Background

Hepatocellular carcinoma is the third-leading cause of cancer-related death worldwide. Preservation of health-related quality of life (HRQOL) during treatment is an important therapeutic goal. The aim of this study was to evaluate the effect of treatment with lenvatinib versus sorafenib on HRQOL.

Methods

REFLECT was a previously published multicentre, randomised, open-label, non-inferiority phase 3 study comparing the efficacy and safety of lenvatinib versus sorafenib as a first-line systemic treatment for unresectable hepatocellular carcinoma. Eligible patients were aged 18 years or older with unresectable hepatocellular carcinoma and one or more measurable target lesion per modified Response Evaluation Criteria in Solid Tumors criteria, Barcelona Clinic Liver Cancer stage B or C categorisation, Child-Pugh class A, Eastern Cooperative Oncology Group (ECOG) performance status of 1 or lower, and adequate organ function. Patients were randomly assigned (1:1) via an interactive voice–web response system; stratification factors for treatment allocation included region; macroscopic portal vein invasion, extrahepatic spread, or both; ECOG performance status; and bodyweight. Patient-reported outcomes (PROs), collected at baseline, on day 1 of each subsequent cycle, and at the end of treatment, were evaluated in post-hoc analyses of secondary and exploratory endpoints in the analysis population, which was the subpopulation of patients with a PRO assessment at baseline. A linear mixed-effects model evaluated change from baseline in PROs, including European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) and hepatocellular carcinoma-specific QLQ-HCC18 scales (both secondary endpoints of the REFLECT trial). Time-to-definitive-deterioration analyses were done based on established thresholds for minimum differences for worsening in PROs. Responder analyses explored associations between HRQOL and clinical response. This study is registered with ClinicalTrials.gov, NCT01761266.

Findings

Of 954 eligible patients randomly assigned to lenvatinib (n=478) or sorafenib (n=476) between March 14, 2013, and July 30, 2015, 931 patients (n=468 for lenvatinib; n=463 for sorafenib) were included in this analysis. Baseline PRO scores reflected impaired HRQOL and functioning and considerable symptom burden relative to full HRQOL. Differences in overall mean change from baseline estimates in most PRO scales generally favoured the lenvatinib over the sorafenib group, although the differences were not nominally statistically or clinically significant. Patients treated with lenvatinib experienced nominally statistically significant delays in definitive, meaningful deterioration on the QLQ-C30 fatigue (hazard ratio [HR] 0·83, 95% CI 0·69–0·99), pain (0·80, 0·66–0·96), and diarrhoea (0·52, 0·42–0·65) domains versus patients treated with sorafenib. Significant differences in time to definitive deterioration were not observed for other QLQ-C30 domains, and there was no difference in time to definitive deterioration on the global health status/QOL score (0·89, 0·73–1·09). For most PRO scales, differences in overall mean change from baseline estimates favoured responders versus non-responders. Across all scales, HRs for time to definitive deterioration were in favour of responders; median time to definitive deterioration for responders exceeded those for non-responders by a range of 4·8 to 14·6 months.

Interpretation

HRQOL for patients undergoing treatment for unresectable hepatocellular carcinoma is an important therapeutic consideration. The evidence of HRQOL benefits in clinically relevant domains support the use of lenvatinib compared with sorafenib to delay functional deterioration in advanced hepatocellular carcinoma.

Funding

Eisai and Merck Sharp & Dohme.

中文翻译：

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乐伐替尼对比索拉非尼用于不可切除肝细胞癌的一线治疗：随机、开放标签、非劣效性 3 期试验的患者报告结果

背景

肝细胞癌是全球癌症相关死亡的第三大原因。在治疗期间保持健康相关生活质量 (HRQOL) 是一个重要的治疗目标。本研究的目的是评估乐伐替尼与索拉非尼治疗对 HRQOL 的影响。

方法

REFLECT 是之前发表的一项多中心、随机、开放标签、非劣效性 3 期研究，比较了乐伐替尼与索拉非尼作为不可切除肝细胞癌一线全身治疗的疗效和安全性。符合条件的患者年龄在 18 岁或以上，患有不可切除的肝细胞癌，并且根据实体瘤标准中的改良反应评估标准、巴塞罗那临床肝癌 B 期或 C 期分类、Child-Pugh A 级、东部肿瘤合作组（Eastern Cooperative Oncology Group）有一个或多个可测量的靶病灶（ ECOG) 体能状态 1 或更低，器官功能正常。通过交互式语音网络响应系统随机分配（1：1）患者；治疗分配的分层因素包括地区；肉眼可见的门静脉侵犯，肝外扩散，或两者兼而有之；ECOG 表现状态；和体重。在基线、每个后续周期的第 1 天和治疗结束时收集的患者报告结果 (PRO) 在分析人群中的次要和探索性终点的事后分析中进行评估，该分析人群是患者的亚群在基线进行 PRO 评估。一个线性混合效应模型评估了 PROs 从基线的变化，包括欧洲癌症研究和治疗组织 (EORTC) 生活质量问卷核心 30 (QLQ-C30) 和肝细胞癌特异性 QLQ-HCC18 量表（两个次要终点REFLECT 试验）。确定性恶化时间分析是根据已建立的 PRO 恶化最小差异阈值进行的。反应者分析探讨了 HRQOL 与临床反应之间的关联。

发现

在 2013 年 3 月 14 日至 2015 年 7 月 30 日期间随机分配至乐伐替尼 (n=478) 或索拉非尼 (n=476) 的 954 名符合条件的患者中，931 名患者（乐伐替尼 n=468；索拉非尼 n=463）被纳入这个分析。基线 PRO 评分反映了 HRQOL 和功能受损，以及相对于完整 HRQOL 的相当大的症状负担。在大多数 PRO 量表中，总体平均变化与基线估计值的差异通常有利于乐伐替尼优于索拉非尼组，尽管这些差异在名义上没有统计学意义或临床意义。接受乐伐替尼治疗的患者在 QLQ-C30 疲劳（风险比 [HR] 0·83，95% CI 0·69–0·99）、疼痛（0·80、0· 66-0·96) 和腹泻 (0·52, 0·42-0·65) 域与接受索拉非尼治疗的患者相比。对于其他 QLQ-C30 领域，未观察到明确恶化时间的显着差异，并且总体健康状况/QOL 评分（0·89、0·73-1·09）在明确恶化的时间上没有差异。对于大多数 PRO 量表，与基线估计相比，总体平均变化的差异有利于响应者与无响应者。在所有量表中，确定恶化时间的 HR 有利于响应者；有反应者明确恶化的中位时间比无反应者高 4·8 至 14·6 个月。与基线估计相比，总体平均变化的差异有利于响应者与无响应者。在所有量表中，确定恶化时间的 HR 有利于响应者；有反应者明确恶化的中位时间比无反应者高 4·8 至 14·6 个月。与基线估计相比，总体平均变化的差异有利于响应者与无响应者。在所有量表中，确定恶化时间的 HR 有利于响应者；有反应者明确恶化的中位时间比无反应者高 4·8 至 14·6 个月。

解释

接受不可切除肝细胞癌治疗的患者的 HRQOL 是一个重要的治疗考虑因素。临床相关领域 HRQOL 获益的证据支持使用乐伐替尼与索拉非尼相比延迟晚期肝细胞癌的功能恶化。

资金

卫材和默克 Sharp & Dohme。