Service d'Hépatologie et Gastroentérologie, Hôpital de la Croix-Rousse, Lyon, France.
Hôpital Haut Lévèque, Pessac, France.
Lancet Gastroenterol Hepatol. 2019 Jun;4(6):454-465. doi: 10.1016/S2468-1253(19)30040-8. Epub 2019 Apr 4.
Cytotoxic chemotherapy is generally ineffective in patients with hepatocellular carcinoma. We assessed the intravenous perfusion of doxorubicin-loaded nanoparticles in patients with hepatocellular carcinoma in whom previous sorafenib therapy had failed.
We did a multicentre, open-label, randomised, controlled phase 3 trial at 70 sites in 11 countries. Patients with hepatocellular carcinoma with one or more previous systemic therapies, including sorafenib, were randomly assigned to receive 30 mg/m doxorubicin-loaded nanoparticles (30 mg/m group), 20 mg/m doxorubicin-loaded nanoparticles (20 mg/m group), or standard care using a computer-generated randomisation list prepared by the funder and stratified by geographic region. Patients in the experimental groups received perfusion of the drug every 4 weeks and those in the control group received any systemic anticancer therapy (except sorafenib) as per investigator decision. The primary endpoint was overall survival in the intention-to-treat population. Safety was assessed in the population of patients who received at least one dose of their assigned treatment. This trial is registered with ClinicalTrials.gov, number NCT01655693.
Between June 15, 2012, and Jan 27, 2017, 541 patients were screened, of whom 144 were excluded and 397 were randomly assigned to one of the groups (133 to the 30 mg/m group; 130 to the 20 mg/m group; and 134 to the control group). Median follow-up was 22·7 months (IQR 11·2-34·9). After pooling the doxorubicin groups for the efficacy analysis, median overall survival was 9·1 months (95% CI 8·1-10·4) in the pooled doxorubicin-loaded nanoparticles group and 9·0 months (7·1-11·8) in the control group (HR 1·00 [95% CI 0·78-1·28], two-sided p=0·99). 227 (94%) of 242 patients who received doxorubicin-loaded nanoparticles and 100 (75%) of 134 patients in the control group had at least one treatment-emergent adverse event. The most common drug-related grade 3 or 4 treatment-emergent adverse events were neutropenia (25 [10%] of 242 treated with doxorubicin-loaded nanoparticles and eight [6%] of 134 in the control group), asthenia (six [2%] and four [3%]), and thrombocytopenia (three [1%] and ten [7%]). Six (2%) patients treated with doxorubicin-loaded nanoparticles and one (1%) of those in the control group were deemed by investigators to have had a drug-related death. Serious adverse events occurred in 74 (31%) patients who received doxorubicin-loaded nanoparticles and 48 (36%) in the control group.
Doxorubicin-loaded nanoparticles did not improve overall survival for patients with hepatocellular carcinoma in whom previous sorafenib treatment had failed.
Onxeo.
细胞毒性化疗在肝细胞癌患者中通常无效。我们评估了多柔比星载药纳米粒在索拉非尼治疗失败的肝细胞癌患者中的静脉灌注。
我们在 11 个国家的 70 个地点进行了一项多中心、开放标签、随机、对照的 3 期试验。患有肝细胞癌且接受过一种或多种系统治疗（包括索拉非尼）的患者被随机分配接受 30mg/m 多柔比星载药纳米粒（30mg/m 组）、20mg/m 多柔比星载药纳米粒（20mg/m 组）或根据研究者决定使用标准护理（除索拉非尼外）。实验组患者每 4 周进行一次药物灌注，对照组患者接受任何系统抗癌治疗。主要终点是意向治疗人群的总生存期。在至少接受一次指定治疗的患者人群中评估安全性。这项试验在 ClinicalTrials.gov 注册，编号为 NCT01655693。
在 2012 年 6 月 15 日至 2017 年 1 月 27 日期间，共有 541 名患者接受了筛选，其中 144 名被排除，397 名被随机分配到一个组中（30mg/m 组 133 名；20mg/m 组 130 名；对照组 134 名）。中位随访时间为 22.7 个月（IQR 11.2-34.9）。在对多柔比星组进行疗效分析后，多柔比星载药纳米粒组的中位总生存期为 9.1 个月（95%CI 8.1-10.4），对照组为 9.0 个月（7.1-11.8）（HR 1.00[95%CI 0.78-1.28]，双侧 p=0.99）。242 名接受多柔比星载药纳米粒治疗的患者中有 227 名（94%）和 134 名对照组患者中有 100 名（75%）至少发生了一次治疗后出现的不良事件。最常见的与药物相关的 3 级或 4 级治疗后不良事件是中性粒细胞减少症（242 名接受多柔比星载药纳米粒治疗的患者中有 25 名[10%]，134 名对照组患者中有 8 名[6%]）、乏力（6 名[2%]和 4 名[3%]）和血小板减少症（3 名[1%]和 10 名[7%]）。多柔比星载药纳米粒组有 6 名（2%）患者和对照组有 1 名（1%）患者被研究者认为与药物相关死亡。多柔比星载药纳米粒组有 74 名（31%）患者和对照组有 48 名（36%）发生严重不良事件。
对于索拉非尼治疗失败的肝细胞癌患者，多柔比星载药纳米粒并未改善总生存期。
Onxeo。
