Biological basis for the interaction of chemotherapeutic agents and radiation therapy.

The ultimate goal of combining chemotherapy and radiotherapy is to improve the therapeutic ratio. When chemotherapy is combined with radiotherapy, improved therapeutic effects may occur as a result of the following: (1) spatial cooperation; (2) enhancement of tumor response with less or no enhancement of normal tissue injury, and (3) diminution of normal tissue injury with less or no diminution of tumor response. Possible mechanisms of interaction between chemotherapeutic agents and radiation that result in an enhanced effect include (1) changes in the slope of the dose response curve, (2) decreased accumulation or inhibition of repair of sublethal damage, (3) decreased recovery from potentially lethal damage, (4) perturbation in cell kinetics with an increase of proportion of cells in the sensitive cell cycle phase and proliferative state, (5) decreased tumor bulk and improved blood supply leading to reoxygenation and recruitment and increased radiosensitivity and chemosensitivity, and (6) increased drug delivery and uptake. The combined effects may be influenced by (1) tumor and normal tissue type, (2) drug type, (3) drug dose and schedule, (4) time sequence between drug and radiation administration, (5) radiation dose and fractionation schedule, and (6) radiation dose rate. Most experimental and clinical data suggest that enhanced tumor effects most often result from simple additivity and therefore do not require direct interaction between drug and radiation, whereas enhanced normal tissue effects are observed most often when drugs are administered in close temporal proximity to radiation. Thus, for the optimal therapeutic effect, it would seem more advantageous to administer chemotherapeutic drugs and radiation in a sequential or alternating manner rather than simultaneously.