Cancer chronotherapy

The cytotoxicity of more than thirty anticancer drugs varies by more than 50% as a function of dosing time along the 24-h time-scale in laboratory animals. Mechanisms involve circadian changes in cellular metabolism and proliferation processes, as well as drug pharmacokinetics. Moreover, the administration of chemotherapy at the least toxic time usually achieves best antitumour efficacy in experimental tumour models. Here we review experiences in utilising these phenomena in the optimization of cancer chemotherapy in the clinic. Chronotherapy has been administered to 1500 patients with metastatic colorectal cancer using 5-fluorouracil and leucovorin with or without oxaliplatin. Sinusoidal chronomodulated delivery of 2- or 3-drug chemotherapy was performed in the patient's home or during usual activities, with a computer-programmed multi-reservoir pump. Courses lasted 4-5 days and were repeated every 14-21 days. Three-drug chronotherapy proved largely superior to flat infusion with respect to both tolerability and antitumour efficacy. The better tolerability of chronotherapy further allowed an increment of both 5-fluorouracil and oxaliplatin doses, which in turn further improved objective tumour response rate to 66%. This enabled surgical removal of previously inoperable metastases and the achievement of > 20% survival at three years. Second generation programmable-in-time pumps have simplified chronotherapy administration and decreased its costs. A broad use of fully ambulatory chronotherapy requires thorough definitions of drug stability, and compatibility with pump reservoirs and other medications.