Effect of X-rays and cyclophosphamide on solid tumors and naturally occurring metastases in mice

Combinations of single doses of X-rays given locally to a transplanted tumor and single i.p. doses of cyclophosphamide (CY) were tested in mice bearing solid transplanted fibrosarcomas. The end points examined were growth delay and local control of the implanted tumor, the incidence of distant metastases, and survival times free of either local recurrence or metastases. Growth delay and local control increased more steeply with X-ray dose than with dose of CY. From 8 to 10 days of extra regrowth delay required only 10 to 20% extra X-ray dose, but it required a doubling of CY dose from three-eighths to three-fourths of the maximum tolerated dose. The incidence of metastases and the survival time of the mice also depended more upon the local dose of X-rays than that of CY. This result was not expected and suggests that metastases are eliminated more certainly if the primary (implanted) tumor is locally controlled on a long-term basis. A significant proportion of mice, over 50%, was cured of both the transplanted tumor and distant metastases only when the highest doses of both X-rays and CY were given simultaneously. Extended intervals between the two agents gave inferior results, intervals of 8 days giving significantly worse results, but 4 days giving not significantly worse results than simultaneous administration, especially when the X-ray treatment was given first. The interval of 4 days would, however, be sufficient to avoid the enhancement of radiation injury in normal tissues in mice.