The importance of schedule and drug dose intensity in combinations of modalities

To review a series of laboratory experiments that have been conducted to investigate the degree to which therapeutic effectiveness is a function of the scheduling of two or more therapeutic agents.

The therapeutic effectiveness of a few combinations of modalities (fractionated irradiation + cis-DDP alone and with 5FU, cyclophosphamide, or etoposide) has been evaluated systematically for a large number of schedules. For every such schedule, therapeutic gain factors were calculated as the ratio of effectiveness for tumor growth inhibition to each of three normal tissue endpoints in laboratory mice: duodenal crypt cell survival, pneumonitis (breathing rate at 5 months after treatment), and pulmonary fibrosis (breathing rate at 10 months).

For every combination tested, at least one schedule was distinctly therapeutically superior to the others. Most often, the greatest therapeutic gain was achieved with divided doses of cis-DDP administered simultaneously with five daily x-ray dose fractions. Even greater gain was found when cyclophosphamide was administered as a single bolus 1 day before fractionated cis-DDP/irradiation. Still greater therapeutic gain was achieved by protecting against normal tissue toxicity by administering the cytokine, interleukin 1, prior to chemotherapy-radiotherapy.

Performing experiments of the type described in this paper can be of great value in the optimization of treatment with combinations of agents or modalities.