PD-1/PD-L1抑制剂联合抗血管生成药物治疗晚期/不可切慢性乙型病毒性肝炎相关肝细胞癌患者的临床观察

Clinical Observation of PD-1/PD-L1 Inhibitors Combined with Anti Angiogenic Drugs in the Treatment of Advanced/Unresectable Chronic Hepatitis B Related Hepatocellular Carcinoma Patients

摘要: 目的：观察PD-1/PD-L1抑制剂联合抗血管生成药物对乙肝相关性肝细胞癌中的疗效及其不良反应，为晚期/不可切肝细胞恶性肿瘤的免疫联合治疗的策略提供临床数据。方法：根据纳入排除标准纳入从2019年1月1日~2023年6月15日所有就诊于新疆医科大学附属肿瘤医院明确诊断为肝细胞癌的使用PD-1/PD-L1抑制剂联合抗血管生成药物治疗方案治疗的慢性乙型病毒相关性晚期/不可切肝细胞癌患者共97例，对其进行疗效观察，评估其临床效果和副作用。同时计算客观缓解率、疾病控制率、疾病无进展生存期和总生存期，并记录及分析其不良反应数据。结果：本研究共纳入了97例晚期/不可切患有慢性乙型病毒性肝炎的肝细胞癌患者。在97例患者中，所有患者均未达到完全缓解，有27例(27.8%)患者达到了部分缓解，58例(59.8%)患者病情稳定，12例(12.4%)患者的原发肿瘤出现了进展。客观缓解率为27.8% (27/97)，疾病控制率为87.6% (85/97)。截至2023年12月15日的随访截止日期，这97名患者均已结束了目前的治疗方案，其中37名患者已经离世，中位无进展生存期为15个月(95%置信区间：13.024~16.975个月)，中位总生存期为27个月(95%置信区间：21.58~32.42个月)，第12个月的总生存率为79.4%，第24个月的总生存率为44.3%。绝大多数病人都在治疗过程中经历了不良反应，其中大部分为I~II级。在血液系统毒性相关的不良反应中，最常见的I~II级反应是血细胞减少，达到了46.4% (45/97)，其次是血小板减少，发生率为36.1% (35/97)。而非血液学毒性主要表现为食欲减退56.7% (55/97)、甲状腺功能减退32.8% (32/97)、高血压19.6% (19/97)及转氨酶升高30.9% (30/97)。共有14例(14.4%)发生了治疗相关严重不良反应(III~IV级)，3例为III级甲状腺功能减退，3例为III级血小板减少，3例为III级转氨酶升高，4例为III级蛋白尿，仅有1例严重皮疹为与治疗相关的IV级毒副反应。虽然有一半以上的患者发生了治疗相关的不良反应，但大多数不良事件均为3级以下。结论：晚期/不可切乙型肝炎相关性肝细胞癌患者，在经过PD-1/PD-L1抑制剂与抗血管生成药物的联合治疗方案后，在临床应用中呈现出较为理想的疗效，并且毒副作用处于可控范围之内。PD-1/PD-L1抑制剂与抗血管生成药物的联合治疗方案有望成为此类患者的有效治疗选择。

Abstract: Objective: To observe the efficacy and adverse reactions of PD-1/PD-L1 inhibitor combined with anti angiogenesis drugs in hepatitis B related hepatocellular carcinoma, and provide clinical data for the strategy of combined immunotherapy of advanced/unresectable hepatocellular carcinoma. Methods: According to the inclusion and exclusion criteria, a total of 97 patients with chronic hepatitis B virus related advanced/unresectable hepatocellular carcinoma who were diagnosed with hepatocellular carcinoma at the Affiliated Cancer Hospital of Xinjiang Medical University from January 1, 2019 to June 15, 2023 and treated with PD-1/PD-L1 inhibitors combined with anti angiogenic drugs were included. The therapeutic effects were observed, and their clinical effects and side effects were evaluated. Simultaneously, the objective response rate, disease control rate, disease progression free survival, and overall survival were calculated, and their adverse reaction data were recorded and analyzed. Results: This study included 97 advanced/unresectable hepatocellular carcinoma patients with chronic hepatitis B admitted to the Affiliated Cancer Hospital of Xinjiang Medical University from January 1, 2019 to June 15, 2023. Among the 97 patients, all patients did not achieve complete remission, with 27 cases (27.8%) achieving partial remission, 58 cases (59.8%) showing stable condition, and 12 cases (12.4%) showing progression of the primary tumor. The objective response rate was 27.8% (27/97), and the disease control rate was 87.6% (85/97). As of the follow-up deadline of December 15, 2023, all 97 patients have completed their current treatment plan, of which 37 patients have passed away. The median progression free survival was 15 months (95% confidence interval: 13.024~16.975 months), the median overall survival was 27 months (95% confidence interval: 21.58~32.42 months), the overall survival rate at 12 months was 79.4%, and the overall survival rate at 24 months was 44.3%. The vast majority of patients have experienced adverse reactions during the treatment process, most of which are I~II grade, mainly divided into hematological toxicity and non hematological toxicity. The most common I~II grade adverse reaction in hematotoxicity is a decrease in blood cells, reaching 46.4% (45/97), followed by a decrease in platelets, with an incidence rate of 36.1% (35/97). The main manifestations of non hematological toxicity are decreased appetite (56.7%, 55/97), hypothyroidism (32.8%, 32/97), hypertension (19.6%, 19/97), and elevated transaminases (30.9%, 30/97). A total of 14 cases (14.4%) experienced treatment-related serious adverse reactions (III~IV), including 3 cases of grade III hypothyroidism, 3 cases of grade III thrombocytopenia, 3 cases of grade III transaminase elevation, 4 cases of grade III proteinuria, and only 1 case of severe rash as a treatment-related grade IV toxic side effect. Although more than half of patients experience treatment-related adverse reactions, most adverse events are below level 3. Conclusion: Patients with