Cleveland Clinic Journal of Medicine

Despite surgery, 40% to 75% of patients with stage I to IIIA non–small cell lung cancer (NSCLC) will die within 5 years. After multiple trials showed no survival advantage to chemotherapy in the adjuvant setting for the treatment of locally advanced NSCLC, the first hint of benefit came in 1995 with the publication of a meta-analysis of 14 clinical trials, which showed a nonsignificant 5% improvement in 5-year survival with chemotherapy after surgery.¹

A second meta-analysis, this one conducted by the Lung Adjuvant Cisplatin Evaluation (LACE) Collaborative Group, demonstrated a hazard ratio (HR) of 0.89 (P = .005) on the end point of overall survival with the use of postoperative cisplatin-based chemotherapy in patients with NSCLC; this translates to a 5-year absolute improvement of 5.4% from chemotherapy.² The survival benefit was confined to patients with stage II and stage III disease.

Post hoc exploratory subgroup analyses of the Cancer and Leukemia Group B (CALGB) 9633³ and Adjuvant Navelbine International Trialist Association (ANITA)⁴ trials revealed a significant survival benefit to four cycles of cisplatin-based adjuvant chemotherapy in patients with stage Ib disease who had tumors 4 cm or larger.

BIOMARKERS

Prognostic and predictive biomarkers beyond cancer stage are needed, as only 10% to 15% of patients with resected NSCLC who receive chemotherapy derive a benefit. Predictive markers can be used to guide therapeutic decision-making, and prognostic markers permit estimation of patient outcome independent of treatment modality.

Reprinted with permission from The New England Journal of Medicine (Olaussen KA, et al. DNA repair by ERCC1 in non–small-cell lung cancer and cisplatin-based adjuvant chemotherapy. N Engl J Med 2006; 355:983–991). Copyright © 2006 MMS.

As with ERCC1, expression of the DNA mismatch repair protein mutS homolog 2 (MSH2)⁷ is both prognostic and predictive after surgery. In a separate biomarker analysis from the IALT study, approximately two-thirds of patients with NSCLC had MSH2-negative tumors by immunohistochemistry, indicating lack of expression of MSH2 in tumors. Patients with expression of MSH2, who have intact mismatch repair, had a better prognosis and benefitted less from systemic chemotherapy than those with an absence of MSH2 expression.⁸

Individually, ERCC1 and MSH2 have similar power in predicting benefit from adjuvant chemotherapy in NSCLC; the HR for death was similar in patients with low expression of either gene.⁸ The two biomarkers combined, however, were more powerful than either alone in their ability to predict a survival advantage with chemotherapy.⁸ In an evaluation of 658 patients with NSCLC for whom both biomarkers were available, patients who expressed low tumor levels of both ERCC1 and MSH2 had an HR for death that was 35% lower with adjuvant chemotherapy compared with surgery alone after median follow-up of 7.5 years; the presence of two positive biomarkers was associated with an increase in the HR for death by 32%. Validation of these findings in a phase 3 setting will be necessary before these biomarkers can be used in the clinical setting.

The Southwest Oncology Group (SWOG) is conducting a trial (SWOG 0720) in patients with stage I NSCLC to determine whether a subset based on ERCC1 and ribonucleotide reductase M1 (RRM1) status will derive benefit from adjuvant therapy with gemcitabine together with cisplatin. Ribonucleotide reductase subunit 1 is the regulatory subunit of ribonuclease reductase, which is an enzyme that catalyzes the deoxynucleotide production required for DNA repair.

Two other clinical trials, under way but not completed, testing various forms of chemotherapy and targeted therapy based on ERCC1 and epidermal growth factor receptor (EGFR) mutation status are the Tailored Post-Surgical Therapy in Early Stage NSCLC (TASTE) and the International Tailored Chemotherapy Adjuvant (ITACA) trials. The TASTE trial is comparing standard chemotherapy (cisplatin plus pemetrexed) with customized adjuvant treatment based on EGFR and ERCC1 status in patients with stage II or IIIa nonsquamous NSCLC. The ITACA trial is a phase 3 study of pemetrexed, cisplatin, and radiotherapy determined by thymidylate synthase (TS) and ERCC1 gene expression levels in patients with stage II to III completely resected NSCLC. TS is an enzyme responsible for maintaining intracellular levels of thymidine, important for DNA synthesis and repair, and may serve as a predictor of response to pemetrexed.

GENE EXPRESSION PROFILING

Gene expression profiles, already used to predict benefit from chemotherapy in early-stage breast cancer, may inform treatment decisions in lung cancer as well. A15-gene signature that could predict risk of recurrence and death after surgery alone for stage Ib or II NSCLC was identified using fresh frozen tissue of patients from the National Cancer Institute of Canada (NCIC) Clinical Trials Group (CTG) JBR.10 trial of vinorelbine/cisplatin.⁹ The risk profile was subsequently validated with reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) in the same cases and in four independent sets of patients.⁹

Reprinted with permission. Copyright © 2010 American Society of Clinical Oncology. All rights reserved. Zhu C-Q, et al. J Clin Oncol 2010; 28:4417–4424.

Among those patients with stage Ib disease, the gene expression profile was both prognostic (HR of 13.22 for disease-specific survival in the high- vs low-risk population) and predictive (HR of 0.44 for the use of adjuvant chemotherapy in the high-risk patients but no survival benefit observed with chemotherapy in low-risk patients).⁹

USE OF BIOMARKERS TO SELECT TREATMENT

As alluded to earlier, the use of biomarker expression to guide treatment selection is an area of intense investigation. In the metastatic setting, therapy targeted to the EGFR mutation has proven to be remarkably beneficial in patients with EGFR-activating mutations. In the adjuvant setting, the NCIC CTG BR.19 trial enrolled an unselected population of patients with completely resected stage Ib to IIIa NSCLC; the patients were randomized to 2 years of treatment with the tyrosine kinase inhibitor gefitinib, which targets EGFR, or placebo. Tissue samples from trial participants were collected and revealed KRAS mutation in 27%, a high EGFR gene copy number by fluorescence in situ hybridization (FISH) in 41%, and an activating EGFR mutation in 21%.

The NCIC CTG BR.19 trial was greatly underpowered because enrollment was stopped at 503 patients when, in 2008, the SWOG 0023 investigators reported a worse overall median survival with maintenance gefitinib after definitive chemoradiation in patients with stage III NSCLC.¹⁰ As a result of the early termination of patient accrual, the median duration of adjuvant gefitinib in NCIC CTG BR.19 was less than 5 months. Further, only 20% were exposed to chemotherapy and only 21% of the final study population had an EGFR mutation. In the overall study population, the HR for overall survival among gefitinib recipients was 1.23, indicating harm, and there was a trend in favor of placebo on the end point of disease-free survival. Neither KRAS nor EGFR copy number was predictive or prognostic, and EGFR mutation status was not prognostic.¹¹ Patients with wild-type EGFR had a trend toward detriment with maintenance gefitinib that was similar to that of the overall population, and those with EGFR mutation experienced no benefit with maintenance gefitinib.

In the Randomized Double-Blind Trial in Adjuvant NSCLC with Tarceva (RADIANT), patients with resected stage I to IIIa NSCLC, with the option for postoperative chemotherapy, were assessed for EGFR expression by immunohistochemistry or FISH and then randomized to erlotinib or placebo for 2 years. The trial completed accrual in 2010 and results are expected in 4 to 5 years.

Cleveland Clinic is currently accruing patients for a phase 2 trial of patients with resected stage I to IIIa NSCLC. All patients will have their tumors screened for activating EGFR mutations; those with activating mutations will receive adjuvant erlotinib for 2 years. starting within 6 months of surgery.

SUMMARY

Although adjuvant chemotherapy has been well established for patients with early-stage NSCLC, stage alone is not an ideal biomarker to predict the utility of chemotherapy, as the vast majority of patients derive no benefit from chemotherapy.

Biomarkers have been poorly validated and therefore are inappropriate for clinical use at this time. Validation of gene arrays has been disappointingly slow in lung cancer because of the absence of large tumor banks that are available in breast cancer and colon cancer.

It remains unclear whether targeted therapies improve outcomes over traditional chemotherapy in the adjuvant setting in NSCLC, as tumors in the metastatic and adjuvant settings are not the same.

Despite surgery, 40% to 75% of patients with stage I to IIIA non–small cell lung cancer (NSCLC) will die within 5 years. After multiple trials showed no survival advantage to chemotherapy in the adjuvant setting for the treatment of locally advanced NSCLC, the first hint of benefit came in 1995 with the publication of a meta-analysis of 14 clinical trials, which showed a nonsignificant 5% improvement in 5-year survival with chemotherapy after surgery.¹

A second meta-analysis, this one conducted by the Lung Adjuvant Cisplatin Evaluation (LACE) Collaborative Group, demonstrated a hazard ratio (HR) of 0.89 (P = .005) on the end point of overall survival with the use of postoperative cisplatin-based chemotherapy in patients with NSCLC; this translates to a 5-year absolute improvement of 5.4% from chemotherapy.² The survival benefit was confined to patients with stage II and stage III disease.

Post hoc exploratory subgroup analyses of the Cancer and Leukemia Group B (CALGB) 9633³ and Adjuvant Navelbine International Trialist Association (ANITA)⁴ trials revealed a significant survival benefit to four cycles of cisplatin-based adjuvant chemotherapy in patients with stage Ib disease who had tumors 4 cm or larger.

BIOMARKERS

Prognostic and predictive biomarkers beyond cancer stage are needed, as only 10% to 15% of patients with resected NSCLC who receive chemotherapy derive a benefit. Predictive markers can be used to guide therapeutic decision-making, and prognostic markers permit estimation of patient outcome independent of treatment modality.

Reprinted with permission from The New England Journal of Medicine (Olaussen KA, et al. DNA repair by ERCC1 in non–small-cell lung cancer and cisplatin-based adjuvant chemotherapy. N Engl J Med 2006; 355:983–991). Copyright © 2006 MMS.

As with ERCC1, expression of the DNA mismatch repair protein mutS homolog 2 (MSH2)⁷ is both prognostic and predictive after surgery. In a separate biomarker analysis from the IALT study, approximately two-thirds of patients with NSCLC had MSH2-negative tumors by immunohistochemistry, indicating lack of expression of MSH2 in tumors. Patients with expression of MSH2, who have intact mismatch repair, had a better prognosis and benefitted less from systemic chemotherapy than those with an absence of MSH2 expression.⁸

Individually, ERCC1 and MSH2 have similar power in predicting benefit from adjuvant chemotherapy in NSCLC; the HR for death was similar in patients with low expression of either gene.⁸ The two biomarkers combined, however, were more powerful than either alone in their ability to predict a survival advantage with chemotherapy.⁸ In an evaluation of 658 patients with NSCLC for whom both biomarkers were available, patients who expressed low tumor levels of both ERCC1 and MSH2 had an HR for death that was 35% lower with adjuvant chemotherapy compared with surgery alone after median follow-up of 7.5 years; the presence of two positive biomarkers was associated with an increase in the HR for death by 32%. Validation of these findings in a phase 3 setting will be necessary before these biomarkers can be used in the clinical setting.

The Southwest Oncology Group (SWOG) is conducting a trial (SWOG 0720) in patients with stage I NSCLC to determine whether a subset based on ERCC1 and ribonucleotide reductase M1 (RRM1) status will derive benefit from adjuvant therapy with gemcitabine together with cisplatin. Ribonucleotide reductase subunit 1 is the regulatory subunit of ribonuclease reductase, which is an enzyme that catalyzes the deoxynucleotide production required for DNA repair.

Two other clinical trials, under way but not completed, testing various forms of chemotherapy and targeted therapy based on ERCC1 and epidermal growth factor receptor (EGFR) mutation status are the Tailored Post-Surgical Therapy in Early Stage NSCLC (TASTE) and the International Tailored Chemotherapy Adjuvant (ITACA) trials. The TASTE trial is comparing standard chemotherapy (cisplatin plus pemetrexed) with customized adjuvant treatment based on EGFR and ERCC1 status in patients with stage II or IIIa nonsquamous NSCLC. The ITACA trial is a phase 3 study of pemetrexed, cisplatin, and radiotherapy determined by thymidylate synthase (TS) and ERCC1 gene expression levels in patients with stage II to III completely resected NSCLC. TS is an enzyme responsible for maintaining intracellular levels of thymidine, important for DNA synthesis and repair, and may serve as a predictor of response to pemetrexed.

GENE EXPRESSION PROFILING

Gene expression profiles, already used to predict benefit from chemotherapy in early-stage breast cancer, may inform treatment decisions in lung cancer as well. A15-gene signature that could predict risk of recurrence and death after surgery alone for stage Ib or II NSCLC was identified using fresh frozen tissue of patients from the National Cancer Institute of Canada (NCIC) Clinical Trials Group (CTG) JBR.10 trial of vinorelbine/cisplatin.⁹ The risk profile was subsequently validated with reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) in the same cases and in four independent sets of patients.⁹

Reprinted with permission. Copyright © 2010 American Society of Clinical Oncology. All rights reserved. Zhu C-Q, et al. J Clin Oncol 2010; 28:4417–4424.

Among those patients with stage Ib disease, the gene expression profile was both prognostic (HR of 13.22 for disease-specific survival in the high- vs low-risk population) and predictive (HR of 0.44 for the use of adjuvant chemotherapy in the high-risk patients but no survival benefit observed with chemotherapy in low-risk patients).⁹

USE OF BIOMARKERS TO SELECT TREATMENT

As alluded to earlier, the use of biomarker expression to guide treatment selection is an area of intense investigation. In the metastatic setting, therapy targeted to the EGFR mutation has proven to be remarkably beneficial in patients with EGFR-activating mutations. In the adjuvant setting, the NCIC CTG BR.19 trial enrolled an unselected population of patients with completely resected stage Ib to IIIa NSCLC; the patients were randomized to 2 years of treatment with the tyrosine kinase inhibitor gefitinib, which targets EGFR, or placebo. Tissue samples from trial participants were collected and revealed KRAS mutation in 27%, a high EGFR gene copy number by fluorescence in situ hybridization (FISH) in 41%, and an activating EGFR mutation in 21%.

The NCIC CTG BR.19 trial was greatly underpowered because enrollment was stopped at 503 patients when, in 2008, the SWOG 0023 investigators reported a worse overall median survival with maintenance gefitinib after definitive chemoradiation in patients with stage III NSCLC.¹⁰ As a result of the early termination of patient accrual, the median duration of adjuvant gefitinib in NCIC CTG BR.19 was less than 5 months. Further, only 20% were exposed to chemotherapy and only 21% of the final study population had an EGFR mutation. In the overall study population, the HR for overall survival among gefitinib recipients was 1.23, indicating harm, and there was a trend in favor of placebo on the end point of disease-free survival. Neither KRAS nor EGFR copy number was predictive or prognostic, and EGFR mutation status was not prognostic.¹¹ Patients with wild-type EGFR had a trend toward detriment with maintenance gefitinib that was similar to that of the overall population, and those with EGFR mutation experienced no benefit with maintenance gefitinib.

In the Randomized Double-Blind Trial in Adjuvant NSCLC with Tarceva (RADIANT), patients with resected stage I to IIIa NSCLC, with the option for postoperative chemotherapy, were assessed for EGFR expression by immunohistochemistry or FISH and then randomized to erlotinib or placebo for 2 years. The trial completed accrual in 2010 and results are expected in 4 to 5 years.

Cleveland Clinic is currently accruing patients for a phase 2 trial of patients with resected stage I to IIIa NSCLC. All patients will have their tumors screened for activating EGFR mutations; those with activating mutations will receive adjuvant erlotinib for 2 years. starting within 6 months of surgery.

SUMMARY

Although adjuvant chemotherapy has been well established for patients with early-stage NSCLC, stage alone is not an ideal biomarker to predict the utility of chemotherapy, as the vast majority of patients derive no benefit from chemotherapy.

Biomarkers have been poorly validated and therefore are inappropriate for clinical use at this time. Validation of gene arrays has been disappointingly slow in lung cancer because of the absence of large tumor banks that are available in breast cancer and colon cancer.

It remains unclear whether targeted therapies improve outcomes over traditional chemotherapy in the adjuvant setting in NSCLC, as tumors in the metastatic and adjuvant settings are not the same.

Despite surgery, 40% to 75% of patients with stage I to IIIA non–small cell lung cancer (NSCLC) will die within 5 years. After multiple trials showed no survival advantage to chemotherapy in the adjuvant setting for the treatment of locally advanced NSCLC, the first hint of benefit came in 1995 with the publication of a meta-analysis of 14 clinical trials, which showed a nonsignificant 5% improvement in 5-year survival with chemotherapy after surgery.¹

A second meta-analysis, this one conducted by the Lung Adjuvant Cisplatin Evaluation (LACE) Collaborative Group, demonstrated a hazard ratio (HR) of 0.89 (P = .005) on the end point of overall survival with the use of postoperative cisplatin-based chemotherapy in patients with NSCLC; this translates to a 5-year absolute improvement of 5.4% from chemotherapy.² The survival benefit was confined to patients with stage II and stage III disease.

Post hoc exploratory subgroup analyses of the Cancer and Leukemia Group B (CALGB) 9633³ and Adjuvant Navelbine International Trialist Association (ANITA)⁴ trials revealed a significant survival benefit to four cycles of cisplatin-based adjuvant chemotherapy in patients with stage Ib disease who had tumors 4 cm or larger.

BIOMARKERS

Prognostic and predictive biomarkers beyond cancer stage are needed, as only 10% to 15% of patients with resected NSCLC who receive chemotherapy derive a benefit. Predictive markers can be used to guide therapeutic decision-making, and prognostic markers permit estimation of patient outcome independent of treatment modality.

Reprinted with permission from The New England Journal of Medicine (Olaussen KA, et al. DNA repair by ERCC1 in non–small-cell lung cancer and cisplatin-based adjuvant chemotherapy. N Engl J Med 2006; 355:983–991). Copyright © 2006 MMS.

As with ERCC1, expression of the DNA mismatch repair protein mutS homolog 2 (MSH2)⁷ is both prognostic and predictive after surgery. In a separate biomarker analysis from the IALT study, approximately two-thirds of patients with NSCLC had MSH2-negative tumors by immunohistochemistry, indicating lack of expression of MSH2 in tumors. Patients with expression of MSH2, who have intact mismatch repair, had a better prognosis and benefitted less from systemic chemotherapy than those with an absence of MSH2 expression.⁸

Individually, ERCC1 and MSH2 have similar power in predicting benefit from adjuvant chemotherapy in NSCLC; the HR for death was similar in patients with low expression of either gene.⁸ The two biomarkers combined, however, were more powerful than either alone in their ability to predict a survival advantage with chemotherapy.⁸ In an evaluation of 658 patients with NSCLC for whom both biomarkers were available, patients who expressed low tumor levels of both ERCC1 and MSH2 had an HR for death that was 35% lower with adjuvant chemotherapy compared with surgery alone after median follow-up of 7.5 years; the presence of two positive biomarkers was associated with an increase in the HR for death by 32%. Validation of these findings in a phase 3 setting will be necessary before these biomarkers can be used in the clinical setting.

The Southwest Oncology Group (SWOG) is conducting a trial (SWOG 0720) in patients with stage I NSCLC to determine whether a subset based on ERCC1 and ribonucleotide reductase M1 (RRM1) status will derive benefit from adjuvant therapy with gemcitabine together with cisplatin. Ribonucleotide reductase subunit 1 is the regulatory subunit of ribonuclease reductase, which is an enzyme that catalyzes the deoxynucleotide production required for DNA repair.

Two other clinical trials, under way but not completed, testing various forms of chemotherapy and targeted therapy based on ERCC1 and epidermal growth factor receptor (EGFR) mutation status are the Tailored Post-Surgical Therapy in Early Stage NSCLC (TASTE) and the International Tailored Chemotherapy Adjuvant (ITACA) trials. The TASTE trial is comparing standard chemotherapy (cisplatin plus pemetrexed) with customized adjuvant treatment based on EGFR and ERCC1 status in patients with stage II or IIIa nonsquamous NSCLC. The ITACA trial is a phase 3 study of pemetrexed, cisplatin, and radiotherapy determined by thymidylate synthase (TS) and ERCC1 gene expression levels in patients with stage II to III completely resected NSCLC. TS is an enzyme responsible for maintaining intracellular levels of thymidine, important for DNA synthesis and repair, and may serve as a predictor of response to pemetrexed.

GENE EXPRESSION PROFILING

Gene expression profiles, already used to predict benefit from chemotherapy in early-stage breast cancer, may inform treatment decisions in lung cancer as well. A15-gene signature that could predict risk of recurrence and death after surgery alone for stage Ib or II NSCLC was identified using fresh frozen tissue of patients from the National Cancer Institute of Canada (NCIC) Clinical Trials Group (CTG) JBR.10 trial of vinorelbine/cisplatin.⁹ The risk profile was subsequently validated with reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) in the same cases and in four independent sets of patients.⁹

Reprinted with permission. Copyright © 2010 American Society of Clinical Oncology. All rights reserved. Zhu C-Q, et al. J Clin Oncol 2010; 28:4417–4424.

Among those patients with stage Ib disease, the gene expression profile was both prognostic (HR of 13.22 for disease-specific survival in the high- vs low-risk population) and predictive (HR of 0.44 for the use of adjuvant chemotherapy in the high-risk patients but no survival benefit observed with chemotherapy in low-risk patients).⁹

USE OF BIOMARKERS TO SELECT TREATMENT

As alluded to earlier, the use of biomarker expression to guide treatment selection is an area of intense investigation. In the metastatic setting, therapy targeted to the EGFR mutation has proven to be remarkably beneficial in patients with EGFR-activating mutations. In the adjuvant setting, the NCIC CTG BR.19 trial enrolled an unselected population of patients with completely resected stage Ib to IIIa NSCLC; the patients were randomized to 2 years of treatment with the tyrosine kinase inhibitor gefitinib, which targets EGFR, or placebo. Tissue samples from trial participants were collected and revealed KRAS mutation in 27%, a high EGFR gene copy number by fluorescence in situ hybridization (FISH) in 41%, and an activating EGFR mutation in 21%.

The NCIC CTG BR.19 trial was greatly underpowered because enrollment was stopped at 503 patients when, in 2008, the SWOG 0023 investigators reported a worse overall median survival with maintenance gefitinib after definitive chemoradiation in patients with stage III NSCLC.¹⁰ As a result of the early termination of patient accrual, the median duration of adjuvant gefitinib in NCIC CTG BR.19 was less than 5 months. Further, only 20% were exposed to chemotherapy and only 21% of the final study population had an EGFR mutation. In the overall study population, the HR for overall survival among gefitinib recipients was 1.23, indicating harm, and there was a trend in favor of placebo on the end point of disease-free survival. Neither KRAS nor EGFR copy number was predictive or prognostic, and EGFR mutation status was not prognostic.¹¹ Patients with wild-type EGFR had a trend toward detriment with maintenance gefitinib that was similar to that of the overall population, and those with EGFR mutation experienced no benefit with maintenance gefitinib.

In the Randomized Double-Blind Trial in Adjuvant NSCLC with Tarceva (RADIANT), patients with resected stage I to IIIa NSCLC, with the option for postoperative chemotherapy, were assessed for EGFR expression by immunohistochemistry or FISH and then randomized to erlotinib or placebo for 2 years. The trial completed accrual in 2010 and results are expected in 4 to 5 years.

Cleveland Clinic is currently accruing patients for a phase 2 trial of patients with resected stage I to IIIa NSCLC. All patients will have their tumors screened for activating EGFR mutations; those with activating mutations will receive adjuvant erlotinib for 2 years. starting within 6 months of surgery.

SUMMARY

Although adjuvant chemotherapy has been well established for patients with early-stage NSCLC, stage alone is not an ideal biomarker to predict the utility of chemotherapy, as the vast majority of patients derive no benefit from chemotherapy.

Biomarkers have been poorly validated and therefore are inappropriate for clinical use at this time. Validation of gene arrays has been disappointingly slow in lung cancer because of the absence of large tumor banks that are available in breast cancer and colon cancer.

It remains unclear whether targeted therapies improve outcomes over traditional chemotherapy in the adjuvant setting in NSCLC, as tumors in the metastatic and adjuvant settings are not the same.

Despite enthusiasm for the use of molecular testing and molecularly targeted agents in patients with advanced non–small cell lung cancer (NSCLC), most patients are not candidates for upfront treatment with molecular agents. Chemotherapy therefore remains the backbone of treatment for this patient population.

This article presents the best available evidence for selection of chemotherapy for patients with advanced NSCLC and examines the controversy surrounding maintenance therapy.

EVOLUTION OF CHEMOTHERAPY IN NSCLC

The first evidence that chemotherapy produced a significant survival benefit in patients with advanced NSCLC came in 1995 when a meta-analysis showed that platinum-based chemotherapy conferred a 2-month improvement in median survival over best supportive care.¹

This finding led to a decade of randomized phase 3 clinical trials that compared different platinum-based regimens. The quintessential trial in this regard was Eastern Cooperative Oncology Group (ECOG) 1594, in which three platinum doublets were compared with cisplatin and paclitaxel on the end point of overall survival (OS) in patients with advanced NSCLC. No significant differences were found among the regimens tested.²

Bevacizumab adds to platinum doublet in nonsquamous NSCLC

With the introduction of bevacizumab, an antibody against vascular endothelial growth factor, knowledge of NSCLC histology became important. In the ECOG 4599 trial, published in 2006, bevacizumab added to platinum doublet chemotherapy in patients with advanced nonsquamous NSCLC significantly improved the response rate, progression-free survival (PFS), and median OS compared with platinum doublet chemotherapy alone.³ This trial was limited to patients with nonsquamous NSCLC because its predecessor trial had revealed an excess of life-threatening pulmonary hemorrhage in association with bevacizumab in patients with squamous cell carcinoma.

Pemetrexed superior to docetaxel in nonsquamous histology

In 2004, Hanna et al⁴ demonstrated pemetrexed to be noninferior to docetaxel on efficacy outcomes as second-line therapy in advanced NSCLC. Pemetrexed had a significantly better toxicity profile, however, which led to its approval for this indication. Post hoc analyses of this trial suggested a differential effect of pemetrexed based on histology. In the pemetrexed arm, patients with nonsquamous histology appeared to have superior survival compared with patients who had squamous histology, whereas in the docetaxel arm, histology did not affect outcome.⁵ Further, the nonsquamous histologic subgroup had superior OS with pemetrexed compared with docetaxel.⁶

Pemetrexed and gemcitabine perform differently based on histology

A phase 3 trial with a noninferiority design compared cisplatin/pemetrexed with cisplatin/gemcitabine as first-line therapy on OS. The noninferiority criteria were met, with no difference in median OS between the two groups (median OS: 10.3 months in both arms).⁷

Based on this evidence, NSCLC is no longer an adequate pathologic diagnosis. Pathologists must differentiate squamous from nonsquamous histology to take full advantage of the safety of angiogenesis inhibitors and the efficacy of pemetrexed.

OPTIMAL FIRST-LINE REGIMEN FOR NONSQUAMOUS NSCLC

Both cisplatin/pemetrexed and carboplatin/paclitaxel plus bevacizumab have level 1 evidence to support their use as first-line treatment of NSCLC with nonsquamous histology. Carboplatin/pemetrexed/bevacizumab is also being used in the community despite the absence of randomized trial evidence to support its use for this indication.

A single-arm phase 2 trial of carboplatin/pemetrexed/bevacizumab followed by maintenance pemetrexed/bevacizumab in 49 patients produced a response rate of 55%, PFS of 7.8 months, and OS of 14 months.¹⁰ Although the results are impressive, they should be considered hypothesis-generating rather than treatment-changing in light of the small number of patients enrolled and the single-arm design.

An open-label randomized phase 3 trial, Point-Break, is comparing two regimens in patients who have advanced nonsquamous NSCLC: (1) carboplatin/pemetrexed/bevacizumab followed by maintenance pemetrexed/bevacizumab and (2) carboplatin/paclitaxel/bevacizumab followed by bevacizumab.¹¹ Although potentially practice-changing, PointBreak will not answer whether bevacizumab adds benefit to cisplatin and pemetrexed, nor will it determine which first-line regimen is superior because of the different maintenance regimens.

SQUAMOUS NSCLC: PLATINUM DOUBLET OPTIMAL

No agents are currently approved specifically for the treatment of squamous cell carcinoma, which appears to have a high level of expression of insulin-like growth factor receptor (IGF-1R). A 64% response rate observed with an IGF-1R antagonist added to paclitaxel/carboplatin in patients with NSCLC of squamous cell histology in a phase 2 trial led to the design of a phase 3 trial in which patients were randomized to carboplatin/paclitaxel with or without the IGF-1R antagonist figitumumab. The trial ended prematurely in 2009 because of an imbalance of deaths in the experimental arm.¹² As expected, hyperglycemia was more common in the experimental arm. Unexpectedly, the incidences of grade 5 infections and cardiovascular events were also significantly higher in the experimental arm.

A randomized phase 3 trial of carboplatin/paclitaxel compared with carboplatin and nanoparticle albumin-bound (nab) paclitaxel was conducted in 1,052 patients with stage IIIb/IV NSCLC with the primary end point being overall response rate (ORR).¹³ The rationale for substituting nab-paclitaxel for paclitaxel was that paclitaxel is dissolved in polyoxyethylated castor oil. This decreases the efficacy of paclitaxel and contributes to its toxicities, including hypersensitivity reactions and neuropathy. In metastatic breast cancer, nab-paclitaxel was shown to be more efficacious than solvent-based paclitaxel.¹⁴

The nab-paclitaxel trial met its primary end point of superior response rate: 33% in the nab-paclitaxel arm versus 25% in the standard paclitaxel arm. However, on final analysis there was no difference in PFS or OS between the two arms, making the difference in ORR of little clinical significance. No hypersensitivity reactions occurred in the nab-paclitaxel arm, while three occurred in the paclitaxel arm. Grade 3 sensory neuropathy occurred significantly less often in the group assigned to nab-paclitaxel compared with paclitaxel (3 vs 10, respectively; P < .001). Although there appears to be no efficacy advantage of nab-paclitaxel over standard paclitaxel for advanced NSCLC patients, use of nab-paclitaxel might be considered in patients with stage IV NSCLC who have poorly controlled diabetes or who already suffer significant neuropathy.

Although not a prespecified end point, the response rate in patients with squamous cell histology nearly doubled among those treated with nab-paclitaxel compared with standard paclitaxel. However, this did not translate into significant differences in PFS or OS in this subgroup, and the use of nab-paclitaxel in this patient population specifically is not advised.

In light of the data, the standard treatment for squamous NSCLC remains a platinum doublet other than pemetrexed. A phase 3 clinical trial, ECLIPSE, is currently enrolling patients at the Cleveland Clinic. The trial will randomize chemotherapy-naïve patients with stage IIIb/IV NSCLC and a Karnofsky performance status of 0 or 1 to receive carboplatin and gemcitabine with or without the polyadenosine diphosphate–ribose polymerase inhibitor iniparib.

MAINTENANCE THERAPY

The utility of maintenance therapy—the uninterrupted continuation of therapy for patients who do not progress after completing first-line chemotherapy—in patients with advanced NSCLC is controversial. Two kinds of maintenance therapy have emerged.

Switch maintenance, also known as early second-line therapy, is so termed because patients are immediately switched to a second-line agent different from the first-line doublet therapy.

Continuation maintenance is the continuation of one or more drugs from the induction regimen, the best example being continuation of single-agent evacizumab in the ECOG 4599 regimen.

Five major trials of successful maintenance therapy for nonprogressors after first-line chemotherapy have been presented over the past 4 years, and these have led to new indications for the maintenance drugs.^8,15–18 PFS in favor of active maintenance has been documented in trials of early versus delayed maintenance docetaxel,¹⁵ pemetrexed versus placebo,⁸ erlotinib versus placebo,¹⁶ bevacizumab/erlotinib versus bevacizumab/placebo (ATLAS trial),¹⁷ and gemcitabine or erlotinib versus placebo (IFCT-GFPC 0502).¹⁸ The magnitude of improved PFS associated with each treatment has been similar. As a result, improved of PFS with maintenance therapy is now widely accepted.

To improve survival: maintenance therapy or better second-line therapy?

The utility of maintenance therapy can be confounded by the lack of a predefined second-line treatment. Some argue that the benefit to maintenance may also be realized by appropriate use of the same agent as salvage therapy in the case of disease progression.

Overall survival improved with maintenance therapy in only two trials; one compared pemetrexed with placebo and the other compared erlotinib with placebo.^8,16 The validity of these findings, however, remains in question. In the trial of pemetrexed, only 19% of the patients in the control arm ever received pemetrexed, and in the erlotinib trial, only 21% of the patients in the control arm ever received erlotinib after progression. Whether maintenance therapy was responsible for an improvement in OS or whether ineffective second-line therapy dampened survival in patients in the control arms is unknown.

In the IFCT-GFPC 0502 phase 3 study, patients received four cycles of cisplatin/gemcitabine.¹⁹ If patients did not progress, they were randomized to observation, continuation maintenance with gemcitabine, or switch maintenance to erlotinib. Predefined second-line therapy in all arms was pemetrexed. The primary end point chosen was PFS, even though maintenance therapy had already been established to extend PFS. The median PFS in the gemcitabine maintenance arm was 3.8 months, compared with 1.9 months in the observation arm. The hazard ratio (HR) of 0.55 (P < .0001) was similar to that observed with pemetrexed in the maintenance trial noted above.¹⁹ Subgroup analysis showed improvement in PFS with the gemcitabine maintenance group compared with observation in all subgroups, including those based on histology. The HR in the erlotinib maintenance arm was 0.82 (P = .002), similar to that observed with erlotinib in the Sequential Tarceva in Unresectable NSCLC (SATURN) trial.¹⁶

In the IFCT-GFPC 0502 study, 60.4% of patients in the gemcitabine arm, 63.2 % of those in the erlotinib arm, and 76.1% in the observation arm received postmaintenance treatment with pemetrexed.¹⁹ Nearly one-half (49.6%) of patients in the observation arm received third-line treatment with erlotinib.

In the overall study population, a trend toward improved OS was observed with maintenance gemcitabine or erlotinib compared with observation, but did not achieve statistical significance, possibly because the trial lacked adequate power to detect a difference on this end point.

A subgroup analysis of patients who received second-line pemetrexed showed a significant improvement in OS in the maintenance arms compared with the observation arm. About 25% of the patients never advanced to second-line pemetrexed. Because patients who never received second-line pemetrexed may represent the sickest patients, the relevance of this finding to the overall population of patients with stage IV NSCLC is unknown.

Ongoing maintenance trials

Two ongoing clinical trials of maintenance are exploring bevacizumab with or without pemetrexed as maintenance following first-line cisplatin/pemetrexed/bevacizumab (AVAPERL) and bevacizumab alone, pemetrexed alone, or a combination of the two as maintenance following first-line therapy with carboplatin/paclitaxel/bevacizumab (Eastern Cooperative Oncology Group). Preliminary results from the AVAPERL study were reported recently and support the use of pemetrexed and bevacizumab as maintenance therapy compared with bevacizumab alone.²⁰

CONCLUSIONS ABOUT MAINTENANCE THERAPY

Pemetrexed and erlotinib significantly prolong OS survival compared with placebo when used as maintenance therapy in advanced NSCLC patients who do not progress after four cycles of first-line chemotherapy. Whether this improvement in OS can be attributed to maintenance therapy or more effective second-line therapy is open to debate.

Maintenance chemotherapy should be discussed with all patients whose tumors do not progress after four cycles of first-line chemotherapy. The use of maintenance therapy may be most reasonable in very symptomatic patients who receive palliative benefit from chemotherapy, or as a means of encouraging noncompliant patients to return for care.

Despite enthusiasm for the use of molecular testing and molecularly targeted agents in patients with advanced non–small cell lung cancer (NSCLC), most patients are not candidates for upfront treatment with molecular agents. Chemotherapy therefore remains the backbone of treatment for this patient population.

This article presents the best available evidence for selection of chemotherapy for patients with advanced NSCLC and examines the controversy surrounding maintenance therapy.

EVOLUTION OF CHEMOTHERAPY IN NSCLC

The first evidence that chemotherapy produced a significant survival benefit in patients with advanced NSCLC came in 1995 when a meta-analysis showed that platinum-based chemotherapy conferred a 2-month improvement in median survival over best supportive care.¹

This finding led to a decade of randomized phase 3 clinical trials that compared different platinum-based regimens. The quintessential trial in this regard was Eastern Cooperative Oncology Group (ECOG) 1594, in which three platinum doublets were compared with cisplatin and paclitaxel on the end point of overall survival (OS) in patients with advanced NSCLC. No significant differences were found among the regimens tested.²

Bevacizumab adds to platinum doublet in nonsquamous NSCLC

With the introduction of bevacizumab, an antibody against vascular endothelial growth factor, knowledge of NSCLC histology became important. In the ECOG 4599 trial, published in 2006, bevacizumab added to platinum doublet chemotherapy in patients with advanced nonsquamous NSCLC significantly improved the response rate, progression-free survival (PFS), and median OS compared with platinum doublet chemotherapy alone.³ This trial was limited to patients with nonsquamous NSCLC because its predecessor trial had revealed an excess of life-threatening pulmonary hemorrhage in association with bevacizumab in patients with squamous cell carcinoma.

Pemetrexed superior to docetaxel in nonsquamous histology

In 2004, Hanna et al⁴ demonstrated pemetrexed to be noninferior to docetaxel on efficacy outcomes as second-line therapy in advanced NSCLC. Pemetrexed had a significantly better toxicity profile, however, which led to its approval for this indication. Post hoc analyses of this trial suggested a differential effect of pemetrexed based on histology. In the pemetrexed arm, patients with nonsquamous histology appeared to have superior survival compared with patients who had squamous histology, whereas in the docetaxel arm, histology did not affect outcome.⁵ Further, the nonsquamous histologic subgroup had superior OS with pemetrexed compared with docetaxel.⁶

Pemetrexed and gemcitabine perform differently based on histology

A phase 3 trial with a noninferiority design compared cisplatin/pemetrexed with cisplatin/gemcitabine as first-line therapy on OS. The noninferiority criteria were met, with no difference in median OS between the two groups (median OS: 10.3 months in both arms).⁷

Based on this evidence, NSCLC is no longer an adequate pathologic diagnosis. Pathologists must differentiate squamous from nonsquamous histology to take full advantage of the safety of angiogenesis inhibitors and the efficacy of pemetrexed.

OPTIMAL FIRST-LINE REGIMEN FOR NONSQUAMOUS NSCLC

Both cisplatin/pemetrexed and carboplatin/paclitaxel plus bevacizumab have level 1 evidence to support their use as first-line treatment of NSCLC with nonsquamous histology. Carboplatin/pemetrexed/bevacizumab is also being used in the community despite the absence of randomized trial evidence to support its use for this indication.

A single-arm phase 2 trial of carboplatin/pemetrexed/bevacizumab followed by maintenance pemetrexed/bevacizumab in 49 patients produced a response rate of 55%, PFS of 7.8 months, and OS of 14 months.¹⁰ Although the results are impressive, they should be considered hypothesis-generating rather than treatment-changing in light of the small number of patients enrolled and the single-arm design.

An open-label randomized phase 3 trial, Point-Break, is comparing two regimens in patients who have advanced nonsquamous NSCLC: (1) carboplatin/pemetrexed/bevacizumab followed by maintenance pemetrexed/bevacizumab and (2) carboplatin/paclitaxel/bevacizumab followed by bevacizumab.¹¹ Although potentially practice-changing, PointBreak will not answer whether bevacizumab adds benefit to cisplatin and pemetrexed, nor will it determine which first-line regimen is superior because of the different maintenance regimens.

SQUAMOUS NSCLC: PLATINUM DOUBLET OPTIMAL

No agents are currently approved specifically for the treatment of squamous cell carcinoma, which appears to have a high level of expression of insulin-like growth factor receptor (IGF-1R). A 64% response rate observed with an IGF-1R antagonist added to paclitaxel/carboplatin in patients with NSCLC of squamous cell histology in a phase 2 trial led to the design of a phase 3 trial in which patients were randomized to carboplatin/paclitaxel with or without the IGF-1R antagonist figitumumab. The trial ended prematurely in 2009 because of an imbalance of deaths in the experimental arm.¹² As expected, hyperglycemia was more common in the experimental arm. Unexpectedly, the incidences of grade 5 infections and cardiovascular events were also significantly higher in the experimental arm.

A randomized phase 3 trial of carboplatin/paclitaxel compared with carboplatin and nanoparticle albumin-bound (nab) paclitaxel was conducted in 1,052 patients with stage IIIb/IV NSCLC with the primary end point being overall response rate (ORR).¹³ The rationale for substituting nab-paclitaxel for paclitaxel was that paclitaxel is dissolved in polyoxyethylated castor oil. This decreases the efficacy of paclitaxel and contributes to its toxicities, including hypersensitivity reactions and neuropathy. In metastatic breast cancer, nab-paclitaxel was shown to be more efficacious than solvent-based paclitaxel.¹⁴

The nab-paclitaxel trial met its primary end point of superior response rate: 33% in the nab-paclitaxel arm versus 25% in the standard paclitaxel arm. However, on final analysis there was no difference in PFS or OS between the two arms, making the difference in ORR of little clinical significance. No hypersensitivity reactions occurred in the nab-paclitaxel arm, while three occurred in the paclitaxel arm. Grade 3 sensory neuropathy occurred significantly less often in the group assigned to nab-paclitaxel compared with paclitaxel (3 vs 10, respectively; P < .001). Although there appears to be no efficacy advantage of nab-paclitaxel over standard paclitaxel for advanced NSCLC patients, use of nab-paclitaxel might be considered in patients with stage IV NSCLC who have poorly controlled diabetes or who already suffer significant neuropathy.

Although not a prespecified end point, the response rate in patients with squamous cell histology nearly doubled among those treated with nab-paclitaxel compared with standard paclitaxel. However, this did not translate into significant differences in PFS or OS in this subgroup, and the use of nab-paclitaxel in this patient population specifically is not advised.

In light of the data, the standard treatment for squamous NSCLC remains a platinum doublet other than pemetrexed. A phase 3 clinical trial, ECLIPSE, is currently enrolling patients at the Cleveland Clinic. The trial will randomize chemotherapy-naïve patients with stage IIIb/IV NSCLC and a Karnofsky performance status of 0 or 1 to receive carboplatin and gemcitabine with or without the polyadenosine diphosphate–ribose polymerase inhibitor iniparib.

MAINTENANCE THERAPY

The utility of maintenance therapy—the uninterrupted continuation of therapy for patients who do not progress after completing first-line chemotherapy—in patients with advanced NSCLC is controversial. Two kinds of maintenance therapy have emerged.

Switch maintenance, also known as early second-line therapy, is so termed because patients are immediately switched to a second-line agent different from the first-line doublet therapy.

Continuation maintenance is the continuation of one or more drugs from the induction regimen, the best example being continuation of single-agent evacizumab in the ECOG 4599 regimen.

Five major trials of successful maintenance therapy for nonprogressors after first-line chemotherapy have been presented over the past 4 years, and these have led to new indications for the maintenance drugs.^8,15–18 PFS in favor of active maintenance has been documented in trials of early versus delayed maintenance docetaxel,¹⁵ pemetrexed versus placebo,⁸ erlotinib versus placebo,¹⁶ bevacizumab/erlotinib versus bevacizumab/placebo (ATLAS trial),¹⁷ and gemcitabine or erlotinib versus placebo (IFCT-GFPC 0502).¹⁸ The magnitude of improved PFS associated with each treatment has been similar. As a result, improved of PFS with maintenance therapy is now widely accepted.

To improve survival: maintenance therapy or better second-line therapy?

The utility of maintenance therapy can be confounded by the lack of a predefined second-line treatment. Some argue that the benefit to maintenance may also be realized by appropriate use of the same agent as salvage therapy in the case of disease progression.

Overall survival improved with maintenance therapy in only two trials; one compared pemetrexed with placebo and the other compared erlotinib with placebo.^8,16 The validity of these findings, however, remains in question. In the trial of pemetrexed, only 19% of the patients in the control arm ever received pemetrexed, and in the erlotinib trial, only 21% of the patients in the control arm ever received erlotinib after progression. Whether maintenance therapy was responsible for an improvement in OS or whether ineffective second-line therapy dampened survival in patients in the control arms is unknown.

In the IFCT-GFPC 0502 phase 3 study, patients received four cycles of cisplatin/gemcitabine.¹⁹ If patients did not progress, they were randomized to observation, continuation maintenance with gemcitabine, or switch maintenance to erlotinib. Predefined second-line therapy in all arms was pemetrexed. The primary end point chosen was PFS, even though maintenance therapy had already been established to extend PFS. The median PFS in the gemcitabine maintenance arm was 3.8 months, compared with 1.9 months in the observation arm. The hazard ratio (HR) of 0.55 (P < .0001) was similar to that observed with pemetrexed in the maintenance trial noted above.¹⁹ Subgroup analysis showed improvement in PFS with the gemcitabine maintenance group compared with observation in all subgroups, including those based on histology. The HR in the erlotinib maintenance arm was 0.82 (P = .002), similar to that observed with erlotinib in the Sequential Tarceva in Unresectable NSCLC (SATURN) trial.¹⁶

In the IFCT-GFPC 0502 study, 60.4% of patients in the gemcitabine arm, 63.2 % of those in the erlotinib arm, and 76.1% in the observation arm received postmaintenance treatment with pemetrexed.¹⁹ Nearly one-half (49.6%) of patients in the observation arm received third-line treatment with erlotinib.

In the overall study population, a trend toward improved OS was observed with maintenance gemcitabine or erlotinib compared with observation, but did not achieve statistical significance, possibly because the trial lacked adequate power to detect a difference on this end point.

A subgroup analysis of patients who received second-line pemetrexed showed a significant improvement in OS in the maintenance arms compared with the observation arm. About 25% of the patients never advanced to second-line pemetrexed. Because patients who never received second-line pemetrexed may represent the sickest patients, the relevance of this finding to the overall population of patients with stage IV NSCLC is unknown.

Ongoing maintenance trials

Two ongoing clinical trials of maintenance are exploring bevacizumab with or without pemetrexed as maintenance following first-line cisplatin/pemetrexed/bevacizumab (AVAPERL) and bevacizumab alone, pemetrexed alone, or a combination of the two as maintenance following first-line therapy with carboplatin/paclitaxel/bevacizumab (Eastern Cooperative Oncology Group). Preliminary results from the AVAPERL study were reported recently and support the use of pemetrexed and bevacizumab as maintenance therapy compared with bevacizumab alone.²⁰

CONCLUSIONS ABOUT MAINTENANCE THERAPY

Pemetrexed and erlotinib significantly prolong OS survival compared with placebo when used as maintenance therapy in advanced NSCLC patients who do not progress after four cycles of first-line chemotherapy. Whether this improvement in OS can be attributed to maintenance therapy or more effective second-line therapy is open to debate.

Maintenance chemotherapy should be discussed with all patients whose tumors do not progress after four cycles of first-line chemotherapy. The use of maintenance therapy may be most reasonable in very symptomatic patients who receive palliative benefit from chemotherapy, or as a means of encouraging noncompliant patients to return for care.

Despite enthusiasm for the use of molecular testing and molecularly targeted agents in patients with advanced non–small cell lung cancer (NSCLC), most patients are not candidates for upfront treatment with molecular agents. Chemotherapy therefore remains the backbone of treatment for this patient population.

This article presents the best available evidence for selection of chemotherapy for patients with advanced NSCLC and examines the controversy surrounding maintenance therapy.

EVOLUTION OF CHEMOTHERAPY IN NSCLC

The first evidence that chemotherapy produced a significant survival benefit in patients with advanced NSCLC came in 1995 when a meta-analysis showed that platinum-based chemotherapy conferred a 2-month improvement in median survival over best supportive care.¹

This finding led to a decade of randomized phase 3 clinical trials that compared different platinum-based regimens. The quintessential trial in this regard was Eastern Cooperative Oncology Group (ECOG) 1594, in which three platinum doublets were compared with cisplatin and paclitaxel on the end point of overall survival (OS) in patients with advanced NSCLC. No significant differences were found among the regimens tested.²

Bevacizumab adds to platinum doublet in nonsquamous NSCLC

With the introduction of bevacizumab, an antibody against vascular endothelial growth factor, knowledge of NSCLC histology became important. In the ECOG 4599 trial, published in 2006, bevacizumab added to platinum doublet chemotherapy in patients with advanced nonsquamous NSCLC significantly improved the response rate, progression-free survival (PFS), and median OS compared with platinum doublet chemotherapy alone.³ This trial was limited to patients with nonsquamous NSCLC because its predecessor trial had revealed an excess of life-threatening pulmonary hemorrhage in association with bevacizumab in patients with squamous cell carcinoma.

Pemetrexed superior to docetaxel in nonsquamous histology

In 2004, Hanna et al⁴ demonstrated pemetrexed to be noninferior to docetaxel on efficacy outcomes as second-line therapy in advanced NSCLC. Pemetrexed had a significantly better toxicity profile, however, which led to its approval for this indication. Post hoc analyses of this trial suggested a differential effect of pemetrexed based on histology. In the pemetrexed arm, patients with nonsquamous histology appeared to have superior survival compared with patients who had squamous histology, whereas in the docetaxel arm, histology did not affect outcome.⁵ Further, the nonsquamous histologic subgroup had superior OS with pemetrexed compared with docetaxel.⁶

Pemetrexed and gemcitabine perform differently based on histology

A phase 3 trial with a noninferiority design compared cisplatin/pemetrexed with cisplatin/gemcitabine as first-line therapy on OS. The noninferiority criteria were met, with no difference in median OS between the two groups (median OS: 10.3 months in both arms).⁷

Based on this evidence, NSCLC is no longer an adequate pathologic diagnosis. Pathologists must differentiate squamous from nonsquamous histology to take full advantage of the safety of angiogenesis inhibitors and the efficacy of pemetrexed.

OPTIMAL FIRST-LINE REGIMEN FOR NONSQUAMOUS NSCLC

Both cisplatin/pemetrexed and carboplatin/paclitaxel plus bevacizumab have level 1 evidence to support their use as first-line treatment of NSCLC with nonsquamous histology. Carboplatin/pemetrexed/bevacizumab is also being used in the community despite the absence of randomized trial evidence to support its use for this indication.

A single-arm phase 2 trial of carboplatin/pemetrexed/bevacizumab followed by maintenance pemetrexed/bevacizumab in 49 patients produced a response rate of 55%, PFS of 7.8 months, and OS of 14 months.¹⁰ Although the results are impressive, they should be considered hypothesis-generating rather than treatment-changing in light of the small number of patients enrolled and the single-arm design.

An open-label randomized phase 3 trial, Point-Break, is comparing two regimens in patients who have advanced nonsquamous NSCLC: (1) carboplatin/pemetrexed/bevacizumab followed by maintenance pemetrexed/bevacizumab and (2) carboplatin/paclitaxel/bevacizumab followed by bevacizumab.¹¹ Although potentially practice-changing, PointBreak will not answer whether bevacizumab adds benefit to cisplatin and pemetrexed, nor will it determine which first-line regimen is superior because of the different maintenance regimens.

SQUAMOUS NSCLC: PLATINUM DOUBLET OPTIMAL

No agents are currently approved specifically for the treatment of squamous cell carcinoma, which appears to have a high level of expression of insulin-like growth factor receptor (IGF-1R). A 64% response rate observed with an IGF-1R antagonist added to paclitaxel/carboplatin in patients with NSCLC of squamous cell histology in a phase 2 trial led to the design of a phase 3 trial in which patients were randomized to carboplatin/paclitaxel with or without the IGF-1R antagonist figitumumab. The trial ended prematurely in 2009 because of an imbalance of deaths in the experimental arm.¹² As expected, hyperglycemia was more common in the experimental arm. Unexpectedly, the incidences of grade 5 infections and cardiovascular events were also significantly higher in the experimental arm.

A randomized phase 3 trial of carboplatin/paclitaxel compared with carboplatin and nanoparticle albumin-bound (nab) paclitaxel was conducted in 1,052 patients with stage IIIb/IV NSCLC with the primary end point being overall response rate (ORR).¹³ The rationale for substituting nab-paclitaxel for paclitaxel was that paclitaxel is dissolved in polyoxyethylated castor oil. This decreases the efficacy of paclitaxel and contributes to its toxicities, including hypersensitivity reactions and neuropathy. In metastatic breast cancer, nab-paclitaxel was shown to be more efficacious than solvent-based paclitaxel.¹⁴

The nab-paclitaxel trial met its primary end point of superior response rate: 33% in the nab-paclitaxel arm versus 25% in the standard paclitaxel arm. However, on final analysis there was no difference in PFS or OS between the two arms, making the difference in ORR of little clinical significance. No hypersensitivity reactions occurred in the nab-paclitaxel arm, while three occurred in the paclitaxel arm. Grade 3 sensory neuropathy occurred significantly less often in the group assigned to nab-paclitaxel compared with paclitaxel (3 vs 10, respectively; P < .001). Although there appears to be no efficacy advantage of nab-paclitaxel over standard paclitaxel for advanced NSCLC patients, use of nab-paclitaxel might be considered in patients with stage IV NSCLC who have poorly controlled diabetes or who already suffer significant neuropathy.

Although not a prespecified end point, the response rate in patients with squamous cell histology nearly doubled among those treated with nab-paclitaxel compared with standard paclitaxel. However, this did not translate into significant differences in PFS or OS in this subgroup, and the use of nab-paclitaxel in this patient population specifically is not advised.

In light of the data, the standard treatment for squamous NSCLC remains a platinum doublet other than pemetrexed. A phase 3 clinical trial, ECLIPSE, is currently enrolling patients at the Cleveland Clinic. The trial will randomize chemotherapy-naïve patients with stage IIIb/IV NSCLC and a Karnofsky performance status of 0 or 1 to receive carboplatin and gemcitabine with or without the polyadenosine diphosphate–ribose polymerase inhibitor iniparib.

MAINTENANCE THERAPY

The utility of maintenance therapy—the uninterrupted continuation of therapy for patients who do not progress after completing first-line chemotherapy—in patients with advanced NSCLC is controversial. Two kinds of maintenance therapy have emerged.

Switch maintenance, also known as early second-line therapy, is so termed because patients are immediately switched to a second-line agent different from the first-line doublet therapy.

Continuation maintenance is the continuation of one or more drugs from the induction regimen, the best example being continuation of single-agent evacizumab in the ECOG 4599 regimen.

Five major trials of successful maintenance therapy for nonprogressors after first-line chemotherapy have been presented over the past 4 years, and these have led to new indications for the maintenance drugs.^8,15–18 PFS in favor of active maintenance has been documented in trials of early versus delayed maintenance docetaxel,¹⁵ pemetrexed versus placebo,⁸ erlotinib versus placebo,¹⁶ bevacizumab/erlotinib versus bevacizumab/placebo (ATLAS trial),¹⁷ and gemcitabine or erlotinib versus placebo (IFCT-GFPC 0502).¹⁸ The magnitude of improved PFS associated with each treatment has been similar. As a result, improved of PFS with maintenance therapy is now widely accepted.

To improve survival: maintenance therapy or better second-line therapy?

The utility of maintenance therapy can be confounded by the lack of a predefined second-line treatment. Some argue that the benefit to maintenance may also be realized by appropriate use of the same agent as salvage therapy in the case of disease progression.

Overall survival improved with maintenance therapy in only two trials; one compared pemetrexed with placebo and the other compared erlotinib with placebo.^8,16 The validity of these findings, however, remains in question. In the trial of pemetrexed, only 19% of the patients in the control arm ever received pemetrexed, and in the erlotinib trial, only 21% of the patients in the control arm ever received erlotinib after progression. Whether maintenance therapy was responsible for an improvement in OS or whether ineffective second-line therapy dampened survival in patients in the control arms is unknown.

In the IFCT-GFPC 0502 phase 3 study, patients received four cycles of cisplatin/gemcitabine.¹⁹ If patients did not progress, they were randomized to observation, continuation maintenance with gemcitabine, or switch maintenance to erlotinib. Predefined second-line therapy in all arms was pemetrexed. The primary end point chosen was PFS, even though maintenance therapy had already been established to extend PFS. The median PFS in the gemcitabine maintenance arm was 3.8 months, compared with 1.9 months in the observation arm. The hazard ratio (HR) of 0.55 (P < .0001) was similar to that observed with pemetrexed in the maintenance trial noted above.¹⁹ Subgroup analysis showed improvement in PFS with the gemcitabine maintenance group compared with observation in all subgroups, including those based on histology. The HR in the erlotinib maintenance arm was 0.82 (P = .002), similar to that observed with erlotinib in the Sequential Tarceva in Unresectable NSCLC (SATURN) trial.¹⁶

In the IFCT-GFPC 0502 study, 60.4% of patients in the gemcitabine arm, 63.2 % of those in the erlotinib arm, and 76.1% in the observation arm received postmaintenance treatment with pemetrexed.¹⁹ Nearly one-half (49.6%) of patients in the observation arm received third-line treatment with erlotinib.

In the overall study population, a trend toward improved OS was observed with maintenance gemcitabine or erlotinib compared with observation, but did not achieve statistical significance, possibly because the trial lacked adequate power to detect a difference on this end point.

A subgroup analysis of patients who received second-line pemetrexed showed a significant improvement in OS in the maintenance arms compared with the observation arm. About 25% of the patients never advanced to second-line pemetrexed. Because patients who never received second-line pemetrexed may represent the sickest patients, the relevance of this finding to the overall population of patients with stage IV NSCLC is unknown.

Ongoing maintenance trials

Two ongoing clinical trials of maintenance are exploring bevacizumab with or without pemetrexed as maintenance following first-line cisplatin/pemetrexed/bevacizumab (AVAPERL) and bevacizumab alone, pemetrexed alone, or a combination of the two as maintenance following first-line therapy with carboplatin/paclitaxel/bevacizumab (Eastern Cooperative Oncology Group). Preliminary results from the AVAPERL study were reported recently and support the use of pemetrexed and bevacizumab as maintenance therapy compared with bevacizumab alone.²⁰

CONCLUSIONS ABOUT MAINTENANCE THERAPY

Pemetrexed and erlotinib significantly prolong OS survival compared with placebo when used as maintenance therapy in advanced NSCLC patients who do not progress after four cycles of first-line chemotherapy. Whether this improvement in OS can be attributed to maintenance therapy or more effective second-line therapy is open to debate.

Maintenance chemotherapy should be discussed with all patients whose tumors do not progress after four cycles of first-line chemotherapy. The use of maintenance therapy may be most reasonable in very symptomatic patients who receive palliative benefit from chemotherapy, or as a means of encouraging noncompliant patients to return for care.

Several important developments in the palliative care of patients with lung cancer have occurred over the past few years, including publication of a landmark study comparing early with as-needed palliative care, the release of new data on the treatment of cancer-related anorexia, elucidation of new mechanisms and treatment options for dyspnea, and the availability of buprenorphine. This article reviews these emerging concepts.

LUNG CANCER SYMPTOMS: COMMON AND SEVERE

The symptom burden of lung cancer is usually great. At least 80% of patients experience fatigue, 65% suffer loss of appetite, 77% have cough, 73% report dyspnea (both from local symptoms and weight loss), 57% have chest pain, and 17% have hemoptysis.¹

When symptoms are present, they are usually severe. Thirty-eight percent of the patients who report fatigue have severe fatigue, 47% have inadequate appetite to the point of requiring intervention, and more than one-half of patients who have chest pain require opioids for relief.¹

Symptom frequency and severity are worse in individuals who survive 3 months or less.¹ Increasing symptom burden is therefore prognostically important, particularly in patients with advanced stages of lung cancer. As a result, self-assessment of quality of life has a significant ability to predict survival in patients with advanced non–small cell lung cancer (NSCLC).²

Patients with lung cancer tend to suffer from groups of symptoms or symptom clusters. Lutz et al¹ found that 79% of patients reported three or more symptoms; these results were similar to the findings of a study by Hollen et al,³ in which 81% of patients suffered from three or more symptoms, all them severe except for cough.

EARLY PALLIATIVE CARE HAS CLINICAL BENEFITS

A landmark study by Temel et al⁴ examined the benefits of early palliative care integrated with standard oncologic care versus standard oncologic care and palliative care only “as needed” on patient-reported outcomes, the use of health services, and the quality of end-of-life care among patients with metastatic NSCLC. The study was a prospective, nonblinded, randomized, controlled trial of outpatients conducted at a single center. The intervention was based on guidelines from the National Consensus Project for Quality Palliative Care, with specific attention to symptom management, goals of care, decision-making regarding treatment, and coordination of care. Patients assigned to the intervention met monthly with both a palliative care service and an oncologist, and 90% of the patients randomized to intervention complied with at least 50% of the visits.

Measures of health-related quality of life and mood were obtained using the Functional Assessment of Cancer Therapy-Lung (FACT-L), the Hospital Anxiety and Depression Scale, and the 9-item depression scale of the Patient Health Questionnaire.

Measures of health care service utilization included use of antitumor therapy within 14 days of death, late or no referral to hospice, hospital admissions, and emergency room visits. Patients were considered to have received aggressive care if they met any one of the following three criteria: chemotherapy within 14 days of death, no hospice care, or admission to hospice within 3 days of death.

Compared with standard care, early palliative care was associated with an increase in the number of advance directives, earlier hospice referral (11 days vs 4 days), fewer hospitalizations and emergency room visits, and fewer instances of inappropriate oncologic care (defined as chemotherapy within 14 days of death). The percentage of patients with depressed mood was also lower among those assigned to early palliative care versus standard care (16% vs 38%).

A 2.7-month difference in median survival (P = .02) in favor of the group assigned to early palliative care was also observed, although survival was not a primary end point of the trial. This outcome needs to be validated in future studies.

CANCER-RELATED ANOREXIA AND CACHEXIA: TREATMENT IMPROVES APPETITE

The main hallmark of cancer-related anorexia and cachexia is weight loss; this symptom cluster is most often associated with hypophagia. The coexistence of anorexia and appetite-related anhedonia is common in lung cancer patients, such that 25% of lung cancer patients with anorexia report no distress with not eating, nor do they derive pleasure from eating. Others report that early satiety and changes in taste dramatically affect appetite. To some, anorexia is a distressful reminder of progression of their cancer.

Megestrol acetate and medroxyprogesterone acetate at least partially improve appetite in a subset of anorectic cancer patients. The use of medroxyprogesterone acetate has resulted in weight gain but not muscle mass in some patients with cancer-related anorexia, but has had less effect on fatigue and quality of life in these patients.

Olanzapine is an atypical antipsychotic with an affinity for multiple neurotransmitter receptors. Several of these, such as the serotonin receptors 5-HT₂ and 5-HT₃, histamine receptors, and dopamine receptors, are implicated in anorexia, nausea, and vomiting. Case reports suggest that olanzapine has antiemetic activity in patients with advanced cancer and usefulness as prophylaxis against chemotherapy-related nausea and vomiting.⁵ Reduced risk of extrapyramidal symptoms compared with standard antiemetics enhances the value of olanzapine for prevention of cancer-related anorexia.

Navari et al⁶ conducted a randomized trial to determine the effectiveness of megestrol acetate and olanzapine for the treatment of cancer-related anorexia. Eighty patients were randomized to receive oral megestrol acetate 800 mg/d, or oral megestrol acetate 800 mg/d plus olanzapine 5 mg once nightly, for 8 weeks. Patients were removed from the study if they did not take the study medication for a 48-hour period or if intolerable toxicity developed that was attributable to the study agents.

The MD Anderson Symptom Inventory (MDASI) was completed weekly to assess key symptom outcome variables. A change of 3 cm on the visual analog scale over two separate time periods for a symptom was considered sufficient to define a change in the symptom.

Quality of life was measured using a valid 28-item self-reported instrument (Functional Assessment of Cancer Therapy-General). Patients were examined by their physicians every 2 weeks.

In the group assigned to megestrol acetate, 15 patients had a weight gain of at least 5%—a change that was considered significant. Appetite improved in two patients, nausea decreased in three patients, and quality of life improved in five patients at both 4 weeks and 8 weeks. The improvements in appetite, nausea, and quality of life for the whole group on megestrol acetate alone were not significant, and there was no improvement in mean symptom scores measured by the MDASI.

There were incremental improvements of all measures in patients randomized to megestrol acetate plus olanzapine. Among patients receiving the combination, 33 had a weight gain of at least 5%; 25 reported an improvement in appetite, 21 experienced a reduction in nausea, and 23 had an improvement in quality of life at both 4 weeks and 8 weeks. All outcome variables were improved on the MDASI

CANCER AND DYSPNEA: NUMEROUS INTERVENTIONS HAVE BEEN ASSESSED

Reduced inspiratory capacity caused by weakened inspiratory muscles results in an increased Borg rating of perceived exertion (RPE) relative to oxygen levels. Both central nervous system activation of muscle and loss of muscle tissue contribute to dyspnea and fatigue in lung cancer patients.⁷ Cancer fatigue, also measured by the Borg RPE scale, appears to be a “central” mechanism that stems from a mismatch between efferent output for afferent inputs in the setting of ventilatory muscle weakness, thereby increasing the perception of dyspnea. Several interventions have been used to relieve dyspnea, ranging from oxygen therapy to treatment with opioids.

Oxygen saturation

The association between hypoxemia and dyspnea is poor.⁸ In a randomized prospective trial, Abernethy et al⁹ found no benefit to oxygen therapy compared with medical air without added supplemental oxygen in individuals who had normal oxygen saturation but symptomatic dyspnea.

Bilevel positive airway pressure

Bilevel positive airway pressure has been shown to reduce the need for invasive ventilation; improve oxygen saturation; and reduce dynamic hyperinflation, thus relieving dyspnea.¹⁰ It has been effective in dyspneic patients with motor neuron disease, cancer, heart failure, status asthmaticus, stroke, drug overdose, and interstitial lung disease.

Indwelling pleural catheters

Tunneled pleural catheters reduce the severity of dyspnea in 95% of patients.¹¹ These catheters are inserted on an outpatient basis, allowing for outpatient drainage. Autopleurodesis occurs in about 45% of patients, in which case the catheter can be removed. Adverse reactions are few (incidence < 10%), but consist of empyema, pneumothorax, cellulitis, or catheter obstruction. The disadvantage is the expense of catheter maintenance.

Nebulized furosemide

Case reports suggest that inhalation of nebulized furosemide, 20 mg four times daily, dramatically improves dyspnea in patients with advanced cancer and severe shortness of breath that is unresponsive to opioids.¹² Nebulized furosemide appears to have a direct effect on either pulmonary stretch receptors or irritant receptors in the airways; it also has a diuretic effect. Response occurs quickly with an onset of effect in 20 to 30 minutes.

B-type natriuretic peptide

The level of N-terminal precursor of B-type natriuretic peptide (NT-pro-BNP) can predict response to sunitinib in renal cancer,¹³ and the BNP level predicts 30-day mortality in pulmonary embolism.¹⁴ Measurement of BNP to detect dyspnea in patients with lung cancer is not useful, however, because the BNP level increases with cardiac and pericardial metastases. The BNP level is also persistently elevated after chest radiation therapy, and it increases with anthracycline cardiotoxicity. It is not a useful marker for distinguishing pulmonary from nonpulmonary or cardiac from noncardiac causes of dyspnea.

Lung ultrasound

Portable diagnostic lung ultrasound can be used to detect pneumonia, pleural effusions, pulmonary emboli, pneumothorax, atelectasis, and lung abscesses as potential causes of dyspnea.^15–18 In addition to the advantage of portability, there is no radiation exposure and the technology permits echocardiography to be conducted.

Opioids

Evidence supports opioids for pharmacologic relief of dyspnea in the palliative care of patients with chronic obstructive pulmonary disease and cancer. Studies have been conducted with morphine sulfate, hydromorphone, dihydrocodeine, intranasal and transmucosal fentanyl, oxycodone, and diamorphine.^19–21

The response to opioids is unrelated to the severity of dyspnea.²² Responses and safe administration occur even in patients with reduced oxygen saturation or elevated carbon dioxide partial pressure.²⁰ Opioids can be used safely in the opioid-naïve population.²⁰ Recommended dosages in these patients are 2.5 to 5.0 mg of morphine sulfate every 4 hours, 5 mg of oxycodone every 4 hours as needed, and 1 mg of hydromorphone every 4 hours in the opioid-naïve. In opioid-tolerant patients, it is recommended that therapy start with these doses and then be increased in 25% increments every 24 hours, as needed.

BUPRENORPHINE: UNIQUE OPIOID

Buprenorphine is a mu- and nociceptin (ORL-1)-receptor partial agonist with intravenous, subcutaneous, sublingual, transdermal, and intranasal routes of delivery.²³ An agent that acts as an ORL-1 agonist can induce analgesia by blocking nociceptive responses at the level of the spinal cord. It is a kappa antagonist (depending upon the kappa ligand used in the assay), which may contribute to its antihyperalgesia. The parent drug has a high affinity and low intrinsic efficacy for the mu receptor. The main metabolite, norbuprenorphine, is a delta opioid-receptor agonist.

Secondary hyperalgesia is an increased sensitivity to painful stimuli around an area of injury and occurs frequently following injury. The increased pain sensation is a result of central sensitization derived from brainstem neurons that facilitate pain; it is not derived from afferent signals from the primary site. Secondary hyperalgesia is less responsive to opioids than primary hyperalgesia at the site of injury.

This figure has been reproduced with permission of the International Association for the Study of Pain® (IASP®) (Koppert W, et al. Different profiles of buprenorphine-induced analgesia and antihyperalgesia in a human pain model. Pain 2005; 118:15–22).

Pain is improved with buprenorphine predominantly through modulation of central sensitization and less so at the primary site. Koppert et al²⁵ demonstrated in human volunteers that buprenorphine reduced the area and duration of secondary hyperalgesia more than pain at the site of injury (half-life of 171 minutes vs 288 minutes, respectively). Buprenorphine had a much greater antihyperalgesic effect than analgesic effect compared with potent opioids such as fentanyl. In contrast, the analgesic effects with fentanyl and alfentanil were much greater than their antihyperalgesic effects (Figure), suggesting the possibility of a combination of opioid therapy for superior pain relief or choices based on pain phenotype (eg, secondary or primary hyperalgesia).

SUMMARY

Early palliative care improves quality of life and decision-making in patients with advanced lung cancer and may improve survival, although survival data need to be confirmed. Olanzapine and megestrol acetate are superior to megestrol acetate alone for the treatment of anorexia. Oxygen is no better than medical air in the management of dyspnea associated with normal oxygen saturation. Buprenorphine is a unique opioid that has value for pharmacologic relief in patients at risk for respiratory depression.

Several important developments in the palliative care of patients with lung cancer have occurred over the past few years, including publication of a landmark study comparing early with as-needed palliative care, the release of new data on the treatment of cancer-related anorexia, elucidation of new mechanisms and treatment options for dyspnea, and the availability of buprenorphine. This article reviews these emerging concepts.

LUNG CANCER SYMPTOMS: COMMON AND SEVERE

The symptom burden of lung cancer is usually great. At least 80% of patients experience fatigue, 65% suffer loss of appetite, 77% have cough, 73% report dyspnea (both from local symptoms and weight loss), 57% have chest pain, and 17% have hemoptysis.¹

When symptoms are present, they are usually severe. Thirty-eight percent of the patients who report fatigue have severe fatigue, 47% have inadequate appetite to the point of requiring intervention, and more than one-half of patients who have chest pain require opioids for relief.¹

Symptom frequency and severity are worse in individuals who survive 3 months or less.¹ Increasing symptom burden is therefore prognostically important, particularly in patients with advanced stages of lung cancer. As a result, self-assessment of quality of life has a significant ability to predict survival in patients with advanced non–small cell lung cancer (NSCLC).²

Patients with lung cancer tend to suffer from groups of symptoms or symptom clusters. Lutz et al¹ found that 79% of patients reported three or more symptoms; these results were similar to the findings of a study by Hollen et al,³ in which 81% of patients suffered from three or more symptoms, all them severe except for cough.

EARLY PALLIATIVE CARE HAS CLINICAL BENEFITS

A landmark study by Temel et al⁴ examined the benefits of early palliative care integrated with standard oncologic care versus standard oncologic care and palliative care only “as needed” on patient-reported outcomes, the use of health services, and the quality of end-of-life care among patients with metastatic NSCLC. The study was a prospective, nonblinded, randomized, controlled trial of outpatients conducted at a single center. The intervention was based on guidelines from the National Consensus Project for Quality Palliative Care, with specific attention to symptom management, goals of care, decision-making regarding treatment, and coordination of care. Patients assigned to the intervention met monthly with both a palliative care service and an oncologist, and 90% of the patients randomized to intervention complied with at least 50% of the visits.

Measures of health-related quality of life and mood were obtained using the Functional Assessment of Cancer Therapy-Lung (FACT-L), the Hospital Anxiety and Depression Scale, and the 9-item depression scale of the Patient Health Questionnaire.

Measures of health care service utilization included use of antitumor therapy within 14 days of death, late or no referral to hospice, hospital admissions, and emergency room visits. Patients were considered to have received aggressive care if they met any one of the following three criteria: chemotherapy within 14 days of death, no hospice care, or admission to hospice within 3 days of death.

Compared with standard care, early palliative care was associated with an increase in the number of advance directives, earlier hospice referral (11 days vs 4 days), fewer hospitalizations and emergency room visits, and fewer instances of inappropriate oncologic care (defined as chemotherapy within 14 days of death). The percentage of patients with depressed mood was also lower among those assigned to early palliative care versus standard care (16% vs 38%).

A 2.7-month difference in median survival (P = .02) in favor of the group assigned to early palliative care was also observed, although survival was not a primary end point of the trial. This outcome needs to be validated in future studies.

CANCER-RELATED ANOREXIA AND CACHEXIA: TREATMENT IMPROVES APPETITE

The main hallmark of cancer-related anorexia and cachexia is weight loss; this symptom cluster is most often associated with hypophagia. The coexistence of anorexia and appetite-related anhedonia is common in lung cancer patients, such that 25% of lung cancer patients with anorexia report no distress with not eating, nor do they derive pleasure from eating. Others report that early satiety and changes in taste dramatically affect appetite. To some, anorexia is a distressful reminder of progression of their cancer.

Megestrol acetate and medroxyprogesterone acetate at least partially improve appetite in a subset of anorectic cancer patients. The use of medroxyprogesterone acetate has resulted in weight gain but not muscle mass in some patients with cancer-related anorexia, but has had less effect on fatigue and quality of life in these patients.

Olanzapine is an atypical antipsychotic with an affinity for multiple neurotransmitter receptors. Several of these, such as the serotonin receptors 5-HT₂ and 5-HT₃, histamine receptors, and dopamine receptors, are implicated in anorexia, nausea, and vomiting. Case reports suggest that olanzapine has antiemetic activity in patients with advanced cancer and usefulness as prophylaxis against chemotherapy-related nausea and vomiting.⁵ Reduced risk of extrapyramidal symptoms compared with standard antiemetics enhances the value of olanzapine for prevention of cancer-related anorexia.

Navari et al⁶ conducted a randomized trial to determine the effectiveness of megestrol acetate and olanzapine for the treatment of cancer-related anorexia. Eighty patients were randomized to receive oral megestrol acetate 800 mg/d, or oral megestrol acetate 800 mg/d plus olanzapine 5 mg once nightly, for 8 weeks. Patients were removed from the study if they did not take the study medication for a 48-hour period or if intolerable toxicity developed that was attributable to the study agents.

The MD Anderson Symptom Inventory (MDASI) was completed weekly to assess key symptom outcome variables. A change of 3 cm on the visual analog scale over two separate time periods for a symptom was considered sufficient to define a change in the symptom.

Quality of life was measured using a valid 28-item self-reported instrument (Functional Assessment of Cancer Therapy-General). Patients were examined by their physicians every 2 weeks.

In the group assigned to megestrol acetate, 15 patients had a weight gain of at least 5%—a change that was considered significant. Appetite improved in two patients, nausea decreased in three patients, and quality of life improved in five patients at both 4 weeks and 8 weeks. The improvements in appetite, nausea, and quality of life for the whole group on megestrol acetate alone were not significant, and there was no improvement in mean symptom scores measured by the MDASI.

There were incremental improvements of all measures in patients randomized to megestrol acetate plus olanzapine. Among patients receiving the combination, 33 had a weight gain of at least 5%; 25 reported an improvement in appetite, 21 experienced a reduction in nausea, and 23 had an improvement in quality of life at both 4 weeks and 8 weeks. All outcome variables were improved on the MDASI

CANCER AND DYSPNEA: NUMEROUS INTERVENTIONS HAVE BEEN ASSESSED

Reduced inspiratory capacity caused by weakened inspiratory muscles results in an increased Borg rating of perceived exertion (RPE) relative to oxygen levels. Both central nervous system activation of muscle and loss of muscle tissue contribute to dyspnea and fatigue in lung cancer patients.⁷ Cancer fatigue, also measured by the Borg RPE scale, appears to be a “central” mechanism that stems from a mismatch between efferent output for afferent inputs in the setting of ventilatory muscle weakness, thereby increasing the perception of dyspnea. Several interventions have been used to relieve dyspnea, ranging from oxygen therapy to treatment with opioids.

Oxygen saturation

The association between hypoxemia and dyspnea is poor.⁸ In a randomized prospective trial, Abernethy et al⁹ found no benefit to oxygen therapy compared with medical air without added supplemental oxygen in individuals who had normal oxygen saturation but symptomatic dyspnea.

Bilevel positive airway pressure

Bilevel positive airway pressure has been shown to reduce the need for invasive ventilation; improve oxygen saturation; and reduce dynamic hyperinflation, thus relieving dyspnea.¹⁰ It has been effective in dyspneic patients with motor neuron disease, cancer, heart failure, status asthmaticus, stroke, drug overdose, and interstitial lung disease.

Indwelling pleural catheters

Tunneled pleural catheters reduce the severity of dyspnea in 95% of patients.¹¹ These catheters are inserted on an outpatient basis, allowing for outpatient drainage. Autopleurodesis occurs in about 45% of patients, in which case the catheter can be removed. Adverse reactions are few (incidence < 10%), but consist of empyema, pneumothorax, cellulitis, or catheter obstruction. The disadvantage is the expense of catheter maintenance.

Nebulized furosemide

Case reports suggest that inhalation of nebulized furosemide, 20 mg four times daily, dramatically improves dyspnea in patients with advanced cancer and severe shortness of breath that is unresponsive to opioids.¹² Nebulized furosemide appears to have a direct effect on either pulmonary stretch receptors or irritant receptors in the airways; it also has a diuretic effect. Response occurs quickly with an onset of effect in 20 to 30 minutes.

B-type natriuretic peptide

The level of N-terminal precursor of B-type natriuretic peptide (NT-pro-BNP) can predict response to sunitinib in renal cancer,¹³ and the BNP level predicts 30-day mortality in pulmonary embolism.¹⁴ Measurement of BNP to detect dyspnea in patients with lung cancer is not useful, however, because the BNP level increases with cardiac and pericardial metastases. The BNP level is also persistently elevated after chest radiation therapy, and it increases with anthracycline cardiotoxicity. It is not a useful marker for distinguishing pulmonary from nonpulmonary or cardiac from noncardiac causes of dyspnea.

Lung ultrasound

Portable diagnostic lung ultrasound can be used to detect pneumonia, pleural effusions, pulmonary emboli, pneumothorax, atelectasis, and lung abscesses as potential causes of dyspnea.^15–18 In addition to the advantage of portability, there is no radiation exposure and the technology permits echocardiography to be conducted.

Opioids

Evidence supports opioids for pharmacologic relief of dyspnea in the palliative care of patients with chronic obstructive pulmonary disease and cancer. Studies have been conducted with morphine sulfate, hydromorphone, dihydrocodeine, intranasal and transmucosal fentanyl, oxycodone, and diamorphine.^19–21

The response to opioids is unrelated to the severity of dyspnea.²² Responses and safe administration occur even in patients with reduced oxygen saturation or elevated carbon dioxide partial pressure.²⁰ Opioids can be used safely in the opioid-naïve population.²⁰ Recommended dosages in these patients are 2.5 to 5.0 mg of morphine sulfate every 4 hours, 5 mg of oxycodone every 4 hours as needed, and 1 mg of hydromorphone every 4 hours in the opioid-naïve. In opioid-tolerant patients, it is recommended that therapy start with these doses and then be increased in 25% increments every 24 hours, as needed.

BUPRENORPHINE: UNIQUE OPIOID

Buprenorphine is a mu- and nociceptin (ORL-1)-receptor partial agonist with intravenous, subcutaneous, sublingual, transdermal, and intranasal routes of delivery.²³ An agent that acts as an ORL-1 agonist can induce analgesia by blocking nociceptive responses at the level of the spinal cord. It is a kappa antagonist (depending upon the kappa ligand used in the assay), which may contribute to its antihyperalgesia. The parent drug has a high affinity and low intrinsic efficacy for the mu receptor. The main metabolite, norbuprenorphine, is a delta opioid-receptor agonist.

Secondary hyperalgesia is an increased sensitivity to painful stimuli around an area of injury and occurs frequently following injury. The increased pain sensation is a result of central sensitization derived from brainstem neurons that facilitate pain; it is not derived from afferent signals from the primary site. Secondary hyperalgesia is less responsive to opioids than primary hyperalgesia at the site of injury.

This figure has been reproduced with permission of the International Association for the Study of Pain® (IASP®) (Koppert W, et al. Different profiles of buprenorphine-induced analgesia and antihyperalgesia in a human pain model. Pain 2005; 118:15–22).

Pain is improved with buprenorphine predominantly through modulation of central sensitization and less so at the primary site. Koppert et al²⁵ demonstrated in human volunteers that buprenorphine reduced the area and duration of secondary hyperalgesia more than pain at the site of injury (half-life of 171 minutes vs 288 minutes, respectively). Buprenorphine had a much greater antihyperalgesic effect than analgesic effect compared with potent opioids such as fentanyl. In contrast, the analgesic effects with fentanyl and alfentanil were much greater than their antihyperalgesic effects (Figure), suggesting the possibility of a combination of opioid therapy for superior pain relief or choices based on pain phenotype (eg, secondary or primary hyperalgesia).

SUMMARY

Early palliative care improves quality of life and decision-making in patients with advanced lung cancer and may improve survival, although survival data need to be confirmed. Olanzapine and megestrol acetate are superior to megestrol acetate alone for the treatment of anorexia. Oxygen is no better than medical air in the management of dyspnea associated with normal oxygen saturation. Buprenorphine is a unique opioid that has value for pharmacologic relief in patients at risk for respiratory depression.

Several important developments in the palliative care of patients with lung cancer have occurred over the past few years, including publication of a landmark study comparing early with as-needed palliative care, the release of new data on the treatment of cancer-related anorexia, elucidation of new mechanisms and treatment options for dyspnea, and the availability of buprenorphine. This article reviews these emerging concepts.

LUNG CANCER SYMPTOMS: COMMON AND SEVERE

The symptom burden of lung cancer is usually great. At least 80% of patients experience fatigue, 65% suffer loss of appetite, 77% have cough, 73% report dyspnea (both from local symptoms and weight loss), 57% have chest pain, and 17% have hemoptysis.¹

When symptoms are present, they are usually severe. Thirty-eight percent of the patients who report fatigue have severe fatigue, 47% have inadequate appetite to the point of requiring intervention, and more than one-half of patients who have chest pain require opioids for relief.¹

Symptom frequency and severity are worse in individuals who survive 3 months or less.¹ Increasing symptom burden is therefore prognostically important, particularly in patients with advanced stages of lung cancer. As a result, self-assessment of quality of life has a significant ability to predict survival in patients with advanced non–small cell lung cancer (NSCLC).²

Patients with lung cancer tend to suffer from groups of symptoms or symptom clusters. Lutz et al¹ found that 79% of patients reported three or more symptoms; these results were similar to the findings of a study by Hollen et al,³ in which 81% of patients suffered from three or more symptoms, all them severe except for cough.

EARLY PALLIATIVE CARE HAS CLINICAL BENEFITS

A landmark study by Temel et al⁴ examined the benefits of early palliative care integrated with standard oncologic care versus standard oncologic care and palliative care only “as needed” on patient-reported outcomes, the use of health services, and the quality of end-of-life care among patients with metastatic NSCLC. The study was a prospective, nonblinded, randomized, controlled trial of outpatients conducted at a single center. The intervention was based on guidelines from the National Consensus Project for Quality Palliative Care, with specific attention to symptom management, goals of care, decision-making regarding treatment, and coordination of care. Patients assigned to the intervention met monthly with both a palliative care service and an oncologist, and 90% of the patients randomized to intervention complied with at least 50% of the visits.

Measures of health-related quality of life and mood were obtained using the Functional Assessment of Cancer Therapy-Lung (FACT-L), the Hospital Anxiety and Depression Scale, and the 9-item depression scale of the Patient Health Questionnaire.

Measures of health care service utilization included use of antitumor therapy within 14 days of death, late or no referral to hospice, hospital admissions, and emergency room visits. Patients were considered to have received aggressive care if they met any one of the following three criteria: chemotherapy within 14 days of death, no hospice care, or admission to hospice within 3 days of death.

Compared with standard care, early palliative care was associated with an increase in the number of advance directives, earlier hospice referral (11 days vs 4 days), fewer hospitalizations and emergency room visits, and fewer instances of inappropriate oncologic care (defined as chemotherapy within 14 days of death). The percentage of patients with depressed mood was also lower among those assigned to early palliative care versus standard care (16% vs 38%).

A 2.7-month difference in median survival (P = .02) in favor of the group assigned to early palliative care was also observed, although survival was not a primary end point of the trial. This outcome needs to be validated in future studies.

CANCER-RELATED ANOREXIA AND CACHEXIA: TREATMENT IMPROVES APPETITE

The main hallmark of cancer-related anorexia and cachexia is weight loss; this symptom cluster is most often associated with hypophagia. The coexistence of anorexia and appetite-related anhedonia is common in lung cancer patients, such that 25% of lung cancer patients with anorexia report no distress with not eating, nor do they derive pleasure from eating. Others report that early satiety and changes in taste dramatically affect appetite. To some, anorexia is a distressful reminder of progression of their cancer.

Megestrol acetate and medroxyprogesterone acetate at least partially improve appetite in a subset of anorectic cancer patients. The use of medroxyprogesterone acetate has resulted in weight gain but not muscle mass in some patients with cancer-related anorexia, but has had less effect on fatigue and quality of life in these patients.

Olanzapine is an atypical antipsychotic with an affinity for multiple neurotransmitter receptors. Several of these, such as the serotonin receptors 5-HT₂ and 5-HT₃, histamine receptors, and dopamine receptors, are implicated in anorexia, nausea, and vomiting. Case reports suggest that olanzapine has antiemetic activity in patients with advanced cancer and usefulness as prophylaxis against chemotherapy-related nausea and vomiting.⁵ Reduced risk of extrapyramidal symptoms compared with standard antiemetics enhances the value of olanzapine for prevention of cancer-related anorexia.

Navari et al⁶ conducted a randomized trial to determine the effectiveness of megestrol acetate and olanzapine for the treatment of cancer-related anorexia. Eighty patients were randomized to receive oral megestrol acetate 800 mg/d, or oral megestrol acetate 800 mg/d plus olanzapine 5 mg once nightly, for 8 weeks. Patients were removed from the study if they did not take the study medication for a 48-hour period or if intolerable toxicity developed that was attributable to the study agents.

The MD Anderson Symptom Inventory (MDASI) was completed weekly to assess key symptom outcome variables. A change of 3 cm on the visual analog scale over two separate time periods for a symptom was considered sufficient to define a change in the symptom.

Quality of life was measured using a valid 28-item self-reported instrument (Functional Assessment of Cancer Therapy-General). Patients were examined by their physicians every 2 weeks.

In the group assigned to megestrol acetate, 15 patients had a weight gain of at least 5%—a change that was considered significant. Appetite improved in two patients, nausea decreased in three patients, and quality of life improved in five patients at both 4 weeks and 8 weeks. The improvements in appetite, nausea, and quality of life for the whole group on megestrol acetate alone were not significant, and there was no improvement in mean symptom scores measured by the MDASI.

There were incremental improvements of all measures in patients randomized to megestrol acetate plus olanzapine. Among patients receiving the combination, 33 had a weight gain of at least 5%; 25 reported an improvement in appetite, 21 experienced a reduction in nausea, and 23 had an improvement in quality of life at both 4 weeks and 8 weeks. All outcome variables were improved on the MDASI

CANCER AND DYSPNEA: NUMEROUS INTERVENTIONS HAVE BEEN ASSESSED

Reduced inspiratory capacity caused by weakened inspiratory muscles results in an increased Borg rating of perceived exertion (RPE) relative to oxygen levels. Both central nervous system activation of muscle and loss of muscle tissue contribute to dyspnea and fatigue in lung cancer patients.⁷ Cancer fatigue, also measured by the Borg RPE scale, appears to be a “central” mechanism that stems from a mismatch between efferent output for afferent inputs in the setting of ventilatory muscle weakness, thereby increasing the perception of dyspnea. Several interventions have been used to relieve dyspnea, ranging from oxygen therapy to treatment with opioids.

Oxygen saturation

The association between hypoxemia and dyspnea is poor.⁸ In a randomized prospective trial, Abernethy et al⁹ found no benefit to oxygen therapy compared with medical air without added supplemental oxygen in individuals who had normal oxygen saturation but symptomatic dyspnea.

Bilevel positive airway pressure

Bilevel positive airway pressure has been shown to reduce the need for invasive ventilation; improve oxygen saturation; and reduce dynamic hyperinflation, thus relieving dyspnea.¹⁰ It has been effective in dyspneic patients with motor neuron disease, cancer, heart failure, status asthmaticus, stroke, drug overdose, and interstitial lung disease.

Indwelling pleural catheters

Tunneled pleural catheters reduce the severity of dyspnea in 95% of patients.¹¹ These catheters are inserted on an outpatient basis, allowing for outpatient drainage. Autopleurodesis occurs in about 45% of patients, in which case the catheter can be removed. Adverse reactions are few (incidence < 10%), but consist of empyema, pneumothorax, cellulitis, or catheter obstruction. The disadvantage is the expense of catheter maintenance.

Nebulized furosemide

Case reports suggest that inhalation of nebulized furosemide, 20 mg four times daily, dramatically improves dyspnea in patients with advanced cancer and severe shortness of breath that is unresponsive to opioids.¹² Nebulized furosemide appears to have a direct effect on either pulmonary stretch receptors or irritant receptors in the airways; it also has a diuretic effect. Response occurs quickly with an onset of effect in 20 to 30 minutes.

B-type natriuretic peptide

The level of N-terminal precursor of B-type natriuretic peptide (NT-pro-BNP) can predict response to sunitinib in renal cancer,¹³ and the BNP level predicts 30-day mortality in pulmonary embolism.¹⁴ Measurement of BNP to detect dyspnea in patients with lung cancer is not useful, however, because the BNP level increases with cardiac and pericardial metastases. The BNP level is also persistently elevated after chest radiation therapy, and it increases with anthracycline cardiotoxicity. It is not a useful marker for distinguishing pulmonary from nonpulmonary or cardiac from noncardiac causes of dyspnea.

Lung ultrasound

Portable diagnostic lung ultrasound can be used to detect pneumonia, pleural effusions, pulmonary emboli, pneumothorax, atelectasis, and lung abscesses as potential causes of dyspnea.^15–18 In addition to the advantage of portability, there is no radiation exposure and the technology permits echocardiography to be conducted.

Opioids

Evidence supports opioids for pharmacologic relief of dyspnea in the palliative care of patients with chronic obstructive pulmonary disease and cancer. Studies have been conducted with morphine sulfate, hydromorphone, dihydrocodeine, intranasal and transmucosal fentanyl, oxycodone, and diamorphine.^19–21

The response to opioids is unrelated to the severity of dyspnea.²² Responses and safe administration occur even in patients with reduced oxygen saturation or elevated carbon dioxide partial pressure.²⁰ Opioids can be used safely in the opioid-naïve population.²⁰ Recommended dosages in these patients are 2.5 to 5.0 mg of morphine sulfate every 4 hours, 5 mg of oxycodone every 4 hours as needed, and 1 mg of hydromorphone every 4 hours in the opioid-naïve. In opioid-tolerant patients, it is recommended that therapy start with these doses and then be increased in 25% increments every 24 hours, as needed.

BUPRENORPHINE: UNIQUE OPIOID

Buprenorphine is a mu- and nociceptin (ORL-1)-receptor partial agonist with intravenous, subcutaneous, sublingual, transdermal, and intranasal routes of delivery.²³ An agent that acts as an ORL-1 agonist can induce analgesia by blocking nociceptive responses at the level of the spinal cord. It is a kappa antagonist (depending upon the kappa ligand used in the assay), which may contribute to its antihyperalgesia. The parent drug has a high affinity and low intrinsic efficacy for the mu receptor. The main metabolite, norbuprenorphine, is a delta opioid-receptor agonist.

Secondary hyperalgesia is an increased sensitivity to painful stimuli around an area of injury and occurs frequently following injury. The increased pain sensation is a result of central sensitization derived from brainstem neurons that facilitate pain; it is not derived from afferent signals from the primary site. Secondary hyperalgesia is less responsive to opioids than primary hyperalgesia at the site of injury.

This figure has been reproduced with permission of the International Association for the Study of Pain® (IASP®) (Koppert W, et al. Different profiles of buprenorphine-induced analgesia and antihyperalgesia in a human pain model. Pain 2005; 118:15–22).

Pain is improved with buprenorphine predominantly through modulation of central sensitization and less so at the primary site. Koppert et al²⁵ demonstrated in human volunteers that buprenorphine reduced the area and duration of secondary hyperalgesia more than pain at the site of injury (half-life of 171 minutes vs 288 minutes, respectively). Buprenorphine had a much greater antihyperalgesic effect than analgesic effect compared with potent opioids such as fentanyl. In contrast, the analgesic effects with fentanyl and alfentanil were much greater than their antihyperalgesic effects (Figure), suggesting the possibility of a combination of opioid therapy for superior pain relief or choices based on pain phenotype (eg, secondary or primary hyperalgesia).

SUMMARY

Early palliative care improves quality of life and decision-making in patients with advanced lung cancer and may improve survival, although survival data need to be confirmed. Olanzapine and megestrol acetate are superior to megestrol acetate alone for the treatment of anorexia. Oxygen is no better than medical air in the management of dyspnea associated with normal oxygen saturation. Buprenorphine is a unique opioid that has value for pharmacologic relief in patients at risk for respiratory depression.

The efficacy of therapy targeted to a specific oncogene is convincing evidence of “oncogene addiction,” or the concept that some cancers rely on or are “addicted to” a specific gene for their survival and proliferation. In the case of non–small cell lung cancer (NSCLC), drugs that target epidermal growth factor receptor (EGFR) have been proven more effective than conventional chemotherapy in patients with sensitizing EGFR mutations.¹

Lung cancer oncogenes can drive oncogenic signaling pathways within tumor cells. Activation of EGFR signaling that drives cell proliferation through pathways such as RAS/RAF/MEK/ERK and the cell survival pathways P13K and AKT has been demonstrated in never-smokers. In heavy smokers, KRAS oncogene mutation is the dominant promoter of activation of oncogenic signaling pathways; it predicts a poor prognosis (especially for lung adenocarcinoma), and it is essentially mutually exclusive with EGFR mutations.

More than 50% of cases of NSCLC have known oncogene mutations for which targeted therapeutics are available.² For example, gefitinib and erlotinib are the effective inhibitors for the EGFR oncogene mutation, sunitinib for platelet-derived growth factor receptor (PDGFR) amplification, and lapatinib for the less common ERBB2 insertion.

• EGFR mutations and amplifications
• EML4-ALK translocation fusions
• KRAS mutations
• PIK3CA mutations
• MET mutations, alternative splicing, amplification, and overexpression

PLATINUM DOUBLET AS STANDARD

Multiple platinum-based combinations of chemotherapy are in use as first-line therapy for advanced NSCLC. An overall survival (OS) benefit has been established with the use of doublet regimens, but no platinum-based doublet regimen has been proven superior to another on the end point of OS in clinical trials.⁴

Adding a third agent increases the response rate in advanced NSCLC but does not improve OS; the exception is bevacizumab, a monoclonal antibody targeted to vascular endothelial growth factor (VEGF). Sandler et al⁵ demonstrated a survival benefit when bevacizumab was added to paclitaxel-carboplatin in a recent study that led to US Food and Drug Administration (FDA) approval of bevacizumab for the treatment of NSCLC.

The next oncogene target explored in advanced NSCLC was EGFR. The tyrosine kinase inhibitors (TKIs) gefitinib, erlotinib, lapatinib, and the monoclonal antibody cetuximab are all clinical inhibitory agents targeting EGFR.

Previously treated NSCLC

In the phase 3 National Cancer Institute of Canada (NCIC) Clinical Trials Group (CTG) BR.21 trial, erlotinib demonstrated significant superiority over placebo as second- or third-line chemotherapy on PFS and OS in unselected patients with NSCLC. The results led to its approval as treatment for advanced NSCLC in patients who have received at least one prior chemotherapy regimen.⁸

Patient survival in NCIC CTG BR. 21 was evaluated in a series of patient subsets in exploratory univariate analyses. The effect of erlotinib on survival was similar across most subsets. A greater effect on survival by erlotinib was observed in patients who had never smoked (hazard ratio [HR] = 0.42). In the subgroup of patients who never smoked, EGFR status was predictive of erlotinib survival benefit. Patients who never smoked and were EGFR-positive had a survival benefit with erlotinib (HR = 0.27). There were too few EGFR-negative patients who never smoked to reach a conclusion.

With the approval and clinical use of EGFR-TKIs came knowledge of EGFR kinase mutations that sensitize the mutated RTK to EGFR-TKI; this mechanism translates into dramatic tumor responses.^9,10 Certain EGFR mutations contribute to sensitivity to EGFR-TKI treatment. The most common sensitizing mutations are the Exon 21 L858R mutation and the Exon 19 short in-frame deletions. The Exon 20 tends to yield resistant alterations (eg, prototypical T790M mutation and some Exon 20 Dup/Ins) in patients who initially derived benefit from targeted therapeutics. Although advances have been made in targeted therapeutics in lung cancer and other cancers, clinical resistance, particularly acquired or secondary resistance, remains the rule rather than the exception, which inherently limits the long-term clinical success of targeted therapeutics. A higher level of understanding of the mechanisms of resistance could have a substantial impact in maintaining the clinical efficacy of these targeted therapies.

The Iressa Pan-Asia Survival Study (IPASS) was a phase 3 study in which patient selection was based on clinical factors that predict a higher probability of harboring sensitizing EGFR mutations, thus enriching the mutant population, rather than screening for mutation status.¹¹ Patients selected for participation were East Asians with advanced lung adenocarcinoma who were never smokers or former light smokers. They were randomized to treatment with platinum-based doublet chemotherapy (carboplatin-paclitaxel) or the EGFR-TKI gefitinib.

The primary end point—PFS—favored gefitinib over the chemotherapy doublet in the overall patient population. Of the 1,217 patients enrolled, EGFR mutation data for 35.9% could be evaluated. Sixty percent of the patients’ tumors harbored sensitizing EGFR mutations and, in this subset, the benefit of gefitinib was greater than it was in the overall population. In patients without an EGFR mutation, particularly those without Exon 19 deletions or Exon 21:L858R mutations (sensitizing mutations), platinum-based doublet chemotherapy performed better than gefitinib on the PFS end point. Of the mutation-positive patients, 4.2% had T790M mutations, which confers resistance to TKIs; this finding underscored the observation that all mutations cannot be treated the same.

The important message from the IPASS results is that even in a population preselected for EGFR mutation occurrence, the actual presence of the alteration of the target (EGFR mutations) leads to better survival with gefitinib. Molecular profiling of the tumor, therefore, is ultimately superior to profiling by patient phenotype or ethnicity. Thus, molecular selection trumps clinical selection.¹²

On the basis of IPASS and four similar phase 3 randomized controlled trials, the American Society of Clinical Oncology issued a clinical opinion that “patients with NSCLC who are being considered for first-line therapy with an EGFR-TKI (patients who have not previously received chemotherapy or an EGFR-TKI) should have their tumor tested for EGFR mutations to determine whether an EGFRTKI or chemotherapy is the appropriate first-line therapy.”¹³

Monoclonal antibody against EGFR

The First-Line Erbitux in Lung Cancer (FLEX) phase 3 worldwide study demonstrated that cetuximab, a monoclonal antibody directed against EGFR, as add-on therapy to a platinum-based doublet (cisplatin and vinorelbine) can extend median OS in patients with advanced EGFR-expressing NSCLC (stage wet IIIB or stage IV).¹⁴ As a result, the use of cetuximab combined with cisplatin-vinorelbine has been endorsed by a National Comprehensive Cancer Network (NCCN) guideline as a first-line option for the treatment of advanced NSCLC.

EML4-ALK fusion gene as target for crizotinib

The EML4-ALK fusion translocation oncogene was first identified in 2007 in a small proportion of patients with NSCLC,^15,16 and a targeted therapy (crizotinib, an inhibitor of the ALK tyrosine kinase) has been developed. A single-arm phase 1 trial of crizotinib in patients selected for the EML4-ALK fusion gene has been completed.¹⁷ Of the approximately 1,500 NSCLC patients screened for the trial, 82 were identified as having advanced ALK-positive disease and were entered. These patients tended to be younger than those with ALK-negative disease, most had little or no exposure to tobacco, and all had adenocarcinoma.

The mean treatment duration was 6.4 months. Most treatment-related side effects were grade 1 or grade 2 gastrointestinal adverse events. The overall response rate was 57%. The disease control rates were 87% at 8 weeks and 66% at 16 weeks. Crizotinib has since moved to phase 2 and phase 3 trials and received FDA approval on August 26, 2011, for treatment of EML4-ALK–positive patients as assayed by a simultaneously approved companion molecular diagnostic test.

Crizotinib-resistant mutations of the ALK-kinase domain have recently been identified; L1196M and C1156Y mutations have been found to confer resistance to crizotinib in initially responsive patients.¹⁸

MET: An emerging molecular target

An emerging molecular target being tested in clinical trials is MET, a multifaceted receptor kinase that, when activated, induces tumor cell activities such as cell proliferation and angiogenesis, epithelial-mesenchymal transition, and cell scattering, leading to tumor cell invasion and metastasis.¹⁹

MET receptors and EGFR in lung cancer often are coexpressed and coactivated. Dual targeting of MET and EGFR pathways simultaneously is an attractive combined targeted strategy and is being studied in the hope of overcoming secondary resistance to EGFRTKI as well as enhance the primary response to targeted therapy. A number of MET targeting agents, including both small molecular inhibitors and monoclonal antibodies, are currently undergoing various stages of clinical development.^20,21

In a phase 2 study, erlotinib plus the MET inhibitor ARQ197 was compared with erlotinib plus placebo in 117 previously treated EGFR-inhibitor–naïve patients with advanced NSCLC.²² In the population of patients with nonsquamous NSCLC, both PFS and OS were extended incrementally by the use of combined inhibition that targeted both the EGFR and MET pathways. Interestingly, the benefit on PFS appears to be more significant in EGFR wild type and KRAS-mutant molecular subgroups. A phase 3 global trial using a similar design, with a goal of enrolling 1,000 patients, has been activated in an attempt to validate the findings from the phase 2 study.

UNDERSTANDING RESISTANCE MECHANISMS WILL OPEN DOORS

Other than novel and more rational combined TKI in lung cancer, a deeper understanding of the resistance mechanisms in the context of oncogene addiction targeting would ultimately have a large impact on the long-term clinical success in lung cancer targeted therapy.

Resistance arises because of cellular heterogeneity within an oncogene-addicted tumor. Tumor shrinkage indicates a response to a molecularly targeted therapy, but residual tumor may be a source of slow-growing drug-tolerant “persistor” cells that promote tumor regrowth, regeneration, and heterogeneity.^23,24 Coaddiction, reversible resistance, and addiction-switching models have been proposed to explain resistance, but it is unlikely that a single mechanism can fully explain tumor cell maintenance.

FUTURE OF TARGETED THERAPY IN LUNG CANCER

Technologic advances provide hope for the future of targeted therapy in lung cancer. Some of these advances are cancer genome deep sequencing and tumor molecular profiling. A greater understanding of tumor heterogeneity at the molecular level and tumor-resistant mechanisms, both intrinsic and acquired, should provide further therapeutic opportunity. In the modern era of targeted cancer therapy, identification of novel “druggable” driver oncogene targets can lead to swift development of inhibitors of those targets and adoption of improved and rational combinations of drugs. It is hoped that a better tumor response and more durable responses can be achieved with targeted therapy.