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Journal of Clinical Oncology, Vol 23, No 4 (February 1), 2005: pp. 927 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.05.490
Observations on the Interpretation of Clinical Trials in Early Ovarian CancerMRC Clinical Trials Unit, London, UK To the Editor: The recent article by Young et al1 illustrates some important points on the design and conduct of clinical trials in general, and early-stage ovarian cancer in particular. The trial started in 1986 and is now published, with a median follow-up of 10 years. Clinical trials in early ovarian cancer take a long time to perform, as the disease is relatively rare with only one third of patients with ovarian cancer being diagnosed with early-stage disease. Survival is relatively good (overall 5-year survival figures of 82% in patients in the International Collaborative Ovarian Neoplasm 1 (ICON1) and Adjuvant Chemotherapy in Ovarian Neoplasm (ACTION) trials receiving adjuvant chemotherapy), and events are therefore slow to accumulate.2 Young et al targeted a difference of 10% in 5-year survival (from 80% to 90%). This was probably rather optimistic, and the trial is probably underpowered to detect realistic differences between the two treatment strategies, which makes it difficult to draw conclusions about the risks and benefits of either treatment. Cumulative incidence of recurrence is reported by randomized treatment. In this analysis, eight deaths, which occurred before recurrence, seem to have been censored. Outcome information used as end points in clinical trials can be ranked hierarchically, with all-cause mortality at the highest level, followed by cause-specific mortality, nonfatal clinical events (such as recurrence), followed by other measures such as symptoms and signs of clinical disease. Distortion can occur when the analysis for an end point other than all-cause mortality ignores information from higher levels.3 An analysis of cumulative incidence of recurrence should not be analyzed without including circumstances (such as death before progression) that would preclude the occurrence of the recurrence. This is particularly true when deaths may be related to treatment. It can be very difficult to be certain that an individual death is not related in some way to treatment or to disease. Combined end points often allow for a better understanding of treatment effects. Details of cause of death are given for two patients, one on each arm. One of the deaths that occurred in the 32P arm was directly related to catheter insertion, and another was said to be a myocardial infarction following a period of neutropenia. Overall, a slightly higher proportion of "other" deaths was seen in the intraperitoneal 32P arm compared with the intravenous cisplatin and cyclophosphamide arm (7.3% and 6.7%, respectively). In the Discussion, the authors imply that the joint analysis of the ICON1 and ACTION trials with 923 patients, reported data by surgical staging, and in the one third who had optimal staging, there was no difference in disease-free or overall survival for those who received adjuvant chemotherapy. Because of the great difficulty in interpreting this subgroup analysis, which included a total of only 151 patients on whom 18 events were observed, these data were not included in the article presenting the combined results of these two trials. We are aware that a number of presentations were made including thess data, but because of the very small number of patients (and events) included in this subgroup, this was not the conclusion of the joint writing committee or of the ICON1 collaborators. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. REFERENCES
1. Young RC, Brady MF, Nieberg R, et al: Adjuvant treatment for early ovarian cancer: A randomized phase III trial of intraperitoneal 32P or intravenous cyclophosphamide and cisplatin- A Gynaecologic Oncology Group study. J Clin Oncol 21:4350-4355, 2003
2. International Collaborative Ovarian Neoplasm 1 (ICON1) and European Organisation for Research and Treatment of Cancer Collaborators: Adjuvant ChemoTherapy in Ovarian Neoplasm (EORTC-ACTION): International Collaborative Ovarian Neoplasm Trial 1 and Adjuvant ChemoTherapy In Ovarian Neoplasm Trial—Two parallel randomized phase III trials of adjuvant chemotherapy in patients with early-stage ovarian carcinoma. J Natl Cancer Inst 95:105-112, 2003 3. Lubsen J, Kirwan B: Combined Endpoints: Can we use them? Stat Med 21:2959-2970, 2002[CrossRef][Medline]
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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