The chemosensitivity of SCLC was first identified 50 years ago, with the recognition that methyl-bis-β-chloroethylamine hydrochloride could cause tumor regression in more than 50% of patients.² Older, active agents include nitrogen mustard, doxorubicin, methotrexate, ifosfamide, etoposide, teniposide, vincristine, vindesine, nitroureas, cisplatin, and its analog carboplatin.³ In the 1990s, six new agents were discovered to have activity against SCLC: paclitaxel, docetaxel, topotecan, irinotecan, vinorelbine, and gemcitabine in untreated and or previously treated patients (Table 58.1).³,⁴,⁵,⁶,⁷,⁸,⁹,¹⁰,¹¹,¹²,¹³,¹⁴,¹⁵,¹⁶,¹⁷,¹⁸,¹⁹,²⁰,²¹,²²,²³,²⁴,²⁵,²⁶,²⁷,²⁸,²⁹,³⁰,³¹,³²,³³,³⁴ This decade, two additional cytotoxic agents have been evaluated (Table 58.1). Pemetrexed, a multitargeted antifolate, an approved agent for the second-line treatment of advanced non-small cell lung cancer (NSCLC), showed no meaningful activity in previously treated SCLC patients in two small studies.²⁷,²⁸ However, pemetrexed was well tolerated and further evaluation focused on combinations with cisplatin and carboplatin. A randomized phase II trial evaluated the use of cisplatin or carboplatin plus pemetrexed in previously untreated ES-SCLC in 78 patients. Median survival time (MST) for cisplatin/pemetrexed was 7.6 months, with a 1-year survivorship of 33.4% and a response rate of 35% (95% confidence interval [CI], 20.6% to 51.7%). The MST for carboplatin/pemetrexed was 10.4 months, with a 1-year survivorship of 39% and a response rate of 39.5% (95% CI, 24.0 to 56.6). Median time to progression (TTP) for cisplatin/pemetrexed was 4.9 months and for carboplatin/pemetrexed was 4.5 months. Grade 3 and 4 hematologic toxicities included neutropenia (15.8% vs. 20.0%) and thrombocytopenia (13.2% vs. 22.9%) in the cisplatin/pemetrexed and carboplatin/pemetrexed treatment groups, respectively. These data compare favorably with other regimens for ES-SCLC.³⁶

An open-label phase III worldwide direct comparison of pemetrexed and carboplatin with the standard first-line etoposide and carboplatin chemotherapy in ES-SCLC is planned to enroll 1820 patients in 23 countries.³⁷

Amirubicin, a topoisomerase II inhibitor, has produced impressive responses in both untreated and treated SCLC.²⁹,³⁰,³¹,³²,³³,³⁴ The promising efficacy and/or tolerability of these drugs have led to their investigation in first-line combination regimens as well as their continued evaluation in the salvage setting.

In the 1970s, randomized trials clearly demonstrated the superiority of combination chemotherapy over single-agent therapy. Furthermore, they showed that simultaneous administration of multiple agents was more efficacious than the sequential administration of the same agents.³⁵,³⁸ Cyclophosphamide-based regimens were commonly used to treat SCLC, including CAV (cyclophosphamide, doxorubicin, and vincristine); CAE or CDE (cyclophosphamide, doxorubicin, and etoposide); and CEV (cyclophosphamide, etoposide, vincristine) until the introduction of cisplatin. Subsequently, randomized trials with the PE (cisplatin and etoposide) regimen were shown to be equally as effective as CAV and less toxic.³⁹,⁴⁰,⁴¹ A metaanalysis of 36 trials demonstrated that regimens containing cisplatin and/or etoposide offered a significant survival advantage to patients with SCLC.⁴² Thus, PE became the preferred regimen for treating ES-SCLC yielding objective response rates (ORR) of 65% to 85% with 10% to 20% complete response (CR) rates and an MS of 8 to 10 months.³⁹,⁴⁰,⁴¹ Full dose (FD) PE can also be combined with thoracic radiotherapy. In LS-SCLC PE plus twice-daily thoracic radiotherapy is the documented standard regimen when feasible producing an 87% ORR with a 56% CR rate, an MS of 23 months and a 5-year survival rate of 44%.⁴² Carboplatin is frequently substituted for cisplatin because of its more favorable toxicity profile. One small randomized trial comparing PE to CE (carboplatin and etoposide) in LS and ES patients showed similar efficacy but CE was significantly less toxic.⁴³

Novel Chemotherapy Years lapsed before the discovery of the newer cytotoxic agents described in Table 58.1. For the first time, an abundance of new agents were available to study and a renewed enthusiasm at the opportunity of improving survival for SCLC patients emerged. A wealth of phase I and II trials with novel combinations were launched. Table 58.2 summarized the results from those promising combinations that were evaluated in phase III trials.⁴⁴,⁴⁵,⁴⁶,⁴⁷,⁴⁸,⁴⁹,⁵⁰,⁵¹,⁵²,⁵³,⁵⁴,⁵⁵ Most provocative were the results from the Japanese trial comparing cisplatin and irinotecan (PI) to PE. This trial was halted prematurely after an interim analysis showed a survival benefit for PI.⁴⁴ One hundred fifty-four patients were randomized to receive four 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 PI, irinotecan 60 mg/m² on days 1, 8, and 15 with cisplatin 60 mg/m² on day 1. Patients treated with PI had a significantly better overall response rate, MS and 1-year survival rate as
compared to those treated with PE (84.4% vs. 67.5% [p = 0.02]; 12.8 vs. 9.4 months; 58.4% vs. 37.7% [p = 0.002]), respectively. The PI combination was associated with a higher rate of grades 3 and 4 diarrhea (p = 0.01), whereas the PE combination was associated with a higher rate of myelosuppression (p = 0.0001). A confirmatory trial using the identical schema by the Southwest Oncology Group (SWOG trial) failed to show a benefit for PI.⁴⁵ In this large 651-patient trial, all efficacy parameters were very similar except that there was a trend toward improved progressionfree survival (PFS) time for PI at 5.7 versus 5.2 months for PE (p = 0.07). Grade 3 or 4 neutropenia and thrombocytopenia were higher in the PE arm, whereas grade 3 or 4 nausea/vomiting and diarrhea were higher in the PI arm. The toxic death rates were low, 4% for PI and 5% for PE. A phase III superiority trial comparing a novel dose and schedule of the PI regimen (irinotecan 65 mg/m² with cisplatin 30 mg/m² both given on days 1 and 8) to standard PE produced similar survival times for both arms.⁴⁶ Two large phase III trial with topotecan, either oral or intravenous (IV) plus cisplatin were compared PE.⁴⁷,⁴⁸ No survival benefit was observed with the experimental topotecan regimen over standard PE. The IV topotecan regimen did show a significantly higher ORR that translated into a prolonged PFS time of 7 versus 6 months for PE (p = 0.004). A European study reported superior survival for irinotecan plus carboplatin over an oral etoposide and carboplatin combination; however, survival in both arms was less than 9 months.⁴⁹ Drug doses and schedules were unconventional and lower than other regimens with irinotecan 175 mg/m² and carboplatin (area under the curve [AUC] = 4) administered on day 1 and in the standard arm, the etoposide was administered at 120 mg/m² orally days 1 to 5 with carboplatin (AUC = 4 on day 1). In contrast, a carboplatin-based doublet with paclitaxel failed to meet its primary end point of improving PFS when compared to CDE.⁵⁰ Most disappointing was the recent failure of the novel regimen of pemetrexed and carboplatin (Pem/C). In a previous randomized phase II study of pemetrexed plus cisplatin or carboplatin, the carboplatin arm produced an MS of 10.4 months and was well tolerated.³⁶ The GALES (Global Analysis of Pemetrexed in SCLC Extensive Stage) was designed to show noninferiority of pemetrexed (500 mg/m²) plus carboplatin (AUC = 5) as compared to etoposide and carboplatin (EC). With 733 randomized patients, the study was terminated prematurely when the predefined PFS futility end point showed inferiority of the experimental arm.⁵¹ The median PFS time was 3.68 months for Pem/C and 5.32 months for EC (p < 0.0001). ORR also favored EC at 41% compared to 25% (p = 0.01). The preliminary overall survival (OS) time was 7.3 months for Pem/C and 9.6 months for EC. Significant neutropenia and more febrile neutropenia were seen in the EC arm. In contrast, deaths on therapy or within 30 days were higher for the pemetrexed arm 16% versus 10% (p = 0.032) and the toxic death rates were 1.4% versus 0 (p = 0.028), respectively. However, the causes of death were atypical and variable.

The favorable toxicity profiles of new agents led several investigators to explore the possibility of integrating them into an active doublet (Table 58.2). Three randomized trials showed that paclitaxel-containing triplets did not result in superior survival compared to traditional doublets; furthermore, they were associated with increased toxicity.⁵³,⁵⁴,⁵⁵ A four-drug regimen has also been evaluated. While building upon a doublet with newer agents was not successful, in a French study, cyclophosphamide and 4′-epidoxorubin were added to PE, the PCDE regimen, and showed a significant improvement in the CR rate (13% vs. 21%; p = 0.02) and OS (9.3 vs. 10.5 months; p = 0.0067) for PCDE over PE.⁵⁵ PCDE, however, was associated with significantly higher hematologic toxicity (22% of patients had documented infections compared with 8% in the PE arm; p = 0.0038). Toxic death rates were similar, 9% for PCDE and 5.5% for PE.

In summary, overall, no major breakthroughs have been seen with newer chemotherapy agents in the first-line setting and currently, platinum plus etoposide remains the standard of care for the treatment of SCLC.

Alternative chemotherapy strategies focus on modifications of the doses and schedules of established regimens, including dose intensification, alternating non-cross-resistant chemotherapy and prolonged treatment duration. Table 58.3 summarizes recent trial results employing these different approaches.

Dose Intensification Dose intensity is defined as the dose per square meter per week. Dose intensification can be
accomplished by either increasing the dose or shortening the interval between doses (dose density). Preclinical tumor models have illustrated that one of the simplest methods to overcoming drug resistance was drug dose escalation.⁵⁶ In the late 1970s, Cohen et al.⁵⁷ randomized patients to receive standard dosages of cyclophosphamide, methotrexate, and lomustine or a higher dose of cyclophosphamide and lomustine and a standard methotrexate dose. Hande et al.⁵⁸ randomized patients with ED SCLC to high dose or low dose methotrexate with leucovorin rescue in combination with cyclophosphamide, doxorubicin, and vincristine alternating with cycles of VP-16, vincristine, and hexamethylmelamine (negative study). They observed both a higher overall response rate and prolonged survival in the highdose chemotherapy group. Long-term survivors were observed only among those patients given high-dose chemotherapy. These studies spawned a series of seven randomized trials comparing high dose to conventional dose chemotherapy in LS- and ESSCLC patients.⁵⁹,⁶⁰,⁶¹,⁶²,⁶³,⁶⁴,⁶⁵ Most of these trials were conducted in the 1980s and did not show a clinical benefit. The Spanish Lung Cancer Group recently reexamined this question (Table 58.3).⁶⁴ They compared high-dose epirubicin at 100 mg/m² plus cisplatin 100 mg/m² administered on day 1 to standard PE (cisplatin 100 mg/m², day 1 and etoposide 100 mg/m², days 1 to 3) in 402 SCLC patients. Efficacy results were similar between the two arms. For LS patients, one study published in 1989 showed a superior 2-year survival rate of 43% when the dose of cisplatin and cyclophosamide was increased by 20% in the first cycle of a PCDE regimen versus 23% for standard PCDE.⁶⁵

Dose dense regimens have shown mixed results. CODE, an intense weekly regimen of cisplatin 25 mg/m² for 9 consecutive weeks; vincristine 1 mg/m² on even weeks for 9 weeks; with doxorubicin 40 mg/m² and etoposide 80 mg/² days 1 to 3 on odd weeks for 9 weeks, reported an impressive 2-year survival rate of 30% in 48 patients with ES-SCLC.⁶⁶ Importantly, the investigators were able to administer close to the intended FDs of all four agents, thereby increasing the dose intensity by twofold. The National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG) in collaboration with SWOG conducted a phase III trial comparing the promising CODE regimen to conventional alternating CAV/PE in patients with ES-SCLC.⁶⁷ Response rates were higher in the CODE arm, but there was no difference in PFS or OS. Although rates of neutropenia and fever were similar, toxic deaths occurred in 9 of 110 patients receiving CODE compared to only 1 of 109 patients given CAV/PE (p = 0.42). Given the high toxic death rate and similar efficacy, CODE was not recommended and the trial was closed prematurely. The Japanese subsequently demonstrated that the addition of 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 vs. 32 weeks; p = 0.0004).⁶⁸ This led to a phase III trial comparing CODE + G-CSF versus CAV/PE.⁶⁹ The response rate was significantly higher for CODE but, once again, no survival advantage was observed. The toxic death rate with CODE + G-CSF was low with only four reported cases.

Seven additional phase III trials incorporating a dose dense strategy with or without colony-stimulating factors have been conducted in Europe.⁷⁰,⁷¹,⁷²,⁷³,⁷⁴,⁷⁵,⁷⁶,⁷⁷ One trial showed a survival advantage for the dose dense arm. This trial performed by the British Medical Research Council (MRC) randomized 403 patients to receive CAE in 2 or 3 weekly schedules.⁷⁴ In this trial, a 34% escalation in dose density was achieved. Although the response rates in the two arms were similar, there was a significant improvement in the CR rate (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 in patients with extensive disease was as large as for limited disease patients. Other subset analyses in LS patients have shown opposing results. Steward et al.⁷³ showed a significant survival benefit for dose intensification, whereas Ardizzoni et al.⁷⁶ showed an inferior survival for the intensified regimen.

A possible explanation for the failure of the prior trials is that the dose intensity was insufficient to produce a survival benefit. To definitively answer the dose intensification question, studies emerged employing stem cell rescue that could allow for a 200% to 300% dose escalation. Multiple, small studies have shown this approach to be feasible. Early studies focused on patients who had achieved a response with conventional cytotoxic therapy who then received high-dose consolidation with stem cell rescue. A randomized trial testing this late-intensification strategy was reported by Humblet et al.⁷⁷ One hundred one patients received standard induction chemotherapy and forty-five chemotherapy-sensitive patients were randomized to receive one additional cycle with high-dose cyclophosphamide, carmustine (BCNU), and etoposide or conventional doses of the same drugs. In this highly selected group of patients, the median OS was 68 weeks for the high-dose arm compared to 55 weeks for the conventional therapy (p = 0.13).

The improved safety and feasibility of peripheral blood stem cells (PBSC) transplantation has largely replaced autologous marrow transplants. The Japanese reported promising results from a phase II study of high-dose ICE (ifosfamide, carboplatin, and etoposide) with autologous PBSC transplantation in 18 patients with LD-SCLC after concurrent, hyperfractionated chemoradiotherapy.⁷⁸ The CR was 61% and the MST was 36.4 months. One toxic death was reported. A randomized trial based on these results is ongoing.

Three randomized trials using high-dose ICE chemotherapy with peripheral blood rescue as first-line treatment for SCLC have been reported.⁷⁹,⁸⁰,⁸¹ The largest trial with 318 predominantly LS-SCLC patients compared six cycles of a dose dense (every 14 days) ICE regimen followed by G-CSF mobilized whole blood hematopoietic progenitors, to six cycles of the standard every 28-day ICE regimen.⁷⁹ Despite doubling of the median dose intensity with the dose dense regimen (182% vs. 88%, respectively), the MST and the 2-year survival rates were comparable, 14.4 months and 22% versus 13.9 months and 19%, respectively. In contrast, an identical study by Buchholz et al.⁸⁰ was halted after 70 patients were enrolled. They reported a favorable MS of 30.3 months (p = 0.001), a 2-year survival rate of 55%, and TTP of 15 months (p = 0.0001)
for the dose intense arm versus an MS of 18.5 months, 2-year survival rate of 39%, and TTP 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.⁸¹ The study 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 did not translate into a survival benefit with a MST of 18.1 months and a 3-year survival rate of 18% versus 14.4 months and 19%, respectively, for the standard ICE arm. None of the subgroups benefited from high-dose ICE.

Overall, the majority of trials employing a dose intensification strategy did not produce a survival advantage over standard therapy for patients with ES-SCLC and were typically associated with greater toxicity. This approach should be abandoned in extensive disease. In LS-SCLC, the optimal drug doses remain unclear with several studies suggesting a possible benefit. Continued evaluation of dose intensity in this 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 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.⁸² suggested that alternating two non-cross-resistant chemotherapy regimens of relatively comparable efficacy potentially could minimize the development of drug resistance while avoiding excessive host toxicity.⁸³ This strategy was particularly appealing for SCLC because both CAV and PE are highly active against SCLC and contain agents from divergent drug classes. Three randomized phase III trials were performed comparing CAV to CAV alternating with PE.³⁹,⁴⁰,⁸⁴ The United States and Japanese studies observed similar efficacy between the study arms, whereas the NCIC-CTG reported superior efficacy for the alternating regimen with an overall response rate of 80% versus 63% (p < 0.002) and a survival time of 9.6 versus 8.0 months (p = 0.03). Investigators at NCIC-CTG went on to test this approach in patients with limited disease SCLC.⁸⁴ Patients were randomized between two induction regimens either alternating CAV/PE or sequential therapy with three cycles of CAV followed by three cycles of PE. Chemotherapy was followed by radiotherapy in responding patients. No significant differences in therapeutic outcomes were observed between the two study groups. SWOG conducted a similar study and found no advantage for the alternating CAV/PE regimen over the EVAC (etoposide, vincristine, adraimycin, and cyclophosphamide) regimen in LS patients.⁸⁵