Marked improvement in tumor cure rates can be achieved by the alternation of cyclophosphamide (CP) with intermittent multiple fractions per day (MFD) radiation schedules compared to the alternating of CP with daily fraction schedules in the ACI rat using hepatoma 3924A. A cure rate of 50% was achieved with 6000 rad intermittent MFD alternated with CP contrasted with 11,250 rad with daily radiation fractions and CP. There were no cures with sequential (LD10) doses of 150 mg/kg (0.9 g/m2) CP every 11 days for bone marrow recovery for 2,3,4 and 5 courses (total doses of 300-750 mg/kg CP). If the radiation was concentrated over a 2-day period as MFD and given every 11 days for 3 courses, no tumor cures were demonstrated over a radiation dose range of 3000-9000 rad. The effects of daily radiation schedules over a dose range of 3000-11,250 rad demonstrated no tumor cures. However, it was possible to achieve a greater than 50% cure rate for the primary tumor and eliminate metastatic dissemination with acceptable limits of toxicity with intermittent MFD radiation alternated with CP. Furthermore, this was not possible with daily radiation schedules alternated with CP. New therapeutic approaches to improving cancer treatment will likely be coordinated with either single or combined chemotherapy-radiotherapy. The results of our experimental studies demonstrate the potential for improvements in cancer management by more effectively utilizing radiotherapy and chemotherapy. We propose to extend our studies by looking for development of resistance to other chemotherapeutic agents (cis-platinum, adriamycin and 5-fluorouracil) and for cross resistance or cross sensitivity with these drugs and radiation. These studies will be carried out in tumor line 3924A shown to be responsive to both radiation and the agents to be evaluated and in tumor line H-4-II-E shown to be resistant to radiation and the agents to be evaluated (neither the sensitivity nor the resistance of cis-platinum has been evaluated). These drugs were chosen for study because of their widespread clinical use and proven effectiveness. We believe that extending our studies to include these other drugs is justified by 1) the success with alternating chemotherapy and radiotherapy experimentally; 2) its promising clinical application to treatment of lung cancer, head and neck cancer and Hodgkin's disease; 3) the clinical studies planned or in progress in this country, Europe and South Africa alternating chemotherapy and radiotherapy in the treatment of cancer of the cervix, ovary, anal-rectal region, pancreas and non-Hodgkin's lymphoma; and 4) the continued clinical problem of development of drug resistance for these and other agents.
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