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Journal of Clinical Oncology, Vol 25, No 5 (February 10), 2007: pp. 606-607 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.09.4763
In ReplyINSERM U 776 and Hôpital Paul Brousse, Assistance Publique-Hôpitaux de Paris, Paris, France
Data Center, European Organisation for Research and Treatment of Cancer, Brussels, Belgium
Istituto Regina Elena, Roma, Italy
INSERM U 776, University Paris Sud, and Hôpital Paul Brousse, Assistance Publique-Hôpitaux de Paris, Paris, France In their Conclusion, Bria et al emphasize that more caution is needed in reporting the effects of sex on survival and tolerability that were derived from the European Organisation for Research and Treatment of Cancer phase III trial 05963.1 Their comment is based on the controversy regarding the generation and the interpretation of subgroups analyses. Indeed, we strongly believe that the abstract serves the purpose of delivering the most clinically relevant findings with honesty. This is why we wrote, "In women, the risk of an earlier death on ChronoFLO4 was increased by 38% compared with FOLFOX2... .In men, the risk of death was decreased by 25% on ChronoFLO4... ." So, we agree with Bria et al that the abstract is the most rapid source for a take home message, but we mean the whole abstract, not the conclusion only. For treatment interaction tests, we considered factors related to patient characteristics (age, sex, WHO performance status [PS] 0 v > 0), baseline hematologic and biochemical data (leukocyte, granulocyte and platelet counts, alkaline phosphatases, gamma glutamyltransferase, transaminases, carcinoembryonic antigen, and CA 19-9), and tumor characteristics (primary site, Duke's stage, liver involvement, number of metastatic sites). At the exception of sex, no other factor displayed any strongly significant interaction with the delivery schedule (P < .01). As mentioned in the article, an imbalance between women and men was found for PS and age. After stratification for age and PS, the interaction tests were not found significant (P > .1) because of a lack of power, but presented the same trend for a higher efficacy in men treated by infusion of fluorouracil, leucovorin, and oxaliplatin for 4 days (chronomodulated FLO4) in the different age and PS strata. Indeed, the difference between men and women could be a true difference or statistical chance. However, in a Cox proportional hazards model a sex x schedule interaction term was found significant in presence of PS, age, number of metastatic sites, and percentage of liver involvement (Table 4).1 This supports that sex effect is a true difference. Lagakos recommends being cautious with subgroups analysis. He advises to perform planned subgroups analysis, appropriate analysis with interaction tests, and to give magnitude of the treatment difference with corresponding confidence interval instead of the P value.2 Bria et al acknowledge that we followed these recommendations, including interaction test and Forrest plot of interaction between schedule and sex. However, we could not plan the subgroups analyses since such effect was largely unknown when we initiated this trial. Thus, a consistent impact of sex on chemotherapy toxicity or patient outcome started to arise in the literature once accrual to our trial was completed.3 We feel that clinical research should aim at discovering new prognostic and predictive factors, new treatments, better treatment schedules, and new strategies. Through the use of chronomodulated delivery of chemotherapy, our group first demonstrated the activity of oxaliplatin against colorectal cancer,4 then the relevance of liver metastases surgery for the survival of patients with downstaged previously unresectable metastases.5,6 Both of these findings initially encountered great scepticism, yet they now have profoundly modified the current treatment of colorectal cancer worldwide. Thus we share the opinion of Lagakos that avoiding any presentation of subgroup analysis because of their history of being overinterpreted would have been a steep price to pay. Rather than advocating for a ready change in clinical practice which could imply the delivery of FOLFOX (2-hour infusion of oxaliplatin and leucovorin on day 1 and 2-hour infusion of leucovorin on day 2, which intercalculated 22-hour constant infusion rate of fluorouracil on days 1 and 2) in women and that of chronomodulated FLO4 in men as standard best practice, we proposed to investigate the mechanisms through which optimal scheduling of chemotherapy differs between men and women. Indeed, increased attention is currently being paid by the medical and scientific community to the role of sex for treatment toxicities and patient outcome in cancer and other diseases. Our correspondence (Bria et al and our reply) emphasizes the need for studies testing new chemotherapy and chronotherapy associations with targeted molecules and a priori planning of effects of sex or other factors identified in subgroup analyses. Already a sex dependency of toxicity and survival has been recently found by our group for two separate studies, including one with cetuximab.7,8 We are currently developing new protocols aimed at the determination of the best schedule in women with metastatic colorectal cancers. Moreover, to better understand the mechanism of the sex effect, translational research projects of molecular clock determinants of optimal schedule are also ongoing. The challenge ahead of us is the administration of tailored chronotherapy (ie, the determination of the right drugs at the right doses and at the right time in the right patient). 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 2. Lagakos SW: The challenge of subgroup analyses–reporting without distorting. N Engl J Med 354:1667-1669, 2006 3. Neugut AI, Jacobson JS: Women and lung cancer: Gender equality at a crossroad? JAMA 296:218-219, 2006 4. Lévi F, Misset JL, Brienza S, et al: A chronopharmacologic phase II clinical trial with 5-fluorouracil, folinic acid and oxaliplatinum using an ambulatory multichannel programmable pump: High antitumor effectiveness against metastatic colorectal cancer. Cancer 69:893-900, 1992[CrossRef][Medline] 5. Giacchetti S, Itzhaki M, Gruia G, et al: Long term survival of patients with unresectable colorectal cancer liver metastases following infusional chemotherapy with 5-flurouracil, leucovorin, oxaliplatin and surgery. Ann Oncol 10:663-669, 1999 6. Adam R, Delvart V, Pascal G, et al: Rescue surgery for unresectable colorectal liver metastases downstaged by chemotherapy: A model to predict long-term survival. Ann Surg 240:644-657, 2004[Medline] 7. Lévi F, Focan C, Karaboué A, et al: Implications of circadian clocks for the rhythmic delivery of cancer therapeutics. Adv Drug Deliv Rev 2006 8. Levi F, Karaboué A, Bralet MP, et al: Determinants of cetuximab (Cetux) reversal of resistance to chronomodulated chemotherapy (Chrono) as 4th line treatment of metastatic colorectal cancer (MCC). Presented in part at the Proc 31st Congress of the European Society for Medical Oncology, Istanbul, Turket, September 9-October 3, 2006. Ann Oncol 17(suppl 9):358, 2006
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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