The emergence of immune checkpoint inhibitors (ICIs) in operable non-small cell lung cancer (NSCLC) has resulted in very promising early outcomes in several neoadjuvant ICI phase I/II clinical trials^1-4 as well as a large, randomized multi-institutional trial of chemotherapy combined with nivolumab followed by surgery for stage IB–IIIA NSCLC (CheckMate 816).⁵ There has been a rather uniform observation that combined chemotherapy plus ICI results in more pathologic tumor regression than either chemotherapy or ICI treatment alone. Moreover, the level of pathologic regression often correlates poorly with tumor response criteria using standard RECIST criteria. While thoracic surgeons are familiar with perioperative adverse events (AEs) related to systemic chemotherapy, toxicities associated with ICI therapy are not as well understood. As the use of ICI and related immune-oncology drugs becomes more standard in the treatment of stage IB–IIIA NSCLC, it is important that thoracic surgeons appreciate the potential immune-related AEs (irAEs) associated with these drugs.

The recent expert opinion publication in Thoracic Cancer offers a comprehensive review of existing clinical trials employing neoadjuvant and adjuvant ICI ± chemotherapy, as well as an assessment and recommended treatment of related irAES.⁶ While the American Society of Clinical Oncology guidelines⁷ focus on irAEs across all cancer types, primarily in late-stage disease, this publication focuses only on patients with lung cancer and specifically those for whom surgery is part of the treatment plan. Heretofore, the more common irAEs observed in neoadjuvant monotherapy ICI studies include endocrinopathies, pneumonitis, and rash. The specific endocrinopathies most reported are hyper- and hypothyroidism and diabetes mellitus. However, instead of focusing solely on irAEs, it is increasingly appreciated that, in a multimodality treatment approach (i.e. ICI, chemotherapy, surgery), overall treatment-related AEs (TRAEs) may be a better assessment of toxicities associated with all treatments. TRAEs offer a more patient-centered assessment while potentially permitting an analysis of the unique surgical AEs and their contribution to the overall TRAE assessment.

There will be some hesitancy on the part of thoracic surgeons and their patients to introduce a neoadjuvant treatment protocol that involves ICIs, instead of moving directly to surgery. However, if the other large, randomized phase III clinical trials examining neoadjuvant chemotherapy plus ICI support the initial observations of CM-816 and if there is an associated improvement in event-free survival and overall survival, then this approach will likely become the standard of care for patients with operable stage IB–IIIA NSCLC who lack targetable oncogenic driver genomic alterations. As such, thoracic surgeons need to be familiar with the important points raised in this expert opinion document on irAEs. A relevant, surgeon-specific concern is whether ICIs in the neoadjuvant setting will result in irAEs that would preclude the patient from undergoing surgery for their primary tumor. All studies reported to date of monotherapy ICI or combined chemotherapy plus ICI have not demonstrated an irAE profile that prevented the patient from undergoing surgery. While some irAEs are different from those commonly observed with chemotherapy alone, as discussed by the authors these irAEs can be medically managed prior to surgery, with most patients proceeding safely to surgical resection and 85–90% having an R0 resection. In my experience, compared to chemotherapy, ICI therapy is better tolerated by patients.

There remain many unanswered questions regarding patient selection for use of neoadjuvant and adjuvant ICI therapy; most notably, which tumors will respond to immunotherapy and which will not. Like with chemotherapy, there currently are no biomarkers that accurately predict response or resistance to ICI therapies. We also do not know how long ICI therapy should be continued in the adjuvant setting – the neoadjuvant ICI trials (AEGEAN, IMpower030, and KEYNOTE-617) as well as the adjuvant IMpower010 study and others all have an additional year of ICI therapy. As mentioned previously, we do not know if the dramatic pathologic tumor regression as measured by complete pathologic response or major pathologic response will translate into improved event-free or overall survival in patients. Finally, to avoid the toxicity profile of chemotherapy, other neoadjuvant immune-priming approaches, such as combined stereotactic radiation and ICI followed by surgery as reported by Altorki et al., deserve more attention.⁸

The role of the thoracic oncologic surgeon in the management of patients with operable NSCLC is rapidly evolving. Over the past two decades, surgeons have been focused on adopting minimally invasive approaches for the resection of NSCLC. While this has been an advance in the field, the rapid development of next-generation sequencing, the discovery of and drug development for known oncogenic driver alterations, and the explosion of immunotherapy as a new backbone of systemic therapy are now an essential part of the care plan for patients with earlier stage NSCLC.⁹ Thoracic surgeons need to refocus attention to these developments and how to best integrate pre-resection molecular testing, participation in clinical trials, and performing safe, complete surgical resections after targeted and immunotherapies. An awareness and understanding of the specific perioperative irAEs as reported by Ni et al. is an important part of this process.

在可手术的非小细胞肺癌 (NSCLC) 中出现的免疫检查点抑制剂 (ICI) 已在几项新辅助 ICI I/II 期临床试验^1-4以及大型、随机多机构研究中产生了非常有希望的早期结果。 IB-IIIA 期非小细胞肺癌化疗联合纳武利尤单抗的试验（CheckMate 816）。⁵有一个相当一致的观察结果表明，联合化疗加 ICI 导致比单独化疗或 ICI 治疗更多的病理性肿瘤消退。此外，病理消退的水平通常与使用标准 RECIST 标准的肿瘤反应标准相关性较差。虽然胸外科医生熟悉与全身化疗相关的围手术期不良事件 (AE)，但与 ICI 治疗相关的毒性尚不清楚。随着 ICI 和相关免疫肿瘤药物的使用在 IB-IIIA 期 NSCLC 的治疗中变得更加标准，胸外科医生了解与这些药物相关的潜在免疫相关 AE (irAE) 非常重要。

最近在胸癌中发表的专家意见对采用新辅助和辅助 ICI ± 化疗的现有临床试验进行了全面回顾，以及对相关 irAES 的评估和推荐治疗。⁶而美国临床肿瘤学会指南⁷重点关注所有癌症类型的 irAE，主要是晚期疾病，本出版物仅关注肺癌患者，特别是那些手术是治疗计划一部分的患者。迄今为止，在新辅助单药治疗 ICI 研究中观察到的更常见 irAE 包括内分泌病、肺炎和皮疹。报道最多的特定内分泌疾病是甲状腺功能亢进和甲状腺功能减退以及糖尿病。然而，人们越来越认识到，在多模式治疗方法（即 ICI、化疗、手术）中，与整体治疗相关的 AE (TRAE) 可能是对与所有治疗相关的毒性的更好评估，而不是仅仅关注 irAE。

胸外科医生及其患者对于引入涉及 ICI 的新辅助治疗方案而不是直接进行手术会有些犹豫。然而，如果其他检查新辅助化疗加 ICI 的大型随机 III 期临床试验支持 CM-816和如果无事件生存期和总生存期有相关改善，那么这种方法可能会成为缺乏可靶向致癌驱动基因组改变的可手术 IB-IIIA 期 NSCLC 患者的治疗标准。因此，胸外科医生需要熟悉这份关于 irAEs 的专家意见文件中提出的要点。一个相关的、外科医生特有的担忧是，新辅助治疗中的 ICI 是否会导致 irAE，从而使患者无法接受原发肿瘤的手术。迄今为止，所有报道的单药 ICI 或联合化疗加 ICI 的研究都没有显示出阻止患者接受手术的 irAE 特征。虽然一些 irAE 与单独化疗时通常观察到的不同，正如作者所讨论的，这些 irAE 可以在手术前进行医学管理，大多数患者可以安全地进行手术切除，85-90% 的患者进行了 R0 切除。根据我的经验，与化疗相比，患者对 ICI 治疗的耐受性更好。

关于选择使用新辅助和辅助 ICI 治疗的患者，仍有许多悬而未决的问题；最值得注意的是，哪些肿瘤会对免疫疗法有反应，哪些不会。与化学疗法一样，目前还没有生物标志物可以准确预测对 ICI 疗法的反应或耐药性。我们也不知道在辅助环境中 ICI 治疗应该持续多长时间——新辅助 ICI 试验（AEGEAN、IMpower030 和 KEYNOTE-617）以及辅助 IMpower010 研究和其他研究都需要额外一年的 ICI 治疗。如前所述，我们不知道通过完全病理反应或主要病理反应衡量的显着病理性肿瘤消退是否会转化为患者无事件或总生存期的改善。最后，为了避免化疗的毒性，⁸

胸外科肿瘤外科医生在可手术非小细胞肺癌患者管理中的作用正在迅速发展。在过去的二十年里，外科医生一直专注于采用微创方法切除 NSCLC。虽然这是该领域的一项进步，但下一代测序的快速发展、已知致癌驱动改变的发现和药物开发，以及免疫疗法作为全身治疗新支柱的爆炸式增长，现在已成为该领域的重要组成部分。早期非小细胞肺癌患者的护理计划。⁹胸外科医生需要重新关注这些发展，以及如何最好地整合切除前分子检测、参与临床试验以及在靶向治疗和免疫治疗后进行安全、完整的手术切除。Ni 等人报告的对特定围手术期 irAE 的认识和理解。是这个过程的重要组成部分。