Solid tumor models for the assessment of different treatment modalities. XIII. Comparison of response and recovery of host and solid tumor to cyclophosphamide and radiation

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Abstract
A study of the effects of local tumor radiation alone (1500R) and cyclophosphamide alone (150 mg/kg) on the experimental solid tumor rat hepatoma 3924A has been completed. Cyclophosphamide was more effective in controlling tumor growth than either radiation or 5-fluorouracil (5-FU) (150 mg/kg) previously reported. Parallel recovery of bone marrow with increasing animal survival in “split dose” cyclophosphamide toxicity studies (as with 5-FU) indicates that bone marrow is the critical organ for sequential chemotherapy. Recovery of intestinal mucosa following cyclophosphamide (and 5-FU) occurred much earlier than recovery of bone marrow, substantiating the fact that bone marrow is the critical organ governing the time of administration of a second series of chemotherapeutic agents. The longest period of time (seven days) between delivery of radiation and administration of cyclophosphamide resulted in the most effective use of the two modalities. Tumor growth delay was 1.2 times greater than the additive effects of each agent given alone. Radiation and cyclophosphamide given at other time intervals resulted in either an additive or less than additive effect. One of the greatest difficulties to overcome in the more effective clinical use of combined modality therapy is increased toxicity. In these studies, the least host toxicity occurred when the effects of combined radiation and cyclophosphamide on the tumor were greatest. Results of experimental studies to date suggest that sequential combined modality therapy may be given at a time of maximum tumor growth rate that occurs following the previous treatment series. Since the time of maximum tumor growth rate occurs after recovery of the bone marrow from the previous treatment series, combined chemotherapy-radiotherapy schedules of this type should permit sequential administration of chemotherapeutic agents, such as 5-FU and cyclophosphamide, at the time of enhanced tumor sensitivity and diminished host toxicity.