Originally published as JCO Early Release 10.1200/JCO.2008.21.1565 on March 30 2009

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CALGB 9633: An Underpowered Trial With a Methodologically Questionable Conclusion

Centro de Oncologia, Hospital Sírio-Libanês, Sao Paulo, Brazil

Everardo D. Saad

Dendrix Research, Sao Paulo, Brazil

To the Editor:

Like many colleagues in the medical oncology community, we have eagerly awaited the final results of Cancer and Leukemia Group B (CALGB) trial 9633, reported by Strauss et al¹ in Journal of Clinical Oncology. Also, like many in the community, we were disappointed by the final negative results of the trial, confirming the second interim analysis presented at the 2006 American Society of Clinical Oncology Annual Meeting.² Such results were not surprising, given the reduced power of the study due to the accrual of fewer patients and to the lower event rates than anticipated. Furthermore, the mortality hazard ratio (HR) of 0.83 suggests that the question of benefit (or lack thereof) from chemotherapy in stage IB non–small-cell lung cancer is one of absolute figures, not of relative-risk reduction. In fact, as mentioned by the authors,¹ this magnitude of relative-risk reduction is in line with the results of the 1995 meta-analysis and recent positive prospective randomized trials. What was surprising, however, was the emphasis placed on the results of a subgroup analysis based on tumor size. Although the authors state that such analysis is exploratory and unplanned, their final conclusion stresses the point that patients with tumors 4.0 cm may benefit from adjuvant paclitaxel plus carboplatin, a conclusion that is based on a P value of .043.¹ Apparently, this P value is one sided. Even though the use of one-sided alpha appeared justified when it came to recalculate the sample size for CALGB 9633 (given the slow accrual and the attempt to maintain power), hypothesis testing at this level of significance does not seem appropriate in a superiority trial such as this, as a vast body of literature gives preference to two-sided P values for final conclusions. Moreover, the lack of a test for interaction does not allow for the conclusion that results in the subgroup with tumors less than 4.0 cm are significantly different from those in the subgroup with tumors 4.0 cm. The practice of performing subgroups analysis is frequent in medicine in general, and in oncology in particular. In fact, in a recent article presenting the use of subgroup analysis in randomized trials published in The New England Journal of Medicine, oncology stood out as the specialty where this practice was most often used (82% of the trials).³ The main purpose of this kind of analysis is to generate hypotheses to be tested in future trials, and its results should be interpreted with extreme caution. The appropriate statistical method for assessing heterogeneity of treatment effects in subgroups of patients is interaction.³ This kind of test was not performed in the CALGB study. In fact, authors of the JBR.10 study performed subgroup analysis according to stage (IB versus II) and found that the survival benefit was most profound in patients with stage II disease. There was no statistically significant survival benefit for stage IB patients. However, in that study, the authors clearly stated that the stage-by-treatment interaction test was not statistically significant.⁴ As a consequence, in their discussion, they rightfully state that not much emphasis should be placed on such analyses, meaning that the trial was positive as a whole and that the results should not be dissected according to different patient subgroups.

A second point worthy of mention is the progressive increase in mortality HRs, when the results of the first interim analysis of CALGB 9633 are compared with those from the second interim analysis and the final analysis. After the first interim analysis, conducted with a median follow-up of 34 months, the HR was 0.62.⁵ After the second, the HR was 0.80 after a median follow-up of 54 months.² At the final analysis, the median follow-up was 74 months, and the HR was 0.83.¹ In IALT (International Adjuvant Lung Trial), the positive HR of 0.86 (after a median follow-up of 56 months⁶) has been recently replaced by a negative HR of 0.91 after 90 months.⁷ Is this a particular finding of CALGB 9633 and IALT, or might this be a general phenomenon in non–small-cell lung cancer, a disease where competing causes of death in a population of fairly advanced age and significant comorbidities may be diluting the benefits from chemotherapy as time passes? Both in CALGB 9633 and in IALT, more deaths from lung cancer occurred in the observation arms (50 and 443, respectively) than in the chemotherapy arms (39 and 390, respectively).^1,7 To our knowledge, no results with longer follow-up than initially reported are available for the JBR.10 and Adjuvant Navelbine International Trialist Association trials.^4,8 It will be interesting to assess whether longer follow-up of these two studies will demonstrate a progressive migration of HRs towards 1.00.

In conclusion, CALGB 9633 is unfortunately negative as a whole. Its limited size seems to have obscured the benefit from adjuvant chemotherapy in patients with stage IB disease, whose risk of recurrence with observation would require a larger sample size. In addition, aging of the population included in the trial and competing causes of death may also have contributed to the final results of the study.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

REFERENCES

1. 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.[Abstract/Free Full Text]

2. Strauss GM, Herndon JE, Maddaus MA, et al: Adjuvant chemotherapy in stage IB non–small-cell lung cancer (NSCLC): Update of Cancer and Leukemia Group B (CALGB) protocol 9633. J Clin Oncol 24:18S; 2006 (suppl) abstr 7007.[CrossRef]

3. 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.[Free Full Text]

4. Winton T, Livingston R, Johnson D, et al: Vinorelbine plus cisplatin vs observation in resected non–small-cell lung cancer. N Engl J Med 352:2589–2597, 2005.[Abstract/Free Full Text]

5. 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 22:14S; 2004 (suppl) abstr 7019.

6. Arriagada R, Bergman B, Dunant A, et al: Cisplatin-based adjuvant chemotherapy in patients with completely resected non–small-cell lung cancer. N Engl J Med 350:351–360, 2004.[Abstract/Free Full Text]

7. 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 26:348s; 2008 (suppl) abstr 7507.[CrossRef]

8. Douillard JY, Rosell R, De Lena M, et al: Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non–small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): A randomised controlled trial. Lancet Oncol 7:719–727, 2006.[CrossRef][Medline]

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				G. M. Strauss, J. E. Herndon II, M. A. Maddaus, R. L. Schilsky, E. E. Vokes, and M. R. Green Reply to A. Katz et al J. Clin. Oncol., May 1, 2009; 27(13): 2301 - 2302. [Full Text] [PDF]

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