Cancer chronotherapy: a drug delivery challenge

The toxicity and/or efficacy of more than twenty anticancer agents have been shown in various experimental systems to be dependent upon the circadian timing of their bolus administration or the circadian shaping of their continuous infusion. In cancer patients, the toxicity of several single agents, given either as bolus or infusion, and a growing number of drug combinations have been shown to similarly depend upon their timing. While clinical trials currently underway demonstrate that the circadian stage of drug toxicity and dose intensity each depend upon their circadian timing, definitive investigations of whether or not cancer control and patient survival are similarly dependent upon circadian treatment timing are currently under way. Both clinical trials of treatment timing and chronotherapy depend totally upon the development and use of programmable wearable and implantable, single-channel and multi-channel, open and eventually closed loop delivery systems. First generation intelligent delivery systems are currently available, work well, are economical and are destined, for economic reasons, to be more widely used. When used, each system requires temporal input, making it impossible to avoid specification of drug sequence, interval between drugs or treatment cycles and circadian treatment timing. The advent of biological therapy with cytokines and growth factors makes it likely that the precise timing of cancer therapies will be of growing importance.