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Originally published as JCO Early Release 10.1200/JCO.2008.21.2126 on March 30 2009 © 2009 American Society of Clinical Oncology.
Reply to A. Katz et alTufts Medical Center, Boston, MA
CALGB Statistical Center, Duke University Medical Center, Durham, NC
University of Minnesota, Minneapolis, MN
University of Chicago, Chicago, IL
Southeast Cancer Control Consortium Inc. Community Clinical Oncology Program, Goldsboro, NC We appreciate the thoughtful letter of Drs Katz and Saad1 which raises several points for discussion. We too are disappointed that the positive findings from the 2004 analysis of Cancer and Leukemia Group B (CALGB)–96332 were not sustained with further follow-up. However we feel, and apparently Katz and Saad do as well, that the primary conclusion presented in our manuscript..."because a significant survival advantage was not observed across the entire cohort, adjuvant chemotherapy should not be considered standard care in stage-IB NSCLC [non–small-cell lung cancer]"3...is appropriate.
Katz and Saad1 are most concerned that we have given excess weight to the findings from an exploratory, posthoc, subgroup analysis using one–sided P value testing to recommend consideration of adjuvant therapy in patients with larger T2 tumors. They cite a recent review by Wang et al4 noting that subgroup analyses appear to be more frequently used in oncology than in other medical specialties, and cautioning against performing multiple subgroup analyses because of the attendant inflated risk of a positive finding. In our analysis of CALGB-9633, the only subgroup analysis performed involved the issue of tumor size ( We agree with Katz and Saad1 that a two-sided P value would be most desirable in this setting. However, there was a solid rationale to utilize one-sided testing in our study. Accrual to CALGB-9633 was highly problematic, which led us to strongly consider protocol termination. As an alternative, we elected to reduce our accrual target from 500 to 384 patients. While originally designed for two-sided hypothesis testing, it was converted to one-sided testing to maintain feasibility and statistical power when sample size was reduced. We were trying to balance the fact that we had already committed a considerable number of patients to a study for which randomization was difficult and there was not complete buy-in from other groups.
In our article, we do not make an explicit recommendation that stage-IB NSCLC patients with tumors In particular, our observation on the effect of tumor size on survival in stage-IB NSCLC led investigators responsible for the National Cancer Institute of Canada JBR-10 adjuvant trial to retrospectively analyze their data in stage IB patients by tumor size. That retrospective analysis also demonstrated a significant survival advantage for stage-IB patients with tumors larger than 4 cm.3 Moreover, a growing body of data indicates that tumor size is a major prognostic factor among patients with stage I NSCLC.5,6 Indeed, more refined tumor-size subsets will soon be incorporated into a revised staging system for lung cancer.7,8 Furthermore, the leadership of the current US Intergroup adjuvant therapy trial Eastern Cooperative Oncology Group–1505 (adjuvant chemotherapy ± bevacizumab) has decided to include stage-IB patients with tumors greater than 4 cm in size in the study population.9 We share with Katz and Saad1 an interest in better understanding the impact of time after completion of adjuvant chemotherapy on freedom from recurrence and death in patients with NSCLC. Our own experience involved carboplatin-based adjuvant therapy, and we initially wondered whether the failure to sustain the initial benefit might be in some way tied to use of carboplatin rather than cisplatin. We still can not rule out a contribution of carboplatin to the late decay of the survival advantage, but the time-dependent regression of the hazard for benefit in the most recent update of the International Adjuvant Lung Cancer Trial trial,10 as noted by Katz and Saad, raises a more systemic concern. We agree that longer follow-up of the JBR-10 and Adjuvant Navelbine International Trialist Association trials may shed additional important light on this critical issue. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. REFERENCES
1. Katz A, Saad ED: CALGB 9633: An underpowered trial with a methodologically questionable conclusion. J Clin Oncol doi:10.1200/JCO.2008.21.1565. 2. Strauss GM, Herndon JE, Maddaus MA, et al: Randomized clinical trial of adjuvant chemotherapy with paclitaxel and carboplatin following resection in Stage IB non–small-cell lung cancer (NSCLC): Report of Cancer and Leukemia Group B (CALGB) Protocol 9633. Proc Am Soc Clin Oncol 22:621s; 2004 abstr 7019. 3. Strauss GM, Herndon JE II, Maddaus MA, et al: Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non–small-cell lung cancer: CALGB 9633 with the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study Groups. J Clin Oncol 26:5043–5051, 2008. 4. 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. 5. Mery CM, Pappas AN, Burt BM, et al: Diameter of non–small-cell lung cancer correlates with long-term survival: Implications for T stage. Chest 128:3255–3260, 2005.[CrossRef][Medline] 6. López-Encuentra A, Duque-Medina JL, Rami-Porta R, et al: Staging in lung cancer: Is 3 cm a prognostic threshold in pathologic stage I non–small-cell lung cancer? A multicenter study of 1,020 patients. Chest 121:1515–1520, 2002.[CrossRef][Medline] 7. Rami-Porta R, Ball D, Crowley J, et al: The IASLC Lung Cancer Staging Project: Proposals for the revision of the T descriptors in the forthcoming (seventh) edition of the TNM classification for lung cancer. J Thorac Oncol 2:593–602, 2007.[CrossRef][Medline] 8. Goldstraw P, Crowley J, Chansky K, et al: The IASLC Lung Cancer Staging Project: Proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM Classification of Malignant Tumours. J Thorac Oncol 2:706–714, 2007.[CrossRef][Medline] 9. Wakelee H, Schiller J, Gandara D: Current status of adjuvant chemotherapy for stage IB non–small-cell lung cancer: Implications for the New Intergroup Trial. Clinical Lung Cancer 8:18–21, 2006.[CrossRef][Medline] 10. Le Chevalier T, Dunant A, Arriagada R, et al: Long-term results of the International Adjuvant Lung Cancer Trial (IALT) evaluating adjuvant cisplatin-based chemotherapy in resected non–small-cell lung cancer (NSCLC). J Clin Oncol 26:398s; 2008 (suppl) abstr 7507.
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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4 cm v < 4 cm). Thus our finding related to tumor size is not suspect based on multiple subgroup analyses. 
