Solid tumor models for the assessment of different treatment modalities: XXIII. A new approach to the more effective utilization of radiotherapy alternated with chemotherapy.

This study with the rat hepatoma 3924A demonstrated the marked improvement in tumor cure rates and control of tumor growth that can be achieved by the addition of cyclophosphamide (CP) to multiple fractions of radiation per day (MFD) schedules given intermittently. MFD radiation was delivered over a 2-day period followed by CP (150 mg/kg or 0.9 g/m2) 1 day later; this combined course was repeated at 11-day intervals (to allow for gastrointestinal tract and bone marrow recovery) for a total of 3 courses over a 23-day period. Cure rates of 30, 50 and 60% were achieved with total radiation doses of 4500, 6000 and 7500 rad, respectively, when the MFD radiation was given with CP. No cures and no complete responses were realized when the same intermittent MFD schedules for radiation were employed up to 9000 rad without CP. Other groups of 10 animals each were treated with daily fractions of 100, 150, 188, 250 and 375 rad given on days 0-9, 11-20 and 22-31. A 150 mg/kg or 0.9 g/m2 dose of CP was given after each course of daily radiation on days 10, 21 and 32 in the combined treatment groups. No complete responses or tumor cures occurred with radiation alone given daily for total radiation doses, which were increased from 3000 to 11,250 rad. Only the highest radiation dose given, 375 rad per day to a total of 11,250 rad, resulted in a complete response rate and tumor cure rate of 50% when CP was added. The addition of CP to the daily fractionation schedules reduced the total dose needed to give a growth delay of 100 days by 39% (5600 rad versus 9200 rad). The addition of CP to the intermittent MFD schedules further reduced the total dose needed to give a growth delay of 100 days to 4200 rad. Major improvements in some types of cancer treatment may be realized if we can develop clinical protocols for the alternate use of chemotherapy and radiotherapy as we have done successfully in our experimental program. The finding that intermittent MFD radiation schedules are as effective as daily schedules when given alone suggests that greater flexibility of patient management in clinical radiotherapy may be possible without a major loss of therapeutic effectiveness. These alternated fractionated schedules offer the possibility of optimizing treatment in terms of patient convenience and economy as well as the potential for improving the effectiveness of the interaction of radiotherapy with radiosensitizers, radioprotectors, and hyperthermia in addition to chemotherapy.