Chronotherapy consists in the administration of medicines according to biological rhythms. Further insight into the mechanisms of the circadian system has led to adapting the delivery of
cancer chemotherapy to rhythms in
drug metabolism or cell proliferation. The pharmacology of
anticancer agents has long been known to vary largely and predictably according to dosing time in mice or rats. Portable programmable multi-channel pumps allowed demonstration of the clinical relevance of the
chronotherapy principle in a sufficiently large patient population. This demonstration was achieved using a 5-day infusion of
5-fluorouracil,
leucovorin, and
oxaliplatin in patients with
colorectal cancer metastases. A further innovation was that
oxaliplatin, a new
drug whose activity in this disease was first shown using chronomodulated infusion, was incorporated early in this novel three-
drug regimen, in view of the good tolerability of this administration schedule. The fully ambulatory nature of treatment courses was an additional constraint put on
chronotherapy. More than 1000 patients with metastatic gastrointestinal
malignancies have now received
chronotherapy protocols in several countries from North America or Europe. Results have clearly indicated that this approach improved
chemotherapy tolerance and allowed safe increases in
drug doses. A clinical phase III trial compared a flat versus the chronomodulated three-
drug regimen, and demonstrated large, simultaneous improvements in both tolerability and response rates in patients with metastatic
colorectal cancer receiving
chronotherapy. This approach may also be beneficial to patients with other gastrointestinal
malignancies, and it was amenable to combination with surgery and
radiotherapy. It also appeared suitable for devising potentially more active dose-intensive yet safe regimens. Incorporation of chronopharmacology into the development stages of new drugs may improve their safe use to the greatest benefit of both
cancer patients and new
drug development, as was done for
oxaliplatin.