VOLUME 26 NUMBER 26 SEPTEMBER 10 2008

JOURNAL OF CLINICAL ONCOLOGY

Progress in Small-Cell Lung Cancer: The Lowest Common Denominator

David R. Gandara and Primo N. Lara Jr, University of California Davis Cancer Center, Sacramento, CA Ronald Natale, Cedars Sinai Cancer Center, Los Angeles, CA Chandra Belani, Penn State Cancer Center, Hershey, PA

Progress in the therapy of small-cell lung cancer (SCLC), commonly viewed at initial presentation as one of the most highly chemotherapy-sensitive solid tumors, has been painfully slow. In fact, it could be argued that little to no therapeutic advances have been made for extensive stage patients in more than 20 years. In a disease uniquely positioned from its causal biology and growth kinetics to be vulnerable to both new chemotherapeutic drug classes and the wealth of targeted therapeutic agents which have entered clinical development within the last decade, why has so little progress been made? In this issue of Journal of Clinical Oncology, Hermes et al1 present a randomized trial in extensive SCLC comparing oral etoposide plus carboplatin (EC) to a newer chemotherapeutic regimen of considerable interest: irinotecan and carboplatin (IC). The authors conclude that IC prolongs survival over EC, without compromising quality of life, supporting the use of this regimen as a new standard in SCLC. Viewed from a North American perspective, the Hermes et al trial clearly raises as many questions as it answers. Are the conclusions warranted? Does the regimen share a common denominator with other recent reports in the literature, or is it a one-of-a-kind experience? Finally, does this study truly represent progress in SCLC? To address these questions, we rst must consider current treatment perspectives for extensive-stage SCLC. Although regional differences exist, in North America and worldwide, rst-line chemotherapy for extensive stage SCLC most commonly consists of a platinum agent (cisplatin or carboplatin) combined with multiday intravenous etoposide. Attempting to build on this platform, several randomized phase III trials, all published in JCO, have disappointingly shown no survival advantage with the addition of topotecan consolidation, paclitaxel, Bec-2 vaccination, or thalidomide to a platinum-etoposide backbone.2-5 However, in 2002, the Japan Clinical Oncology Group published the striking results of J9511, a small phase III trial demonstrating the superiority of irinotecan and cisplatin (IP) over etoposide and cisplatin (EP) in response rate, progression-free survival (PFS) and survival, both overall and at 1 and 2 years.6 Was this the advance we had been waiting for? In view of pharmacogenomic considerations for irinotecan in Japanese populations7 and the limited patient sample size in J9511 due to Data Safety Monitoring Boardmandated early closure, conrmatory studies were
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launched. Using a modied dose schedule of IP, Hanna et al8 were unable to demonstrate superiority over EP. Most recently, at the 2008 Annual Meeting of the American Society of Clinical Oncology, the Southwest Oncology Group reported results of S0124, a large phase III study comparing IP to EP, in which the treatment regimens utilized in J9511 were exactly duplicated. While there were no signicant efcacy differences observed between IP and EP in this North American population, a patient-level toxicity comparison of S0124 and J9511 conrmed greater toxicity in the Japanese study.9 Table 1 compares key parameters regarding patient demographics and end points of the four phase III trials comparing irinotecan and platinum to etoposide and platinum regimens.1,6,8,9 Clearly, the study by Hermes et al1 stands out in several ways: eligibility criteria (performance status [PS] 0 to 4 and brain metastases), use of oral etoposide, dose of carboplatin (area under the curve, 4), and age-mandated cycle 1 dose reductions, to name some of the most obvious. These differences in study design and patient characteristics may explain differences in survival outcomes; the Hermes et al trial reports the shortest overall survival times; response rates and PFS were not reported. Moreover, arbitrary dose reductions for patients older than age 70 may also have adversely affected survival times in the Hermes et al study. More than half of all new lung cancer patients are older than 70 years of age. The rationale for empiric age-related dose reductions in the Hermes et al study is unclear because older patients appear to tolerate chemotherapy as equally well as younger patients with similar PS and equal degrees of comorbidities. Potential pharmacogenomic variability in irinotecan metabolism due to genetic polymorphisms of uridine diphosphateglucuronosyltransferase is another dimension worth considering. Both interindividual and population-related differences are well recognized.7,10,11 While this factor was not assessed in the Hermes et al trial, other recent studies suggest it is of clinical signicance in predicting the therapeutic index of this agent, including a preliminary report from the S0124 study.10-12 In addition, the treatment regimens selected for the Hermes et al trial may have contributed to reduced efcacy in both arms of the study. For example, despite initial enthusiasm, use of oral etoposide has fallen substantially in the United States. This is in part due to interpatient differences in bioavailability and pharmacodynamics,
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Editorial

Table 1. Phase III Trials of Irinotecan-Platinum in Small-Cell Lung Cancer Parameter Drug regimen Patients Age, years Range, cap 70 Performance status Response Progression-free survival, months Median survival, months J95116 IP/EP 154 (77/77) 63/63 30-70/41-70 0-2 87%/68% 6.9/4.8 12.8/9.4 Hanna et al8 IP/EP 331 (221/110) 63/62 37-82/38-83 0-2 48%/44% 4.1/4.6 9.3/10.2 Hermes et al1 IC/oEC 209 (105/104) 66/72 46-81/42-82 0-4 NA NA 8.5/7.1 S01249 IP/EP 651 (324/327) 62/63 22-86/35-86 0-1 60%/57% 5.7/5.2 9.7/8.9

Abbreviations: IP, irinotecan and cisplatin; EP, etoposide and cisplatin; IC, irinotecan and carboplatin; oEC, oral etoposide plus carboplatin. Time to progression.

potentially leading to underdosing in some patients and unacceptable toxicity in others. A randomized trial in SCLC by Souhami et al13 comparing oral etoposide with intravenous cyclophosphamide, doxorubicin, and vincristine (CAV) hypothesized that single-agent oral etoposide would be equally as efcacious as CAV and less toxic. Instead, orally administered etoposide proved to be less effective (PFS, 3.6 v 5.6 months; P .001) than CAV and more toxic. With the exception of emesis, all parameters of symptom control and quality of life were either the same or worse in the oral etoposide group. These authors concluded that oral etoposide should not be used in the rst-line therapy of SCLC. Further, by most standards, the Hermes et al trial may have underdosed carboplatin in patients older than age 70 due to the required baseline dose reductions. So, are the conclusions of the Hermes et al study warranted? If so, then adding within the context of the current study design and patient population studied1 to the Conclusion appears appropriate. Does the strategy employed share a common denominator with other recent reports in the literature, or is it a one-of-a-kind experience? Realizing that health care systems differ throughout the world, and that the benets of protocol-directed therapy have largely been limited to only the most t, there is a growing interest in conducting clinical trials in special populations such as those with poor PS or the elderly. Such efforts are to be applauded. The major question is whether clinical trials are best designed for these special populations only, or whether general eligibility and treatment criteria should be expanded or modied, as in the Hermes et al study. Unfortunately, based on the considerations described earlier, the common denominator between the Hermes et al study and other recent trials evaluating irinotecan in SCLC is limited. To a large extent, comparing the Hermes et al trial to the three other randomized studies is a case of comparing apples and oranges. Finally, if this trial does represent progress in SCLC, it is perhaps not by identifying a new and better treatment, but by expanding our horizons on patient populations who may derive palliative benet from therapy: a regression to the lowest common denominator.
AUTHORS DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

description of the disclosure categories, or for more information about ASCOs conict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: David R. Gandara, Pzer Oncology (C); Chandra Belani, Pzer Oncology (C) Stock Ownership: None Honoraria: David R. Gandara, Pzer Oncology; Ronald Natale, Eli Lilly & Co, Genentech/OSI Pharmaceuticals Research Funding: Ronald Natale, Amgen, AstraZeneca, Eli Lilly & Co, Genentech/OSI Pharmaceuticals, Millenium Expert Testimony: None Other Remuneration: None
AUTHOR CONTRIBUTIONS

Conception and design: David R. Gandara, Chandra P. Belani Provision of study materials or patients: Primo N. Lara, Ronald Natale Collection and assembly of data: Primo N. Lara, Ronald Natale Data analysis and interpretation: Ronald Natale Manuscript writing: David R. Gandara, Primo N. Lara, Chandra P. Belani Final approval of manuscript: David R. Gandara
REFERENCES
1. Hermes A, Bergman B, Bremnes R, et al: Irinotecan plus carboplatin versus oral etoposide plus carboplatin in extensive small-cell lung cancer: A randomized phase III trial. J Clin Oncol 26:4261-4267, 2008 2. Schiller JH, Adak S, Cella D, et al: Topotecan versus observation after cisplatin plus etoposide in extensive stage small-cell lung cancer: E7593A phase III trial of the Eastern Cooperative Oncology Group. J Clin Oncol 19:2114-2122, 2001 3. Niell HB, Herndon JE II, Miller AA, et al: Randomized phase III intergroup trial of etoposide and cisplatin with or without paclitaxel and granulocyte colonystimulating factor in patients with extensive-stage small-cell lung cancer: Cancer and Leukemia Group B Trial 9732. J Clin Oncol 23:3752-3759, 2005 4. Giaccone G, Debruyne C, Felip E, et al: Phase III study of adjuvant vaccination with Bec2/Bacille Calmette-Guerin in responding patients with limited-disease smallcell lung cancer (European Organisation for Research and Treatment of Cancer 08971-08971B; Silva Study). J Clin Oncol 23:6854-6864, 2005 5. Pujol JL, Breton JL, Gervais R, et al: Thalidomide in extensive-disease small-cell lung cancer after response to chemotherapy: An intergroup study FNCLCC cleo04 IFCT 00-01. J Clin Oncol 25:3945-3951, 2007 6. Noda K, Nishiwaki Y, Kawahara M, et al: Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small-cell lung cancer. N Engl J Med 346:85-91, 2002 7. Beutler E, Gelbart E, Demina A: Racial variability in the UDPglucuronosyltransferase 1 (UGT1A1) promoter: A balanced polymorphism for regulation of bilirubin metabolism? Proc Natl Acad Sci U S A 95:8170-8174, 1998 8. Hanna N, Bunn P Jr, Langer C, et al: Randomized phase III trial comparing irinotecan/cisplatin with etoposide/cisplatin in patients with previously untreated extensive-stage disease small-cell lung cancer. J Clin Oncol 24:20382043, 2006 9. Natale R, Lara PN Jr, Crowley JC, et al: S0124: A randomized phase III trial of cisplatin irinotecan (PI) versus cisplatin etoposide (PE) in patients (pts) with extensive stage small cell lung cancer (E-SCLC). J Clin Oncol 26:400s, 2008 (suppl; abstr 7512) 4237

Although all authors completed the disclosure declaration, the following author(s) indicated a nancial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a U are those for which no compensation was received; those relationships marked with a C were compensated. For a detailed
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10. Lara P, Redman M, Lenz H, et al: Cisplatin (cis)/etoposide (VP16) compared to cis/irinotecan (CPT11) in extensive stage small cell lung cancer (E-SCLC): Pharmacogenomic (PG) and comparative toxicity analysis of JCOG 9511 and SWOG 0124. J Clin Oncol 25:390s, 2007 (suppl; abstr 7524) 11. Innocenti F, Undevia SD, Iyer L, et al: Genetic variants in the UDPglucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. J Clin Oncol 22:1382-1388, 2004

12. Han JY, Lim HS, Shin ES, et al: Comprehensive analysis of UGT1A polymorphisms predictive for pharmacokinetics and treatment outcome in patients with nonsmall-cell lung cancer treated with irinotecan and cisplatin. J Clin Oncol 24:2221-2224, 2006 13. Shouhami RL, Spiro SG, Rudd RM, et al: Oral etoposide for advanced small cell lung cancer: Randomized comparison with intravenous chemotherapy. JNCI 89:577-580, 1997

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