New designs for radiation oncology research in clinical trials.

Abstract

A research logic model and matrix’ is presented to serve as a framework for combining treatment modalities utilized in current cancer management and for developing innovations in radiation oncology. The stimulus for this effort is the need for a better scientific basis for launching clinical trials, particularly when such new modes as radiosensitizers, radioprotectors, hyperthermia, high linear energy transfer (LET), and radiolabeled tumor antibodies are added to the existing established modes such as surgery, radiation, and chemotherapy. Since common research themes are being explored with radiation and drugs, many opportunities exist to integrate these two major research approaches. Radiobiology research received its major impetus at the beginning of the atomic era, when the biologic effects of high dose and low chronic dose radiation exposure required definition. As a by-product of this effort, radiation has acted as a noninvasive probe into living organisms. Radiation perturbs biologic systems through its selective action on dividing cells, and has led to observations of prime biologic importance. As methods of cell quantification were developed in in vitro and in vivo systems, more research was directed toward understanding the mechanisms of action of radiation at the cellular and tissue levels The four “R’s“ of clinical radiobiologic research as stated by Whitmore’-repair, reoxygenation, repopulation, and reassortment-have been the main currents of tumor biology research during the past decade. Unlike the radiation research program, the drug development program3 of the National Cancer Institutue (NCI) evolved a linear treatment array from pharmacology research programs. The initial step involves the use of a drug prescreening program based on tumor response in one or two sensitive cell lines to evaluate thousands of drugs. Once a drug is shown to have an antitumor effect, a more intensive screening analysis is made using a panel of mouse tumors and xenografts of common human tumors. If the drug is effective and not too toxic in this panel of mouse tumors, large scale production and