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Should Subgroup Analysis of Randomized Clinical Trials Have a Direct Impact on Clinical Practice?

Department of Medical Oncology, Regina Elena National Cancer Institute, Rome, Italy

Massimo Di Maio

National Cancer Institute, Naples, Italy

Federica Cuppone, Cecilia Nisticò, Francesco Cognetti

Department of Medical Oncology, Regina Elena National Cancer Institute, Rome, Italy

Diana Giannarelli

Biostatistics, Regina Elena National Cancer Institute, Rome, Italy

To the Editor:

The recent publication in the Journal of Clinical Oncology of the randomized clinical trial performed by the European Organisation for Research and Treatment of Cancer Chronotherapy Group did raise the issue of the clinical reliability of sex subgroup analysis in clinical trials.¹ The primary end point of this large cooperative multicentric phase III trial was 2-year survival, and the sample size was then calculated to determine a 10% survival difference (from 30% to 40%) in favor of the chronomodulated arm (superiority trial). Patients were stratified according to performance status, liver involvement, and center. In the abstract (which has to be considered the most rapid source for a take-home message), the authors conclude that "both regimens achieved similar median survival times more than 18 months with an acceptable toxicity" and that "chronomodulated schedule produced a survival advantage in men."¹ A controversy exists regarding the correct interpretation of subgroup analysis of randomized clinical trials, given that the risk to provide misinterpretation could lead to wrong treatment guidelines. Although the trial is adequately powered for its main end point, it is not able to detect differences in efficacy between subgroups with adequate power. Moreover, the sex analysis lead to both a significantly better effect for chronotherapy in men, but also a significantly better effect for standard chemotherapy in women, and this is not mentioned in the abstract conclusion.¹ Actually, in the article a balanced discussion about the subgroup issues is present. Although the multivariate analysis should protect over baseline prognostic factors' interaction (when adequately studied), the list of the patients' characteristics, which the authors decided to consider for subgroup analysis, should be reported in the article as well. A number of pieces of specific literature have been published regarding the risk of the erroneous interpretation of subgroup analyses and the most common conclusions are those analyses can be overinterpreted and may lead to suboptimal patient care.² A sort of methodologic recommendation for subgroup analyses and their interpretation has been recently produced by Brookes et al^3,4—only previously planned subgroup analyses should be performed; any trial should be powered taking into account the prespecified subgroup analyses; notwithstanding all these considerations, any specific analysis is affected by several bias, and the conclusions need to be softened. In absence of strong common evidence, this is an hypothesis-generating exercise for further specifically addressed randomized trial. The risk in subgroup analysis to provide errors has been also quantified, and seems to be not related to the patient sample size.²

Correctly, Giacchetti et al¹ performed a sex-treatment interaction analysis, and this interaction resulted significantly at the multivariate analysis. This result is interesting. However, the observed survival differences by sex could be due to imbalance in unmeasured baseline prognostic factors (demographic and/or molecular characteristics). According to article's results, "Patients' characteristics according to sex were well balanced except for age and PS. Age 50 years and PS of 1 or 2 were more frequent in women than in men (21% v 14%; and 59% v 46.5%, respectively). After stratification for age and PS, the interaction tests were not found significant (P > .1)." If not due to imbalance, the difference of outcome between males and females could be a true difference or could be due to statistical chance alone, especially because not only sex but a long list of patient characteristics has been analyzed. So, in our opinion, more caution should be used when authors decide to put the results of secondary, exploratory analyses in the abstract of an article.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The authors indicated no potential conflicts of interest.

REFERENCES

1. Giacchetti S, Bjarnason G, Garufi C, et al: Phase III trial comparing 4-day chronomodulated therapy versus 2-day conventional delivery of fluorouracil, leucovorin, and oxaliplatin as first-line chemotherapy of metastatic colorectal cancer: The European Organisation for Research and Treatment of Cancer Chronotherapy Group. J Clin Oncol 24:3562-3569, 2006[Abstract/Free Full Text]

2. Lagakos SW: The challenge of subgroup analyses–reporting without distorting. N Engl J Med 354:1667-1669, 2006[Free Full Text]

3. Brookes ST, Whitley E, Peters TJ, et al: Subgroup analyses in randomized controlled trials: Quantifying the risks of false-positives and false-negatives. Health Technol Assess 5:1-56, 2001[Medline]

4. Brookes ST, Whitely E, Egger M, et al: Subgroup analyses in randomized trials: Risks of subgroup-specific analyses; power and sample size for the interaction test. J Clin Epidemiol 57:229-236, 2004[CrossRef][Medline]

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This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Bria, E. Articles by Giannarelli, D. Search for Related Content PubMed PubMed Citation Articles by Bria, E. Articles by Giannarelli, D. Social Bookmarking                            What's this?