Systemic Therapy for Small Cell Lung Cancer

780 Original Article

Benjamin Levy, MDa; Ashish Saxena, MD, PhDb; and Bryan J. Schneider, MDb

Abstract mall cell lung cancer (SCLC) constitutes approxi- Small cell lung cancer is an aggressive tumor characterized by ge- S netic complexity, rapid doubling time, and early development of mately 15% of all lung cancers, with an estimated 33,900 1 disseminated disease. Unfortunately, few chemotherapeutic ad- new cases occurring in the United States in 2012. SCLC vances have been made in the treatment of extensive-stage dis- is an aggressive tumor characterized by genetic complexi- ease, and cisplatin/etoposide has remained the standard of care ty, rapid doubling time, and early development of dissem- for more than 30 years. Other regimens with comparable efficacy inated disease. Approximately 60% to 70% of patients include cisplatin/irinotecan and carboplatin/etoposide. Each of these combinations is associated with a different toxicity profile present with extensive-stage disease (ES-SCLC) that is that must be considered when selecting an initial regimen. Sev- beyond curative potential. Despite response rates of up eral strategies, including maintenance chemotherapy, 3-drug com- to 80% with induction chemotherapy, most patients will binations, alternating combination chemotherapy regimens, and inevitably experience disease relapse and die. Unfortu- high-dose chemotherapy, have consistently failed to demonstrate nately, scientific research has yielded few advances over improvements in survival when compared with 4 to 6 cycles of the past 30 years, resulting in a dismal median survival platinum doublets. Several options are available for patients who experience progression during or relapse after induction therapy, time for ES-SCLC of 8 to 10 months. However, renewed although topotecan is the only FDA-approved agent for second- interest has been shown in characterizing the biologi- line treatment. Recently, scientific efforts have identified poten- cal pathways responsible for tumor growth, leading to tially actionable genetic alterations in small cell tumors that may the development of new chemotherapeutic and targeted lead to the development of effective, targeted therapies. (JNCCN agents. This article reviews the current role of systemic 2013;11:780–787) chemotherapy in ES-SCLC, unsuccessful therapeutic approaches, and the therapeutic implications of emerging treatment strategies in this disease.

Platinum Versus Non–Platinum-Based Regimens Initial clinical trials evaluating chemotherapy for SCLC used single-agent therapy, including cyclophosphamide, methotrexate, and vincristine.2,3 Alkylator-based combination chemotherapy regimens, such as cyclophos- From the aDivision of Hematology/Oncology, Department of Internal Medicine, Beth Israel Comprehensive Cancer Center, and phamide, doxorubicin, and vincristine (CAV), were the bDivision of Hematology/Oncology, Department of Internal the first to show improvement in overall survival (OS) Medicine, Weill Cornell Medical College, New York, New York. Submitted January 2, 2013; accepted for publication compared with single-agent therapy, yielding response March 27, 2013. rates of 60% to 80% and median survival times of 7 The authors have disclosed that they have no financial interests, 4,5 arrangements, affiliations, or commercial interests with the to 10 months. These results led to the evaluation of manufacturers of any products discussed in this article or their many combination therapies, most notably cisplatin/et- competitors. Correspondence: Bryan J. Schneider, MD, Weill Cornell Medical oposide (EP). Two phase III studies suggested improved College, 525 East 68th Street, Payson Pavilion, 3rd Floor, New York, clinical benefit with EP over nonplatinum regimens. NY 10021. E-mail: [email protected] Sundstrom et al6 randomized 436 patients with both

Systemic Therapy for Small Cell Lung Cancer limited (n=214) and extensive disease (n=222) to platinum-based regimens compared with non–plat- EP or cyclophosphamide, epirubicin, and vincristine inum-based therapies.11 Although platinum-based (CEV). Although this study reported an improvement therapy did show a significantly higher rate of com- in median OS with EP (10.2 vs 7.8 mo; P=.0004), this plete response, no differences in overall tumor re- benefit was restricted to patients with limited-stage sponse (relative risk [RR], 1.09; 95% CI, 0.97–1.21) disease. A nonsignificant improvement in median OS or 1-year survival (RR, 1.08; 95% CI, 0.68–1.71) were for patients with ES-SCLC was identified (8.4 vs 6.5 seen in patients with ES-SCLC. In addition, plati- mo; P=.21). Quality-of-life analysis revealed no sig- num-based treatment was associated with higher rates nificant differences between the treatment arms. The of anemia (RR, 1.6; 95% CI, 1.22–2.08), thrombocy- Manchester Lung Cancer Group7 randomized 280 pa- topenia (RR, 2.10; 95% CI, 1.54–2.86), and nausea tients with limited-stage (n=165) and extensive-stage and vomiting (RR, 1.51; 95% CI, 1.20–1.90). Despite disease (n=112) to either EP or ACE (doxorubicin, the Cochrane review, EP remains the most accepted cyclophosphamide, and etoposide). In contrast to the initial treatment of ES-SCLC in the United States. study by Sundstrom et al,6 no difference was seen in This is supported by an acceptable and more easily response rate (77% vs 72%) or 1-year survival (34% managed toxicity profile compared with multidrug vs 38%; P=.497) between EP and ACE, respective- nonplatinum regimens, and the survival advantage ly. Additionally, no difference in the 1-year survival shown in the 2 aforementioned meta-analyses. rate was seen in the subset of patients with ES-SCLC (17% and 15%; P=.9). More grade 3/4 adverse events occurred in the ACE arm, including anemia (27% vs Etoposide Versus Irinotecan 18%; P=.03), neutropenia (90% vs 57%; P<.005), The combination of irinotecan with cisplatin (IP) and infection (73% vs 29%; P<.0005), leading to is also an effective regimen for untreated ES-SCLC. more days of hospitalization and greater intravenous A median OS of 13 months was demonstrated in antibiotic use. This trial and several others suggest- a small phase II study,12 and the Japanese Clinical ed that EP may be the optimal choice for the initial Oncology Group (JCOG) subsequently compared treatment of ES-SCLC given the comparable clinical IP with EP in a randomized phase III study of 154 benefit and favorable toxicity profile compared with chemo-naïve patients with ES-SCLC. However, multidrug, nonplatinum therapy. this study was stopped prematurely when an interim Because of conflicting results of randomized stud- analysis revealed a longer median OS with the IP ies, several meta-analyses have evaluated platinum regimen (12.8 vs 9.4 mo; P=.02).13 Although more versus nonplatinum regimens to identify a superior grade 3/4 neutropenia was seen in the EP group treatment approach.8–11 Pujol et al8 evaluated 4054 (92.2% vs 65.3%; P<.0001), more grade 3/4 diarrhea patients from 19 studies and found a significant re- was identified in the IP group (16% vs 0%; P<.001). duction in risk of death at 1 year (hazard ratio [HR], This study generated significant interest in irinote- 0.8; 95% CI, 0.69–0.93; P=.002) for patients ran- can as the preferred agent in the front-line setting. domized to platinum-based regimens. Importantly, However, 3 subsequent phase III studies involving the benefit was not associated with increased risk Western patients failed to confirm a survival advan- of treatment-related mortality. Similarly, in a meta- tage of IP over EP14–16 (Table 1). analysis of 7173 patients from 36 trials, the European Hanna et al14 randomized 331 patients with ES- Lung Cancer Working Party showed improved out- SCLC to IP or EP and found no statistically signifi- comes with platinum-based treatment. Specifically, cant difference in the response rate (48% vs 43.6%) a survival advantage was demonstrated with the use or median OS (9.3 vs 10.2 mo; P=.74). This trial of regimens containing either etoposide without cis- has been criticized for using different chemotherapy platin (HR, 0.72; CI, 0.67–0.78; P<.001) or EP (HR, doses and schedules than the JCOG trial. However, 0.57; CI, 0.51–0.64; P<.001) compared with non- similar findings were identified in a phase III SWOG platinum, non-etoposide regimens.9 study that randomized 651 patients to the identical In contrast to these results, a recent meta-analysis doses and schedules of IP and EP used in the JCOG of 5530 patients from 29 trials by the Cochrane Col- study. Again, no difference was seen between IP and laboration failed to show a significant benefit with EP in tumor response rate (60% vs 57%; P=.56) or

Levy et al

Table 1 Phase III Studies Comparing Irinotecan and Cisplatin Versus Etoposide and Cisplatin for Extensive-Stage Small Cell Lung Cancer Study Arm n ORR (%) PFS (mo) OS (mo) P Value Noda et al13 Cisplatin, 80 mg/m2 q3wk 77 67.5 4.8 9.4 .002 Etoposide, 100 mg/m2 days 1–3 q3wk Cisplatin, 60 mg/m2 q4wk 77 84.4 6.9 12.8 Irinotecan, 60 mg/m2 days 1, 8, 15 q4wk Hanna et al14 Cisplatin, 60 mg/m2 day 1 q3wk 110 50.9 4.6 10.2 .74 Etoposide, 120 mg/m2 days 1–3 q3wk Cisplatin, 30 mg/m2 days 1, 8 q3wk 221 52.1 4.1 9.3 Irinotecan, 65 mg/m2 days 1, 8 q3wk Lara et al15 Cisplatin, 80 mg/m2 day 1 q3wk 327 57.0 5.2 9.1 .71 Etoposide, 100 mg/m2 days 1–3 q3wk Cisplatin, 60 mg/m2 day 1 q4wk 324 60.0 5.7 9.9 Irinotecan, 60 mg/m2 days 1, 8, 15 q4wk Zatloukal et Cisplatin, 80 mg/m2 day 1 q3wk 203 39.1 NR 10.2 .06 al16 Etoposide, 100 mg/m2 days 1–3 q3wk Cisplatin, 80 mg/m2 day 1 q3wk 202 46.6 NR 9.7 Irinotecan, 65 mg/m2 days 1, 8 q3wk

Abbreviations: NR, not reported; ORR, overall response rate; OS, overall survival; PFS, progression-free survival.

median OS (9.9 vs 9.1 mo; P=.71).15 Similar to the Cisplatin Versus Carboplatin JCOG study, more grade 3/4 neutropenia in the EP Although EP has become a preferred initial regimen arm (68% vs 33%) and more grade 3/4 diarrhea in for ES-SCLC in the United States, the undesirable the IP arm (19% vs 3%) was observed. In an effort to reconcile the discrepant outcomes and toxicities toxicity profile of cisplatin (including severe nausea, shown in patients treated with irinotecan in these nephrotoxicity, ototoxicity, and peripheral neuro- studies, the SWOG trial assayed patient DNA for pathy) has led to greater use of carboplatin. Re- genetic polymorphisms involved in irinotecan me- cently, a meta-analysis of 663 patients from 4 tri- tabolism. Although single polymorphisms in the als compared cisplatin-based therapy (n=328) and ABCB1 and UGT1A1 genes were associated with carboplatin-based therapy (n=325) for first-line increased risk of diarrhea and neutropenia, respec- treatment of SCLC.17 This meta-analysis found no tively, neither genotype correlated with efficacy out- difference between cisplatin and carboplatin in re- comes (progression-free survival [PFS], OS). In summary, although IP was found to be superior sponse rate (67.1% vs 66%; P=.83), median PFS (5.5 to EP in one Japanese study, larger phase III studies and 5.3 mo; P=.25) or median OS (9.6 and 9.4 mo; failed to show similar results in Western patients. Al- P=.37), respectively. Although carboplatin-based though EP is associated with more myelosuppression, regimens were associated with more grade 3/4 myelo- this toxicity is typically less distressing for patients suppression, a higher incidence of any-grade nausea/ when compared with the diarrhea associated with vomiting, neurotoxicity, and renal toxicity was seen irinotecan. Finally, the SWOG trial suggested that in patients treated with cisplatin-based regimens. specific genetic polymorphisms correlated with spe- Results of this meta-analysis suggest that carbopla- cific toxicities, but whether pharmacogenomic dif- tin-based therapy is at least as effective as cisplatin- ferences can explain population-related differences in outcome or toxicity with irinotecan remains un- based regimens, with a more manageable toxicity clear. Both regimens are acceptable for initial treat- profile. Therefore, EP should be considered an ac- ment of ES-SCLC, and the toxicity profile of each ceptable front-line therapy for ES-SCLC, especially should guide the clinician’s choice. for patients with contraindications to cisplatin.

Systemic Therapy for Small Cell Lung Cancer

Further Chemotherapeutic Strategies to 6 cycles,30–32 induction chemotherapy followed 33,34 Because of a plateau in survival rates with standard che- by switch maintenance etoposide or topotecan, motherapy regimens, additional strategies have been and induction cytotoxic therapy followed by switch investigated for ES-SCLC. These include adding a maintenance vandetanib, thalidomide, or interferon- 35–42 third agent to a standard 2-drug regimen, maintenance based therapy have not improved survival in a chemotherapy, alternating combination chemotherapy meaningful way compared with standard chemo- regimens, and high-dose chemotherapy with growth therapy for 4 to 6 cycles. Supporting these results factor support and/or hematopoietic stem cell rescue.18 is a recent meta-analysis of 3688 patients from 21 Although a handful of studies incorporating these strat- randomized controlled trials of maintenance therapy egies have shown a modest survival advantage, most that showed no statistical advantage in median PFS have failed to show a consistent benefit. The 2 strate- (HR, 0.98; 95% CI, 0.91–1.06; P=.63) or OS (HR, 43 gies that have garnered the most attention are high-dose 0.93; 95% CI, 0.87–1.00; P=.05). Currently, main- chemotherapy and maintenance therapy. tenance therapy for ES-SCLC should not be consid- In attempts to exploit the inherent chemosensi- ered outside of a clinical trial. tivity of ES-SCLC, several investigators have evaluated the role of higher-dose chemotherapy (adminis- tering up to 2 times the conventional doses) with and Treatment of Relapsed/Resistant Disease without growth factor or stem cell support. A phase II A durable response to initial platinum-based chemo- study using high-dose cyclophosphamide, methotrex- therapy beyond 3 months of the last cycle is deemed ate, and lomustine initially reported a response rate of chemosensitive disease. Progression during front-line 96% (complete response rate 30%).19 However, this therapy or within 3 months of completion is con- strategy has failed to demonstrate a consistent survival sidered chemoresistant disease.44 Patients with the advantage in phase III studies. Ihde et al20 randomized latter typically derive less benefit from second-line 90 patients with ES-SCLC to 2 cycles of high-dose therapies and, in the absence of any further therapy, EP (cisplatin, 27 mg/m2 day 1–5; etoposide, 80 mg/m2 have a median OS of approximately 3 months.45 Un- day 1–5 every 3 weeks) or standard-dose EP (cisplatin, fortunately, few phase III clinical trials have been 80 mg/m2 day 1; etoposide, 80 mg/m2 day 1–3 every 3 performed for relapsed/resistant ES-SCLC. Patients weeks) followed by standard-dose EP for cycle 3 and who experience recurrence beyond 6 months after 4 in both arms. No difference in complete response completing first-line therapy are generally retreated rate (23% vs 22%; P=.99) or median OS (10.7 and with the initial regimen. This strategy has shown re- 11.4 months; P=.68) was identified, and more hema- sponse rates of 50% to 67% and a median survival of tologic toxicity was reported in the high-dose arm. 5 to 6 months.46 Growth factors (granulocyte colony-stimulating fac- Several options are available for patients who tor, granulocyte-macrophage colony-stimulating fac- relapse 3 to 6 months after completing initial che- tor) have been evaluated in combination with high- motherapy. Currently, topotecan is the only FDA- dose chemotherapy in 3 phase III studies. Although approved agent for second-line treatment of SCLC. one showed a modest improvement in survival (HR, A phase III trial of intravenous topotecan versus 0.8; 95% CI, 0.65–0.99; P<.04),21 the other 2 showed CAV enrolled 200 patients with relapsed SCLC, but no significant benefit in tumor response rate or -me excluded patients with a progression-free interval of dian OS, with more hematologic and nonhematolog- less than 2 months after initial therapy.47 The rates ic toxicities noted in the high-dose arms.22,23 Similar of response (24.3% vs 18.3%) and 1-year survival outcomes showing higher rates of toxicity with no (14.2% vs 14.4%) were similar for topotecan and improvement in survival have been noted in 2 phase CAV, respectively. Topotecan provided better con- III studies comparing high-dose ICE (ifosfamide, car- trol of dyspnea, anorexia, and fatigue. In retrospec- boplatin, etoposide) followed by autologous stem cell tive analyses, topotecan has shown clinical benefit rescue versus standard-dose ICE.24,25 in patients older than 65 years and patients with a Maintenance strategies have repeatedly failed Zubrod performance status of 2.48,49 A phase III study to show a survival advantage in ES-SCLC.26–29 Con- compared oral topotecan with best supportive care tinuation of the induction chemotherapy beyond 4 and found a median OS of 6.0 versus 3.2 months,

Levy et al

respectively.50 This was the first trial to clearly show treatment of SCLC in Japan.63 A phase III trial in the a survival benefit for second-line chemotherapy in United States of amrubicin versus topotecan showed ES-SCLC. Another phase III trial compared second- response rates of 31% and 17%, respectively.64 How- line oral topotecan with intravenous topotecan in ever, OS was similar in both arms and thus far there patients with chemosensitive ES-SCLC and showed are no plans to obtain FDA approval for the drug in similar response rates and median OS with compa- the United States. rable tolerability.51 Statistically, the study was unable to prove noninferiority of oral versus intravenous topotecan. Emerging Therapies Commonly used agents in relapsed/resistant Recently, a greater understanding of the molecular SCLC include irinotecan, oral etoposide, paclitax- pathways driving carcinogenesis has led to the devel- el, and docetaxel. Weekly irinotecan has shown a opment of effective, novel agents in multiple tumor response rate of 50% and a median survival of 6.1 types, including non–small cell lung cancer. Unfor- months in a small phase II study.52 Oral etoposide tunately, SCLC has not shared these advances, be- has shown response rates of 23% to 45% and median cause targeted agents have repeatedly failed to show survivals of 3.5 to 4.1 months.53,54 Patients who had improvements in survival, including antiangiogen- not responded to front-line therapy did not respond esis drugs (bevacizumab, thalidomide, sorafenib, to oral etoposide, suggesting its lack of clinical ben- sunitinib, vandetanib), inhibitors of cell-signaling efit for chemoresistant disease. Paclitaxel showed a pathways (imatinib, dasatinib, gefitinib, everolimus, response rate of 29% with a median survival of 3.3 tipifarnib), and vaccine therapy (BEC-2 vaccine, months in patients who had received at least 2 prior BB-10901). In addition to these failed agents, very lines of treatment.55 Because of its activity in this little insight has been gained into predictive bio- heavily pretreated population, paclitaxel is a reason- markers that may help define patients most likely to able option for chemoresistant disease. Two small benefit from a targeted approach. phase II trials with docetaxel have shown response Despite these well-conceived but disappoint- rates of 13% and 25%; however, no survival data ing approaches, a significant effort remains to bet- were reported.56,57 ter characterize SCLC tumor biology in an attempt Gemcitabine and vinorelbine have also shown to develop more effective therapies (Table 2). For modest clinical benefit as monotherapy for SCLC example, the antiapoptotic protein bcl-2 and a key in the second-line setting.58,59 Ifosfamide has shown transcription factor of the hedgehog pathway GLI1 activity in chemoresistant disease, although it is not are overexpressed in SCLC. Defining these 2 path- often used in the palliative setting because of the ways has led to the clinical development and current inconvenience of prolonged infusions and its unde- testing of obatoclax and vismodegib, 2 small mo- sirable toxicities.60 A small phase II study of CAV lecular inhibitors of apoptotic and hedgehog path- that included 29 patients previously treated with ways, respectively. The insulin-like growth factor 1 platinum-based chemotherapy showed a response receptor (IGF-1R) pathway may be deregulated in rate of 28% and a median survival of 3.5 months.61 SCLC, and studies with the monoclonal antibody Recently, a phase II trial evaluated temozolomide in cixutumumab (IGF-1R antagonist) are underway.65 relapsed/resistant SCLC.62 Sixty-four patients who The anti–CTLA-4 antibody ipilimumab has shown had received 1 to 2 prior chemotherapy regimens re- promise in a phase II study when combined with car- ceived temozolomide at 75 mg/m2 for 21 days of a 28- boplatin/paclitaxel.66 A median OS of 12.9 versus day cycle. The overall response rate was 20%, which 9.9 months with chemotherapy alone was reported did not meet the study’s prespecified criteria for suffi- (HR, 0.75; P=.13), and a phase III study is currently cient activity. However, the response rate in patients accruing. with chemoresistant disease and in those receiving Most recently, 2 groups of investigators have the drug as third-line therapy were 13% and 19%, re- used high-throughput sequencing technologies to al- spectively. A 38% response rate for brain metastases low the rapid identification of potential actionable was also noted. Finally, amrubicin, an anthracycline- mutations in SCLC tumor samples.67,68 Relevant class topoisomerase II inhibitor, is approved for the genetic alterations include PTEN, TP53, and PI3K

Systemic Therapy for Small Cell Lung Cancer

Table 2 Select Investigational Agents in Clinical Trials for Small Cell Lung Cancer Agent Pathway/Target/MOA Phase Manufacturer Obatoclax mesylate Apoptotic Pathway, anti-BCL2 II/III Gemin X Pharmaceuticals LDE 225 Hedgehog inhibitor I Novartis GDC 0449 Hedgehog inhibitor III Genentech LY 2940680 Hedgehog Inhibitor II Eli Lilly Cixutumumab (IMC-A12) IGFR inhibition III ImClone OS1-9606 IGFR inhibition II Astellas Tivantinib c-Met inhibitor I ArQule Ipilimumab Anti-CTLA-4; augments T cell III Bristol-Myers Squibb Vorinostat HDAC inhibition I/II Merck Belinostat HDAC inhibition I Topotarget/Spectrum Lorvotuzumab (IMGN901) CD56-targeting TAP compound I/II ImmunoGen BAY 1000394 pan-CDK inhibitor I/II Bayer Veliparib PARP 1 and 2 I/II Abbott Dendritic Cell-Adenovirus p53 Elicits T-cell response against p53 II Introgen Therapeutics (INGN-225) ZD6474 VEGF-2 II AstraZeneca NTX-010 Oncolytic tumor virus II Neotropix Ganetespib (STA-9090) HSP 90 inhibitor II Synta ADI-PEG 20 Pegylated arginine deiminase II Polaris Pharmaceuticals BIBF 1120 VEGF, PDGFR, FGFR II Boehringer Ingelheim

Abbreviations: CDK: cyclin-dependent kinase; FGFR, fibroblast growth factor receptor; HDAC, histone deacetylase; HSP, heat-shock protein; IGFR, insulin-like growth factor receptor; MOA, mechanism of action; PARP, poly(ADP-ribose) polymerase; PDGFR, platelet-derived growth factor receptor; TAP, targeted antibody payload; VEGF, vascular endothelial growth factor. mutations and fibroblast growth factor receptor 1 bronchogenic carcinoma. Am J Med 1969;46:516–525. amplification. In addition, SOX 2, a transcription 3. DeVita VT Jr, Hellman S, Rosenberg SA. Cancer: Principles & Practice of Oncology, 6th edition. Philadelphia, PA: Lippincott factor necessary for maintaining self-renewal of un- Williams and Wilkins; 2001. differentiated stem cells, was found to be amplified 4. Lowenbraun S, Bartolucci A, Smalley RV, et al. The superiority 68 in 27% of SCLC tumor samples. Although it is of combination chemotherapy over single agent chemotherapy in too early to know whether these aberrant biologi- small cell lung carcinoma. Cancer 1979;44:406–413. cal pathways are both drivers of the oncogenic phe- 5. Ihde DC. Chemotherapy of lung cancer. N Engl J Med notype and actionable with targeted agents, their 1992;327:1434–1441. 6. Sundstrom S, Bremnes RM, Kaasa S, et al. Cisplatin and discovery has created a new framework in which etoposide regimen is superior to cyclophosphamide, epirubicin, to develop innovative therapies that will hopefully and vincristine regimen in small-cell lung cancer: results from a translate into clinically meaningful improvements in randomized phase III trial with 5 years’ follow-up. J Clin Oncol survival. To optimally evaluate these new strategies, 2002;20:4665–4672. more patients with SCLC need to be referred to on- 7. Baka S, Califano R, Ferraldeschi R, et al. Phase III randomised trial of doxorubicin-based chemotherapy compared with platinum-based going clinical trials (Table 2), preferably early in the chemotherapy in small-cell lung cancer. Br J Cancer 2008;99:442– course of their disease when their performance status 447. and organ function are still preserved. 8. Pujol JL, Carestia L, Daures JP. Is there a case for cisplatin in the treatment of small-cell lung cancer? A meta-analysis of randomized trials of a cisplatin-containing regimen versus a regimen without this alkylating agent. Br J Cancer 2000;83:8–15. References 9. Mascaux C, Paesmans M, Berghmans T, et al. A systematic review 1. Siegel RD, Naishadham D, Jemal A. Cancer statistics, 2012. CA of the role of etoposide and cisplatin in the chemotherapy of small Cancer J Clin 2012;62:10–29. cell lung cancer with methodology assessment and meta-analysis. 2. Green RA, Humphrey E, Close H, Patno ME. Alkylating agents in Lung Cancer 2000;30:23–36.

Levy et al

10. Chute JP, Chen T, Feigal E, et al. Twenty years of phase III trials intensity treatment with ifosfamide, carboplatin, and etoposide for patients with extensive-stage small-cell lung cancer: perceptible for patients with small cell lung cancer: a randomized trial. J Natl progress. J Clin Oncol 1999;17:1794–1801. Cancer Inst 2008;100:533–541. 11. Amarasena IU, Walters JA, Wood-Baker R, Fong K. Platinum 26. Einhorn LH, Crawford J, Birch R, et al. Cisplatin plus etoposide versus non-platinum chemotherapy regimens for small cell lung consolidation following cyclophosphamide, doxorubicin, and cancer. Cochrane Database Syst Rev 2008;CD006849. vincristine in limited small-cell lung cancer. J Clin Oncol 12. Kudoh S, Fujiwara Y, Takada Y, et al. Phase II study of irinotecan 1988;6:451–456. combined with cisplatin in patients with previously untreated 27. Spiro SG, Souhami RL, Geddes DM, et al. Duration of small-cell lung cancer. West Japan Lung Cancer Group. J Clin chemotherapy in small cell lung cancer: a Cancer Research Oncol 1998;16:1068–1074. Campaign trial. Br J Cancer 1989;59:578–583. 13. Noda K, Nishiwaki Y, Kawahara M, et al. Irinotecan plus cisplatin 28. Johnson DH, Bass D, Einhorn LH, et al. Combination compared with etoposide plus cisplatin for extensive small-cell lung chemotherapy with or without thoracic radiotherapy in limited- cancer. N Engl J Med 2002;346:85–91. stage small-cell lung cancer: a randomized trial of the Southeastern 14. Hanna N, Bunn PA Jr, Langer C, et al. Randomized phase III trial Cancer Study Group. J Clin Oncol 1993;11:1223–1229. comparing irinotecan/cisplatin with etoposide/cisplatin in patients 29. Bozcuk H, Artac M, Ozdogan M, Savas B. Does maintenance/ with previously untreated extensive-stage disease small-cell lung consolidation chemotherapy have a role in the management of cancer. J Clin Oncol 2006;24:2038–2043. small cell lung cancer (SCLC)? A metaanalysis of the published 15. Lara PN Jr, Natale R, Crowley J, et al. Phase III trial of irinotecan/ controlled trials. Cancer 2005;104:2650–2657. cisplatin compared with etoposide/cisplatin in extensive-stage 30. Cullen M, Morgan D, Gregory W, et al. Maintenance chemotherapy small-cell lung cancer: clinical and pharmacogenomic results from for anaplastic small cell carcinoma of the bronchus: a randomised, SWOG S0124. J Clin Oncol 2009;27:2530–2535. controlled trial. Cancer Chemother Pharmacol 1986;17:157–160. 16. Zatloukal P, Cardenal F, Szczesna A, et al. A multicenter 31. Ettinger DS, Finkelstein DM, Abeloff MD, et al. A randomized international randomized phase III study comparing cisplatin in comparison of standard chemotherapy versus alternating combination with irinotecan or etoposide in previously untreated chemotherapy and maintenance versus no maintenance therapy small-cell lung cancer patients with extensive disease. Ann Oncol for extensive-stage small-cell lung cancer: a phase III study of the 2010;21:1810–1816. Eastern Cooperative Oncology Group. J Clin Oncol 1990;8:230– 17. Rossi A, Di Maio M, Chiodini P, et al. Carboplatin- or cisplatin- 240. based chemotherapy in first-line treatment of small-cell lung 32. Giaccone G, Dalesio O, McVie GJ, et al. Maintenance cancer: the COCIS meta-analysis of individual patient data. J Clin chemotherapy in small-cell lung cancer: long-term results of Oncol 2012;30:1692–1698. a randomized trial. European Organization for Research and 18. Hanna NH, Einhorn LH. Small-cell lung cancer: state of the art. Treatment of Cancer Lung Cancer Cooperative Group. J Clin Clin Lung Cancer 2002;4:87–94. Oncol 1993;11:1230–1240. 19. Cohen MH, Creaven PJ, Fossieck BE Jr, et al. Intensive 33. Schiller JH, Adak S, Cella D, et al. Topotecan versus observation chemotherapy of small cell bronchogenic carcinoma. Cancer Treat after cisplatin plus etoposide in extensive-stage small-cell lung Rep 1977;61:349–354. cancer: E7593--a phase III trial of the Eastern Cooperative 20. Ihde DC, Mulshine JL, Kramer BS, et al. Prospective randomized Oncology Group. J Clin Oncol 2001;19:2114–2122. comparison of high-dose and standard-dose etoposide and cisplatin 34. Hanna NH, Sandier AB, Loehrer PJ Sr, et al. Maintenance daily chemotherapy in patients with extensive-stage small-cell lung oral etoposide versus no further therapy following induction cancer. J Clin Oncol 1994;12:2022–2034. chemotherapy with etoposide plus ifosfamide plus cisplatin in 21. Thatcher N, Girling DJ, Hopwood P, et al. Improving survival extensive small-cell lung cancer: a Hoosier Oncology Group without reducing quality of life in small-cell lung cancer patients randomized study. Ann Oncol 2002;13:95–102. by increasing the dose-intensity of chemotherapy with granulocyte 35. Mattson K, Niiranen A, Pyrhönen S, et al. Natural interferon alfa colony-stimulating factor support: results of a British Medical as maintenance therapy for small cell lung cancer. Eur J Cancer Research Council Multicenter Randomized Trial. Medical 1992;28A:1387–1391. Research Council Lung Cancer Working Party. J Clin Oncol 36. Kelly K, Crowley JJ, Bunn PA Jr, et al. Role of recombinant 2000;18:395–404. interferon alfa-2a maintenance in patients with limited-stage 22. Pujol JL, Douillard JY, Rivière A, et al. Dose-intensity of a four- small-cell lung cancer responding to concurrent chemoradiation: drug chemotherapy regimen with or without recombinant human a Southwest Oncology Group study. J Clin Oncol 1995;13:2924– granulocyte-macrophage colony-stimulating factor in extensive- 2930. stage small-cell lung cancer: a multicenter randomized phase III 37. Tummarello D, Mari D, Graziano F, et al. A randomized, controlled study. J Clin Oncol 1997;15:2082–2089. phase III study of cyclophosphamide, doxorubicin, and vincristine 23. Ardizzoni A, Tjan-Heijnen VC, Postmus PE, et al. Standard versus with etoposide (CAV-E) or teniposide (CAV-T), followed by intensified chemotherapy with granulocyte colony-stimulating recombinant interferon-alpha maintenance therapy or observation, factor support in small-cell lung cancer: a prospective European in small cell lung carcinoma patients with complete responses. Organization for Research and Treatment of Cancer-Lung Cancer Cancer 1997;80:2222–2229. Group phase III trial-08923. J Clin Oncol 2002;20:3947–3955. 38. Jett JR, Maksymiuk AW, Su JQ, et al. Phase III trial of recombinant 24. Lorigan P, Woll PJ, O’Brien ME, et al. Randomized phase III trial of interferon gamma in complete responders with small-cell lung dose-dense chemotherapy supported by whole-blood hematopoietic cancer. J Clin Oncol 1994;12:2321–2326. progenitors in better-prognosis small-cell lung cancer. J Natl Cancer 39. van Zandwijk N, Groen HJ, Postmus PE, et al. Role of recombinant Inst 2005;97:666–674. Erratum in J Natl Cancer Inst 2005;97:941. interferon-gamma maintenance in responding patients with small 25. Leyvraz S, Pampallona S, Martinelli G, et al. A threefold dose cell lung cancer. A randomised phase III study of the EORTC Lung

Systemic Therapy for Small Cell Lung Cancer

Cancer Cooperative Group. Eur J Cancer 1997;33:1759–1766. lung cancer: a phase II trial. J Clin Oncol 1990;8:1613–1617. 40. Giaccone G, Debruyne C, Felip E, et al. Phase III study of adjuvant 55. Smit EF, Fokkema E, Biesma B, et al. A phase II study of paclitaxel vaccination with Bec2/bacille Calmette-Guerin in responding in heavily pretreated patients with small-cell lung cancer. Br J patients with limited-disease small-cell lung cancer (European Cancer 1998;77:347–351. Organisation for Research and Treatment of Cancer 08971- 56. Yokoyama A, Kurita Y, Watanabe K, et al. [Early phase II clinical 08971B; Silva Study). J Clin Oncol 2005;23:6854–6864. study of RP56976 (docetaxel) in patients with primary pulmonary 41. Pujol JL, Breton JL, Gervais R, et al. Phase III double-blind, cancer. Docetaxel Cooperative Study Group for Lung Cancer]. placebo-controlled study of thalidomide in extensive-disease small- Gan To Kagaku Ryoho 1994;21:2609–2616 [in Japanese]. cell lung cancer after response to chemotherapy: an intergroup 57. Smyth JF, Smith IE, Sessa C, et al. Activity of docetaxel (Taxotere) study FNCLCC cleo04 IFCT 00-01. J Clin Oncol 2007;25:3945– in small cell lung cancer. The Early Clinical Trials Group of the 3951. EORTC. Eur J Cancer 1994;30A:1058–1060. 42. Arnold AM, Seymour L, Smylie M, et al. Phase II study of 58. Masters GA, Declerck L, Blanke C, et al. Phase II trial of vandetanib or placebo in small-cell lung cancer patients after gemcitabine in refractory or relapsed small-cell lung cancer: complete or partial response to induction chemotherapy with or Eastern Cooperative Oncology Group trial 1597. J Clin Oncol without radiation therapy: National Cancer Institute of Canada 2003;21:1550–1555. Clinical Trials Group Study BR.20. J Clin Oncol 2007;25:4278– 59. Furuse K, Kubota K, Kawahara M, et al. Phase II study of vinorelbine 4284. in heavily previously treated small cell lung cancer. Japan Lung 43. Rossi A, Garassino MC, Cinquini M, et al. Maintenance or Cancer Vinorelbine Study Group. Oncology 1996;53:169–172. consolidation therapy in small-cell lung cancer: a systematic review 60. Cantwell BM, Bozzino JM, Corris P, Harris AL. The multidrug and meta-analysis. Lung Cancer 2010;70:119–128. resistant phenotype in clinical practice; evaluation of cross 44. Schneider BJ. Management of recurrent small cell lung cancer. J resistance to ifosfamide and mesna after VP16-213, doxorubicin Natl Compr Canc Netw 2008;6:323–331. and vincristine (VPAV) for small cell lung cancer. Eur J Cancer 45. Owonikoko TK, Behera M, Chen Z, et al. A systematic analysis Clin Oncol 1988;24:123–129. of efficacy of second-line chemotherapy in sensitive and refractory 61. Shepherd FA, Evans WK, MacCormick R, et al. Cyclophosphamide, small-cell lung cancer. J Thorac Oncol 2012;7:866–872. doxorubicin, and vincristine in etoposide- and cisplatin-resistant 46. Giaccone G, Ferrati P, Donadio M, et al. Reinduction chemotherapy small cell lung cancer. Cancer Treat Rep 1987;71:941–944. in small cell lung cancer. Eur J Cancer Clin Oncol 1987;23:1697– 62. Pietanza MC, Kadota K, Huberman K, et al. Phase II trial of 1699. temozolomide in patients with relapsed sensitive or refractory 47. von Pawel J, Schiller JH, Shepherd FA, et al. Topotecan versus small cell lung cancer, with assessment of methylguanine-DNA cyclophosphamide, doxorubicin, and vincristine for the treatment methyltransferase as a potential biomarker. Clin Cancer Res of recurrent small-cell lung cancer. J Clin Oncol 1999;17:658–667. 2012;18:1138–1145. 48. Garst J, Buller R, Lane S, Crawford J. Topotecan in the treatment 63. Onoda S, Masuda N, Seto T, et al. Phase II trial of amrubicin for of elderly patients with relapsed small-cell lung cancer. Clin Lung treatment of refractory or relapsed small-cell lung cancer: Thoracic Cancer 2005;7:190–196. Oncology Research Group study 0301. J Clin Oncol 2006;24:5448– 49. Treat J, Huang CH, Lane SR, Levin J. Topotecan in the treatment 5453. of relapsed small cell lung cancer patients with poor performance 64. Jotte R, Conkling P, Reynolds C, et al. Randomized phase II trial status. Oncologist 2004;9:173–181. of single-agent amrubicin or topotecan as second-line treatment in 50. O’Brien ME, Ciuleanu TE, Tsekov H, et al. Phase III trial patients with small-cell lung cancer sensitive to first-line platinum- comparing supportive care alone with supportive care with oral based chemotherapy. J Clin Oncol 2011;29:287–293. topotecan in patients with relapsed small-cell lung cancer. J Clin 65. Nakanishi Y, Mulshine JL, Kasprzyk PG, et al. Insulin-like growth Oncol 2006;24:5441–5447. factor-I can mediate autocrine proliferation of human small cell 51. Eckardt JR, von Pawel J, Pujol JL, et al. Phase III study of oral lung cancer cell lines in vitro. J Clin Invest 1988;82:354–359. compared with intravenous topotecan as second-line therapy in 66. Reck M, Bondarenko I, Luft A, et al. Ipilimumab in combination small-cell lung cancer. J Clin Oncol 2007;25:2086–2092. with paclitaxel and carboplatin as first-line therapy in extensive- 52. Masuda N, Fukuoka M, Kusunoki Y, et al. CPT-11: a new derivative disease-small-cell lung cancer: results from a randomized, double- of camptothecin for the treatment of refractory or relapsed small- blind, multicenter phase 2 trial. Ann Oncol 2013;24:75–83. cell lung cancer. J Clin Oncol 1992;10:1225–1229. 67. Peifer M, Fernández-Cuesta L, Sos ML, et al. Integrative genome 53. Einhorn LH, Pennington K, McClean J. Phase II trial of daily oral analyses identify key somatic driver mutations of small-cell lung VP-16 in refractory small cell lung cancer: a Hoosier Oncology cancer. Nat Genet 2012;44:1104–1110. Group study. Semin Oncol 1990;17(Suppl 2):32–35. 68. Rudin CM, Durinck S, Stawiski EW, et al. Comprehensive genomic 54. Johnson DH, Greco FA, Strupp J, et al. Prolonged administration analysis identifies SOX2 as a frequently amplified gene in small-cell of oral etoposide in patients with relapsed or refractory small-cell lung cancer. Nat Genet 2012;44:1111–1116.