Hepatocellular carcinoma (HCC) is the most common malignancy worldwide, and is especially common in China. A total of 70%-80% of patients are diagnosed at an advanced stage and can receive only palliative care. Sorafenib has been the standard of care for a decade, and promising results for regorafenib as a second-line and lenvatinib as a first-line treatment were reported only 1 or 2 years ago. FOLFOX4 was recently recommended as a clinical practice guideline by the China Food and Drug Administration. All approved systemic therapies remain unsatisfactory, with limited objective response rates and poor overall survival. Immune checkpoint inhibitors (CPIs) offer great promise in the treatment of a rapidly expanding spectrum of solid tumors. Immune checkpoint molecules are involved in almost the whole process of viral-related hepatitis with cirrhosis and HCC and in the most important resistance mechanism of sorafenib. The approval of nivolumab by the U.S. Food and Drug Administration on September 23, 2017, for the treatment of patients with HCC, based only on a phase I/II clinical trial, is a strong hint that immunotherapy will introduce a new era of HCC therapy. CPI-based strategies will soon be a main approach in anticancer treatment for HCC, and we will observe the rapid advances in the therapeutic use of CPIs, even in an adjuvant setting, with great interest. How shall we face the opportunities and challenges? Can we dramatically improve the prognosis of patients with HCC? This review may provide some informed guidance. IMPLICATIONS FOR PRACTICE: Immune checkpoint molecules are involved in almost the whole process of viral-related hepatitis with cirrhosis and hepatocellular carcinoma (HCC) and in the most important resistance mechanism of sorafenib. As all approved systemic therapies in HCC remain unsatisfactory, checkpoint inhibitor (CPI)-based strategies will soon be a main approach in anticancer treatment for advanced stage of HCC, even in an adjuvant setting. In virus-related HCC, especially hepatitis B virus-related HCC, whether CPIs can control virus relapse should be further investigated. Combination strategies involving conventional therapies and immunotherapies are needed to increase clinical benefit and minimize adverse toxicities with regard to the underlying liver disease.
摘要
肝细胞癌 (HCC) 是世界上最常见的恶性肿瘤，在中国尤为普遍。高达 70% ~ 80% 的患者被确诊时已经进入晚期，只能接受姑息治疗。近十年来，索拉非尼一直是标准治疗方案，只是在一二年前才有报告称，瑞格拉非尼作为二线治疗以及乐伐替尼作为一线治疗的结果颇具前景。最近，中国食品药品监督管理总局建议将 FOLFOX4 作为临床实践指南。所有经过批准的系统疗法效果仍不理想，客观缓解率较低并且整体存活率不佳。免疫检查点抑制剂 (CPI) 在治疗迅速恶化的实体瘤方面具有大好前景。在病毒相关肝炎所致肝硬化和 HCC以及索拉非尼最重要的耐药机制中，免疫检查点分子几乎都参与整个过程。美国食品药品监督管理局于 2017 年 9 月 23 日正式批准将纳武单抗用于 HCC 患者的治疗，仅基于一项 I /II 期临床试验，这一举措强烈暗示免疫疗法将纳入 HCC 治疗的新纪元。基于 CPI 的方案很快将成为 HCC 抗癌治疗的主要方法，我们将有幸见证 CPI 治疗用途的长足进展，即便在辅助治疗中也将获益匪浅。我们将如何面对机遇与挑战?我们是否能明显改善 HCC 患者的预后?本篇综述将提供一些详细的指南。
实践意义:在病毒相关肝炎所致肝硬化和肝细胞癌 (HCC)以及索拉非尼最重要的耐药机制中，免疫检查点分子几乎都参与整个过程。所有经过批准的 HCC 系统疗法效果仍不理想，基于免疫检查点抑制剂 (CPI) 的方案将成为晚期 HCC 抗癌治疗的主要方法，即便在辅助治疗中亦是如此。在病毒引发的 HCC，尤其是乙型肝炎病毒引发的 HCC 中，对于CPI 能否扼制病毒复发，应该对其进行进一步研究。因此，需要包含常规疗法和免疫疗法的组合方案来增加临床受益，并且组合方案将最大程度减少与潜在肝病相关的不良毒性。
Keywords: Combinatorial immunotherapy strategies; Hepatitis B virus; Hepatocellular carcinoma; Immune checkpoint inhibitors; Underlying liver disease.
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