Modification of tumor response to cyclophosphamide and irradiation by preirradiation of the tumor bed: prolonged growth delay but reduced curability

Abstract

The effect of tumor bed irradiation (TBX) on subsequent tumor response to treatment with cyclophosphamide (CY) or further irradiation was studied in mice. Using the growth delay assay, the therapeutic response was enhanced by prior TBX: for example, in mice receiving 3000 rad TBX 1 day before fibrosarcoma cell inoculation, the growth delay from 8 to 12 mm produced by CY (150 mg/kg) was 18.8 days compared with 9.4 days without prior TBX. This effect was independent of time between TBX and tumor cell inoculation over the range 1-56 days. When tumor cure experiments were performed, however, the effect of prior TBX was to decrease significantly the proportion of tumors controlled by either CY or irradiation and to make the dose-response curve for radiocurability less steep. These data are best interpreted by postulating that TBX increases the environmental heterogeneity of tumors growing in preirradiated sites, with an overall net decrease in the cell kill achieved by a given dose of CY or radiation. This results in increased resistance to cure and a lack of dose response. However, the TBX also causes slower regrowth of surviving cells, so that an increase in tumor growth delay is realized. Thus, although eradication of postirradiation recurrences by chemotherapy is compromised, their palliation may actually be enhanced.