MULTIVARIATE DETERMINANTS OF RADIOCURABILITY .1. PREDICTION OF SINGLE FRACTION TUMOR-CONTROL DOSES

Purpose: The relationship between various laboratory determinants of radiocurability considered alone and in combination, and the observed 50% tumor control dose, has been examined in rodent and xenografted human tumors. Methods and Materials: The single fraction 50% tumor control dose (TCD50) under normal and clamp hypoxic conditions, 50% tumor cell transplant dose (Td(50)), and in vitro estimated tumor cell radiosensitivity parameters, were determined in each of six tumor types (four isografted murine and two xenografted human tumors). Subcutaneous transplant sites and identical or similar tumor generations were used for both the Td(50) and TCD50 studies. Radiosensitivity parameters were obtained using the clonogenic assay, after allowing cells to enter the active growth phase to recover from trypsin induced alterations of cell radiosensitivity. Both control and irradiated cells were multiplicity corrected. Results: No single parameter (InTd(50), hypoxic fraction, or intrinsic radiosensitivity) correlated with the observed tumor control doses under aerobic or hypoxic conditions. However, when considered in combination, clonogenic fraction (estimated by Td(50)(-1)), and intrinsic radiosensitivity, predicted the rank-order of tumor control doses with a significant degree of accuracy, and tumor hypoxia influenced the value of the control dose. All parameters were demonstrated to be significant determinants of radiocurability, with substantial tumor to tumor variation in the relative importance of each. For the six tumor types, the combined laboratory determinants predicted 50% tumor control doses which differed from the observed TCD(50)s by an average of approximately 9 Gy under hypoxic conditions. Conclusion: The results obtained demonstrate: (a) the necessity of simultaneously considering all determinants of radiocurability if the role of a single determinant is to be assessed; (b) laboratory determinants may accurately predict tumor radiocurability.