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Journal of Clinical Oncology, Vol 26, No 1 (January 1), 2008: pp. 160 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.14.6951
Thalidomide in Small-Cell Lung Cancer: Is It a Tombstone?Division of Medical Oncology, "S.G. Moscati" Hospital, Avellino, Italy
Department of Medical Oncology, "Regina Elena" National Cancer Institute, Rome, Italy To the Editor: Pujol et al reported the final results of a two-step, randomized, double-blind, placebo-controlled phase III trial aimed to determine whether thalidomide prolonged survival of patients affected by extensive-disease small-cell lung cancer (ED-SCLC). After two courses of etoposide, cisplatin, cyclophosphamide, and 4'-epidoxorubicin (step one), only responder patients were randomized to four additional cycles of the etoposide, cisplatin, cyclophosphamide, and 4'-epidoxorubicin regimen with or without thalidomide (step two). Thalidomide did not demonstrate to improve significantly the survival of ED-SCLC.1 This trial gives physicians the opportunity to make few considerations. The main point influencing the entire trial is the statistical design. The trial planned to randomly assign 200 patients, and the main end point was a 20% improvement in the survival at 7 months from random assignment (ie, 9 months after registration) in the thalidomide group. Due to a low accrual rate, the study was shortened, with only 92 patients having been assigned. The authors discussed the results and reported final considerations, omitting any comments regarding this main flaw. Moreover, no data about the survival percentage of patients at 7 months, the primary end point of the trial, are available in the text. In our opinion, when the statistical design of a trial was not respected (accrual and, consequently, number of expected events failure), the entire trial failed, and the data should be discussed in the appropriate way describing them and without any conclusion drawn. The 119 registered patients were accrued throughout a long period (39 months, from October 2000 to January 2004). A median of 3.05 patients a month were enrolled in 21 participating institutions. Such a slow accrual could reflect a selection of enrolled patients biasing the external validity of study results. Accrual rate seems to be crucial, particularly in a two-step design where the sequential enrollment may complicate final time-to-event data analysis.2 This possible bias is also underlined by the slightly low percentage (9.3%) of performance status (PS) 2 patients accrued. Recently, a pooled analysis of 1,623 SCLC patients enrolled in 15 clinical trials was reported. PS was investigated as a predicting factor of survival. A total of 17.3% of PS 2 patients (double of those enrolled in the Pujol trial) was analyzed reporting a statistical significant worse survival for this setting of patients respect to PS 0 patients (P < .0001).3 Therefore, in the trial by Pujol et al, there are no enough figures of PS 2 patients to state that "survival did not significantly differ according to PS." Although the authors did carefully approaches this issue, all the risks in interpreting subgroup analyses all well known,4 and, even in presence of a preplanned stratification, these risks are magnified when the expected accrual and events have not been reached. So, thalidomide in SCLC—is it a tombstone? In our opinion, the answer should be yes. Actually, this answer does not immediately come from the trial of Pujol et al because of the already described statistical power limitations; rather, this consideration arises from the results of a recent phase III randomized, double-blind, placebo-controlled trial in which 724 patients affected by both limited disease and ED-SCLC received carboplatin plus etoposide regimen with or without thalidomide. In this powerful trial, thalidomide in combination with chemotherapy and as maintenance treatment failed to improve any outcomes when compared with chemotherapy alone.5 In conclusion, to date, all the trials employing targeted agents in the treatment of SCLC failed to improve any outcomes both in combination with chemotherapy or as maintenance treatment.6 Probably, this is more of a strategy issue than a failure of the tested drugs. Further preclinical studies evaluating the best way to combine chemotherapy with new biologic agents could help to better address this issue. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. REFERENCES
1. Pujol JL, Breton JL, Gervais R, et al: Phase III double-blind, placebo-controlled study of 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 2. Case DL, Morgan TM: Duration of accrual and follow-up for two-stage clinical trials. Lifetime Data Anal 7:21-37, 2001[CrossRef][Medline] 3. Foster NR, Mandrekar SJ, Schild SE, et al: Age, gender, performance status, and stage outperformed stage alone in predicting overall survival (OS) in patients with small cell lung cancer: A pooled analysis of 1,623 patients from the North Central Cancer Treatment Group. J Clin Oncol 25:439s, 2007 (suppl; abstr 7723) 4. Lagakos SW: The challenge of subgroup analyses-reporting without distorting. N Engl J Med 354:1667-1669, 2006 5. Lee SM, Woll PJ, James LE, et al: A phase III randomised, double blind, placebo controlled trial of etoposide/carboplatin with or without thalidomide in advanced small cell lung cancer (SCLC). J Thor Oncol 2:S306-S307 (suppl 4; abstr PRS-04), 2007 6. Gridelli C, Maione P, Palazzolo G, et al: New targeted therapies and small-cell lung cancer. CML Lung Cancer 1:37-43, 2007
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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