Division of Hematology and Oncology, Taipei Veterans General Hospital, Taipei, Taiwan.
School of Medicine, National Yang-Ming University, Taipei, Taiwan.
Asia Pac J Clin Oncol. 2022 Feb;18(1):19-27. doi: 10.1111/ajco.13443. Epub 2020 Sep 22.
Survival benefit from chemotherapy in advanced hepatocellular carcinoma (HCC) was limited till now. New chemoregimens with cytotoxicity modulators were explored to improve efficacy. Chemotherapy modulated with valproic acid (VA) as a deacetylation inhibitor of histone and DNA damage response proteins, and hydralazine (HZ) as a DNA hypomethylating agent, hypothetically suppressing DNA repair, were used in phase II trial here for advanced HCC.
Between July 2008 and March 2016, patients with chemo-naive advanced HCC, regardless of previous sorafenib treatment, not amenable to local therapy and with Child Pugh score ≤7, were treated with VA (200 mg thrice per day) and HZ (12.5 mg twice per day) in conjunction with gemcitabine and cisplatin (GCGG): gemcitabine (1000 mg/m , D1; 800 mg/m D8, 15) and cisplatin (70 mg/m , D1) every 28 days till disease progression and then with Dox-DTIC: doxorubicin (45 mg/m ) and dacarbazine (450 mg/m ) every 28 days. The primary endpoint was overall survival (OS); the secondary endpoints were safety, progression-free survival (PFS) and response rate (RR).
Thirty-seven patients with 16 sorafenib-experienced, underwent GCGG treatment, and 30 of them underwent the following Dox-DTIC treatment. The median OS was 14.6 months (95% confidence interval: 6.0-23.1). The median PFSs for patients treated with VA- and HZ-combined GCGG and Dox-DTIC were 3.7 and 4.2 months, respectively; the RRs were 10/37 (27.0%) and 7/30 (23.3%); and grade 3/4 neutropenia were 54% and 51%. However, there were no chemotherapy-related deaths.
VA- and HZ-combined sequential chemotherapy was effective in advanced HCC with manageable toxicities.
化疗在晚期肝细胞癌（HCC）中的生存获益有限。新的化疗方案，联合细胞毒性调节剂，旨在提高疗效。我们在此进行了一项 II 期临床试验，研究用组蛋白去乙酰化酶抑制剂丙戊酸（VA）和 DNA 去甲基化剂肼（HZ）化疗调节方案，联合吉西他滨和顺铂（GCGG）治疗晚期 HCC。
2008 年 7 月至 2016 年 3 月，我们对未经化疗的初治晚期 HCC 患者（无论之前是否接受过索拉非尼治疗），以及不适宜局部治疗且 Child-Pugh 评分≤7 的患者，采用 VA（200mg，每日 3 次）和 HZ（12.5mg，每日 2 次）联合吉西他滨和顺铂（GCGG）：吉西他滨（1000mg/m 2，D1；800mg/m 2，D8，15）和顺铂（70mg/m 2，D1），每 28 天为一个周期，直到疾病进展，然后采用多柔比星-达卡巴嗪（Dox-DTIC）：多柔比星（45mg/m 2）和达卡巴嗪（450mg/m 2），每 28 天为一个周期。主要终点为总生存期（OS）；次要终点为安全性、无进展生存期（PFS）和缓解率（RR）。
37 例患者中有 16 例曾接受索拉非尼治疗，接受 GCGG 治疗，其中 30 例患者接受了随后的 Dox-DTIC 治疗。中位 OS 为 14.6 个月（95%置信区间：6.0-23.1）。接受 VA 和 HZ 联合 GCGG 及 Dox-DTIC 治疗的患者中位 PFS 分别为 3.7 和 4.2 个月，缓解率分别为 10/37（27.0%）和 7/30（23.3%）；3/4 级中性粒细胞减少症发生率分别为 54%和 51%。但无化疗相关死亡。
VA 和 HZ 联合序贯化疗治疗晚期 HCC 有效，且毒性可耐受。
