Chronotherapy for gastrointestinal cancers

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.