Clinical implications of heterogeneity of tumor response to radiation therapy

Abstract

Heterogeneity of response of tumor tissue to radiation clearly exists. Major parameters include histopathologic type, size (number of tumor rescue units (TRUs)), hemoglobin concentration, cell proliferation kinetics and immune rejection reaction by host. Further, normal and presumably tumor tissue response is altered in certain genetic diseases, e.g. ataxia telangiectasia. Any assessment of response of tumor tissue to a new treatment method or the testing of a new clinical response predictor is optimally based upon a narrow strata, viz., uniform with respect to known parameters of response, e.g. size, histological type. Even among tumors of such a clinically defined narrow strata, there will be residual heterogeneity with respect to inherent cellular radiation sensitivity, distributions of pO 2, (SH), cell proliferation etc. The value of a response predictor of an individual tumor will be determined by the heterogeneity of values for these and or other characteristics and by the coefficient of variation (CV) of the measured values of the individual parameters. Heterogeneity of one or more parameters of response is reflected in the slope of the dose response curve for local control, viz. the greater the heterogeneity the less steep the slope. To examine for this effect, the slope of dose response curves for control of model tumors of 10 8 tumor rescue units (TRU) and the SF 2 = 0.5 (survival fraction after a single dose of 2 Gy) has been used to assess the impact of inter- and intea-tumoral variation of SF 2 on slope, defined as γ 50 values. The γ 50 is the increase in local control expressed in percent points for a one percentage increment in dose, at the mid-point on the dose-response curve. The γ 50 was 6.5 for CV =0.0. For inter-tumoral CVs of 10%, 20% and 40%, the γ 50 rapidly decreased to 2.4, 1.3 and 0.7. Intra-tumoral variation was less important, viz., for CVs of 10%, 20%, and 40% the γ 50 values were reduced to 5.3, 3.8 and 2.2. Combining inter- and intea-tumoral variation reduced the γ 50 only slightly below that for inter-tumoral variation alone. For example, were the CV 10% for inter- and intea-tumoral variation, the γ 50 would be 2.1 as compared to 2.4 for inter-tumoral variation alone. The number of TRUs also affects slope, viz. γ 50 increased from 1 to 9.7 as the TRU number increased from 10 1 to 10 12. However, the number of TRUs within a specified T stage would be expected to vary over a rather limited range, e.g. ⩽ a factor of 10 1−2. Accordingly, the effect of heterogeneity with respect to TRU numbers would affect γ 50 to a lesser degree than the probable heterogeneity of cellular radiation sensitivity. The CVs for response of tumor and normal tissue in rodents (TCD 50 of independent tumor systems or LD 50 for different strains of mice) were in the range of 9–20%, i.e. less than found for SF 2 of human tumor cells as determined in vitro, 20–50%. Were the γ 50 for a narrow strata of human tumors to be ≈2, as judged likely, then the CV of radiation sensitivity of cells in vivo would be ⩽ 10–15%, a value comparable with that found for independent tissue systems.