Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea; Yonsei Liver Center, Severance Hospital, Seoul, Republic of Korea.
Department of Radiation Oncology, Yonsei University College of Medicine, Seoul, Republic of Korea.
Int J Radiat Oncol Biol Phys. 2020 May 1;107(1):106-115. doi: 10.1016/j.ijrobp.2020.01.027. Epub 2020 Feb 19.
Although sorafenib as a standard of care for advanced hepatocellular carcinoma (HCC) prolongs overall survival (OS), its efficacy is limited owing to its unsatisfactory objective response and marginal survival benefit. To counter these limitations, we designed a single-arm, phase II trial with liver-directed concurrent chemoradiotherapy (LD-CCRT) and sequential sorafenib treatment in patients with advanced HCC.
We enrolled advanced HCC patients diagnosed between 2014 and 2017 who were ineligible for curative treatment. During the first and last 5 days of 5-week radiation therapy, concurrent hepatic arterial infusion with 5-fluorouracil (500 mg/d) and leucovorin (50 mg/d) through an implanted port was administered 4 weeks after initiation of LD-CCRT and sequential sorafenib treatment (400 mg, twice daily). The primary endpoint was OS. This trial has been registered at clinicaltrials.gov.
Among the enrolled patients (n = 47), objective response rates 4 weeks after LD-CCRT and during/up to sorafenib maintenance were 44.7% and 53.2%, respectively. Overall, 9 patients (19.1%) underwent curative resection or transplantation after down staging. The median radiation dose was 60 Gy. The median OS was 24.6 months for the entire cohort and 13.0 months for the subgroup with tumor invasion into the main portal trunk or its first branch, whereas the median progression-free survival for the cohort and subgroup was 6.8 and 5.6 months, respectively. The most frequent treatment-related adverse events were diarrhea (36.2%) and hand-foot skin reaction (34%), which were manageable with conservative treatment.
LD-CCRT and sequential sorafenib treatment provided favorable OS and progression-free survival with good tolerability. Tumor reduction using an initial LD-CCRT enabled down staging, subsequent curative treatment, and long-term survival in about 20% of the patients with advanced HCC. However, further randomized trials are required to confirm these results.
索拉非尼作为晚期肝细胞癌（HCC）的标准治疗方法可以延长总生存期（OS），但其疗效有限，因为其客观反应不理想，生存获益有限。为了克服这些局限性，我们设计了一项单臂、II 期临床试验，对晚期 HCC 患者进行肝定向同期放化疗（LD-CCRT）和序贯索拉非尼治疗。
我们招募了 2014 年至 2017 年间诊断为晚期 HCC 且不符合治愈性治疗条件的患者。在 5 周放疗的第 1 天和最后 5 天，在 LD-CCRT 开始后 4 周，同时通过植入的端口进行肝动脉输注 5-氟尿嘧啶（500mg/d）和亚叶酸（50mg/d），并进行序贯索拉非尼治疗（400mg，每日两次）。主要终点是 OS。该试验已在 clinicaltrials.gov 注册。
在入组的患者（n=47）中，LD-CCRT 后 4 周和索拉非尼维持期间/直至期间的客观缓解率分别为 44.7%和 53.2%。总体而言，有 9 例（19.1%）患者在降期后接受了根治性切除或移植。中位放疗剂量为 60Gy。全队列的中位 OS 为 24.6 个月，主门静脉主干或其第一分支受侵亚组的中位 OS 为 13.0 个月，而队列和亚组的中位无进展生存期分别为 6.8 个月和 5.6 个月。最常见的治疗相关不良事件是腹泻（36.2%）和手足皮肤反应（34%），通过保守治疗即可控制。
LD-CCRT 和序贯索拉非尼治疗提供了良好的 OS 和无进展生存期，且耐受性良好。初始 LD-CCRT 可使肿瘤缩小，从而使约 20%的晚期 HCC 患者能够进行降期、随后进行根治性治疗和长期生存。然而，需要进一步的随机试验来证实这些结果。
