Chronotherapy of colorectal cancer.

Author(s): Giacchetti S

Affiliation(s): Chronotherapy Unit, Federation des maladies Sanguines Immunitaires et tumorales and INSERM EPI 0118, Hjpital Paul Brousse, Villejuif, France. . sylvie.giacchetti@pbr.ap-hop-paris.fr

Publication date & source: 2002-01, Chronobiol Int., 19(1):207-19.

Publication type: Clinical Trial; Clinical Trial, Phase I; Clinical Trial, Phase II; Clinical Trial, Phase III; Randomized Controlled Trial

Chronotherapy consists of chemotherapy delivery according to circadian rhythms. These genetically based rhythms modulate cellular metabolism and cell proliferation in normal tissues. As a result, both the host tolerance and antitumor efficacy of 5-fluorouracil (5-FU) and oxaliplatin (L-OHP), like 30 other anticancer drugs, vary largely according to the dosing time in laboratory rodents. The transfer of this concept to the clinic is aimed primarily at increasing the dose-intensity of the therapy through adjustment of drug-delivery to 24h rhythms in host tolerance. A specific technology (programmable-in-time infusion pumps) enables administration of chronotherapy to fully ambulatory patients. Phase I-III clinical trials show chronotherapy significantly increases tolerance to high doses of cancer drugs and improves antitumor activity in patients with metastatic colorectal cancer. These safe conditions of drug-delivery led to the first demonstration of the high activity of the 5-FU-leucovorin-L-OHP protocol. Chronotherapy with these three drugs also allows surgical removal of previously unresectable liver and lung metastases. This novel medico-surgical management provides hope for the cure of metastatic disease in patients with unresectable colorectal cancer metastases.