Among patients with metastatic colorectal cancer, administration of the chemotherapy drugs Eloxatin® (oxaliplatin), 5-fluorouracil, and leucovorin on a schedule that is adjusted to circadian rhythms (chronomodulated) appears to improve outcomes in men but not in women. These results were published in the Journal of Clinical Oncology.
Colorectal cancer remains the second leading cause of cancer-related deaths in the U.S. Metastatic colorectal cancer refers to cancer that has spread from its site of origin to distant sites in the body. Since metastatic colorectal cancer is often incurable, treatment is typically aimed at improving the duration of survival while maintaining quality of life.
Treatment for metastatic colorectal cancer often includes a combination of chemotherapy agents. One commonly used chemotherapy regimen is referred to as FOLFOX. FOLFOX includes the chemotherapy agents Eloxatin, 5-flourouracil, and leucovorin.
In an attempt to improve outcomes among patients treated with chemotherapy, researchers in Europe recently studied the effects of varying the delivery chemotherapy according to a patient’s circadian rhythm (the body’s 24-hour cycle). The idea behind this approach is that there may be certain points in the circadian rhythm when chemotherapy drugs will have the greatest effect with the least toxicity. Varying delivery of treatment according to the circadian rhythm is referred to as chronomodulated therapy.
The effect of chronomodulated therapy was assessed in a phase III clinical trial involving 564 patients with metastatic colorectal cancer. Half the patients received two-day delivery of Eloxatin, 5-flourouracil, and leucovorin using a conventional approach (FOLFOX2), and half were treated with four-day delivery of these same drugs using a chronomodulated approached (chronoFLO4).
- Overall, survival was similar in the two treatment groups: Among patients treated with FOLFOX2, 36.9% of patients survived for two years or longer. Among patients treated with chronoFLO4, 37% of patients survived for two years or longer.
- The frequency of serious side effects was similar in the two treatment groups, but the types of side effects varied. Patients treated with FOLFOX2 were more likely to experience low white blood cell counts (neutropenia), and patients treated with chronoFLO4 were more likely to experience problems such as diarrhea.
- The effect of chronoFLO4 differed by sex. Among men, those treated with chronoFLO4 had a 25% reduction in risk of death compared to those treated with FOLFOX2. Among women, those treated with chronoFLO4 had a 38% increase in risk of death compared to those treated with FOLFOX2. The reasons for this difference between men and women are uncertain.
The researchers conclude that overall, chronoFLO4 and FOLFOX2 produce similar survival results among patients with metastatic colorectal cancer. The effects of chronoFLO4 appear to differ notably by sex, however, with men experiencing improved survival with chronoFLO4 and women experiencing worse survival.
Reference: Giacchetti S, Bjarnason G, Garufi C et al. Phase III Trial Comparing 4-day Chronomodulated Therapy Versus 2-day Conventional Delivery of Fluorouracil, Leucovorin, and Oxaliplatin as First-line Chemotherapy for Metastatic Colorectal Cancer: The European Organisation for Research and Treatment of Cancer Chemotherapy Group. Journal of Clinical Oncology. 2006;24:3562-3569.