Chiesa C, Mira M, Maccauro M, Romito R, Spreafico C, Sposito C, Bhoori S, Morosi C, Pellizzari S, Negri A, Civelli E, Lanocita R, Camerini T, Bampo C, Carrara M, Seregni E, Marchianò A, Mazzaferro V, Bombardieri E
Department of Nuclear Medicine, Istituto Nazionale Tumori IRCCS Foundation, Milan, Italy.
Q J Nucl Med Mol Imaging. 2012 Dec;56(6):503-8.
Our goal was to limit liver toxicity and to obtain good efficacy by developing a dosimetric treatment planning strategy. While several dosimetric evaluations are reported in literature, the main problem of the safety of the treatment is rarely addressed. Our work is the first proposal of a treatment planning method for glass spheres, including both liver toxicity and efficacy issues.
Fifty-two patients (series 1) had been treated for intermediated/advanced hepatocellular carcinoma (HCC) with glass spheres, according to the Therasphere® prescription of 120 Gy averaged on the injected lobe. They were retrospectively evaluated with voxel dosimetry, adopting the local deposition hypothesis. Regions of interest on tumor and non tumor parenchyma were drawn to determine the parenchyma absorbed dose, averaged also on non irradiated voxels, excluding tumor voxels. The relationship between the mean non tumoral parenchyma absorbed dose D and observed liver decompensation was analyzed.
Basal Child-Pugh strongly affected the toxicity incidence, which was 22% for A5, 57% for A6, 89% for B7 patients. Restricting the analysis to our numerically richest class (basal Child-Pugh A5 patients), D median values were significantly different between toxic (median 90 Gy) and non toxic treatments (median 58 Gy) at a Mann-Withney test, (P=0.033). Using D as a marker for toxicity, the separation of the two populations in terms of area under ROC curve was 0.75, with 95% C.I. of [0.55-0.95]. The experimental Normal Tissue Complication Probability (NTCP) curve as a function of D resulted in the following values: 0%, 14%, 40%, 67% for D interval of [0-35] Gy, [35-70] Gy, [70-105] Gy, [105-140] Gy.
A limit of about 70 Gy for the mean absorbed dose to parenchyma was assumed for A5 patients, corresponding to a 14% risk of liver decompensation. This result is applicable only to our administration conditions: glass spheres after a decay interval of 3.75 days. Different safety limit (40 Gy) are published for resin spheres, characterized by higher number of particle per GBq (more uniform irradiation, bigger biological effect for the same absorbed dose).
As result of this study we suggest a constraint of about 70 Gy mean absorbed dose to liver non tumoral parenchyma, corresponding to about 15% probability of radioinduced liver decompensation while still aiming at achieving an absorbed of several hundreds of Gy to lesions.
我们的目标是通过制定剂量测定治疗计划策略来限制肝脏毒性并获得良好疗效。虽然文献中报道了几种剂量测定评估，但治疗安全性的主要问题很少得到解决。我们的工作是首次提出一种针对玻璃微球的治疗计划方法，包括肝脏毒性和疗效问题。
52例患者（系列1）根据Therasphere®处方接受玻璃微球治疗中晚期肝细胞癌（HCC），注入肝叶的平均剂量为120 Gy。采用局部沉积假设，通过体素剂量测定法对他们进行回顾性评估。在肿瘤和非肿瘤实质区域绘制感兴趣区，以确定实质吸收剂量，也对未受照射的体素（不包括肿瘤体素）进行平均。分析了平均非肿瘤实质吸收剂量D与观察到的肝脏失代偿之间的关系。
基础Child-Pugh分级对毒性发生率有强烈影响，A5患者为22%，A6患者为57%，B7患者为89%。将分析限于我们数据最丰富的类别（基础Child-Pugh A5患者），在Mann-Withney检验中，毒性治疗（中位数90 Gy）和非毒性治疗（中位数58 Gy）的D中位数显著不同（P = 0.033）。以D作为毒性标志物，根据ROC曲线下面积对两组人群进行区分，结果为0.75，95%置信区间为[0.55 - 0.95]。实验性正常组织并发症概率（NTCP）曲线作为D的函数，在D区间[0 - 35] Gy、[35 - 70] Gy、[70 - 105] Gy、[105 - 140] Gy时分别得出以下值：0%、14%、40%、67%。
假设A5患者实质平均吸收剂量的限值约为70 Gy，这对应14%的肝脏失代偿风险。该结果仅适用于我们的给药条件：衰变间隔3.75天后的玻璃微球。对于树脂微球公布了不同的安全限值（40 Gy），其特征是每GBq的粒子数更多（照射更均匀，相同吸收剂量下生物效应更大）。
作为本研究的结果，我们建议将肝脏非肿瘤实质的平均吸收剂量限制在约70 Gy，这对应约15%的放射性肝失代偿概率，同时仍旨在使病变达到数百Gy的吸收剂量。
