Development of the practical methods to detect the hypoxic cell fraction of the tumor for prediction of results of radiotherapy

背景：低剂量率（LDR）近距离放射治疗是治疗口腔舌癌的有效方法，尤其是在早期。然而，很少有人知道这种治疗的生物学机制，其特征在于提供连续暴露的LDR照射，或如何在临床上取得良好的效果。据报道，高微血管密度（MVD）和高Ki-67指数与外照射患者的良好预后有关。低MVD与肿瘤的缺氧分数相关。方法：采用Ki-67指数和微血管密度（microvessel density，MVD）对60例舌癌行LDR近距离放射治疗后的肿瘤细胞生长分数（growth fraction，GFA）和临床病理因素进行分析。结果：单因素和多因素分析显示，T分期与局部控制有显著相关性。在T1、T2和T3期肿瘤患者中，5年的精确局部无复发率分别为100%、76.4%和26.9%。Ki-67免疫反应性范围为8 - 75%（中位数：34%）。在单变量分析中，低Ki-67标记指数与较好的局部控制弱相关（P=0.0805）。MVD范围为5 - 45支微血管/视野（50.391 mm^2）（中位数：23支血管/视野）。结论：低剂量LDR照射能克服静止期肿瘤细胞和低密度细胞的放射抵抗，与外照射的结果完全不同。以这种方式，LDR近距离放射治疗可以具有与外部照射不同的生物学特性，这是有利的。

Background : Low dose rate (LDR) brachytherapy is an effective treatment for oral tongue cancer, especially in the early stage. However, little is known about the biological mechanism underlying this therapy, characterized by delivery of continuous exposures of LDR irradiation, or how the good results are achieved in clinics. It is reported that a high microvessel density (MVD) and high Ki-67 index is related to the good prognosis of patients treated with external irradiation. A low MVD is related to the hypoxic fraction of the tumor . The lower MVD indicates that the tumor has the more hypoxic cells and is more radioresistent.METHODS : The prognostic value of the growth fraction determined by Ki-67 index and the microvessel density (MVD) was assessed in 60 tongue cancers treated with LDR brachytherapy, in addition to clinicopathological factors. The specimens were taken from the tongue cancers before radiation therapy and immunohistochemically stained with anti Ki-67 antibody and anti CD 34 antibody.RESULTS : There were significant correlations between T stage and local control in univariate and multivariate analyses. The actuarial local recurrence-free rate at 5 years was 100%, 76.4%, and 26.9% in the patients with T1, T2, and T3 tumors, respectively.The Ki-67 immunoreactivity ranged from 8 to 75% (median : 34%). In univariate analysis, a low Ki-67-labeling index was weakly correlated with better local control (P=0.0805).MVD ranged from 5 to 45 microvessels per field (50.391 mm^2)(median : 23 vessels/field ). There were no differences in local control between tumors with high MVD and those with low MVD.CONCLUSIONS : These results are totally different from reports obtained with external irradiation, suggesting that LDR irradiation could overcome the radoioresistance caused by quiescent tumor cells and hypoic cells. In this way, LDR brachytherapy may have different biological characteristics from external irradiation, which are advantageous.