Physical Address

304 North Cardinal St.
Dorchester Center, MA 02124

Treatment of Extensive-Stage Small Cell Lung Cancer


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 platinum-based 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-β-chloroethyl amine hydrochloride could cause tumor regression in more than 50% of patients. 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. In the 1990s, six new agents were discovered to have activity against SCLC in untreated patients, including paclitaxel, docetaxel, topotecan, irinotecan, vinorelbine, and gemcitabine. 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. 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. Furthermore, studies showed that simultaneous administration of multiple agents was more efficacious than the sequential administration of the same agents. 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. A meta-analysis of 36 trials demonstrated that regimens containing cisplatin and/or etoposide offered a significant survival advantage to patients with SCLC. 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. 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%. 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. 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. 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 ). 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. One hundred and fifty-four patients were randomly assigned to receive either four cycles of etoposide (100 mg/m 2 ) on days 1, 2, and 3 with cisplatin (80 mg/m 2 ) on day 1 every 3 weeks or four cycles of irinotecan (60 mg/m 2 ) on days 1, 8, and 15, and cisplatin (60 mg/m 2 ) 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. 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/m 2 ] with cisplatin [30 mg/m 2 ] given on days 1 and 8) with standard cisplatin and etoposide produced similar survival in both arms. In Europe, a different schedule of PI (irinotecan [65 mg/m 2 ] on days 1 and 8 with cisplatin [80 mg/m 2 ] on day 1) was assessed in comparison with standard cisplatin and etoposide. 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. Irinotecan was administered on days 1 and 8 with cisplatin on day 1, and cisplatin and etoposide 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.

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. (2002) PI
PE		 77
77		 84.4 a
67.5		 6.9 b
4.8		 12.8 c
9.4		 58.4
37.7
Lara, Jr. et al. (2009) PI
PE		 324
327		 60
57		 5.8
5.2		 9.9
9.1		 41
34
Hanna et al. (2006) PI
PE		 221
110		 48
44		 4.1
4.6		 9.3
10.2		 35
35
Zatloukal et al. (2010) PI
PE		 202
203		 39
47		 5.4
6.2		 10.2
9.7		 42
39
Kim et al. (2013) PI
PE		 173
189		 62 d
48		 6.5
5.8		 10.9
10.3		 NR
NR
Hermes et al. (2008) IC
EC		 105
104		 NR
NR		 NR
NR		 8.5
7.1		 37 b
19
Schmittel et al. (2011) IC
EC		 106
110		 54
52		 6.0
6.0		 10.0
9.0		 37
30
Eckardt et al. (2006) PT
PE		 389
395		 63
69		 6.0 b
6.2		 9.8
10.0		 31
31
Fink et al. (2012) PT
PE		 357
346		 56 e
46		 6.9 e
6.1		 10.3
9.4		 40
36
de Jong et al. (2007) CDE
CT		 102
101		 60
61		 4.9
5.2		 6.8
6.7		 24
26
Socinski et al. (2009) PemC
EC		 364
369		 31
52 f 		3.8
5.4 g 		8.1
10.6 g 		NR
NR
Kotani et al. (2012) AP
IP		 142
142		 78
72		 5.1
5.7		 15.3
18.3		 NR
NR
Mavroudis et al. (2001) PET
PE		 62
71		 50
48		 11.0 b
9.0		 9.5
10.5		 38
37
Reck et al. (2003) CET CEV 301
307		 72
69		 8.1 h
7.5		 12.7
11.7		 48
51
Niell et al. (2005) PET
PE		 293
294		 75
68		 6.0
5.9		 10.6
9.9		 38
37
Pujol et al. (2001) PCDE PE 117
109		 76 b
61		 7.2 i
6.3		 10.0
9.3		 40 j
29

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.

a p = 0.02.

b p = 0.003.

c p = 0.0004.

d p = 0.0064.

e p = 0.01.

f p < 0.001.

g p < 0.01.

h p = 0.033.

i p < 0.0001.

j p = 0.0067.

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. Drug dosages and schedules were unconventional and lower than other published regimens, with irinotecan (175 mg/m 2 ) and carboplatin (area under the curve [AUC] 4) administered on day 1, and etoposide (120 mg/m 2 ) 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/m 2 ) on days 1, 8, and 15 with carboplatin (AUC 5) or intravenous (IV) etoposide (140 mg/m 2 ) on days 1–3 with carboplatin (AUC 5). 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). 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. 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. 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. A phase III study, the Global Analysis of Pemetrexed in SCLC Extensive Stage, was designed to show noninferiority of pemetrexed (500 mg/m 2 ) 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. 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 progression-free survival was 3.8 months for pemetrexed and carboplatin and 5.4 months for etoposide and carboplatin ( p < 0.01), and the 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. Two hundred and eighty-four patients were randomly assigned to receive either amrubicin (35 mg/m 2 to 40 mg/m 2 ) on days 1–3 and cisplatin (60 mg/m 2 ) every 3 weeks or cisplatin (60 mg/m 2 ) on day 1 and irinotecan (60 mg/m 2 ) 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. 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. 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.

You're Reading a Preview

Become a Clinical Tree membership for Full access and enjoy Unlimited articles

Become membership

If you are a member. Log in here