大分割放疗联合免疫检查点抑制剂治疗晚期转移性实体瘤的临床疗效研究

Clinical efficacy of hypofractionated radiotherapy combined with immune checkpoint inhibitors in treating advanced metastatic solid tumors

目的探讨大分割放疗(HFRT)联合程序性细胞死亡蛋白-1/程序性细胞死亡配体-1(PD-1/PD-L1)抑制剂序贯粒细胞-巨噬细胞集落刺激因子(GM-CSF)及白细胞介素-2(IL-2)治疗晚期转移性实体肿瘤的效果。方法对南通大学附属江阴医院放疗科收治的经标准治疗失败的晚期难治性实体瘤患者行前瞻性单中心单臂研究,符合条件的患者给予四联治疗:每21 d接受1次HFRT(5~8 Gy×2~3 f),至少2个周期;从放疗开始第1~7天接受200μg的GM-CSF,从第8~14天接受200万IU的IL-2。在HFRT完成后1周内,使用PD-1/PD-L1抑制剂进行治疗。重复上述治疗策略。GM-CSF和IL-2治疗6个周期,后续使用PD-1/PD-L1抑制剂维持,直到疾病进展(PD)或出现不可耐受的毒性。对客观缓解率(ORR)和治疗相关不良事件进行分析。结果2021年1月9日—2023年6月15日,共有40例患者入选,随访时间2.8~31.0个月,中位随访时间为9.9个月,其中39例患者(97.5%)完成了至少1次非放射治疗靶区内的肿瘤部位评估。97.5%患者为癌症,2.5%为软组织肉瘤,20.0%在基线检查时曾接受过免疫检查点抑制剂(ICIs)。ORR为30.8%,疾病控制率(DCR)为71.8%;非小细胞肺癌(NSCLC)的ORR为28.6%,DCR为57.1%;结直肠癌的ORR为14.3%,DCR为71.4%;胃癌的ORR为16.7%,DCR为66.7%;28例患者(70.0%)发生治疗相关不良事件(TRAE),4例患者(10%)发生≥3级TRAE,最常见的TRAE是乏力、发热及甲状腺功能减退。结论HFRT联合免疫检查点抑制剂序贯GM-CSF和IL-2的治疗在晚期转移性实体瘤患者中耐受性良好,毒性可接受,可能为晚期转移性实体肿瘤患者的挽救治疗提供了一种新的方法。

Objective To investigate the efficacy of hypofractionated radiotherapy(HFRT)combined with programmed cell death protein-1/programmed cell death ligand-1(PD-1/PD-L1)inhibitors in sequential with granulocyte-macrophage colony-stimulating factor(GM-CSF)and interleukin-2(IL-2)for the treatment of advanced metastatic solid tumors.Methods A prospective single-center single-arm study was designed for patients failed standard treatments for advanced refractory solid tumors in the Department of Radiotherapy of Jiangyin Hospital affiliated to Nantong University,and eligible patients were given quadruple therapy:HFRT(5 to 8 Gy×2 to 3 f)once every 21 days for at least 2 cycles;200μg GM-CSF from the 1st to 7th day of radiotherapy,and 2 million IU IL-2 from the 8thto 14th day.Within 1 week after the completion of HFRT,PD-1/PD-L1 inhibitors were used for treatment.The above treatment strategy was repeated.GM-CSF and IL-2 were treated for 6 cycles,followed by maintenance with PD-1/PD-L1 inhibitors until disease progression(PD)or intolerable toxicity occurred.Objective response rate(ORR)and treatment-related adverse events were analyzed.Results From January 9,2021 to June 15,2023,totally 40 patients were enrolled,with follow-up of 2.8 to 31.0 months and a median follow-up of 9.9 months,and 39 patients(97.5%)completed at least one time tumorsite evaluation within the non-radiotherapy target area.97.5%of patients had cancers,2.5%had soft tissue sarcomas,and 20.0%had received immune checkpoint inhibitors(ICIs)at baseline check.The ORR was 30.8%,and the disease control rate(DCR)was 71.8%;the ORR for non-small cell lung cancer(NSCLC)was 28.6%,and the DCR was 57.1%;the ORR for colorectal cancer was 14.3%,and the DCR was 71.4%;the ORR for gastric cancer was 16.7%,and the DCR was 66.7%;28 patients(70.0%)had treatment-related adverse events(TRAE),4 patients(10%)had TRAE≥level 3,and the most common types of TRAE were fatigue,fever and hypothyroidism.Conclusion The treatment of HFRT combined with immune checkpoint inhibitors in sequential with GM-CSF and IL-2 is well tolerated and toxicity accepted in patients with advanced metastatic solid tumors,which may provide a new method for salvage treatment of patients with advanced metastatic solid tumors.