Aoki Tomoko, Kudo Masatoshi, Nishida Naoshi, Ueshima Kazuomi, Tsuchiya Kaoru, Tada Toshifumi, Morita Masahiro, Chishina Hirokazu, Takita Masahiro, Hagiwara Satoru, Ida Hiroshi, Minami Yasunori, Kuroda Hidekatsu, Nakamura Noriaki, Hiraoka Atsushi, Tomonari Tetsu, Tani Joji, Naganuma Atsushi, Kakizaki Satoru, Ogawa Chikara, Hatanaka Takeshi, Ishikawa Toru, Kawata Kazuhito, Takebe Atsushi, Matsumoto Ippei, Hidaka Masaaki, Kurosaki Masayuki, Kumada Takashi, Izumi Namiki
Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, 589-8511, Japan.
Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan.
J Gastroenterol. 2025 Jun;60(6):738-753. doi: 10.1007/s00535-025-02233-z. Epub 2025 Mar 7.
Achieving complete response (CR) is a desirable goal in early-to-intermediate-stage hepatocellular carcinoma (HCC). While systemic and locoregional therapies show promise, optimal drug discontinuation criteria remain unclear. This study aims to investigate drug-off criteria for atezolizumab plus bevacizumab as a proof-of-concept study.
This retrospective multicenter study included child-pugh class A patients with unresectable HCC without extrahepatic spread or macrovascular invasion who received atezolizumab plus bevacizumab as first-line therapy. Modified clinical CR (mCCR) was defined as CR per mRECIST with sustained normal alpha-fetoprotein (AFP) levels (< 10.0 ng/dl). Recurrence-free survival (RFS) and overall survival (OS) were analyzed based on the "drug-off" criteria defined by following: (1) mRECIST CR with locoregional therapies, (2) sustained normalization of AFP/AFP-L3/ des-gamma-carboxy prothrombin (DCP) for 12-24 weeks, and (3) complete tumor vascularity disappearance by contrast-enhanced ultrasonography (CEUS) or pathological curative resection.
The median follow-up was 16.5 months (95% CI 15.2-17.8). Among 51 patients achieving mCCR, 11 underwent surgery, with pathological CR in three cases. In contrast, viable lesions were observed in 7 of 40 cases assessed using CEUS. All patients meeting the drug-off criteria (n = 9) showed no recurrence and none of them experienced mortality, while 45.2% (19/42) of those not meeting the criteria experienced recurrence (median RFS: 12.8 months, p = 0.007). The median OS was not reached in dug-off criteria met patients (n = 9), 37.7 months (95% CI: NA) in non-criteria met patients (n = 42), and 27.1 months (95% CI 16.7-37.6) in non-mCCR patients (n = 184) (p < 0.001).
In patients with unresectable and TACE-unsuitable early-to-intermediate-stage HCC who met the drug-off criteria, significantly improved RFS and OS were observed compared those who did not meet the criteria. However, further validation studies are required to confirm the utility of the criteria.
实现完全缓解（CR）是早期至中期肝细胞癌（HCC）治疗中一个理想的目标。虽然全身治疗和局部区域治疗显示出前景，但最佳停药标准仍不明确。本研究旨在探讨阿替利珠单抗联合贝伐单抗的停药标准，作为一项概念验证研究。
这项回顾性多中心研究纳入了Child-Pugh A级、不可切除、无肝外转移或大血管侵犯的HCC患者，这些患者接受阿替利珠单抗联合贝伐单抗作为一线治疗。改良临床CR（mCCR）定义为根据mRECIST标准达到CR且甲胎蛋白（AFP）水平持续正常（<10.0 ng/dl）。基于以下定义的“停药”标准分析无复发生存期（RFS）和总生存期（OS）：（1）经局部区域治疗达到mRECIST标准的CR；（2）AFP/AFP-L3/异常凝血酶原（DCP）持续正常12 - 24周；（3）通过超声造影（CEUS）或病理根治性切除实现肿瘤血管完全消失。
中位随访时间为16.5个月（95%CI 15.2 - 17.8）。在51例达到mCCR的患者中，11例接受了手术，3例病理证实为CR。相比之下，在40例接受CEUS评估的患者中，7例观察到存活病灶。所有符合停药标准的患者（n = 9）均未复发，也无死亡，而不符合标准的患者中有45.2%（19/42）复发（中位RFS：12.8个月，p = 0.007）。达到停药标准的患者（n = 9）未达到中位OS，未达到标准的患者（n = 42）中位OS为37.7个月（95%CI：NA），未达到mCCR的患者（n = 184）中位OS为27.1个月（95%CI 16.7 - 37.6）（p < 0.001）。
在不可切除且不适合经动脉化疗栓塞的早期至中期HCC患者中，符合停药标准的患者与不符合标准的患者相比，RFS和OS显著改善。然而，需要进一步的验证研究来证实这些标准的实用性。
