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A Prospective Phase II Study of Safety and Efficacy of Sorafenib Followed by 90Y Glass Microspheres for Patients with Advanced or Metastatic Hepatocellular Carcinoma
Journal of Hepatocellular Carcinoma ( IF 4.1 ) Pub Date : 2021-09-09 , DOI: 10.2147/jhc.s318865 Ahmed Omar Kaseb 1 , S Cheenu Kappadath 2 , Sunyoung S Lee 1 , Kanwal Pratap Raghav 1 , Yehia I Mohamed 1 , Lianchun Xiao 3 , Jeffrey S Morris 4 , Chimela Ohaji 1 , Rony Avritscher 5 , Bruno C Odisio 5 , Joshua Kuban 5 , Mohamed E Abdelsalam 5 , Beth Chasen 6 , Khaled M Elsayes 7 , Mohamed Elbanan 7 , Robert A Wolff 1 , James C Yao 1 , Armeen Mahvash 2
Journal of Hepatocellular Carcinoma ( IF 4.1 ) Pub Date : 2021-09-09 , DOI: 10.2147/jhc.s318865 Ahmed Omar Kaseb 1 , S Cheenu Kappadath 2 , Sunyoung S Lee 1 , Kanwal Pratap Raghav 1 , Yehia I Mohamed 1 , Lianchun Xiao 3 , Jeffrey S Morris 4 , Chimela Ohaji 1 , Rony Avritscher 5 , Bruno C Odisio 5 , Joshua Kuban 5 , Mohamed E Abdelsalam 5 , Beth Chasen 6 , Khaled M Elsayes 7 , Mohamed Elbanan 7 , Robert A Wolff 1 , James C Yao 1 , Armeen Mahvash 2
Affiliation
Purpose: The most common cause of death in advanced/metastatic hepatocellular carcinoma (HCC) is liver failure due to tumor progression. While retrospective studies and meta-analyses of systemic therapy combined with liver-directed therapy have been performed, prospective studies of safety/efficacy of antiangiogenesis followed by intra-arterial therapies are lacking. We tested our hypothesis that sorafenib followed by yttrium 90 glass microspheres (90Y GMs) is safe and that survival outcomes may improve by controlling hepatic tumors.
Methods: We enrolled 38 Child–Pugh A patients with advanced/metastatic HCC. In sum, 34 received sorafenib, followed after 4 weeks by 90Y GMs. Analysis of safety and survival outcomes was performed to assess adverse events, median progression-free survival, and overall survival.
Results: A total of 34 patients were evaluable: 14 (41.2%) with chronic hepatitis, nine (26.5%) with vascular invasion, and eleven (32.4%) with extrahepatic diseases. Safety analysis revealed that the combination therapy was well tolerated. Grade III–IV adverse events comprised fatigue (n=3), diarrhea (n=2), nausea (n=1), vomiting (n=2), hypertension (n=4), thrombocytopenia (n=1), hyperbilirubinemia (n=1), proteinuria (n=1), hyponatremia (n=1), and elevated alanine or aspartate aminotransferase (n=5). Median progression-free and overall survival were 10.4 months (95% CI 5.8– 14.4) and 13.2 months (95% CI 7.9– 18.9), respectively. Twelve patients (35.3%) achieved partial responses and 16 (47.0%) stable disease. Median duration of sorafenib was 20 (3– 90) weeks, and average dose was 622 (466– 800) mg daily. Dosimetry showed similar mean doses between planned and delivered calculations to normal liver and tumor:normal liver uptake ratio, with no significant correlation with adverse events at 3 and 6 months post-90Y treatment.
Conclusion: This is the first prospective study to evaluate sorafenib followed by 90Y in patients with advanced HCC. The study validated our hypothesis of safety with encouraging efficacy signals of the sequencing treatment, and provides proof of concept for future combination modalities for patients with advanced or metastatic HCC.
Clinical Trial Registration Number: NCT01900002.
Keywords: HCC, sorafenib, yttrium 90, BCLC, hepatocellular carcinoma
中文翻译：
索拉非尼继以 90Y 玻璃微球治疗晚期或转移性肝细胞癌患者的安全性和有效性的前瞻性 II 期研究
目的：晚期/转移性肝细胞癌 (HCC) 最常见的死亡原因是肿瘤进展导致的肝功能衰竭。虽然已经进行了全身治疗联合肝脏定向治疗的回顾性研究和荟萃分析，但缺乏抗血管生成后动脉内治疗的安全性/有效性的前瞻性研究。我们检验了我们的假设，即索拉非尼后接钇 90 玻璃微球 ( 90 Y GM) 是安全的，并且通过控制肝肿瘤可能会改善生存结果。
方法：我们招募了 38 名患有晚期/转移性 HCC 的 Child–Pugh A 级患者。总之，34 人接受了索拉非尼治疗，4 周后90 人接受了索拉非尼治疗Y GM。对安全性和生存结果进行分析以评估不良事件、中位无进展生存期和总生存期。
结果：共有 34 名患者接受评估：14 名 (41.2%) 患有慢性肝炎，9 名 (26.5%) 患有血管侵犯，11 名 (32.4%) 患有肝外疾病。安全性分析显示联合治疗耐受性良好。III-IV 级不良事件包括疲劳 (n=3)、腹泻 (n=2)、恶心 (n=1)、呕吐 (n=2)、高血压 (n=4)、血小板减少症 (n=1)、高胆红素血症(n=1)、蛋白尿 (n=1)、低钠血症 (n=1) 和丙氨酸或天冬氨酸转氨酶升高 (n=5)。中位无进展生存期和总生存期分别为 10.4 个月（95% CI 5.8-14.4）和 13.2 个月（95% CI 7.9-18.9）。12 名患者 (35.3%) 获得部分缓解，16 名 (47.0%) 患者病情稳定。索拉非尼的中位持续时间为 20 (3–90) 周，平均剂量为每天 622 (466–800) mg。90 Y处理。
结论：这是第一项在晚期 HCC 患者中评估索拉非尼继之以90 Y 的前瞻性研究。该研究通过令人鼓舞的测序治疗疗效信号验证了我们的安全性假设，并为晚期或转移性 HCC 患者的未来联合疗法提供了概念证明。
临床试验注册号： NCT01900002。
Keywords: HCC, 索拉非尼, 钇90, BCLC, 肝细胞癌
更新日期：2021-09-08
Methods: We enrolled 38 Child–Pugh A patients with advanced/metastatic HCC. In sum, 34 received sorafenib, followed after 4 weeks by 90Y GMs. Analysis of safety and survival outcomes was performed to assess adverse events, median progression-free survival, and overall survival.
Results: A total of 34 patients were evaluable: 14 (41.2%) with chronic hepatitis, nine (26.5%) with vascular invasion, and eleven (32.4%) with extrahepatic diseases. Safety analysis revealed that the combination therapy was well tolerated. Grade III–IV adverse events comprised fatigue (n=3), diarrhea (n=2), nausea (n=1), vomiting (n=2), hypertension (n=4), thrombocytopenia (n=1), hyperbilirubinemia (n=1), proteinuria (n=1), hyponatremia (n=1), and elevated alanine or aspartate aminotransferase (n=5). Median progression-free and overall survival were 10.4 months (95% CI 5.8– 14.4) and 13.2 months (95% CI 7.9– 18.9), respectively. Twelve patients (35.3%) achieved partial responses and 16 (47.0%) stable disease. Median duration of sorafenib was 20 (3– 90) weeks, and average dose was 622 (466– 800) mg daily. Dosimetry showed similar mean doses between planned and delivered calculations to normal liver and tumor:normal liver uptake ratio, with no significant correlation with adverse events at 3 and 6 months post-90Y treatment.
Conclusion: This is the first prospective study to evaluate sorafenib followed by 90Y in patients with advanced HCC. The study validated our hypothesis of safety with encouraging efficacy signals of the sequencing treatment, and provides proof of concept for future combination modalities for patients with advanced or metastatic HCC.
Clinical Trial Registration Number: NCT01900002.
Keywords: HCC, sorafenib, yttrium 90, BCLC, hepatocellular carcinoma
中文翻译：
索拉非尼继以 90Y 玻璃微球治疗晚期或转移性肝细胞癌患者的安全性和有效性的前瞻性 II 期研究
目的：晚期/转移性肝细胞癌 (HCC) 最常见的死亡原因是肿瘤进展导致的肝功能衰竭。虽然已经进行了全身治疗联合肝脏定向治疗的回顾性研究和荟萃分析，但缺乏抗血管生成后动脉内治疗的安全性/有效性的前瞻性研究。我们检验了我们的假设，即索拉非尼后接钇 90 玻璃微球 ( 90 Y GM) 是安全的，并且通过控制肝肿瘤可能会改善生存结果。
方法：我们招募了 38 名患有晚期/转移性 HCC 的 Child–Pugh A 级患者。总之，34 人接受了索拉非尼治疗，4 周后90 人接受了索拉非尼治疗Y GM。对安全性和生存结果进行分析以评估不良事件、中位无进展生存期和总生存期。
结果：共有 34 名患者接受评估：14 名 (41.2%) 患有慢性肝炎，9 名 (26.5%) 患有血管侵犯，11 名 (32.4%) 患有肝外疾病。安全性分析显示联合治疗耐受性良好。III-IV 级不良事件包括疲劳 (n=3)、腹泻 (n=2)、恶心 (n=1)、呕吐 (n=2)、高血压 (n=4)、血小板减少症 (n=1)、高胆红素血症(n=1)、蛋白尿 (n=1)、低钠血症 (n=1) 和丙氨酸或天冬氨酸转氨酶升高 (n=5)。中位无进展生存期和总生存期分别为 10.4 个月（95% CI 5.8-14.4）和 13.2 个月（95% CI 7.9-18.9）。12 名患者 (35.3%) 获得部分缓解，16 名 (47.0%) 患者病情稳定。索拉非尼的中位持续时间为 20 (3–90) 周，平均剂量为每天 622 (466–800) mg。90 Y处理。
结论：这是第一项在晚期 HCC 患者中评估索拉非尼继之以90 Y 的前瞻性研究。该研究通过令人鼓舞的测序治疗疗效信号验证了我们的安全性假设，并为晚期或转移性 HCC 患者的未来联合疗法提供了概念证明。
临床试验注册号： NCT01900002。
Keywords: HCC, 索拉非尼, 钇90, BCLC, 肝细胞癌
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