免疫保护性放疗与围手术期免疫治疗在III期非小细胞肺癌中的应用：IIIA/IIIB期非小细胞肺癌当前管理与未来方向的叙述性综述
Immune-preserving radiotherapy and perioperative immunotherapy in stage III NSCLC: a narrative review of current management and future directions for IIIA/IIIB NSCLC.
作者
作者单位
- The Ohio State University, Columbus, OH, USA.
- New York Proton Center, New York, NY, USA.
- JunXin Oncology Group, Jinan, China.
- Department of Radiation Medicine, University of Kentucky College of Medicine, Lexington, KY, USA.
摘要
中文
III期非小细胞肺癌（NSCLC）是一种异质性疾病，其预后受远处失败、治疗相关毒性和放化疗期间免疫适能丧失的限制。随机试验支持对可切除疾病采用围手术期免疫治疗（IO），对不可切除疾病在同步放化疗（cCRT）后采用度伐利尤单抗巩固治疗。免疫保护性放疗（RT）——包括免疫器官危及器官（iOAR）和免疫细胞有效剂量（EDIC）感知的计划、审慎的大分割放疗、立体定向放射治疗（SBRT）或空间分割放射治疗（SFRT）——正在成为治疗期间优化免疫适能的新兴杠杆。本研究旨在通过双轨框架（可切除与不可切除疾病）综合IIIA/IIIB期管理的当代证据，概述整合手术、RT和全身治疗的实用算法，并强调包括SFRT和基于肿瘤浸润淋巴细胞（TIL）的方法在内的转化策略，同时明确区分既定标准与探索性概念。我们对关键试验和改变实践的研究进行了叙述性综述，重点关注围手术期IO（新辅助化疗-IO±辅助IO）、PACIFIC模式、RT剂量/分割策略以及减轻RT相关淋巴细胞减少的方法。我们提出了一条循证临床路径和免疫保护性RT检查清单。新辅助纳武利尤单抗-化疗可改善可切除疾病的病理完全缓解（pCR）、无事件生存（EFS）和总生存（OS）（CheckMate 816）。围手术期帕博利珠单抗（KEYNOTE-671）、度伐利尤单抗（AEGEAN）和纳武利尤单抗（CheckMate 77T）显著延长EFS。在不可切除的III期疾病中，cCRT后度伐利尤单抗带来持久的OS获益（5年OS为42.9%），而统一剂量递增至74 Gy并未改善生存。RT相关淋巴细胞减少常见且具有预后意义；减少低剂量浴、最小化iOAR暴露和优化靶区选择可能保护免疫适能。SBRT/SFRT整合和基于TIL的细胞治疗方法值得前瞻性测试，但仍处于研究阶段。双轨算法——可切除的IIIA期采用围手术期化疗-IO，不可切除的IIIA/IIIB期采用cCRT后度伐利尤单抗——仍是循证标准。优先考虑免疫保护的精化方案（iOAR感知计划、限野和大分割策略）是有前途的研究领域，不应以牺牲肿瘤控制为代价。对于致癌基因驱动的疾病，应考虑靶向治疗。进行手术切除时，获取组织进行分子分型，以及在临床试验背景下进行TIL扩增，可能支持个体化治疗策略。这些探索性方法需要前瞻性验证。
English
Stage III non-small cell lung cancer (NSCLC) is a heterogeneous disease with outcomes limited by distant failure, treatment-related toxicities, and loss of immune fitness during chemoradiation. Randomized trials support perioperative immunotherapy (IO) for resectable disease and consolidation durvalumab after concurrent chemoradiotherapy (cCRT) for unresectable disease. Immune-preserving radiotherapy (RT)-encompassing immune organ-at-risk (iOAR) and effective dose to immune cells (EDIC)-aware planning, judicious hypofractionation, and stereotactic body radiation therapy (SBRT) or spatially fractionated radiation therapy (SFRT)-is an emerging lever to optimize immune competence during treatment. This study aims to synthesize contemporary evidence for stage IIIA/IIIB management through a dual-track framework (resectable versus unresectable disease), outline practical algorithms integrating surgery, RT, and systemic therapy, and highlight translational strategies including SFRT and tumor-infiltrating lymphocyte (TIL)-based approaches, while clearly distinguishing established standards from investigational concepts. We conducted a narrative review of pivotal trials and practice-shaping studies, emphasizing perioperative IO (neoadjuvant chemo-IO ± adjuvant IO), the PACIFIC paradigm, RT dose/fractionation strategies, and approaches to mitigate RT-related lymphopenia. We propose an evidence-anchored clinical pathway and a checklist for immune-preserving RT. Neoadjuvant nivolumab-chemotherapy improves pathological complete response (pCR), event-free survival (EFS), and overall survival (OS) in resectable disease (CheckMate 816). Perioperative pembrolizumab (KEYNOTE-671), durvalumab (AEGEAN), and nivolumab (CheckMate 77T) significantly prolong EFS. In unresectable stage III, durvalumab after cCRT confers durable OS benefit (5-year OS 42.9%), whereas uniform dose escalation to 74 Gy did not improve survival. RT-related lymphopenia is frequent and prognostic; reducing low-dose bath, minimizing exposure to iOARs, and optimizing target selection may preserve immune competence. SBRT/SFRT integrations and TIL-based cellular approaches warrant prospective testing but remain investigational. A dual-track algorithm-perioperative chemo-IO for operable IIIA and cCRT followed by durvalumab for unresectable IIIA/IIIB-remains the evidence-based standard. Refinements that prioritize immune preservation (iOAR-aware planning, limited-field and hypofractionated strategies) represent promising areas of investigation that should not compromise tumor control. In patients with oncogene-driven disease, targeted therapy should be considered. When surgical resection is performed, tissue acquisition for molecular profiling and, in the context of clinical trials, TIL expansion may support personalized treatment strategies. These investigational approaches require prospective validation.
分类与指标
- 研究类型
- 综述Meta
- 病种
- 肺癌
- JCR 分区
- Q2
- 影响因子
- 3.4
- 新锐分区
- 3区