The Therapeutic Index of Cytotoxic Chemotherapy Depends upon Circadian Drug Timing

Cytotoxic drug doses and schedules used to administer anticancer treatments are by necessity a balance between excessive toxicity to the host and antitumor activity. Biological rhythms along daily, monthly, and annual time scales may determine cell susceptibility to cytotoxic agents as well as drug pharmacokinetics. Susceptibility rhythms have been determined for more than 20 of the most commonly used anticancer drugs in animals standardized to an artificial light/dark schedule. For these agents, the maximum tolerated dose (MTD) is dependent upon the circadian time of administration. Differences between best and worst tolerance may exceed 50% of the median MTD. Similarly, the antitumor activity may differ depending on the treatment time. Circadian stages of maximum tumor activity and maximal host toxicity are frequently separated, allowing improved therapeutic index through optimal drug timing. Extrapolations from preclinical findings have led to clinical treatment schedules that specify times of drug delivery. To date, small randomized clinical trials comparing 2 opposite schedules (e.g., treatment given at the presumed times of best or worst drug tolerance) have shown significant toxicity differences for patients receiving cisplatin, doxorubicin or analogues, and 5-fluoro-2'-deoxyuridine (FUDR). Toxicity advantages coincided with equal or better antitumor activity and even survival advantage for ovarian cancer patients receiving optimally timed doxorubicin/cisplatin. Current evidence allows the recommendation to administer doxorubicin in the early morning hours and cisplatin in the afternoon. Future trials need to incorporate monitoring of marker rhythm parameters in patients and individual adjustments of treatment schedules to those rhythms.