阿帕替尼联合调强放疗治疗不可切除肝细胞癌的Ⅰ期临床试验。
Phase 1 trial of apatinib combined with intensity-modulated radiotherapy in unresectable hepatocellular carcinoma.
机构信息
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Radiation Oncology, Peking University Cancer Hospital and Institute, No. 52 Fu-cheng Road, Haidian District, Beijing, 100142, People's Republic of China.
出版信息
BMC Cancer. 2022 Jul 15;22(1):771. doi: 10.1186/s12885-022-09819-3.
BACKGROUND
To investigate the maximum tolerated dose (MTD) of apatinib delivered during and after intensity-modulated radiotherapy (IMRT) for unresectable hepatocellular carcinoma (HCC).
METHODS
Patients with unresectable HCC who were not eligible for radiofrequency ablation (RFA), transcatheter arterial chemoembolization (TACE), or residual/ recurrent after the prior local treatment were enrolled. Patients were scheduled to be treated with IMRT at 50-60 Gy/25-30 fractions. Oral apatinib tablets were administered concurrently with IMRT and continued thereafter. We used a 3 + 3 dose-escalation design, with three dose levels of apatinib (250, 500, and 750 mg). Grade 3 or more severe adverse events (AEs) were defined as dose-limiting toxicities (DLTs). The treatment response was calculated using the Modified Response Evaluation Criteria in Solid Tumours.
RESULTS
Nine patients with Barcelona Clinic Liver Cancer Stage C were included. One patient withdrew from the apatinib 250 mg group and another patient was added. No DLTs occurred in the apatinib 250 mg group. Five patients were included in the apatinib 500 mg group, and 2 cases of DLT (grade 3 leukopenia) were found among them. Dose escalation was terminated and the MTD was determined to be 250 mg. Common grade 1-2 AEs included fatigue, hypertension, dizziness, bone marrow suppression, and hyperbilirubinemia. The median follow-up time for all patients was 16.0 months. Three patients achieved complete response and another three achieved partial response. The objective response rate was 6/9 (66.7%), and the disease control rate was 9/9 (100%). Three patients relapsed out of the radiation field. The median progression-free survival was 17.0 months, and the median overall survival was 16.7 months.
CONCLUSIONS
When combined with IMRT, apatinib 250 mg daily was recommended for a phase 2 study of unresectable HCC. The antitumor activity of the combination treatment was encouraging. The safety and efficacy of apatinib combined with IMRT for unresectable HCC should be further investigated in future studies.
TRIAL REGISTRATION
Registration No. ChiCTR1800018309 . Registered 11 September 2018. Retrospectively registered, https://www.chictr.org.cn/showproj.aspx?proj=30461 .
背景
研究不可切除肝细胞癌（HCC）患者在调强放疗（IMRT）期间和之后使用阿帕替尼的最大耐受剂量（MTD）。
方法
本研究纳入了不符合射频消融（RFA）、经导管动脉化疗栓塞（TACE）或局部治疗后残留/复发适应证的不可切除 HCC 患者。患者接受 50-60Gy/25-30 次分割的调强放疗。同时给予口服阿帕替尼片治疗，调强放疗后继续服用。我们采用 3+3 剂量递增设计，阿帕替尼的三个剂量水平分别为 250、500 和 750mg。3 级或更严重的不良事件（AE）定义为剂量限制性毒性（DLT）。采用实体瘤改良疗效评价标准（mRECIST）计算治疗反应。
结果
本研究纳入了 9 例巴塞罗那临床肝癌分期 C 期患者。1 例患者退出阿帕替尼 250mg 组，另加 1 例患者。阿帕替尼 250mg 组未发生 DLT。5 例患者纳入阿帕替尼 500mg 组，其中 2 例发生 DLT（3 级白细胞减少症）。终止剂量递增，确定 MTD 为 250mg。常见的 1-2 级 AE 包括乏力、高血压、头晕、骨髓抑制和高胆红素血症。所有患者的中位随访时间为 16.0 个月。3 例患者达到完全缓解，3 例患者达到部分缓解。客观缓解率为 6/9（66.7%），疾病控制率为 9/9（100%）。3 例患者肿瘤在放疗野外复发。中位无进展生存期为 17.0 个月，中位总生存期为 16.7 个月。
结论
当与调强放疗联合应用时，推荐每日使用阿帕替尼 250mg 进行不可切除 HCC 的 2 期研究。联合治疗的抗肿瘤活性令人鼓舞。在未来的研究中，应进一步探讨阿帕替尼联合调强放疗治疗不可切除 HCC 的安全性和有效性。
试验注册
注册号 ChiCTR1800018309。注册日期 2018 年 9 月 11 日。回顾性注册，https://www.chictr.org.cn/showproj.aspx？proj=30461。
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