CLINICAL IMPLICATIONS OF HETEROGENEITY OF TUMOR RESPONSE TO RADIATION-THERAPY
CLINICAL IMPLICATIONS OF HETEROGENEITY OF TUMOR RESPONSE TO RADIATION-THERAPY
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DOI：
10.1016/0167-8140(92)90244-o
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发表时间：
1992-12-01
影响因子：
5.7
通讯作者：
EFIRD, JT
中科院分区：
文献类型：
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作者：
SUIT, H;SKATES, S;EFIRD, JT
肿瘤组织对辐射的反应存在明显的异质性。主要参数包括组织病理学类型、大小（肿瘤挽救单位（TRUs）数量）、血红蛋白浓度、细胞增殖动力学和宿主免疫排斥反应。此外，在某些遗传性疾病中，例如共济失调毛细血管扩张症，正常和可能的肿瘤组织反应发生改变。肿瘤组织对新治疗方法的反应的任何评估或新临床反应预测因子的测试最好基于狭窄的层，即，相对于已知的响应参数，例如大小、组织学类型，是均匀的。即使在这种临床定义的狭窄层的肿瘤中，在固有的细胞辐射敏感性、pO 2分布、（SH）、单个肿瘤的反应预测因子的值将由这些和/或其他特征的值的异质性和变异系数（CV）确定。单个参数的测量值。一个或多个响应参数的异质性反映在局部对照的剂量响应曲线的斜率中，即异质性越大，斜率越不陡。为了检查这种效应，使用10（8）个肿瘤挽救单位（TRU）和SF 2 = 0.5（2戈伊单次剂量后的存活分数）的模型肿瘤对照的剂量反应曲线的斜率来评估SF 2的肿瘤间和肿瘤内变化对斜率的影响，定义为γ 50值。γ 50是在剂量-反应曲线中点处，剂量增加一个百分点时局部控制的增加，以百分点表示。当CV = 0.0时，γ 50为6.5。对于10%、20%和40%的肿瘤间CV，γ 50迅速降低至2.4、1.3和0.7。肿瘤内变异不太重要，即，对于10%、20%和40%的CV，γ 50值降低至5.3、3.8和2.2。结合肿瘤间和肿瘤内的变化减少γ 50仅略低于单独的肿瘤间的变化。例如，如果肿瘤间和肿瘤内变异的CV为10%，则gamma 50将为2.1，而单独的肿瘤间变异则为2.4。TRU的数量也影响斜率，即，当TRU数量从10（1）增加到10（12）时，γ 50从1增加到9.7。然而，预期指定T级内的TRU的数量在相当有限的范围内变化，例如，小于或等于10（1-2）的因子。因此，与细胞辐射敏感性的可能异质性相比，相对于TRU数量的异质性的影响将在较小程度上影响γ 50。啮齿类动物中肿瘤和正常组织的反应CV（独立肿瘤系统的TCD 50或不同品系小鼠的LD 50）在9- 20%的范围内，即小于体外测定的人肿瘤细胞的SF 2的20- 50%。如果一个狭窄的人类肿瘤层的γ 50几乎等于2，那么体内细胞辐射敏感性的CV将小于或等于10- 15%，该值与独立组织系统的值相当。
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 pO2, (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 SF2 = 0.5 (survival fraction after a single dose of 2 Gy) has been used to assess the impact of inter- and intra-tumoral variation of SF2 on slope, defined as gamma50 values. The gamma50 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 gamma50 was 6.5 for CV = 0.0. For inter-tumoral CVs of 10%, 20% and 40%, the gamma50 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 gamma50 values were reduced to 5.3, 3.8 and 2.2. Combining inter- and intra-tumoral variation reduced the gamma50 only slightly below that for inter-tumoral variation alone. For example, were the CV 10% for inter- and intra-tumoral variation, the gamma50 would be 2.1 as compared to 2.4 for inter-tumoral variation alone. The number of TRUs also affects slope, viz. gamma50 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. less-than-or-equal-to a factor of 10(1-2). Accordingly, the effect of heterogeneity with respect to TRU numbers would affect gamma50 to a lesser degree than the probable heterogeneity of cellular radiation sensitivity. The CVs for response of tumor and normal tissue in rodents (TCD50 of independent tumor systems or LD50 for different strains of mice) were in the range of 9-20%, i.e. less than found for SF2 of human tumor cells as determined in vitro, 20-50%. Were the gamma50 for a narrow strata of human tumors to be almost-equal-to 2, as judged likely, then the CV of radiation sensitivity of cells in vivo would be less-than-or-equal-to 10-15%, a value comparable with that found for independent tissue systems.