Clinical cancer chronotherapy trials: a review.

Experimental studies have documented that both toxicity and antitumor activity of cancer drugs are time dependent. The mechanism behind this observation is at least in part related to circadian changes in pharmacokinetics, pharmacodynamics, and DNA synthesis in both normal organs and tumors. The results of published studies designed to test chronotherapy in cancer patients are reviewed. The possible mechanisms behind the circadian-stage-dependent pharmacokinetics and pharmacodynamics are reviewed briefly for all drug classes but in detail for the fluoropyrimidines. Clinical trials have confirmed that both toxicity and achievable dose intensity for several cancer drugs are time dependent. Ongoing prospective randomized studies will determine whether this scheduling method impacts on response rate and overall survival in cancer patients.