Keynote address: modulation of normal tissue toxicity by combined modality therapy: considerations for improving the...

The aim of combined modality treatment schedules is to achieve increased killing in the tumor cell populations without an equivalent increase in normal tissue damage. There is, however, some increased risk of normal tissue toxicity that must be taken into account when assessing the therapeutic potential. An understanding of the mechanisms involved in combined modality therapy, for example, increased radiosensitivity, inhibition or stimulation of cellular proliferation, or independent additive toxicities, should improve the chances of of achieving a therapeutic gain. A review of the literature of normal tissue effects after combined treatment with drugs and radiation has lead to the following general conclusions: a) The sequence and timing of the two agents have a marked influence on the extent of normal tissue damage, with the most damage occurring when simultaneous drug and irradiation are given within a few days of each other; b) Separation of the two modalities can lead to an improved therapeutic gain since tumor effects are less strongly dependent on the interval between drug and X rays; and c) Chemotherapy can markedly alter the time of expression of radiation damage, particularly in slowly dividing normal tissues, where more rapid expression of injury occurs after combined modality therapy. The above concepts and some possible ways for improving the therapeutic gain in future trials are discussed in this review.