局限期小细胞肺癌胸部放疗靶区关键科学问题的研究

Our prospective randomized clinical study had indicated that for limited-stage small-cell lung cancer (SCLC) received induction chemotherapy, thoracic radiation target volume included only the post-chemotherapy residual primary lesions and metastatic lymph node regions (involved field irradiation), without prophylactic mediastinal lymph node irradiation did not increase out-of field recurrence of primary lesion and mediastinal lymph node, but the mechanisms are not clear. The first part of this study intends to conduct surgical resection to limited-stage SCLC patients who are staged as T1-2N0-1M0, to observe the tiny infiltrating nidus around the primary gross lesions and simultaneously measure the distances between the tiny nidus and the primary gross lesions via pathological examination. In addition, SCLC is inclined to metastasis to mediastinal lymph nodes. But the use of involved field irradiation will also deliver a certain dosage of incidental irradiation to uninvolved lymph node regions. The incidental radiation dosage may be sufficient to kill tiny lymphatic metastases that are only microscopically visible. The second part of this study intends to quantitatively determine the incidental radiation dosage to the mediastinal lymph node regions, by using radiation therapy treatment planning system, in limited-stage SCLC patients receive definitive radiotherapy. Therefore, this study will resolve the results of clinical studies from the perspective of pathology and radiation dosimetry, and to provide sufficient evidences for the settlement of controversies existed for years in thoracic radiotherapy target volumes of limited-stage SCLC.

我们的前瞻性随机临床研究发现，对诱导化疗后的局限期小细胞肺癌(small-cell lung cancer, SCLC)，胸部放疗靶区仅包括化疗后残留的原发病灶及转移的纵隔淋巴结区（累及野照射），不做淋巴结区的预防性照射，不会增加原发病灶及纵隔淋巴结区的照射野外复发，但机制尚不明确。本研究第一部分拟对分期为T1-2N0-1M0的SCLC行手术切除，通过病理检查，观察大体原发病灶周围的微小浸润病变并测量二者之间的距离，以此确定临床靶体积的范围。此外，SCLC易发生纵隔淋巴结转移，但采用累及野照射时，未发生转移的淋巴结区也会受到一定剂量的附带照射，并可能足以杀灭微小的淋巴结转移灶。研究第二部分拟通过放疗计划系统定量测定接受根治性放疗的局限期SCLC患者纵隔淋巴结区的附带照射剂量。因此，本研究将从病理学及辐射剂量学角度解释临床研究结果，为解决争议多年的局限期SCLC胸部放疗靶区问题提供充分依据。

胸部放疗在局限期小细胞肺癌(SCLC)的综合治疗中必不可少。放疗靶区的准确定义和精确勾画是实现放疗消灭肿瘤作用的最大化及放疗相关毒副作用最小化的基本前提。但二十多年来，国内外放射肿瘤学界对局限期SCLC胸部放疗的临床靶区(CTV)范围无统一的勾画标准。而病理学研究是判定CTV范围的金标准。.本研究主要内容：1.手术切除初治或经2程EP方案化疗后的T1-2N0-1M0的SCLC患者肿瘤所在完整肺叶。留取肺部肿瘤标本，于显微镜下观察大体肿瘤周边的微小卫星病灶范围以确定CTV。2.于治疗计划系统上勾画接受根治性放化疗的局限期SCLC纵隔1-10组淋巴结，进行辐射剂量学分析。根据随访过程中淋巴结复发情况与其所受到的辐射剂量找出二者的量效关系，为优化纵隔淋巴结的放疗靶区勾画提供依据。.2014年11月至2017年4月，共有8例T1-2N0-1M0的SCLC纳入研究。其中4例接受2程术前新辅助化疗，其中1例术后常规病理为鳞癌而不纳入进一步分析，1例达到完全缓解。其余4例未接受新辅助化疗而直接进行手术。在接受和未接受新辅助化疗的患者中，其显微镜下病灶中位浸润范围分别为0.4mm（0.05mm-2.76mm）和1.7mm（0.08mm-12.7mm），而1.4mm和10.2mm可以分别包括95%的微小浸润病灶（P=0.00）。.在辐射剂量学研究中，共勾画了105例患者的1680组淋巴结区。其中76例患者接受三维适形放疗，29例患者接受调强放疗，纵隔淋巴结区域均采用累及野放疗，不做未未转移的区域的预防性放疗。在疾病确诊时，淋巴结区的总体转移率超过50%的区域有：4R (68.7%), 4L (57.9%), 10R (57.9%), 2R (56.6%), 7 (51.3%)。除第8组淋巴结以外，其余阳性淋巴结所在区域都接受了处方剂量照射。而淋巴结阴性的区域受到平均附带照射剂量超过3000cGy的区域有： 3P (3670.7 cGy), 4L (3476.1 cGy), 7 (3442.7 cGy), 6 (3441.0 cGy), 4R (3239.2 cGy), 5 (3166.7 cGy), 2L (3153.5 cGy) 。研究中未发现纵隔淋巴结复发情况与其所受到的辐射剂量之间的量效关系。