Treatment of Extensive-Stage Small Cell Lung Cancer

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Treatment of Extensive-Stage Small Cell Lung Cancer Mamta Parikh, Karen Kelly, Primo N. Lara, Jr., and Egbert F. Smit

SUMMARY OF KEY POINTS • Performance status is universally recognized as an independent prognostic factor and typically correlates with the extent of tumor burden. • As first-line therapy, platinum agent plus etoposide or irinotecan remains the standard of care for the treatment of small cell lung cancer (SCLC). • The ideal number of chemotherapy cycles for SCLC has not been defined; however, four to six cycles are considered the standard based on results from randomized trials. • Despite an initially high response rate to frontline platinum-based chemotherapy, extensive-stage SCLC will universally relapse, often within 3 to 6 months. • Alternative chemotherapy strategies have focused on modifying the dosage and schedules of established regimens. • Dose-dense regimens have shown mixed results. • Most trials employing a dose-intensification strategy did not show a survival advantage over standard therapy for patients with extensive-stage SCLC, and higher doses were typically associated with greater toxicity. • Patients who receive no further therapy have a median survival of less than 3 months. • Patients who have previously received platinumbased therapy are grouped into two general categories reflecting the platinum-sensitivity status of their disease: platinum sensitive and platinum refractory. • Topotecan is approved as second-line treatment for patients with platinum-sensitive, relapsed disease based on symptom control. An oral formulation of topotecan was also developed for patients’ convenience. • Despite progress in the understanding of genomic alterations and signaling pathways in SCLC, clinical experiments with tyrosine kinase inhibitors, other small-molecule inhibitors, and antiangiogenic agents have been disappointing Other therapeutic areas of interest more recently evaluated include epigenetic modifiers, inhibitors of DNA repair and the cell cycle, immunocheckpoint inhibitors and inhibitors of the Notch pathway.

The chemosensitivity of small cell lung cancer (SCLC) was first identified 50 years ago with the recognition that methyl-bis-βchloroethyl amine hydrochloride could cause tumor regression in more than 50% of patients.1 Since then, numerous antineoplastic agents have been shown to produce objective response rates of at least 20% in previously untreated patients. Older active agents included nitrogen mustard, doxorubicin, methotrexate, ifosfamide, etoposide, teniposide, vincristine, vindesine, nitrosureas, and cisplatin and its analog carboplatin.2 In the 1990s, six new agents were discovered to have activity against SCLC in untreated patients, including paclitaxel, docetaxel, topotecan, irinotecan, vinorelbine,

and gemcitabine.3–11 In this century, two additional cytotoxic agents were evaluated: pemetrexed, a multitargeted antifolate agent evaluated as monotherapy in the relapse setting, and amrubicin, a topoisomerase II inhibitor that has produced impressive responses as first-line therapy.12,13 This chapter discusses first-line and second-line therapy for patients with extensive-stage SCLC.

FIRST-LINE CHEMOTHERAPY Combination Chemotherapy Given the large number of active agents in SCLC, the evaluation of combination regimens quickly ensued. In the 1970s, randomized trials demonstrated the superiority of combination chemotherapy over single-agent therapy.14 Furthermore, studies showed that simultaneous administration of multiple agents was more efficacious than the sequential administration of the same agents.15,16 Cyclophosphamide-based regimens were commonly used to treat SCLC, including cyclophosphamide, doxorubicin, and vincristine (CAV); cyclophosphamide, doxorubicin, and etoposide (CDE); and cyclophosphamide, etoposide, and vincristine (CEV). After the introduction of cisplatin, randomized trials with a regimen of cisplatin and etoposide showed that this combination was as effective as CAV and less toxic.17,18 A meta-analysis of 36 trials demonstrated that regimens containing cisplatin and/or etoposide offered a significant survival advantage to patients with SCLC.19 Thus cisplatin and etoposide became the preferred regimen for the treatment of extensive-stage SCLC, yielding overall response rates of 65% to 85%, complete response rates of 10% to 20%, and a median survival of 8 months to 10 months.16–18 For patients with limited-stage SCLC, cisplatin and etoposide plus twice-daily thoracic radiotherapy was also considered the treatment of choice, producing an 87% overall response rate, a 56% complete response rate, a median survival of 23 months, and a 5-year survival rate of 44%.20 Carboplatin is frequently substituted for cisplatin because of its more favorable toxicity profile. One small randomized trial comparing cisplatin and etoposide with carboplatin and etoposide in patients with limited- and extensive-stage disease showed similar efficacy, but the carboplatin-based combination was significantly less toxic.21 A meta-analysis of individual data from 633 patients who participated in four clinical trials did not demonstrate any difference in efficacy between cisplatin- and carboplatin-based regimens, with a median survival of 9.6 months and 9.4 months, respectively.22 Significant differences in toxicity were found; more neutropenia, anemia, and thrombocytopenia occurred with carboplatin-based regimens, whereas more nausea, vomiting, neurotoxicity, and renal toxicity developed with cisplatin-based regimens. Years elapsed before the discovery of newer cytotoxic agents such as the topoisomerase II inhibitors, taxanes, gemcitabine, and vinorelbine, which were shown to have antitumor activity in SCLC. Many studies have summarized the results from novel combinations that were evaluated in phase III trials (Table 52.1).23–55 Enthusiasm for the combination of cisplatin and irinotecan (PI) arose when Japanese researchers halted their phase III trial prematurely after an interim analysis showed a survival benefit for PI over cisplatin and etoposide.23 One hundred and fifty-four patients were randomly assigned to receive either four

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SECTION IX  Chemotherapy and Targeted Agents for Lung Cancer

TABLE 52.1   Randomized Trials Comparing First-Line Combination Chemotherapy Regimens for Small Cell Lung Cancer Author (y)

Regimen

No. of Patients

Overall Response Rate (%)

Progression-Free Survival (mo)

Median Survival (mo)

1-Year Survival Rate (%)

Noda et al.23 (2002)

PI PE PI PE PI PE PI PE PI PE IC EC IC EC PT PE PT PE CDE CT PemC EC AP IP PET PE CET CEV

77 77 324 327 221 110 202 203 173 189 105 104 106 110 389 395 357 346 102 101 364 369 142 142 62 71 301 307 293 294 117 109

84.4a 67.5 60 57 48 44 39 47 62d 48 NR NR 54 52 63 69 56e 46 60 61 31 52f 78 72 50 48 72 69 75 68 76b 61

6.9b 4.8 5.8 5.2 4.1 4.6 5.4 6.2 6.5 5.8 NR NR 6.0 6.0 6.0b 6.2 6.9e 6.1 4.9 5.2 3.8 5.4g 5.1 5.7 11.0b 9.0 8.1h 7.5 6.0 5.9 7.2i 6.3

12.8c 9.4 9.9 9.1 9.3 10.2 10.2 9.7 10.9 10.3 8.5 7.1 10.0 9.0 9.8 10.0 10.3 9.4 6.8 6.7 8.1 10.6g 15.3 18.3 9.5 10.5 12.7 11.7 10.6 9.9 10.0 9.3

58.4 37.7 41 34 35 35 42 39 NR NR 37b 19 37 30 31 31 40 36 24 26 NR NR NR NR 38 37 48 51 38 37 40j 29

Lara, Jr. et al.24 (2009) Hanna et al.25 (2006) Zatloukal et al.26 (2010) Kim et al.27 (2013) Hermes et al.28 (2008) Schmittel et al.29 (2011) Eckardt et al.31 (2006) Fink et al.32 (2012) de Jong et al.33 (2007) Socinski et al.35 (2009) Kotani et al.36 (2012) Mavroudis et al.37 (2001) Reck et al.38 (2003) Niell et al.39 (2005) Pujol et al.40 (2001)   

PET PE PCDE PE

ap

= 0.02. = 0.003. = 0.0004. dp = 0.0064. ep = 0.01. fp < 0.001. gp < 0.01. hp = 0.033. ip < 0.0001. jp = 0.0067. AP, amrubicin and cisplatin; CDE, cyclophosphamide, doxorubicin, and etoposide; CET, carboplatin, etoposide, and paclitaxel; CEV, carboplatin, etoposide, and vincristine; CT, carboplatin and paclitaxel; EC, etoposide and carboplatin; IC, irinotecan and carboplatin; IP, irinotecan and cisplatin; NR, not reported; PCDE, cyclophosphamide, carboplatin, doxorubicin, and epirubicin; PE, cisplatin and etoposide; PemC, pemetrexed and carboplatin; PET, cisplatin, etoposide, and paclitaxel; PI, cisplatin and irinotecan; PT, cisplatin and topotecan. bp cp

  

cycles of etoposide (100 mg/m2) on days 1, 2, and 3 with cisplatin (80 mg/m2) on day 1 every 3 weeks or four cycles of irinotecan (60 mg/m2) on days 1, 8, and 15, and cisplatin (60 mg/m2) on day 1. Patients treated with PI had a significantly better overall response rate (84.4% vs. 67.5%; p = 0.02), median survival (12.8 months vs. 9.4 months), and 1-year survival rate (58.4% vs. 37.7%; p = 0.002) than patients treated with cisplatin and etoposide. The PI combination was associated with a higher rate of grade 3 or grade 4 diarrhea (p = 0.01), whereas cisplatin and etoposide were associated with a higher rate of myelosuppression (p = 0.0001). The Southwest Oncology Group (SWOG) conducted a confirmatory trial using the identical study design but found no survival benefit for PI.24 In this large trial of 651 patients, all efficacy parameters were very similar except for a trend toward improved progression-free survival time for PI (5.7 months vs. 5.2 months for cisplatin and etoposide; p = 0.07). Grade 3 or grade 4 neutropenia and thrombocytopenia were higher in the cisplatin and etoposide arm, whereas grade 3 or grade 4 nausea/vomiting and diarrhea were higher in the PI arm. A phase III superiority trial

comparing a novel dose and schedule of the PI regimen (irinotecan [65 mg/m2] with cisplatin [30 mg/m2] given on days 1 and 8) with standard cisplatin and etoposide produced similar survival in both arms.25 In Europe, a different schedule of PI (irinotecan [65 mg/m2] on days 1 and 8 with cisplatin [80 mg/m2] on day 1) was assessed in comparison with standard cisplatin and etoposide.26 The data showed that the PI regimen was noninferior to cis­platin and etoposide, as hypothesized. The median overall survival rates were 10.2 months and 9.7 months, respectively, with a hazard ratio (HR) of 0.81 (95% confidence interval [CI], 0.61–1.01; p = 0.06). Overall response rates were 39% for PI and 47% for cisplatin and etoposide, and time to progression was 5.4 months and 6.2 months, respectively. The number of grade 3 or grade 4 adverse events was similar between the arms, but more patients in the PI arm had gastrointestinal toxicity and more patients in the cisplatin and etoposide arm had neutropenia. In 2013, Korean investigators reported the results from a phase III trial comparing PI with cisplatin and etoposide.27 Irinotecan was administered on days 1 and 8 with cisplatin on day 1, and cisplatin and etoposide

CHAPTER 52  Treatment of Extensive-Stage Small Cell Lung Cancer

were given in the standard fashion. The trial, however, did not demonstrate the superiority of PI (HR, 0.88; 95% CI, 0.73–1.05; p = 0.12). The median overall survival was 10.9 months for PI and 10.3 months for cisplatin and etoposide. The overall response rate was significantly higher for PI (62.3% vs. 48.2%; p = 0.0064), but progression-free survival was not significantly different (6.5 months vs. 5.8 months, respectively). The frequency of anemia, nausea, and diarrhea was greater with PI. Irinotecan has also been evaluated in combination with carboplatin. The IRIS study demonstrated superior survival for irinotecan plus carboplatin compared with oral etoposide plus carboplatin; however, overall survival in both study arms was low, at less than 9 months.28 Drug dosages and schedules were unconventional and lower than other published regimens, with irinotecan (175 mg/m2) and carboplatin (area under the curve [AUC] 4) administered on day 1, and etoposide (120 mg/m2) orally on days 1–5 with carboplatin (AUC 4) on day 1. Another trial, conducted in Germany, randomly assigned 216 patients to receive either irinotecan (50 mg/m2) on days 1, 8, and 15 with carboplatin (AUC 5) or intravenous (IV) etoposide (140 mg/m2) on days 1–3 with carboplatin (AUC 5).29 The irinotecan regimen was not found to be superior to the etoposide regimen in terms of overall survival (HR, 1.34; 95% CI, 0.97–1.85; p = 0.072). The median survival was 10 months and 9 months, respectively. The overall response rate and progression-free survival were similar for both treatment arms. A meta-analysis of seven randomized trials including 2027 patients that compared irinotecan plus a platinum agent with etoposide plus a platinum agent showed a survival advantage for irinotecan regimens (HR, 0.81; 95% CI, 0.71–0.93; p = 0.003).30 No significant differences in progression-free survival or overall response rate were noted. Irinotecan regimens produced significantly less hematologic toxicity but more gastrointestinal toxicity than etoposide regimens. Overall, the data suggest that combinations of irinotecan or etoposide plus a platinum compound are reasonable options as first-line therapy for patients with extensive-stage SCLC. Topotecan, a drug with activity for disease relapse, was evaluated in the frontline setting. Two large phase III trials with oral or IV topotecan plus cisplatin did not show a survival advantage over standard cisplatin and etoposide. Efficacy parameters were similar between the regimens, with median survival times of 9 months to 10 months.31,32 The IV topotecan regimen did produce a significantly higher overall response rate (56% vs. 46%; p = 0.01) and prolonged progression-free survival (7 months vs. 6 months; p = 0.004), but was associated with more hematologic toxicity. Several other novel platinum combinations have been studied. One trial comparing paclitaxel plus carboplatin with CDE showed no benefit of the doublet over the standard regimen, but survival was modest in both arms, at less than 7 months.33 A phase III trial of the combination of pemetrexed and carboplatin unexpectedly showed inferior efficacy to standard treatment. In a previous randomized phase II study of pemetrexed plus cisplatin or carboplatin, the carboplatin arm produced a median survival of 10.4 months and was well tolerated.34 A phase III study, the Global Analysis of Pemetrexed in SCLC Extensive Stage, was designed to show noninferiority of pemetrexed (500 mg/m2) and carboplatin (AUC 5) compared with etoposide and carboplatin. With 733 patients randomly assigned to treatment, the study was terminated prematurely when the predefined futility end point for progression-free survival showed inferiority of the experimental arm.35 In the final analysis, overall survival was inferior (HR, 1.56; 95% CI, 1.27–1.92; p < 0.01). The median overall survival was 8.1 months for pemetrexed and carboplatin and 10.6 months for etoposide and carboplatin. The median progressionfree survival was 3.8 months for pemetrexed and carboplatin and 5.4 months for etoposide and carboplatin (p < 0.01), and the

527

overall response rate also favored the etoposide and carboplatin combination (52% vs. 31%; p < 0.001). Significant neutropenia and more febrile neutropenia were seen in the etoposide arm. By contrast, death during therapy or within 30 days was higher for the pemetrexed arm than for the etoposide arm (16% vs. 10%; p = 0.032), and the rate of toxicity-related death was higher (1.4% vs. 0%; p = 0.028). Another novel cytotoxic agent with promising early results that failed to show a survival advantage in the phase III setting was amrubicin. A phase III randomized study showed that amrubicin plus cisplatin was inferior to PI.36 Two hundred and eightyfour patients were randomly assigned to receive either amrubicin (35 mg/m2 to 40 mg/m2) on days 1–3 and cisplatin (60 mg/m2) every 3 weeks or cisplatin (60 mg/m2) on day 1 and irinotecan (60 mg/m2) on days 1, 8, and 15 every 4 weeks. The median overall survival for amrubicin plus cisplatin was 15 months, compared with 18.3 months for PI (HR, 1.33; 95% CI, 1.01–1.74; p = 0.681), and this result exceeded the noninferiority margin. The progression-free survival was 5.1 months for amrubicin plus cisplatin and 5.7 months for PI with an overall response rate of 78% and 72%, respectively. An increased incidence of grade 4 neutropenia (79% vs. 23%) and febrile neutropenia (32% vs. 11%) was found in the amrubicin plus cisplatin arm. The favorable toxicity profiles of most of the newer agents led investigators to explore the possibility of integrating them into an active doublet (see Table 52.1). Three randomized trials evaluating the addition of paclitaxel to cisplatin and etoposide or carboplatin and etoposide did not produce a survival benefit over traditional doublets and were associated with increased toxicity.37–39 French investigators evaluated a four-drug regimen in which they added cyclophosphamide and 4′-epidoxorubicin to cisplatin and etoposide (PCDE). A significant improvement in the complete response rate (13% vs. 21%; p = 0.02) and overall survival (9.3 months vs. 10.5 months; p = 0.0067) was noted for PCDE.40 However, PCDE was associated with a significantly higher hematologic toxicity rate, with 22% of patients having a documented infection, compared with 8% in the cisplatin and etoposide arm (p = 0.0038). Toxicity-related death rates were similar, at 9% for PCDE and 5.5% for cisplatin and etoposide. Since the early 1990s, there have been no major breakthroughs with newer chemotherapy agents in the first-line setting. A platinum agent plus etoposide or irinotecan remains the standard of care for the treatment of SCLC. 

Alternative Chemotherapy Strategies Alternative chemotherapy strategies have focused on modifying the dosage and schedules of established regimens, including dose intensification, alternating non–cross-resistant chemotherapy, and prolonged treatment durations. However, with the discovery of molecularly targeted agents, investigators have largely abandoned the pursuit of optimizing current chemotherapy regimens.

Dose Intensification Dose intensity is defined as the dose per meter squared per week. Dose intensification can be accomplished by increasing the dose administered or by shortening the interval between doses (dose density). Results from preclinical tumor models suggested that one of the simplest ways to overcome drug resistance was dose escalation.41 In the late 1970s, Cohen et al.42 randomly assigned patients to receive either standard dosages of cyclophosphamide, methotrexate, and lomustine or a higher dose of cyclophosphamide and lomustine plus a standard dose of methotrexate. Patients treated in the high-dose arm had a higher overall response rate that led to prolonged survival, and a subset of these patients were long-term survivors. These data

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SECTION IX  Chemotherapy and Targeted Agents for Lung Cancer

resulted in a series of seven randomized trials comparing highdose and conventional-dose chemotherapy in patients with limited-stage and extensive-stage SCLC.43–49 Most of these trials were conducted in the 1980s and did not show a clinical benefit. The Spanish Lung Cancer Group reexamined this question in 2004.49 They compared high-dose epirubicin (100 mg/m2) plus cisplatin (100 mg/m2) administered on day 1 with standard cisplatin and etoposide (cisplatin [100 mg/m2] on day 1 and etoposide [100 mg/m2] on days 1–3) in 402 patients with SCLC. Efficacy results were similar between the arms. A study of patients with limited-stage disease published in 1989 showed a superior 2-year survival rate of 43% when the dose of cisplatin and cyclophosphamide was increased by 20% in the first cycle of a PCDE regimen, compared with a 2-year survival rate of 23% for standard PCDE.50 Dose-dense regimens have shown mixed results. One such combination was an intense weekly regimen of cisplatin (25 mg/ m2) for 9 consecutive weeks, vincristine (1 mg/m2) on even weeks for 9 weeks, and doxorubicin (40 mg/m2) and etoposide (80 mg/ m2) on days 1–3 on odd weeks for 9 weeks (CODE). This was the first regimen to be associated with an impressive 2-year survival rate of 30% among 48 patients with extensive-stage SCLC.51 The investigators were able to administer close to the intended full doses of all four agents, thereby increasing the dose intensity by twofold. The National Cancer Institute of Canada–Cancer Treatment Group (NCIC–CTG) in collaboration with SWOG conducted a phase III trial comparing the CODE regimen and conventional alternating CAV/cisplatin and etoposide for patients with extensive-stage SCLC.52 Response rates were higher in the CODE arm, but no differences were found in progression-free or overall survival. Although rates of neutropenia and fever were similar, toxicity-related deaths occurred in 9 of 110 patients receiving CODE, compared with one of 109 patients receiving CAV/cisplatin and etoposide (p = 0.42). Given the high toxicityrelated death rate and similar efficacy, CODE was not recommended. Japanese investigators subsequently demonstrated that adding granulocyte colony-stimulating factor (G-CSF) to CODE increased the mean total dose intensity received, reduced neutropenia and febrile neutropenia, and significantly prolonged survival (59 weeks vs. 32 weeks; p = 0.0004).53 This led to a phase III trial of CODE plus G-CSF compared with CAV/cisplatin and etoposide.54 The response rate was significantly higher for CODE, but there was no survival advantage. The toxicity-related death rate with CODE plus G-CSF was low, with only four reported deaths. European investigators evaluated the dose-dense strategy with or without colony stimulation in seven phase III trials published between 1993 and 2002.55–61 Two trials showed a survival advantage for the dose-dense arm, and the other trials reported similar outcomes between the standard and experimental arms. The trial by Steward et al.58 showed a significant prolongation in survival with dose intensification of vincristine, ifosfamide, carboplatin, and etoposide (ICE) chemotherapy compared with standard dosing of this regimen. The median survival time was 443 days in the dose-dense arm and 351 days in the standard arm (p = 0.0014), with 2-year survival rates of 33% and 18%, respectively. There was no difference in response rate, despite the 26% increase in dose intensity in the experimental arm. The British Medical Research Council randomly assigned 403 patients to receive doxorubicin, cyclophosphamide, and etoposide in two or three weekly schedules.59 In this trial, a 34% escalation in dose density was achieved. Although the response rates in the two arms were similar, a significant improvement was found in the complete response rate in the dose-dense arm (40% vs. 28%; p = 0.02) that translated into a 2-year survival benefit (13% vs. 8%; p = 0.04). Subgroup analysis showed that the survival advantage among patients with extensive disease was as large as that for patients with limited disease.

A possible explanation for the failure of the previous trials is that the dose intensity was insufficient to produce a survival benefit. To definitively answer the question about dose intensification, studies were conducted using stem cell rescue, which would allow for a 200% to 300% dose escalation of chemotherapy. Multiple small studies have shown this approach to be feasible. The original studies focused on patients who had a response with conventional cytotoxic therapy and then received high-dose consolidation with stem cell rescue. A randomized trial testing this late-intensification strategy was reported by Humblet et al.62 in 1987. One hundred and one patients received standard induction chemotherapy, and 45 patients with chemotherapy sensitivity were randomly assigned to receive either one additional cycle with high-dose cyclophosphamide, carmustine, and etoposide or conventional doses of the same drugs. In this highly selected group of patients, the median overall survival was 68 weeks for the high-dose arm compared with 55 weeks for the conventional therapy (p = 0.13). Because of its improved safety and feasibility, peripheral blood stem cell transplantation has largely replaced autologous marrow transplants. Japanese investigators reported promising results from a phase II study of high-dose ICE with autologous peripheral blood stem cell transplantation in 18 patients with limitedstage SCLC after concurrent, hyperfractionated chemoradiation therapy.63 The complete response rate was 61% and the median survival time was 36.4 months. One toxicity-related death was reported. At the time of publication, a randomized trial based on these results was ongoing. Three randomized trials using highdose ICE chemotherapy with peripheral blood rescue as first-line treatment for SCLC have also been reported.64–66 The largest trial included 318 patients with predominantly limited-stage SCLC and compared six cycles of a dose-dense ICE regimen every 14 days, with G-CSF–mobilized whole-blood hematopoietic progenitors, with six cycles of the standard 28-day ICE regimen.64 Despite doubling of the median dose intensity with the dose-dense regimen (182% vs. 88%, respectively), the median survival time and the 2-year survival rate were comparable (14.4 months and 22% vs. 13.9 months and 19%, respectively). By contrast, an identical study by Buchholz et al.65 was halted after 70 patients were enrolled. They reported a favorable median survival of 30.3 months (p = 0.001), a 2-year survival rate of 55%, and a time to progression of 15 months (p = 0.0001) for the doseintense arm compared with a median survival of 18.5 months, a 2-year survival rate of 39%, and a time to progression of 11 months for the standard-dose arm in this small, single-institution study. The European Group for Blood and Marrow Transplant conducted a similar study.66 The study was closed after 140 of the planned 340 patients were enrolled because of poor accrual. The median dose intensity for the high-dose arm was 293%, but this dose did not yield a survival benefit; the median survival time was 18.1 months and the 3-year survival rate was 18% for the highdose arm, compared with 14.4 months and 19%, respectively, for the standard ICE arm. None of the subgroups benefited from high-dose ICE. Overall, most trials using a dose-intensification strategy did not show a survival advantage over standard therapy for patients with extensive-stage SCLC, and the higher doses were typically associated with greater toxicity. This approach should be abandoned in patients with extensive disease. In limited-stage SCLC, the optimal drug doses remain unclear, with several studies suggesting a possible benefit. Continued evaluation of dose intensity in the curative setting is reasonable. 

Alternating Non–Cross-Resistant Chemotherapy Regimens To achieve maximal antitumor effects using multiple active agents, they should be administered simultaneously at their

CHAPTER 52  Treatment of Extensive-Stage Small Cell Lung Cancer

optimal single-agent dose. However, because drug toxicities often overlap, strict adherence to this approach is often not possible in the clinical setting. In the 1980s, Goldie et al.67 suggested that alternating two non–cross-resistant chemotherapy regimens of relatively comparable efficacy could minimize the development of drug resistance while avoiding excessive host toxicity. This strategy was particularly appealing for SCLC because both CAV and cisplatin and etoposide are highly active against SCLC and contain agents from divergent drug classes. Three randomized phase III trials were performed to evaluate CAV and CAV alternating with cisplatin and etoposide.16,17,68 Studies from the United States and Japan showed similar efficacy between the study arms, whereas the NCIC–CTG reported superior efficacy for the alternating regimen, with overall response rates of 80% and 63%, respectively (p < 0.002), and survival times of 9.6 months and 8.0 months (p = 0.03). Investigators at the NCIC– CTG went on to test this approach in patients with limited-stage SCLC.69 Patients were randomly assigned between two induction regimens, either alternating CAV/cisplatin and etoposide or sequential therapy with three cycles of CAV followed by three cycles of cisplatin and etoposide. Chemotherapy was followed by radiotherapy in patients with a disease response. The therapeutic outcomes in the study groups were not significantly different. SWOG conducted a similar study and found no advantage for the alternating CAV/cisplatin and etoposide regimen over the etoposide, vincristine, doxorubicin, and cyclophosphamide regimen in patients with limited-stage disease.70 The European Organization for Research and Treatment of Cancer reported a trial testing two relatively non–cross-resistant regimens: CDE and vincristine, carboplatin, ifosfamide, and mesna.71 Patients with extensive-stage SCLC were randomly assigned to receive either a maximum of five courses of CDE or an alternating regimen consisting of CDE in cycles 1, 3, and 5 and vincristine, carboplatin, ifosfamide, and mesna in cycles 2 and 4. The trial accrued only 148 of the 360 planned patients. The median survival time was 7.6 months in the standard arm and 8.7 months in the alternating arm (p = 0.243). Although no survival benefit for the alternating drug hypothesis was demonstrated, the emergence of newer active agents for the treatment of SCLC justified revisiting this strategy. The North Central Cancer Treatment Group conducted a trial of etoposide and cisplatin alternating with topotecan and paclitaxel.72 The overall response rate was 77%, including four complete responses among 44 evaluable patients. The median survival was 10.5 months, with 1- and 2-year survival rates of 37% and 12%, respectively. This alternating regimen was associated with a high rate of grade 3 and grade 4 neutropenia (95%) despite the use of filgrastim in cycles 2, 4, and 6. The Hellenic Oncology Research Group treated 36 previously untreated patients with extensive-stage SCLC with cisplatin and etoposide alternating with topotecan.73 The overall response rate was 64%, and 14% of patients had a complete response. Grade 3 and grade 4 neutropenia occurred in 39% of patients during the cycles of cisplatin and etoposide and in 55% after the topotecan treatment. These limited data incorporating newer chemotherapy agents into an alternating strategy were disappointing. Taken together, alternating newer and/or older cytotoxic agents to overcome drug resistance is an unsuccessful strategy and should not be pursued. 

Treatment Duration and Maintenance Therapy The ideal number of chemotherapy cycles for SCLC has not been defined; however, four to six cycles is considered the standard based on the results from the randomized trials described previously. Clinical trials specifically designed to investigate the role of prolonged treatment using a consolidation or maintenance approach have been performed. Three of 14 trials produced positive results.74–76 All three trials were initiated in 1982.

529

In two trials of patients with limited-stage SCLC, two cycles to four cycles of consolidation therapy with cisplatin and etoposide were given to patients who had a response after induction CAV with or without thoracic radiotherapy.74,75 The remaining trial randomly assigned patients with nonprogressing limited or extensive-stage disease to four additional cycles of CEV or observation.76 Although this trial showed that four cycles of CEV were inferior, a second randomization to salvage chemotherapy compared with palliative care given at the time of disease progression demonstrated that the subset of patients who received eight cycles of CEV with or without salvage therapy did not live longer than patients who received four cycles of CEV and salvage therapy at the time of relapse. The role of consolidation and/ or maintenance therapy with topotecan was evaluated by the Eastern Cooperative Oncology Group (ECOG).77 Two hundred and twenty-three patients with nonprogressing, extensive-stage SCLC were randomly assigned to receive either four cycles of topotecan or observation. Progression-free survival from the date of randomization was significantly better with topotecan than with observation alone (3.6 months vs. 2.3 months; p < 0.001), but overall survival from randomization was not significantly different between the arms (8.9 months vs. 9.3 months; p = 0.43). A meta-analysis of 14 randomized trials of maintenance chemotherapy involving 1806 patients was published in 2013.78 Maintenance chemotherapy failed to increase survival when compared with observation alone, with an odds ratio for 1-year mortality of 0.88 (95% CI, 0.66–1.19; p = 0.414). Maintenance treatment did, however, significantly prolong progression-free survival for patients with extensive-stage disease (HR, 0.72; 95% CI, 0.58–0.89; p = 0.003). This benefit was limited to patients who had switch maintenance therapy. Overall, chemotherapy after four to six cycles of a combination regimen is not warranted. Patients should be followed closely for signs and symptoms of relapse. Clinical trials evaluating maintenance regimens with molecularly targeted agents were ongoing at the time of publication. In summary, a platinum-based doublet with etoposide or irinotecan remains the standard of care for patients with SCLC. Although extensive research has not altered the standard of care for SCLC in many years, an analysis of the Surveillance, Epidemiology, and End Results database showed a modest but significant improvement in survival with current therapies.79 In 1973, the 2-year survival rate for extensive-stage SCLC was 1.5%, compared with 4.6% in 2000, whereas the 5-year survival rate for limited-stage SCLC increased from 4.9% to 10% during a similar period (Fig. 52.1). Moreover, the recent genomic characterization of SCLC provides optimism that novel, efficacious agents are forthcoming. 

FIRST-LINE CHEMOTHERAPY FOR OLDER PATIENTS According to the Surveillance, Epidemiology, and End Results database, 42% of patients with SCLC were aged 70 years or older at diagnosis.80 Similar age distributions are seen worldwide.81,82 Furthermore, the 5-year survival rate for SCLC was significantly worse for older patients than for younger patients (p < 0.0001) and had not changed over the 15 years studied.80 For the period between 1998 and 2003, 5-year survival rates were 6.5% for patients younger than 70 years of age, 3.4% for patients aged 70 to 79 years, and 2.4% for patients aged 80 years or older. Retrospective reviews to identify prognostic factors in SCLC have shown variable results with regard to age. The largest experience comes from SWOG.83 An analysis of 2580 patients enrolled in six SWOG studies, of whom approximately 10% were older, showed that patients over the age of 70 years had a significant risk of death, with a HR of 1.5 (p ≤ 0.0001) for limited-stage disease and a HR of 1.3 (p = 0.006) for extensive-stage disease. By contrast, a smaller study from 1991 reviewed 614 patients with limited- and extensive-stage disease from the University of Toronto

52

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SECTION IX  Chemotherapy and Targeted Agents for Lung Cancer 16 Females

8

Patients (%)

Patients (%)

10

6 4 Males

2 0

8 Males

4

73 19 75 19 77 19 79 19 81 19 83 19 85 19 87 19 89 19 91 19 93 19 95 19 97

00

19

20

97 19

94 19

91 19

88 19

85 19

82 19

79 19

19

76

0

73 19

Females

12

Year of Diagnosis

1.4%

Year of Diagnosis

4.9%

4.6%

A

10%

B Fig. 52.1. All-cause survival trends in (A) extensive-stage small cell lung cancer (SCLC) from 1973 to 2000 and (B) limited-stage SCLC from 1973 to 1997. (Modified with permission from Govindan R, Page N, Morgensztern D, et al. Changing epidemiology of small-cell lung cancer in the United States over the last 30 years: analysis of the Surveillance, Epidemiologic, and End Results database. J Clin Oncol. 2006;24(28):4539–4544.)

clinical trial database and showed that age over 70 years was not a significant predictor of a poorer outcome.84 A meta-analysis published by Pignon et al.83 in 1992 examined 2140 patients with limited-stage disease from 13 randomized trials that were designed to determine the role of thoracic radiotherapy combined with chemotherapy compared with chemotherapy alone. The relative risk of death in patients older than 70 years of age receiving combination therapy was 1.07, higher than that of older patients receiving chemotherapy alone. Since this meta-analysis, a review of two NCIC–CTG trials, BR.3 and BR.6, involving 618 patients with limited-stage SCLC who received the same chemotherapy regimen, showed no difference in survival between patients aged younger and older than 70 years.84 In the United States Intergroup study comparing once-daily and twice-daily radiotherapy for limited-stage SCLC, survival of younger patients was better than that for patients older than 70 years of age, with borderline significance (p = 0.051).85 Advanced age has been perceived as a strong rationale for the use of less aggressive therapies or no therapy, for fear of increasing toxicity. The literature is conflicting on this topic. Some retrospective reviews have reported that older age is associated with an increased risk of chemotherapy-related morbidity and mortality, whereas other studies have shown that despite toxicity and dose reductions, older patients receive a survival benefit with chemotherapy and/or radiotherapy compared with no treatment.86–93 A review by the Royal Marsden Hospital investigated the survival outcomes of 322 older patients (aged 70 years or older) with SCLC treated with chemotherapy from 1982 to 2003.94 Patients treated between 1995 and 2003 had a median survival of 43 weeks and a 1-year survival rate of 37%, compared with 25 weeks and 14%, respectively, for patients treated between 1982 and 1994 (p < 0.001). Patients who received a platinum combination had significantly better survival (p < 0.001) than patients who received single agents or another combination. No survival difference was found between a cisplatin and a carboplatin regimen. In a 2005 analysis of 54 older patients with limited-stage disease who participated in the North Central Cancer Treatment Group phase III trial of cisplatin and etoposide plus twice-daily or once-daily thoracic radiotherapy, survival was not different from that of their younger counterparts despite higher toxicity.95 These results corroborate the United States Intergroup findings. More data are needed from phase III trials regarding age-specific outcomes. To formally address the question of dose tolerability among older patients with SCLC, Ardizzoni et al.96 randomly assigned

patients aged 70 years or older either to four cycles of cisplatin (25 mg/m2) on days 1–2 with etoposide (60 mg/m2) IV on days 1–3 every 3 weeks (the attenuated-dose regimen; 28 patients) or to cisplatin (40 mg/m2) on days 1–2 plus etoposide (100 mg/ m2) IV on days 1–3 with prophylactic G-CSF (the full-dose regimen; 67 patients). Patients treated with the attenuated-dose regimen had a poorer outcome. The response rate was 39% in the attenuated-dose arm and 68% in the full-dose arm, with 1-year survival rates of 18% and 39%, respectively. No grade 3 or grade 4 myelotoxicity was reported in the attenuated-dose group, but 10% was noted in the full-dose group. There was one toxicityrelated death in the full-dose arm. The median number of cycles was four in both groups; 75% of patients in the attenuated-dose group and 72% in the full-dose group completed all planned cycles. Japanese investigators conducted a phase III trial to test whether nearly full doses of carboplatin and etoposide were superior to their standard regimen for older patients, which consisted of a split dose of cisplatin and etoposide. Older was defined as an age of 70 years or more with an ECOG performance status of 0 to 2. Patients younger than 70 years of age with a performance status of 3 were also allowed to participate.97 A total of 220 patients with extensive-stage SCLC were entered in the study, with 110 patients receiving carboplatin (AUC 5) on day 1 and etoposide (80 mg/m2 IV) on days 1–3 every 3–4 weeks for four cycles, and 109 patients receiving cisplatin (25 mg/m2) on days 1–3 with etoposide (80 mg/m2 IV) on days 1–3 every 3–4 weeks for four cycles. G-CSF was recommended in both treatment arms. As many as 92% of the patients met the criteria for older status, and 8% were poor risk. Objective response rates were identical in both treatment arms (73%). The median survival for the carboplatin and etoposide arm was 10.6 months and the 1-year survival rate was 41%, as compared with 9.9 months and 35%, respectively, for the split-dose cisplatin and etoposide arm. The rate of grade 3 or grade 4 neutropenia was high in both arms (95% for the carboplatin and etoposide arm and 90% for the split-dose cisplatin and etoposide arm). A significant difference in the rate of grade 3 or 4 thrombocytopenia was noted (56% for carboplatin and etoposide and 16% for split-dose cisplatin and etoposide; p = 0.01). There were four treatment-related deaths, three in the carboplatin and etoposide arm and one in the split-dose cisplatin and etoposide arm. The authors concluded that either regimen was a reasonable treatment option. The optimal chemotherapy regimen for older patients with SCLC is not known. We have learned that chronologic age

CHAPTER 52  Treatment of Extensive-Stage Small Cell Lung Cancer

should not be the sole determinant of treatment decisions. Physiologic age determined by comorbidities and performance status provides a clearer framework for guiding treatment decisions. Among patients aged 70 years or older, categories such as fit elderly (performance status of 0 or 1) and frail (performance status of 2–4) are emerging as beneficial terms in both the clinical and research settings. Despite the limited data, we are encouraged that a survival benefit can be achieved in a subset of older patients with acceptable toxicity. As the older population continues to increase, it is crucial that we develop evidence-based treatment plans. Additional clinical research in this population is needed. 

FIRST-LINE CHEMOTHERAPY FOR PATIENTS WITH POOR PERFORMANCE STATUS Performance status is universally recognized as an independent prognostic factor and typically correlates with the extent of tumor burden. Several retrospective studies of large databases have confirmed that shorter survival times among patients with SCLC are associated with poor performance status.98–100 Despite poor survival, patients with a performance status of 2 have routinely been eligible for clinical trials because our experience has taught us that patients whose poor performance status is attributed to tumor burden can respond to treatment with meaningful symptom palliation, improved performance status, and prolonged survival. However, the number of patients with poor performance status enrolling in clinical trials is low, and outcome data specific to performance status are not available. Clinical trials specifically including patients with poor performance status are few and were conducted more than 20 years ago. Two trials evaluated the oral formulation of etoposide because it was presumed to be efficacious but less toxic. The first study randomly assigned previously untreated patients with a performance status of 2–4 to either oral etoposide (50 mg twice a day) for 10 days (171 patients) or standard chemotherapy with cisplatin and etoposide or CAV (168 patients).101 The primary end point was palliation of symptoms at 3 months. The data safety and monitoring board stopped the trial early because of an inferior survival rate with oral etoposide. Survival was 130 days in the oral etoposide arm and 183 days in the standard arm (p = 0.03). Palliation rates were similar in both arms (41% vs. 46%, respectively). Grade 2 or greater hematologic toxicity was low in both arms (21% vs. 26%, respectively). The second trial, conducted by the London Lung Cancer Group, enrolled patients younger than 75 years of age with a performance status of 2 or 3 or patients equal to or older than 75 years of age with any performance status to receive 100 mg etoposide orally for 5 days (75 patients) or CAV alternating with cisplatin and etoposide (80 patients).102 The authors hypothesized that oral etoposide would produce a similar survival rate but with improved quality of life. This study, too, was stopped prematurely because of a significantly inferior survival rate in the oral etoposide arm. The median survival was 4.8 months, with a 1-year survival rate of 9.8% for oral etoposide, compared with 5.9 months and 19.3%, respectively, for CAV/cisplatin and etoposide (p < 0.05). Grade 3 and grade 4 toxicities were infrequent and similar between the treatment groups, except that more nausea and vomiting were reported in the CAV/cisplatin and etoposide arm. In another study, the Medical Research Council Lung Cancer Working Party randomly assigned 310 patients with poor performance status either to a four-drug regimen of etoposide, cyclophosphamide, methotrexate, and vincristine (control arm) or to a less intense two-drug regimen of etoposide and vincristine.103 No differences were found in symptom palliation, response rates, or survival times between the groups; however, more early deaths occurred with the four-drug regimen. Grade 2 or greater hematologic toxicity and mucositis were also worse with the four-drug regimen.

531

Despite the lack of data, experts generally agree that if a poor performance status is due to the disease itself, patients should be offered standard platinum-based chemotherapy with close monitoring because they have a reasonable chance of symptom palliation and prolonged survival. 

SECOND-LINE CHEMOTHERAPY Despite an initially high response rate to frontline platinum-based chemotherapy, extensive-stage SCLC will universally relapse, often within 3 to 6 months. The precise mechanisms of drug resistance that result in disease progression have not been well defined, but are likely to be multifactorial.104 Relapse generally heralds a poor outcome. Patients who receive no further therapy have a median survival of less than 3 months.105 Traditionally, patients who have previously received platinum-based therapy are grouped into two general categories reflecting the platinumsensitivity status of their disease.106 These categories include platinum sensitive, referring to relapse 90 days or more after the last dose of platinum; and platinum refractory, referring to relapse within 90 days of the last treatment. A third category, platinum resistant, has sometimes been assigned to patients whose disease progressed during platinum-based therapy; these patients are typically grouped together with the platinumrefractory category. The practice of categorizing disease according to platinum sensitivity arose from seminal observations in a small, single-arm phase II trial of salvage teniposide published in 1988.107 In that experience involving 50 patients, the response to second-line teniposide appeared to be associated with a previous response to platinum-based therapy and with the length of time between the last line of therapy and the initiation of teniposide. Since then, clinical trials in the second-line setting have routinely stratified patients according to the platinum sensitivity of their disease, resulting in higher sample sizes and increased resource use. More recent data from SWOG among patients treated in a series of phase II trials in the second-line setting and beyond strongly suggest that platinum-sensitivity status may no longer be relevant in the modern era. In a pooled analysis of 329 patients with platinum-treated SCLC enrolled in three SWOG phase II trials, 151 patients had platinum-sensitive disease and 178 had platinum-refractory disease.108 In this analysis, Cox proportional hazards models adjusted for baseline prognostic factors showed that only an elevated serum lactate dehydrogenase level (HR, 2.04; p < 0.001), male gender (HR, 1.36; p = 0.04), performance status of 1 (HR, 1.25; p = 0.02), and weight loss of at least 5% (HR, 1.53; p = 0.01) were independently associated with overall survival. Platinum-sensitivity status was not associated with either progression-free survival (HR, 1.11; p = 0.49) or overall survival (HR, 1.25; p = 0.14). However, these data must be prospectively validated before clinical use. As a historic footnote, it is notable that before the establishment of cisplatin and etoposide as the frontline regimen for extensive-stage SCLC, systemic therapy consisted mostly of other multiagent chemotherapy regimens, most commonly CAV. During that era, cisplatin plus etoposide was a typical treatment choice for SCLC that had failed to respond to CAV. In a phase III SWOG trial, 103 patients with disease relapse who were categorized as having good or poor risk were randomly assigned either to cisplatin and etoposide or to a four-drug regimen (carmustine, thiotepa, vincristine, and cyclophosphamide). For goodrisk patients, the median survival was 35 weeks with cisplatin and etoposide and 10 weeks with the four-drug regimen. Poor-risk patients in both treatment arms had an unfavorable response rate (9%) and a short median survival (10 to 12 weeks). In addition, CAV had no clear benefit for patients whose disease had failed to respond to cisplatin and etoposide.16,17,107 Subsequently, several phase III trials of newer approaches have evaluated the role of these systemic therapies in the pretreated setting (Table 52.2).

52

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SECTION IX  Chemotherapy and Targeted Agents for Lung Cancer

TABLE 52.2   Phase III Trials of Second-Line Chemotherapy Regimens for Small Cell Lung Cancer Author (y)

Regimen

No. of Patients

Overall Response Rate (%)

Median Survival

1-Year Survival Rate (%)

von Pawel et al.109 (1999)

Topotecan CAV

O’Brien et al.110 (2006)

Topotecan Best supportive care Topotecan (IV) Topotecan (PO) Topotecan (IV) Amrubicin

107 104 71 70 151 153 424 213

24.3 18.3 NR 7 21.9 18.3 31 17

25 wk 18.3 wk 25.5 wka 13.9 wk 35 wk 33 wk 7.5 mo 7.8 mo

14.2 14.4 NR NR 29 33 28 25

Eckardt et al.111 (2003) Jotte et al.112 (2011)   

ap

< 0.05. CAV, cyclophosphamide, doxorubicin, and vincristine; IV, intravenous; NR, not reported; PO, oral.   

The topoisomerase-1 inhibitor topotecan became available in the late 1990s and was found in early phase trials to have efficacy in previously treated SCLC. In a small phase III trial of 211 patients who had disease relapse more than 60 days after completion of induction therapy, topotecan (1.5 mg/m2/day on days 1–5 every 21 days) was found to be comparable in efficacy with conventional CAV.113 This trial had a primary end point of objective response, with a secondary end point of overall survival. At the final analysis, the overall response rates and median survival were not significantly different between the treatment arms (24.3% vs. 18.3% and 25 weeks vs. 24.7 weeks, respectively). In other words, topotecan failed to demonstrate a clear efficacy advantage over CAV. However, symptoms such as dyspnea, fatigue, anorexia, and hoarseness appeared to have been significantly improved with topotecan, despite a higher rate of grade 3 or grade 4 anemia and thrombocytopenia in that arm. The United States Food and Drug Administration (FDA) approved topotecan as second-line treatment for patients with platinum-sensitive, relapsed disease based on symptom control. An oral formulation of topotecan was later developed for patients’ convenience. To evaluate the efficacy of this formulation, 141 patients with disease relapse were randomly assigned to receive either oral topotecan (2.3 mg/m2/ day for 5 days) plus best supportive care or best supportive care alone every 21 days.109 Oral topotecan was superior to best supportive care, with a median survival time of 25.9 weeks, compared with 13.9 weeks for best supportive care (p = 0.01). A survival advantage was recognized in patients who had disease relapse both less than 60 days and more than 60 days from the end of their previous therapy. The most common toxicities with oral topotecan were hematologic events. Grade 3 and grade 4 neutropenia occurred in 61%, thrombocytopenia in 38%, and anemia in 25% of patients. Subsequently, oral topotecan was compared with IV topotecan in patients with platinum-sensitive disease that relapsed more than 90 days after chemotherapy.110 One hundred and fifty-three patients received oral topotecan (2.3 mg/m2/ day on days 1–5 every 21 days), and 151 patients received standard doses of IV topotecan (1.5 mg/m2/day on days 1–5 every 21 days). The response rate, median survival, and 1-year survival for the oral agent were 18.3%, 33 weeks, and 33%, respectively, compared with 21.9%, 35 weeks, and 29%, respectively, for IV administration. The incidence of grade 4 neutropenia was 47% with oral topotecan and 64% with the IV formulation. Quality of life appeared comparable between the arms. The FDA subsequently approved oral topotecan for the treatment of both sensitive and resistant/refractory SCLC. The early years of the 21st century saw a renewed interest in the role of anthracyclines in relapsed SCLC. Specifically, amrubicin was developed principally in Japan, and this agent is currently approved for commercial use in Japan for treating SCLC. Two phase II Japanese trials were initially completed. One trial enrolled 60 patients with relapsed SCLC, 16 of whom had relapse within 60 days of platinum-based therapy (refractory)

and 44 who had relapse after 60 days (sensitive). Patients received amrubicin (40 mg/m2) for 3 days every 3 weeks.112 A median of four cycles were delivered. Overall response rates were 50% (95% CI, 25% to 75%) and 52% (95% CI, 37% to 58%) for the refractory and sensitive cohorts, respectively. Overall median survival was 10.3 months and 11.6 months in the refractory and sensitive groups, respectively. Amrubicin resulted in high rates of myelotoxicity, with grade 3 or grade 4 neutropenia occurring in 83%. However, the rate of febrile neutropenia was only 5%, and no toxicity-related deaths were reported. In another phase II trial, 34 Japanese patients with relapsed SCLC (10 refractory, 24 sensitive) received amrubicin (45 mg/m2) for 3 days every 3 weeks.114 A median of four cycles were administered. Response rates were 60% (95% CI, 23% to 97%) for patients with refractory disease and 53% (95% CI, 35% to 70%) for patients with sensitive disease. The median survival was 6.8 months for patients with refractory disease and 10.4 months for patients with sensitive disease. Again, rates of myelosuppression were high, with grade 3 or grade 4 neutropenia reported for more than 70% of patients. At the higher amrubicin dose, however, the rate of febrile neutropenia was 35%, with one toxicity-related death from pneumonia. In a randomized phase II trial from Japan, 60 patients were assigned to receive either amrubicin (40 mg/m2 on days 1–3) or topotecan (1 mg/m2 IV on days 1–5) every 3 weeks.115 Overall response rates were 38% (95% CI, 20% to 56%) for amrubicin and 13% (95% CI, 1% to 25%) for topotecan. Among patients with so-called sensitive relapse, the response rates were 53% and 21% for the amrubicin and topotecan arms, respectively. Among patients with so-called refractory relapse, 17% responded to amrubicin compared with 0% for topotecan. The median progression-free survival was 3.5 months for patients in the amrubicin arm and 2.2 months for patients in the topotecan arm. In the United States, a randomized phase II study was performed to evaluate the response rate of amrubicin compared with topotecan in patients with so-called sensitive-relapse disease.116 Seventy-six patients were randomly assigned in a 2:1 fashion to receive the same dose of amrubicin (50 patients) or topotecan (26 patients) at 1.5 mg/m2 IV on days 1–5 every 3 weeks. Treatment with amrubicin was associated with a higher response rate (44% vs. 15%; p = 0.021). The median progression-free survival and overall survival were 4.5 months and 9.2 months, respectively, with amrubicin, and 3.3 months and 7.6 months, respectively, with topotecan. Grade 3 or higher neutropenia and thrombocytopenia appeared to be more frequent in the topotecan group (78% and 61% vs. 61% and 39%, respectively). No evidence of anthracycline-induced cardiotoxicity was reported. In a phase II North American trial of amrubicin in patients with refractory or resistant disease progressing within 90 days,117 75 patients received amrubicin at 40 mg/m2 on days 1–3 every 3 weeks. An overall response rate of 21.3% was reported, with an acceptable safety profile. Notably, no patient had early cardiotoxicity.

CHAPTER 52  Treatment of Extensive-Stage Small Cell Lung Cancer

Lastly, a large global phase III trial was conducted to compare amrubicin and topotecan.118 In this study, 637 patients were randomly assigned 2:1 to receive either amrubicin (40 mg/m2 IV) on days 1–3 (424 patients) or topotecan (1.5 mg/m2 IV) on days 1–5 (213 patients). The primary end point was overall survival. Patients with refractory relapse represented approximately 45% of the group. Grade 3 or higher adverse events (all p < 0.05) in the respective amrubicin and topotecan groups included neutropenia (41% vs. 53%), thrombocytopenia (21% vs. 54%), anemia (16% vs. 30%), infections (16% vs. 10%), and febrile neutropenia (10% vs. 4%). Transfusion rates were 32% in the amrubicin arm and 53% in the topotecan arm (p < 0.01). Despite a higher response rate in the amrubicin arm (31% vs. 17%; p = 0.0002), no difference was found in overall survival (HR, 0.88; p = 0.17). The median survival was 7.5 months and 7.8 months for the amrubicin and topotecan arms, respectively. This pivotal trial thus failed to show a survival benefit for amrubicin, precluding its commercial approval outside of Japan. Using the same regimen as that in the frontline setting as salvage therapy can also be an option for selected patients. Two small case series totaling 18 patients have reported outcomes on 10 patients who had disease relapse more than 10 months after the end of previous therapy. In this database, durable responses were seen after treatment with the original regimen.119,120 Thus considering salvage treatment with the original regimen is reasonable, particularly for patients with a long relapse-free interval. Other agents commonly used in the salvage setting (second line and beyond), often as single agents, are taxanes (docetaxel and paclitaxel), gemcitabine, vinorelbine, ifosfamide, and other topoisomerase inhibitors (irinotecan and oral etoposide).121 In general, clinical trials of these chemotherapeutic agents have yielded modest clinical benefits in this pretreated population, with response rates ranging from 10% to 20% and median survival of 2 months to 5 months. As expected, rates of response to subsequent therapies tend to be lower for patients with platinumrefractory disease, whereas the likelihood of response is better for patients with platinum-sensitive disease. In summary, the topoisomerase inhibitor topotecan (whether delivered IV or orally) represents a reasonable standard of care for patients with relapsed SCLC. In Japan, amrubicin is also approved for SCLC therapy. However, efficacy for either of these agents is fairly modest and must be weighed against their known toxicities, particularly myelosuppression. Given the generally poor outcome of patients with relapsed or refractory SCLC, participation in clinical trials with novel approaches represents the principal standard of care. 

NEW DRUGS Improvements in clinical outcome after treatment of patients with extensive-stage SCLC will necessitate more effective systemic treatments. Drug development for extensive-stage SCLC has, however, been slow during the past 20 years. In contrast to treatments for nonsmall cell lung cancer, neither cytotoxic agents with novel mechanisms of action nor targeted agents have entered the clinical arena for SCLC. Cytotoxic agents that have generated some interest in the past decade include belotecan, a novel camptothecin analog, and picoplatin, a platinum analog. Belotecan has been studied in patients with both untreated and pretreated extensive-stage SCLC. In untreated patients, a single-arm phase II study showed an overall response rate of 54%, a 4.6-month time to progression, and a 10.4-month median overall survival. As with other topoisomerase I inhibitors, myelosuppression was the main toxic effect, with grade 3 or grade 4 neutropenia occurring in more than 70% of patients.122 Subsequently, the combination of belotecan and cisplatin was investigated in two phase II studies, which found an overall response rate of greater than 70% and a median overall

533

survival of more than 10 months.123,124 At the time of publication, this doublet was undergoing phase III testing in untreated patients. In pretreated patients, the efficacy of belotecan seems to be no different from that of currently available topoisomerase I inhibitors. Three phase II studies demonstrated an overall response rate ranging from 14% to 24%, a median progressionfree survival of 1.6 months to 3.7 months, and a median overall survival of 4.0 months to 13.9 months.125–127 Of note, all three studies were performed in Asian populations, in whom this class of drugs seems to have more efficacy in SCLC. Taken together, the results obtained with belotecan suggest that this drug will not constitute a major step forward in the treatment of SCLC. In vitro studies identified picoplatin (ZD0473) as a platinum analog capable of circumventing resistance to both cisplatin and carboplatin. After single-agent phase II studies in which no compelling results were obtained, a randomized phase III study was launched in which 401 patients with SCLC relapse (within 6 months of completing first-line therapy) were randomly assigned in a 2:1 fashion compared with best supportive care. No difference was found in overall survival between the treatment arms.128 Despite progress in our understanding of genomic alterations and signaling pathways in SCLC,129–132 clinical experiments with tyrosine kinase inhibitors, other small-molecule inhibitors, and antiangiogenic agents have been disappointing (Table 52.3). Other therapeutic areas of interest more recently evaluated include epigenetic modifiers and inhibitors of DNA repair and the cell cycle. In a phase II study, romidepsin (a histone deacetylase inhibitor) did not show a meaningful benefit in relapsed extensive-stage disease SCLC (ED-SCLC).133 Another phase II study of the histone deacetylase inhibitor panobinostat was stopped prematurely as patients did not meet Response Evaluation Criteria in Solid Tumors criteria for partial response.134 Veliparib, a poly(ADP-ribose) polymerase inhibitor implicated in the DNA damage repair pathway, was recently studied in a small phase I dose-escalation study in combination with cisplatin and etoposide in newly diagnosed ED-SCLC.135 Of the seven evaluable patients, 14.3% had a complete response, 57.1% had a partial response, and 28.6% had stable disease. As such, veliparib continues to be under investigation, including in one study of the combination of temozolomide, another DNA damaging agent, and veliparib. Inhibition of aurora A kinase, which regulates cell cycle transit from G2 to cytokinesis, has shown promising preclinical activity and thus a phase I/II trial of alisertib was conducted in a variety of tumor types.136 One arm enrolled 60 patients with relapsed or refractory SCLC; objective partial responses of 21% (95% CI, 10% to 35%) were seen in this trial. A follow-up phase II trial combining alisertib with paclitaxel in patients with platinum-refractory ED-SCLC has completed accrual. Investigators hope that novel immune-modulating agents may alter the therapeutic landscape of SCLC. Mounting evidence suggests that these agents may work in concert with classic cytotoxic chemotherapy and, more importantly, with radiotherapy. Although phase III trials examining the role of tumor vaccines, mainly performed in the maintenance setting of responding patients, have been uniformly negative, results of early studies with immune checkpoint modulators have been encouraging. Ipilimumab, a monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4, has been studied in a randomized phase II study including 130 patients with extensive-stage SCLC not previously treated with chemotherapy.156 A total of 135 patients were treated with carboplatin and paclitaxel or the same regimen plus two schedules of ipilimumab. Although no differences were found in progression-free survival or overall survival, the so-called phased schedule of ipilimumab (i.e., administered after two courses of carboplatin and paclitaxel without ipilimumab) resulted in a higher immune-related progression-free survival and numerically increased overall survival (12.9 vs. 9.9 months). Concurrent ipilimumab and carboplatin and paclitaxel provided no benefit even

52

534

SECTION IX  Chemotherapy and Targeted Agents for Lung Cancer

TABLE 52.3   Selected Targets and Agents Studied for Small Cell Lung Cancer Target

Agent

Phase

Result

Comment

VEGF-A

Bevacizumab137

III

Negative

In combination with cisplatin + etoposide Statistically significant improvement in PFS but not OS

VEGFR-I–III VEGFR, PDGFR, Raf-1 VEGFR, PDGFR, Flt-3, RET, Kit VEGF-A, B

Cediranib138 Sorafenib139, thalidomide140 Sunitinib141 Aflibercept142 NGR-hTNF143 Vandetanib144 Imatinib145 Dasatinib,146 saracatinib147 Everolimus,148 temsirolimus149 Gefitinib150 Oblimersen,151 navitoclax,152 obatoclax,153 AT101154 R115777155 Alisertib136 Romidepsin,133 panobinostat134 Veliparib135

II II, III II, III II II II II II II II I/II

Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative Negative

II I/II II I

Negative 21% PR Negative Acceptable safety profile

VEGF, EGFR cKit Src mTOR EGFR BCl-2 RAS Aurora A kinase HDAC PARP   

cKit expression required Responses in EGFR MT patients

Relapsed/refractory disease In combination with cisplatin + etoposide in newly diagnosed ED-SCLC

BCl-2, B-cell CLL/lymphoma 2; ED-SCLC, extensive-stage disease small cell lung cancer; EGFR, epidermal growth factor receptor; Flt-3, Fms-like tyrosine kinase 3; HDAC, histone deacetylase; MT, mutated; mTOR, mammalian target of rapamycin; NGR-hTNF, CNGRC-human Tumor Necrosis Factor-alfa fusion protein; OS, overall survival; PARP, poly(ADP) ribose polymerase; PDGFR, platelet-derived growth factor receptor; PFS, progression-free survival; PR, partial response; RAS, rat sarcoma gene; RET, rearranged during transfection proto-oncogene; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor.   

in numerical terms for progression-free survival or overall survival. Near doubling of the incidence of grade 3 or grade 4 adverse events was observed when ipilimumab-containing regimens were compared with standard chemotherapy. These findings prompted a phase III clinical trial evaluating the combination with standard platinum and etoposide.157 In total, 1132 patients with newly diagnosed ED-SCLC were enrolled to randomized, blinded arms, with one arm treated with etoposide and platinum with placebo, and the other arm with etoposide and platinum and ipilimumab. As in the phase II study, ipilimumab or placebo was administered in a phased schedule. Unfortunately, the trial demonstrated no difference in median progression-free survival or overall survival between the arms. Patients treated with the combination of platinum, etoposide, and ipilimumab were found again to have a higher incidence of treatment-related diarrhea, colitis, and rash and more treatment-related deaths. Thus the combination of standard chemotherapy with ipilimumab did not result in improved efficacy in ED-SCLC but did result in added toxicity. Ipilimumab was also recently studied in combination with a programmed cell death protein 1 (PD1) inhibiting antibody, nivolumab, in the CheckMate 032 trial. This phase I/II trial enrolled patients with limited and extensive-stage SCLC who had progressed after platinum-based chemotherapy.158 Of the 216 patients enrolled, 98 were treated with nivolumab (3 mg/kg IV) every 2 weeks, with the remainder of patients enrolled into initial treatment with nivolumab (1 mg/kg IV) and ipilimumab (1 mg/kg IV) every 3 weeks. Patients who received the latter regimen could then undergo dose escalation such that 61 patients received nivolumab (1 mg/kg) and ipilimumab (3 mg/kg IV) every 3 weeks, and 54 received nivolumab (3 mg/kg) and ipilimumab (1 mg/kg) every 3 weeks, whereas three patients remained at the initial dose. All arms showed potential benefit, though treatment with nivolumab alone resulted in a modest 10% objective response rate. Although the study was not designed to detect efficacy differences between arms, the combination of nivolumab and ipilimumab did result in higher objective response rates (23% for nivolumab [1 mg/kg] + ipilimumab [3 mg/kg] and 19% for nivolumab [3 mg/kg] + ipilimumab [1 mg/kg], respectively).

However, patients treated with the combination discontinued therapy due to treatment-related adverse effects, and there were more grade 3 and grade 4 adverse effects with combination treatment, most commonly lipase elevation and diarrhea. In addition to the aforementioned data with nivolumab, PD1 inhibition in ED-SCLC was also investigated in the KEYNOTE-028 trial.159 This phase Ib trial has screened a cohort of 135 patients with ED-SCLC who had progressed on platinum-based chemotherapy, with 27% of patients subsequently testing positive for greater or equal to 1% PD1 ligand expression. Ultimately, 17 patients with ED-SCLC were treated with pembrolizumab (10 mg/kg IV) every 2 weeks. Of these patients, 25% had a partial response to treatment, with durable responses at greater than 16 weeks. There was also a high rate of drugrelated adverse events; although there was only one patient with a greater than or equal to grade 3 drug-related adverse event, 53% of drug-related adverse events were reported. As of this publication, final results of this trial have not been reported. As such, while immune checkpoint inhibition remains of interest, to date modest efficacy findings have been tempered by significant toxicity. A new target, DLL3, part of the Notch signaling pathway, has been identified due to its high expression in SCLC cells. DLL3 is thought to play a key role in the function and survival of tumor-initiating cells. An antibody–drug conjugate, rovalpituzumab tesirine, has been designed to bind DLL3. In a phase Ia/ Ib trial, patients with SCLC who had progressed after first- or second-line therapy were treated with rovalpituzumab tesirine.160 Although the trial was small and reported a modest partial response of 34% with 31% of patients achieving disease stability, duration of response was more than 178 days with no cases of disease progression. Moreover, although DLL3 status was not required for treatment, patients did require sufficient tumor sample for testing. About 67% of patients had tumor DLL3 expression greater than or equal to 50%; these patients tended to have better responses and an overall survival of 5.8 months. It is hoped that this novel targeted agent will demonstrate efficacy upon further investigation, and a phase II study is currently underway. 

CHAPTER 52  Treatment of Extensive-Stage Small Cell Lung Cancer

CONCLUSION The optimal first-line treatment for good performance score ED-SCLC, regardless of age, is a platinum doublet with either etoposide or irinotecan. Although poor performance status (ECOG PS 2–4) patients are less able to tolerate platinum doublets, because the disease itself attributes most to the deterioration of performance status, a platinum-based regimen at standard doses should be offered with close monitoring. For second-line treatment, the standard of care consists of the topoisomerase I inhibitor topotecan, and in Japan, damrubicin. Because the therapeutic results of second-line treatments remain poor, enrollment of relapsed ED-SCLC in clinical trials with novel agents is also an acceptable standard of care. No new agents with clinically relevant activity have been identified during the last two decades in ED-SCLC, underscoring the unmet need in this area.

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