, breath practice, and meditation performed in synchrony. Tai chi easy (TCE) is a simplified set of common, repetitive tai chi movements. In a trial, qigong/TCE was compared with sham qigong, which had physical movements but no breathing or meditative practice. Breast cancer survivors in the qigong/TCE group had improved fatigue scores, and the effect persisted for 3 months.⁷¹ Additional research is needed in this area.

Acupuncture. A randomized controlled trial in breast cancer patients with CRF showed an improvement in the mean general fatigue score (per the Multidimensional Fatigue Inventory) in patients who received acupuncture versus those who did not (−3.11 [95% confidence interval −3.97 to −2.25]; P < 0.001) at 6 weeks. Improvements were seen in both the mental and physical aspects of fatigue.⁷² However, Deng et al noted that true acupuncture was no more effective than sham acupuncture for reducing post-chemotherapy chronic fatigue.⁷³ Presently, there is not sufficient evidence to evaluate the benefits of acupuncture in CRF.

Other modalities. Massage therapy, music therapy, hypnosis, therapeutic touch, biofield therapies, relaxation, and reiki are other therapies for which few studies have been done; of the studies that have been done, the results are mixed, and additional research is needed.⁷⁴ Currently, there are not sufficient data to recommend any of these modalities.

 

Pharmacologic Interventions

Psychostimulants. Methylphenidate and modafinil are psychostimulants or wakefulness-promoting agents. Pilot studies showed benefit from methylphenidate and modafinil in CRF,^75–77 but randomized controlled trials have yielded mixed results. Therefore, in patients with severe fatigue during cancer therapy, the initial management strategy involves evaluation and treatment of medical conditions such as anemia and a trial of nonpharmacological strategies as discussed above. If symptoms persist, then a therapeutic trial of a psychostimulant may be considered per NCCN guidelines for patients undergoing active cancer treatment.³⁷

Methylphenidate directly stimulates adrenergic receptors and indirectly releases dopamine and norepinephrine from presynaptic terminals, which may explain why the drug benefits patients receiving opioid-induced sedation. It is a commonly studied psychostimulant, though its mechanism of action in CRF is unclear. Randomized controlled trials of methylphenidate have resulted in a wide range of findings due to the heterogeneity of study populations and variations in the dosage of methylphenidate. A meta-analysis of 7 studies indicates that methylphenidate benefitted the subgroup of patients with CRF.⁷⁸ Likewise, in an analysis of 5 randomized controlled trials, Minton et al showed a benefit of psychostimulants in fatigue compared with placebo.⁷⁹ However, another study of methylphenidate in patients with CRF showed a benefit only in patients with severe fatigue or advanced disease.⁸⁰ Methylphenidate was found to benefit cancer patients receiving opioid-induced sedation, as methylphenidate promotes wakefulness, though fatigue was not studied specifically.⁸¹ In a trial with 30 hospice patients in which the methylphenidate dose was titrated based on response and adverse effects, Kerr at al found that the drug improved fatigue in a dose-dependent manner.⁸² However, a study in patients with CRF at the University of Texas MD Anderson Cancer Center found no significant difference in BFI scores between patients receiving methylphenidate and those receiving placebo at the end of 2 weeks of treatment.⁸³ Also, other randomized controlled trials in patients undergoing adjuvant chemotherapy for breast cancer⁸⁴ and patients receiving radiation therapy for brain tumors⁸⁵ failed to demonstrate the efficacy of methylphenidate in CRF. It should be used cautiously after ruling out other causes of fatigue. The drug is overall well tolerated and side effects include headache and nausea.

Modafinil is a non-amphetamine psychostimulant that has been approved for the treatment of narcolepsy. In a trial studying the effect of modafinil on patients receiving docetaxel-based chemotherapy for metastatic breast or prostate cancer, there was a modest but not statistically significant improvement in fatigue scores on the MD Anderson Symptom Inventory compared with placebo. Nausea and vomiting were higher in the modafinil arm than in the placebo arm.⁸⁶ Similarly, modafinil was not superior to placebo for CRF in 208 patients with non-squamous cell lung cancer not undergoing chemotherapy or radiation.⁸⁷ A placebo effect was also noted in patients with multiple myeloma⁸⁸ and patients with primary brain tumors.⁸⁹ In a phase 3, multicenter, randomized, placebo-controlled, double-blind clinical trial of modafinil for CRF in 867 patients undergoing chemotherapy, there was a reduction in fatigue only for patients with severe baseline fatigue, with no significant effect on mild to moderate fatigue.⁹⁰ In another recent study, modafinil was shown to reduce depressive symptoms only in patients with severe fatigue (BFI item 3 score ≥ 7).⁹¹ This finding is consistent with previous studies showing benefit in patients with high baseline fatigue, but additional randomized controlled trials are needed to provide clarity. NCCN guidelines do not recommend the use of modafinil to treat CRF.³⁷

Other pharmacologic interventions. Corticosteroids are often used for symptom control in cancer patients. These drugs have anti-inflammatory effects through their modulation of pro-inflammatory cytokines.⁹² In a randomized controlled trial evaluating the efficacy of corticosteroids, patients receiving dexamethasone (4 mg twice daily) experienced significant improvement in their FACT-F scores compared with patients receiving placebo.⁹³ A similar benefit in fatigue was demonstrated in another study of methylprednisolone (32 mg daily) versus placebo.⁹⁴ Despite the benefits of steroids, their adverse effects, such as mood swings, gastritis, hyperglycemia, and immune suppression, limit their long-term use. Therefore, the use of steroids should be restricted to terminally ill fatigued patients with other symptoms such as anorexia, brain metastasis, or pain related to bone metastasis.³⁷

Testosterone replacement has been shown to diminish fatigue in non-cancer patients. Many men with advanced cancer have hypogonadism leading to low serum testosterone, which may cause fatigue. In a small trial in which cancer patients with hypogonadism received intramuscular testosterone every 14 days or placebo, the group receiving testosterone showed improvement in FACT-F scores, but there was no significant difference in FACT-F scores between the 2 groups.⁹⁵

Antidepressants have failed to demonstrate benefit in CRF without depression.⁸ However, if a patient has both fatigue and depression, antidepressants may help.⁹⁶ A selective serotonin receptor inhibitor is recommended as a first-line antidepressant.⁹⁷ Patients with cancer are often receiving multiple medications, and medication interactions should be considered to prevent adverse events such as serotonin syndrome.

 

Complementary and Alternative Supplements

Studies using vitamin supplementation have been inconclusive in patients with CRF.⁷⁴ The use of other dietary supplements has yielded mixed results, and coenzyme Q has shown no benefit for patients with CRF.⁹⁸

The benefit of ginseng was studied in a RCT involving 364 patients with CRF. There was an improvement in Multidimensional Fatigue Symptom Inventory-short form (MFSI-SF) scores at 8 weeks in patients receiving 2000 mg of Wisconsin ginseng compared with patients receiving placebo.⁹⁹ Patients on active treatment had greater improvement as compared to the post-treatment group in this trial. In another study of high-dose panax ginseng (ginseng root) at 800 mg daily for 29 days, patients had improvement of CRF as well as overall quality of life, appetite, and sleep at night. It was also well tolerated with few adverse effects.¹⁰⁰ Interaction with warfarin, calcium channel blockers, antiplatelet agents, thrombolytic agents, imatinib, and other agents may occur; therefore, ginseng must be used with careful monitoring in selected patients. There is not enough evidence at this time to support the routine use of ginseng in CRF.

The seed extract of the guarana plant (Paullinia cupana) traditionally has been used as a stimulant. An improvement in fatigue scores was seen with the use of oral guarana (100 mg daily) at the end of 21 days in breast cancer patients receiving chemotherapy.¹⁰¹ Further studies are needed for these results to be generalized and to understand the adverse effects and interaction profile of guarana.

Reevaluation

Patients who have completed cancer treatment must be monitored for fatigue over the long term, as fatigue may exist beyond the period of active treatment. Many studies have shown fatigue in breast cancer survivors, and fatigue has been demonstrated in survivors of colorectal, lung, and prostate cancers as well as myeloproliferative neoplasms.²⁸ Therefore, it is important to screen patients for fatigue during follow-up visits. There are currently no studies evaluating the long-term treatment of fatigue. In our experience, the timing of follow-up depends on the level of fatigue and interventions prescribed. Once fatigue is stabilized to a level with which the patient is able to cope, the time interval for follow-up may be lengthened. Annual visits may suffice in patients with mild fatigue. Follow-up of patients with moderate to severe fatigue depends on the level of fatigue, the ability to cope, choice of treatment, and presence of contributing factors.

CONCLUSION

CRF is a complex condition that places a significant burden on patients and caregivers, resulting in emotional distress, poor functioning, and suffering. Fatigue can occur before, during, and long after cancer treatment. The approach to CRF begins with screening for and educating patients and their caregivers about the symptoms. Many screening scales are available that may be used to follow patients’ progress over time. The evaluation and management of contributing conditions may help improve fatigue. If the fatigue persists, an individualized approach with a combination of nonpharmacologic and pharmacologic approaches should be considered. More research is needed to understand brain signaling pathways, cytokine changes, and genomic changes in cancer patients with fatigue. Though many hypotheses have been proposed, to date there is no biological marker to assess this condition. Biomarker research needs to be advanced to help to identify patients at risk for fatigue. As cytokines have a major role in CRF, targeted therapy to block cytokine pathways may also be explored in the future.

Acknowledgment: The authors thank Bryan Tutt for providing editorial assistance during the writing of this article.