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Journal of Clinical Oncology, Vol 22, No 14 (July 15), 2004: pp. 2971-2972 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.99.042
A Recent Illustration of Some Essentials of Circadian Chronotherapy Study Design
W.J.B. Dorn Veterans' Administration Medical Center, Columbia, SC To the Editor: In 1985, a comparison of the circadian timing of doxorubicin 60 mg/m2 and cisplatin 60 mg/m2 given every 28 days to patients with large-volume stage III and stage IV ovarian cancer was published.1 This comparison of morning doxorubicin and evening cisplatin with evening doxorubicin and morning cisplatin was based on studies in a rat model that predicted that morning doxorubicin followed by evening cisplatin would be less toxic and more effective.2 The two circadian schedules, compared with one another, kept the order of the drugs constant and the interval between them constant, because other studies had shown that the sequence of and intervals between cytotoxic drugs are also temporal sources of potential relevance to both cytotoxic drug toxicity and efficacy. Patients treated with the morning doxorubicin and evening cisplatin schedule had fewer infections and fewer bleeding episodes; required fewer RBC transfusions; had less nausea, fewer vomiting episodes, and less emesis; had less severe renal damage; and experienced less frequent and less severe peripheral neuropathy. The WBC and platelet counts in patients treated with this schedule recovered by day 21, while the opposite circadian schedule resulted in cumulative marrow toxicity. This resulted in diminished dose intensity. At the same time, the patients treated with the least toxic schedule had a four-fold greater 5-year rate of survival.3 These findings were confirmed with related drugs in European ovarian cancer patients.4A presentation of these data to the members of the Gynecologic Oncology Group (GOG) followed. The ovarian cancer committee had other priorities, but the endometrial cancer committee expressed interest, even though no chronotherapeutic data were available for that cancer. A single-arm study of 6 AM doxorubicin, followed by cisplatin 12 hours later, resulted in an unexpectedly high objective response rate in advanced endometrial cancer.5 GOG investigators subsequently wished to determine whether circadian doxorubicin and cisplatin timing was relevant to toxicity and outcome in patients with advanced endometrial cancer, and insisted that the control arm not specify drug timing. The ultimate study design specified the order of drugs for both regimens, doxorubicin first and cisplatin second, and required that in the control arm, both drugs be given together, while in the circadian arm, these agents were to be given 12 hours apart. A recent publication of the results of this study is instructive.6 The actual timing of each drug across successive cycles of chemotherapy (Figures 3 and 4 of the article6) demonstrates that cisplatin timing was not at all random in the control arm, and was actually quite similar in both groups. It can be seen that doxorubicin timing in the circadian arm quickly drifted substantially over the course of therapy, so that by the second and third cycles, increasing overlap of doxorubicin timing between contrasted groups is obvious. This study actually tested, for the most part, evening doxorubicin and evening cisplatin in the control arm against doxorubicin in morning and/or evening, along with evening or nighttime cisplatin in the test arm. This mixture and similarity of circadian timings in both the control and timed arms, makes sensible circadian analysis problematic. Furthermore, the most consistent temporal difference between these two therapeutic arms is not at all time of day, but rather, related to the time span between the two drugs (< 1 hour v 1 to 12 hours). Given the limitations of the original study design, the conclusion of "no significant [circadian therapy] benefit" is not supportable by these data. The most reasonable conclusion one can draw from this study is that unless circadian-based questions are asked in a way that can elicit clear answers, no useful information can result. The science of chronotherapeutic clinical study design, which is progressing on both sides of the Atlantic, must be thoughtfully applied in order to ask and answer such questions, and to avoid wasting clinical resources and money.7,8 Programmable pump-based technology to ensure accurately timed drug administration is helpful for making such studies work.9 Optimally timed treatments, which assume gross circadian synchrony of the population to be treated, can diminish toxicity and enhance therapeutic efficacy.3 In principle, chronotherapy may be further improved by selecting treatment timing according to individual circadian marker rhythms, further diminishing between-individual differences, and further enhancing the therapeutic index of cancer treatment.10 Such individualization needs to be tested more broadly. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. REFERENCES
1. Hrushesky W: Circadian timing of cancer chemotherapy. Science 228:73-75, 1985
2. Sothern R, Levi F, Haus E, et al: Control of a murine plasmacytoma with doxorubicin-cisplatin depends upon circadian stage of treatment. J Natl Cancer Inst 81:135-145, 1989
3. Hrushesky W, Bjarnason G: Circadian cancer therapy. J Clin Oncol 11:1403-1417, 1993 4. Levi F, Benavides M, Chevelle C, et al: Chemotherapy of advanced ovarian cancer with 4'-0-tetrahydropyranyl doxorubicin and cisplatin: A randomized phase II trial with an evaluation of circadian timing and dose-intensity. J Clin Oncol 8:705-714, 1990[Abstract] 5. Barrett RJ, Blessing JA, Homesley HD, et al: Circadian-timed combination doxorubicin-cisplatin chemotherapy for advanced endometrial carcinoma: A phase II study of the Gynecologic Oncology Group. Am J Clin Oncol 16:494-496, 1993[Medline]
6. Gallion H, Brunetto V, Cibull M, et al: Randomized phase III trial of standard timed doxorubicin plus cisplatin versus circadian timed doxorubicin plus cisplatin in stage III and IV or recurrent endometrial carcinoma: A gynecologic oncology group study. J Clin Oncol 21:3808-3813, 2003
7. Levi F, Zidani R, Vannetzel J, et al: Chronomodulated versus fixed-infusion-rate delivery of ambulatory chemotherapy with oxaliplatin, fluorouracil, and folinic acid (leucovorin) in patients with colorectal cancer metastases: A randomized multi-institutional trial. J Natl Cancer Inst 86:1608-1617, 1994 8. Hrushesky W: Predictable within individual temporal variability and clinical trial design. Presented at Clinical Trials in Oncology: Improving Their Design and Analysis, Toronto, Ontario, Canada, October 28-30, 1993 9. Baron B, Legrand C, Levi F, et al: Chronomodulation: Optimal time finding design. Presented at Society of Clinical Trials Meeting, Denver, CO, May 20-23, 2001 10. Halberg F, Cornélissen G, Wang Z, et al: Chronomics: Circadian and circaseptan timing of radiotherapy, drugs, calories, perhaps nutriceutals and beyond. J Exp Ther Oncol 3:223-260, 2003[CrossRef][Medline]
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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