靶向肝癌肿瘤微环境：原理、当前进展和未来展望。

Targeting Tumor Microenvironment in Liver Cancers: Rationale, Current Progress, and Future Perspective.

机构信息

Director of Translational Research in GI Radiation Oncology Investigator, Massachusetts General Hospital Research Institute Associate Professor, Harvard Medical School, USA.

出版信息

Keio J Med. 2022;71(3):71. doi: 10.2302/kjm.71-004-ABST.

DOI:10.2302/kjm.71-004-ABST

PMID:36155490

Abstract

Surgical treatments offer the chance for cure in primary or metastatic liver cancers. However, many patients experience disease progression after surgical interventions, or cannot undergo surgery as they present with unresectable disease at diagnosis. In such cases, available treatment options (local and systemic) have been limited in efficacy, which led to dismal survival rates in advanced hepatocellular carcinoma (HCC), intrahepatic colangiocarcinoma (ICC) or metastatic pancreatic ductal adenocarcinoma (PDAC). More recent developments in oncology have offered renewed hope for advanced liver cancer patients. Hypofractionated radiation has shown feasibility and promise in unresectable setting, and is now being tested in a randomized phase III trial in HCC (clinicaltrials.gov identifier NCT03186898). Antiangiogenic agents have strongly impacted the management of advanced HCC, with multiple drug options in first line setting (sorafenib, lenvatinib) and second line setting (regorafenib, cabozantinib, ramucirumab). Chemotherapy based regimens are standard of care in ICC and PDAC. Immunotherapy with anti-PD-1/PD-L1 or anti-CTLA4 antibodies has shown real potential to transform advanced HCC therapy, both in first line and second line settings. Finally, combinations of these new strategies are very attractive approaches, as they promise durable and profound responses in advanced HCC. But in order to achieve this promise more broadly, these concepts require greater understanding based on mechanistic preclinical studies and validation in correlative studies in clinical trials as a basis to establish optimal combinatorial strategies. The insights gained from this "bench to the bedside and back" approach raise the hope for a more efficient development of targeted agents in combination, and in earlier stages of the disease, with the goal of increasing survival in patients afflicted with this aggressive and deadly diseases. (Presented at the 2001st Meeting, July 4, 2022).

摘要

手术治疗为原发性或转移性肝癌提供了治愈的机会。然而，许多患者在手术后会出现疾病进展，或者由于诊断时存在不可切除的疾病而无法进行手术。在这种情况下，可用的治疗选择（局部和全身）在疗效方面受到限制，这导致晚期肝细胞癌（HCC）、肝内胆管细胞癌（ICC）或转移性胰腺导管腺癌（PDAC）的生存率非常低。肿瘤学的最新进展为晚期肝癌患者带来了新的希望。在不可切除的情况下，低分割放疗已经显示出可行性和潜力，目前正在 HCC 的一项随机 III 期试验中进行测试（clinicaltrials.gov 标识符 NCT03186898）。抗血管生成药物强烈影响了晚期 HCC 的治疗管理，一线治疗有多种药物选择（索拉非尼、仑伐替尼）和二线治疗（regorafenib、卡博替尼、ramucirumab）。基于化疗的方案是 ICC 和 PDAC 的标准治疗方案。抗 PD-1/PD-L1 或抗 CTLA4 抗体的免疫疗法在一线和二线治疗中都显示出了真正改变晚期 HCC 治疗的潜力。最后，这些新策略的联合非常有吸引力，因为它们有望在晚期 HCC 中产生持久而深刻的反应。但是，为了更广泛地实现这一承诺，这些概念需要基于机制的临床前研究和临床试验中的相关性研究来获得更深入的理解，作为确定最佳联合策略的基础。这种“从实验室到病床再回到实验室”的方法所获得的见解，为联合靶向药物的更有效开发以及在疾病的早期阶段提供了希望，目标是提高患有这种侵袭性和致命性疾病的患者的生存率。（在 2022 年 7 月 4 日举行的第 2001 次会议上发表）。