van Kempen-Harteveld M Loes, Belkacémi Yazid, Kal Henk B, Labopin Myriam, Frassoni Francesco
Department of Radiotherapy, University Medical Centre, Utrecht, The Netherlands.
Int J Radiat Oncol Biol Phys. 2002 Apr 1;52(5):1367-74. doi: 10.1016/s0360-3016(01)02758-4.
To determine a dose-effect relationship for cataract induction, the tissue-specific parameter, alpha/beta, and the rate of repair of sublethal damage, mu value, in the linear-quadratic formula have to be known. To obtain these parameters for the human eye lens, a large series of patients treated with different doses and dose rates is required. The data of patients with acute leukemia treated with single-dose total body irradiation (STBI) and bone marrow transplantation (BMT) collected by the European Group for Blood and Marrow Transplantation were analyzed.
The data of 495 patients who underwent BMT for acute leukemia, who had STBI as part of their conditioning regimen, were analyzed using the linear-quadratic concept. The end point was the incidence of cataract formation after BMT. Of the analyzed patients, 175 were registered as having cataracts. Biologic effective doses (BEDs) for different sets of values for alpha/beta and mu were calculated for each patient. With Cox regression analysis, using the overall chi-square test as the parameter evaluating the goodness of fit, alpha/beta and mu values were found. Risk factors for cataract induction were the BED of the applied TBI regimen, allogeneic BMT, steroid therapy for >14 weeks, and heparin administration. To avoid the influence of steroid therapy and heparin on cataract induction, patients who received steroid or heparin treatment were excluded, leaving only the BED as a risk factor. Next, the most likely set of alpha/beta and mu values was obtained. With this set, the cataract-free survival rates were calculated for specific BED intervals, according to the Kaplan-Meier method. From these calculations, cataract incidences were obtained as function of the BED at 120 months after STBI.
The use of BED instead of the TBI dose enabled the incidence of cataract formation to be predicted in a reasonably consistent way. With Cox regression analysis for all STBI data, a maximal chi-square value was obtained for alpha/beta = 1.75 Gy and mu = 0.75 h(-1). When Cox regression analysis was applied for patients who had no steroid treatment after BMT, a maximal chi-square value was obtained for alpha/beta = 1 Gy and mu = 0.6 h(-1). Cox regression analysis was repeated using the data of patients who had not received posttransplant steroid treatment and also no heparin administration; we found alpha/beta = 0.75 Gy and mu= 0.65 h(-1). An increased cataract incidence was observed after steroid treatment of >14 weeks and heparin administration.
The alpha/beta value of 0.75 Gy and mu value of 0.65 h(-1) found for the eye lens are characteristic for late-responding tissues. The incidence of cataract formation can now be quantified, taking into account the values calculated for alpha/beta and mu, TBI dose, and dose rate. Also, the reduction in cataract incidence as a result of lens dose reduction by eye shielding can be estimated.
为确定白内障诱发的剂量效应关系，必须知晓线性二次方程中的组织特异性参数α/β以及亚致死损伤修复率μ值。为获取人眼晶状体的这些参数，需要大量接受不同剂量和剂量率治疗的患者数据。对欧洲血液和骨髓移植组收集的接受单剂量全身照射（STBI）及骨髓移植（BMT）治疗的急性白血病患者的数据进行了分析。
对495例接受BMT治疗急性白血病且将STBI作为预处理方案一部分的患者数据，采用线性二次概念进行分析。终点指标为BMT后白内障形成的发生率。在分析的患者中，175例被登记患有白内障。为每位患者计算了不同α/β和μ值组合的生物等效剂量（BED）。通过Cox回归分析，以总体卡方检验作为评估拟合优度的参数，得出α/β和μ值。白内障诱发的危险因素为所应用的全身照射方案的BED、异基因BMT、超过14周的类固醇治疗以及肝素给药。为避免类固醇治疗和肝素对白内障诱发的影响，排除接受类固醇或肝素治疗的患者，仅将BED作为危险因素。接下来，获得了最可能的α/β和μ值组合。利用该组合，根据Kaplan-Meier方法计算特定BED区间的无白内障生存率。通过这些计算，得出STBI后120个月时白内障发生率与BED的函数关系。
使用BED而非全身照射剂量能够以合理一致的方式预测白内障形成的发生率。对所有STBI数据进行Cox回归分析时，α/β = 1.75 Gy且μ = 0.75 h⁻¹时获得最大卡方值。对BMT后未接受类固醇治疗的患者进行Cox回归分析时，α/β = 1 Gy且μ = 0.6 h⁻¹时获得最大卡方值。使用未接受移植后类固醇治疗且未使用肝素的患者数据重复进行Cox回归分析；我们发现α/β = 0.75 Gy且μ = 0.65 h⁻¹。在超过14周的类固醇治疗和肝素给药后观察到白内障发生率增加。
为人眼晶状体所发现的α/β值为0.75 Gy且μ值为0.65 h⁻¹是晚反应组织的特征。现在可以考虑α/β和μ的计算值、全身照射剂量及剂量率来量化白内障形成的发生率。此外，还可以估计通过眼部屏蔽降低晶状体剂量所导致的白内障发生率降低情况。
