目的：通过免疫检查点抑制剂联合调强放疗一线治疗局部晚期肺鳞癌15例回顾性观察，进一步验证免疫联合放疗的可行性及安全性，高效性，前景值得期待。方法：2019年7月至2020年7月共15例肺鳞癌患者，均有明确病理及临床分期(IIIA-IIIB)。无免疫治疗及放疗禁忌。15例患者均一线接受国产免疫检查点抑制剂信迪利单抗联合局部调强放疗。放疗首日同步信迪利单抗(PD-1) 200 mg静滴，放疗期间至放疗结束继续维持免疫治疗至12个月。放疗模式选择IMRT，验证方法每周CBCT验证。总剂量：95% PTV 6000 CGy/30 f。疗效评估采用回访至2022年8月。结果：15例患者目前均在随访中。评价目标肿瘤主要参考RECIST1.1标准。其中1年：9例PR，CR 6例。ORR 100%。一年生存率100%，2年：CR 5例，PR 7例，SD 2例，PD 1例。2年局部控制率 > 85%，2年生存率100%。中位PFS (Progression-Free Survival)未达到。继续观察中。毒副作用主要依据CTC2.0版药物治疗毒作用分级标准，CSCO指南的免疫治疗毒作用分级标准。15例患者均未出现II度以上毒副作用。结论：免疫联合放疗一线治疗局部晚期非小细胞肺癌方法可行，近期疗效显著，远期生存继续观察评估。值得进一步扩大样本观察推广。 Objective: To retrospectively observe 15 cases of locally advanced lung squamous cell carcinoma treated with immune checkpoint inhibitors combined with intensity-modulated radiotherapy (IMRT), and to further verify the feasibility, safety, efficiency of immunotherapy combined with radiotherapy, and the prospect of it is worth looking forward to. Methods: From July 2019 to July 2020, a total of 15 patients with squamous cell carcinoma of the lung were enrolled. All patients had clear pathological and clinical stages (IIIA-IIIB). There were no contraindications of immunotherapy and radiotherapy in all cases. All 15 patients received first-line immune checkpoint inhibitor Sindilizumab combined with local intensity modulated radiotherapy. On the first day of radiotherapy, Sindilizumab (pd-1) 200 mg was simultaneously intravenous dripped, and the immunotherapy was maintained until 12 months after the end of radiotherapy. Radiotherapy Way: IMRT, Verification method: weekly CBCT validation. Totol dose: 95% PTV 6000 cGY/30 f. The efficacy was evaluated by follow-up visits until August 2022. Results: All 15 patients are currently under follow-up. Target tumor was evaluated mainly according to RECIST1.1 criteria. Among them, 9 cases had partial response in one year, and 6 cases had complete response. ORR was 100%. The one-year survival rate was 100%. There were 7 cases with partial remission, 5 cases with complete remission, 2 cases with stable disease, and 1 case with progressive disease. The 2-year local control rate was more than 85%, and the 2-year survival rate was 100%. The median PFS was not reached. The toxicity and side effects were mainly based on the toxicity grading standards of drug therapy (CTC2.0) and immunotherapy toxicity grading standards of CSCO guidelines. None of the 15 patients had toxic side effects more severe than grade II. Results: Immunotherapy combined with radiotherapy was feasible for the first-line treatment of locally advanced non-small cell lung cancer, and the short-term efficacy was significant. Long-term survival is continuing to be assessed under observation. It is worth further expanding the sample observation and promotion.
目的：通过免疫检查点抑制剂联合调强放疗一线治疗局部晚期肺鳞癌15例回顾性观察，进一步验证免疫联合放疗的可行性及安全性，高效性，前景值得期待。方法：2019年7月至2020年7月共15例肺鳞癌患者，均有明确病理及临床分期(IIIA-IIIB)。无免疫治疗及放疗禁忌。15例患者均一线接受国产免疫检查点抑制剂信迪利单抗联合局部调强放疗。放疗首日同步信迪利单抗(PD-1) 200 mg静滴，放疗期间至放疗结束继续维持免疫治疗至12个月。放疗模式选择IMRT，验证方法每周CBCT验证。总剂量：95% PTV 6000 CGy/30 f。疗效评估采用回访至2022年8月。结果：15例患者目前均在随访中。评价目标肿瘤主要参考RECIST1.1标准。其中1年：9例PR，CR 6例。ORR 100%。一年生存率100%，2年：CR 5例，PR 7例，SD 2例，PD 1例。2年局部控制率 > 85%，2年生存率100%。中位PFS (Progression-Free Survival)未达到。继续观察中。毒副作用主要依据CTC2.0版药物治疗毒作用分级标准，CSCO指南的免疫治疗毒作用分级标准。15例患者均未出现II度以上毒副作用。结论：免疫联合放疗一线治疗局部晚期非小细胞肺癌方法可行，近期疗效显著，远期生存继续观察评估。值得进一步扩大样本观察推广。
免疫 + IMRT，一线，肺鳞癌
Yong Liu*, Hongmei Li, Jie Leng, Lishan Li, Bao Cao
Department of Radiotherapy, Pizhou People’s Hospital, Pizhou Jiangsu
Received: Dec. 18th, 2022; accepted: Jan. 12th, 2023; published: Jan. 19th, 2023
Objective: To retrospectively observe 15 cases of locally advanced lung squamous cell carcinoma treated with immune checkpoint inhibitors combined with intensity-modulated radiotherapy (IMRT), and to further verify the feasibility, safety, efficiency of immunotherapy combined with radiotherapy, and the prospect of it is worth looking forward to. Methods: From July 2019 to July 2020, a total of 15 patients with squamous cell carcinoma of the lung were enrolled. All patients had clear pathological and clinical stages (IIIA-IIIB). There were no contraindications of immunotherapy and radiotherapy in all cases. All 15 patients received first-line immune checkpoint inhibitor Sindilizumab combined with local intensity modulated radiotherapy. On the first day of radiotherapy, Sindilizumab (pd-1) 200 mg was simultaneously intravenous dripped, and the immunotherapy was maintained until 12 months after the end of radiotherapy. Radiotherapy Way: IMRT, Verification method: weekly CBCT validation. Totol dose: 95% PTV 6000 cGY/30 f. The efficacy was evaluated by follow-up visits until August 2022. Results: All 15 patients are currently under follow-up. Target tumor was evaluated mainly according to RECIST1.1 criteria. Among them, 9 cases had partial response in one year, and 6 cases had complete response. ORR was 100%. The one-year survival rate was 100%. There were 7 cases with partial remission, 5 cases with complete remission, 2 cases with stable disease, and 1 case with progressive disease. The 2-year local control rate was more than 85%, and the 2-year survival rate was 100%. The median PFS was not reached. The toxicity and side effects were mainly based on the toxicity grading standards of drug therapy (CTC2.0) and immunotherapy toxicity grading standards of CSCO guidelines. None of the 15 patients had toxic side effects more severe than grade II. Results: Immunotherapy combined with radiotherapy was feasible for the first-line treatment of locally advanced non-small cell lung cancer, and the short-term efficacy was significant. Long-term survival is continuing to be assessed under observation. It is worth further expanding the sample observation and promotion.
Keywords:Immunotherapy + IMRT, First-Line, Lung Squamous Cell Carcinoma
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肺癌是全世界发病率和死亡率最高的恶性肿瘤。国家肿瘤质控中心最新发布的《2020年全国癌症报告》提示我国目前发病率男性第一，致死率男性及女性均为第一位。并且保持上升趋势 [
2019年7月至2020年7月共15例患者接受国产免疫检查点抑制剂信迪利单抗联合放疗一线治疗。体力状况：ECOG 1级11例，2级4例。全组病例均有明确鳞癌病理诊断。其中13例为男性，2例为女性，临床分期依据AJCC肺癌分期第八版，其中III期a 3例，IIIb 12例。年龄分布57岁至75岁。中位年龄68岁。15例患者均有吸烟史，且>10年，15至20支/天。
一般血液学检查血常规，肝功能，肾功能，心肌酶谱，甲状腺功能等。器械检查心电图，心脏超声。15例患者均无放疗及免疫治疗禁忌症。签署知情同意书。
1) 定位：热塑膜体位固定，放疗专用大孔径CT扫描。2) 完善靶区勾画。肺内病灶肺窗勾画，淋巴结纵隔窗勾画。靶区定义：根据ICRU50及ICRU60号报告，GTV，CTV，PTV及ITV分别定义为：GTV肺部原发病灶及转移淋巴结；CTV：亚临川病灶及区域淋巴引流区。ITV：CTV因呼吸运动形成范围；PTV：包括CTV，ITV，摆位误差及系统误差及治疗中验证调整靶位置及靶体积变化等形成范围。3) 全程调强放疗(IMRT)，每周CBCT验证。95% PTV6000CGY/30f。
放疗首日同步信迪利单抗(PD-1) 200 mg静滴，首次60分钟，以后每周周期静滴30分钟。一次/3周。放疗全程及放疗结束继续维持免疫治疗至12月。
随访主要通过专科门诊及电话和微信进行。放疗结束4周第一次复诊，后每4周期免疫治疗评估一次。目前随访至2022年8月。内容：一般状况、生命体征、体格检查，血常规，肝功能，肾功能，甲状腺共功能，心肌酶谱，肾上腺皮质醇等，相关影像学及其他器械检查，如ECG，胸部CT检查等。不良事件(AE，Adverse Event)记录内容：发生起始时间，发生部位、持续情况、严重程度分级，药物干预情况，AE的转归情况。
评价内容主要为疗效及毒副作用。根据实体瘤免疫治疗疗效评价标准(iRECIST)，客观评效依据实体瘤RECIST v1.1标准。通过影像学检查及血液学检测评估和记录所有的可测量及可评价的肿瘤病灶及毒副作用。治疗初期可测量病灶长径及短径为基线。放疗结束4周并两周期免疫治疗后进行首次评效，而后每4周期免疫治疗进行再次评估，评价目标肿瘤RECIST1.1标准：完全缓解CR (complete response)：所有目标病灶消失。部分缓解PR (partial response)：基线病灶长径总和缩小30%。疾病稳定SD (stable disease)：基线病灶长径总和有缩小但未达PR或有增加但未达PD。疾病进展PD (progressive disease)：基线病灶长径总和增加20%或出现新病灶。毒副作用评估依据CTC2.0版药物治疗毒作用分级标准及免疫治疗毒作用分级标准。
结果分析：疗效1年：6例PR，PR：9，ORR：100%。一年生存率100%；两年5例CR，PR：7例，SD 2例，PD 1例。生存率100%，局部控制率 > 85%。中位PFS未达到。完成本组治疗计划15例患者均未出现III度并以上毒副作用。血液学毒副作用I级14人次，II级7人次，III~IV级0人III次。甲状腺功能下降I级2例，II级1例，III~IV级0例。免疫性心肌炎0例。免疫性肺炎I~II级3例，III~IV级 0例。具体如表1和表2：
| 胸部CT评估 | 第一次 | 第二次 | 第三次 | 第四次 | 第五次 | 第六次 | 第七次 |
|---|---|---|---|---|---|---|---|
| CR | 6例 | 6例 | 6例 | 6例 | 6例 | 5例 | 5例 |
| PR | 9例 | 9例 | 9例 | 8例 | 7例 | 8例 | 7例 |
| SD | 0例 | 0例 | 0例 | 1例 | 2例 | 2例 | 2例 |
| PD | 0例 | 0例 | 0例 | 0例 | 0例 | 0例 | 1例 |
表1. RECIST1.1标准评效
| 分级 | 血常规 | 肝功能 | 肾功能 | 甲状腺功能 | 心脏EF | 免疫性肺炎 |
|---|---|---|---|---|---|---|
| I度 | 12例 | 2例 | 0例 | 2例甲减 | 0例 | 2例 |
| II度 | 2例 | 2例 | 1例 | 1例甲减 | 0例 | 1例 |
| III度 | 0例 | 0例 | 0例 | 0例甲减 | 0例 | 0例 |
| IV度 | 0例 | 0例 | 0例 | 0例甲减 | 0例 | 0例 |
表2. 毒副作用评估：未出现II度以上毒副作用。(主要为血液学毒副作用)
我国肺癌病理类型85%以上为非小细胞肺癌。鳞癌约占30%~40%。NSCLC 5年总的生存率 < 10%。远低于欧美发达国家。虽然手术治疗NSCLC 3年生存率约60%，5年生存率约39%为最高。而80%左右患者初诊时就失去了根治性手术机会。特别针对驱动基因阴性的局部晚期非小细胞肺癌，放化疗仍然为主要治疗方式。然而单纯化疗5年生存率单纯 < 5%，放疗5年生存率5%~10%，放化疗结合5年生存率10%~15% [
免疫治疗是调动体内免疫系统识别和杀死肿瘤细胞的一种治疗方式 [
免疫联合化疗治疗驱动基因阴性晚期非小细胞肺癌取得很大成功。对于无法手术的局部晚期肺鳞癌患者，随着PD-1/PD-L1为代表的免疫检查点抑制剂研究深入，免疫治疗取得了明显进展。2019年美国lmfinzi在III期不可切除非小细胞肺癌的PACIFIC试验的三年总生存率(OS)结果表明，接受lmfinzi治疗的患者3年的OS率为57%，而安慰剂组为43.5%。lmfinzi组的中位OS尚未达到，而安慰剂组为29.1个月。Lmfinzi显示出了持久和持续的OS获益。2019年帕博利珠单抗联合化疗中国获批晚期肺鳞癌患者。以PD-1/PD-L1为代表的免疫治疗带来长期治愈的机会。III期KEYNOTE-407研究结果，帕博利珠单抗联合化疗组和化疗组中位OS分别为17.3个月vs. 12.6个月，联合组较化疗组降低了56%的死亡风险；联合组和化疗组中位PFS分别为8.3个月vs. 4.2个月，联合组较化疗组降低了68%的疾病进展或死亡风险 [
免疫联合放疗在动物中已取得了令人期待的结果。Kim等让HCC小鼠模型局部接受放疗并监测其PD-L1的表达水平 [
放疗可以激活一些先天免疫通路，调节T细胞免疫活性。放疗可以调节免疫微环境，增加肿瘤微环境部分趋化因子CXCL10和CXCL16的水平，促进免疫治疗的作用持久、稳定且强大。放疗上调肿瘤细胞PD-L1的表达以及T细胞PD-1的表达，PD-1通路可抑制放疗介导的远隔效应的产生，而PD-1/PD-L1免疫检查点抑制剂可抑制PD-1通路，从而增强抗肿瘤的能力。可刺激免疫应答、产生远隔效应。晚期NSCLC在接受pembrolizumab治疗前有无接受放疗对预后有影响。接受放疗的患者中位PFS为4.4个月，中位OS为10.7个月，未接受放疗的患者中位PFS为2.1个月，中位OS为5.3个月，两者之间存在统计学差异，且放疗产生的毒性反应在可接受范围内 [
目前，随着放疗设备更新，更精确、精准的SBRT/IMRT放疗新疗法实施，放疗在实体恶性肿瘤治疗中所扮演的角色越来越重要。先进的放疗技术(IMRT)优点：优化射野内各射束的权重，适形度比3D-CRT更优化，靶区内剂量分布更均匀，靶区边缘计量梯度更陡峭 [
鉴于上述研究基础，我科自2019年7月至2020年7月进行免疫联合放疗一线治疗肺鳞癌15例。随访至2022年8月。疗效1年：6例CR，9例PR，ORR：100%。一年生存率100%；两年5例CR，7例PR，SD 2例，PD 1例。生存率100%，局部控制率 > 85%。随访继续，中位疾病控制时间未达到。实际临床工作中部分肺鳞癌病人因为各种原因不宜同步放化或联合化疗。肺鳞癌基本无驱动基因表达，传统针对EGFR突变的靶向治疗药物不可用。抗血管生成的靶向药物主要适宜外周肺鳞癌III线治疗 [
吴阶平医学会临床科研专项资助基金课题。课题编号：320.6750.2020-10-71。
刘 永,李红梅,冷 洁,李俐姗,曹 宝. 免疫联合放疗一线治疗局部晚期肺鳞癌15例临床观察Clinical Observation of 15 Cases of Locally Advanced Lung Squamous Cell Carcinoma Treated with Immunotherapy Combined with Radiotherapy[J]. 世界肿瘤研究, 2023, 13(01): 7-13. https://doi.org/10.12677/WJCR.2023.131002