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Journal of Clinical Oncology, Vol 26, No 12 (April 20), 2008: pp. 2064-2065 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2008.16.3220
Meaningful Subset Analyses Contribute to Optimal Patient CareDepartment of Hematology and Medical Oncology, Emory University, Winship Cancer Institute, Atlanta, GA
Dana Farber Cancer Institute, Boston, MA
Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA
Department of Medicine, Penn State Cancer Institute, Hershey, PA
The Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD
Vanderbilt-Ingram Cancer Center, Nashville, TN
University of Texas Southwestern Medical Center, Dallas, TX
Vanderbilt-Ingram Cancer Center, Nashville, TN To the Editor: We appreciate the opportunity to respond to the comments regarding our article reporting differences in outcomes for elderly patients treated with carboplatin and paclitaxel with or without the addition of bevacizumab.1 We performed this subset analysis from the pivotal Eastern Cooperative Oncology Group (ECOG) 4599 study that led to US Food and Drug Administration approval of bevacizumab for advanced nonsquamous non–small-cell lung cancer (NSCLC).2 Because approximately half of all new cases of lung cancer are diagnosed in patients at least 70 years old, this was used for the subset analysis in our report.3 This cut point is consistent with several other reports on lung cancer in elderly patients.4-6 We would also like to emphasize that the differences in toxicity profile between younger and elderly patients is a crucial aspect of our report. We respectfully disagree with Dr Goel regarding the utility of subset analyses from randomized phase III studies. The current predilection for treating elderly NSCLC patients with combination chemotherapy is only supported by subset analyses of phase III studies.4-6 Although this is not optimal, subset analyses are important in managing elderly patients (particularly when new treatment advances are made), until appropriate, elderly-specific, prospective studies are conducted. For instance, the subset analysis by Pepe et al7 has provided valuable information regarding the use of adjuvant chemotherapy for elderly patients with early-stage NSCLC. The value of such analyses has also been underscored recently in the article by Wang et al,8 which outlines guidelines for publication of subset analyses from randomized clinical trials. It is implicit that subset analyses do not have the same power to detect statistically significant differences as the primary analysis. Dr Goel overinterprets the results of the age-by-treatment interaction test to translate to lack of difference between younger and elderly patients with the addition of bevacizumab. This test merely states that the magnitude of the treatment effect does not vary by age group despite the fact that no difference in overall survival was observed among the elderly. In addition, Dr Goel fails to mention which test he used to calculate the significance of the 2-year survival rate differences in his letter. Assuming he conducted a test of proportions, his assumptions inappropriately fail to account for censoring and assume that all patients were observed to the 2-year time point. Our 2-year estimates are Kaplan-Meier estimates, and, as was stated in our article, the log-rank test was used to test for differences in the survival distributions. Therefore, Dr Goel's criticism that the subset analysis was not conducted appropriately is incorrect and is not supported by any of the claims made in his letter. Dr Atkins's letter rightly points out that reliance on median survival alone as a marker of efficacy of an intervention is not entirely appropriate. However, his point regarding the Cox model is taken out of context because it was fitted to the entire data set and simultaneously adjusted for treatment, age group, sex, and adrenal involvement. In the elderly patients, the log-rank P value for survival was .4, as noted in Figure 1A of the article1. Therefore, the observation of inferior survival with paclitaxel and carboplatin (P = .01) refers to the result from a multivariable Cox model and is not directly comparable to the results presented in Figure 1A. Furthermore, we tested the validity of proportional hazards assumption and found the P value to be .07. Although this was not stated in the article, it does not suggest a violation of the assumption. Therefore, the last two points of his letter do not apply. Overall, we wish to re-emphasize that the purpose of our analysis was to generate a hypothesis regarding the use of the novel carboplatin, paclitaxel, and bevacizumab regimen in elderly patients. As we stated in our concluding remarks, additional studies are required to determine the utility of three-drug regimens in elderly NSCLC patients. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial 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 description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Suresh S. Ramalingam, Genentech (C); Corey J. Langer, Genentech (C); Chandra P. Belani, Genentech (C); Julie R. Brahmer, Genentech (C); Alan B. Sandler, Genentech (C); Joan H. Schiller, Genentech (C) Stock Ownership: None Honoraria: Suresh S. Ramalingam, Genentech; Corey J. Langer, Genentech; Chandra P. Belani, Genentech; Alan B. Sandler, Genentech Research Funding: Corey J. Langer, Genentech; Robert Gray, Genentech; Julie R. Brahmer, Genentech; Alan B. Sandler, Genentech Expert Testimony: None Other Remuneration: None REFERENCES
1. Ramalingam SS, Dahlberg SE, Langer CJ, et al: Outcomes for elderly, advanced-stage non small-cell lung cancer patients treated with bevacizumab in combination with carboplatin and paclitaxel: Analysis of Eastern Cooperative Oncology Group Trial 4599. J Clin Oncol 26:60-65, 2008 2. Sandler A, Gray R, Perry MC, et al: Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 355:2542-2550, 2006 3. Owonikoko TK, Ragin CC, Belani CP, et al: Lung cancer in elderly patients: An analysis of the surveillance, epidemiology, and end results database. J Clin Oncol 25:5570-5577, 2007 4. Langer CJ, Vangel M, Schiller J, et al: Age-specific subanalysis of ECOG 1594: Fit elderly patients (70-80 yrs) with NSCL do as well as younger pts (< 70 years). Proc Am Soc Clin Oncol 22:639, 2003 5. Lilenbaum RC, Herndon JE II, List MA, et al: Single-agent versus combination chemotherapy in advanced non-small-cell lung cancer: The Cancer and Leukemia Group B (Study 9730). J Clin Oncol 23:190-196, 2005 6. Langer CJ, Manola J, Bernardo P, et al: Cisplatin-based therapy for elderly patients with advanced non-small-cell lung cancer: Implications of Eastern Cooperative Oncology Group 5592, a randomized trial. J Natl Cancer Inst 94:173-181, 2002 7. Pepe C, Hasan B, Winton TL, et al: Adjuvant vinorelbine and cisplatin in elderly patients: National Cancer Institute of Canada and Intergroup Study JBR. 10. J Clin Oncol 25:1553-1561, 2007 8. Wang R, Lagakos SW, Ware JH, et al: Statistics in medicine–reporting of subgroup analyses in clinical trials. N Engl J Med 357:2189-2194, 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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