Perioperative immunotherapy for resectable hepatocellular carcinoma.

# Perioperative immunotherapy for resectable hepatocellular carcinoma *The Lancet 2026* Correspondence Perioperative treatment strategies. Updates in global strategy optimisation in high-risk immunotherapy for guidelines from Asia–Pacific countries3 hepatocellular carcinoma after surgery. and US associations4 are reconsidering This milestone finding from Wang resectable the potential benefit of a surgery- and colleagues is expected to improve hepatocellular centred multidisciplinary strategy for surgical outcomes for patients with advanced hepatocellular carcinoma. hepatocellular carcinoma through carcinoma Given the differences in the aetiological a surgery-centred multidisciplinary profiles and tumour characteristics treatment strategy. Nevertheless, We read with great interest the Article of hepatocellular carcinoma between further exploration is still required by Zheng Wang and colleagues,1 populations worldwide, cross-sectional in areas such as the cross-sectional and appreciate their novel findings. validations are urgently required to validation, the selection of optimal The study, centred around surgery, facilitate the generalisation of the neoadjuvant and adjuvant regimens, proposed a novel treatment of proposed strategies. and the identification of actual high- neoadjuvant therapy, radical Second, the sequential treatment risk populations. surgery, and adjuvant therapy, with incorporating neoadjuvant and adjuvant We declare no competing interests. This camrelizumab plus rivoceranib, in therapy has been shown to significantly Correspondence was supported by the Science and patients with resectable hepatocellular improve long-term surgical outcomes,1 Technology Plan Joint Program of Liaoning Province (2024JH2/102600286) awarded to YT. carcinoma at intermediate or high but patients with suboptimal response risk of recurrence. The trial showed to neoadjuvant therapy might derive Zhenli Li, *Yufu Tang that, compared with surgery alone, little survival benefit from the same tangyufu0227@163.com this approach significantly improved adjuvant regimen. In addition, although Department of Hepatobiliary Surgery, General the median event-free survival in the the IMbrave050 trial5 did not achieve Hospital of Northern Theater Command, Shenyang 110016, China (ZL, YT); Department of General selected population (42·1 months positive efficacy in the adjuvant setting, Surgery, the 963rd Hospital of the Joint Service [95% CI 23·2 to not estimable] vs a separate control group specifically for Support Force of the PLA, Jiamusi, China (ZL) 19·4 months [14·9 to not estimable]). adjuvant therapy should be established 1 Wang Z, Fan J, Zhou S, et al. Perioperative This study represents the first in a future study design, given the camrelizumab plus rivoceranib versus surgery alone in patients with resectable hepatocellular phase 2/3 clinical trial to achieve differences in medication regimens and carcinoma at intermediate or high risk of positive perioperative outcomes. enrolled populations. recurrence (CARES-009): a randomised phase 2/3 trial. Lancet 2025; 406: 4089–99. These encouraging findings will shift Third, the definition of patients with 2 Sangro B, Argemi J, Ronot M, et al, and the the current mainstream approach intermediate or high recurrence risk European Association for the Study of the from passive surveillance to an active primarily included a tumour diameter of Liver. EASL Clinical Practice Guidelines on the management of hepatocellular carcinoma. anti-recurrence strategy, offering new more than 5 cm, multiple tumours, and J Hepatol 2025; 82: 315–74. tactics for improving surgical outcomes macrovascular invasion—criteria that 3 Lau G, Obi S, Zhou J, et al. APASL clinical in patients at intermediate or high risk are broad and insufficient for identifying practice guidelines on systemic therapy for hepatocellular carcinoma—2024. Hepatol Int of recurrence. However, we would like the candidates that truly benefit from 2024; 18: 1661–83. to raise the following comments about adjuvant therapy. The IMbrave050 trial5 4 Taddei TH, Brown DB, Yarchoan M, Mendiratta-Lala M, Llovet JM. Critical Update: the Article. explicitly included poorly differentiated AASLD Practice Guidance on prevention, First, the controversy regarding the hepatocellular carcinoma and micro- diagnosis, and treatment of hepatocellular resectability criteria for hepatocellular vascular invasion in its definition of the carcinoma. Hepatology 2025; 82: 272–74. 5 Qin S, Chen M, Cheng AL, et al, and the carcinoma has existed between different population at high risk; however, these IMbrave050 investigators. Atezolizumab plus medical communities for decades. specific pathological variables were bevacizumab versus active surveillance in patients with resected or ablated high-risk Wang and colleagues defined patients not reported or incorporated into the hepatocellular carcinoma (IMbrave050): with Barcelona Clinic Liver Cancer subgroup analysis in this study. With a randomised, open-label, multicentre, stage B or stage C disease without the advancement of liquid biopsy, the phase 3 trial. Lancet 2023; 402: 1835–47. 6 Powles T, Kann AG, Castellano D, et al, and the Vp4 involvement or extrahepatic detection of minimal residual disease to IMvigor011 Investigators. ctDNA-guided metastasis as resectable populations. guide adjuvant therapy has become an adjuvant atezolizumab in muscle-invasive bladder cancer. N Engl J Med 2025; However, according to guidelines increasing focus of research. The latest 393: 2395–408. from the European Association for findings show that circulating tumour the Study of the Liver, these patients DNA can guide adjuvant atezolizumab already fall into the extremely high- in muscle-invasive bladder cancer,6 The CARES-009 trial showed that risk stratification and constitute a which is independent of stage and perioperative camrelizumab plus surgical contraindication.2 Substantial PD-L1 status. These findings provide rivoceranib significantly improves challenges will therefore arise from a new direction for future research event-free survival compared with the global adoption of the proposed on patient selection and treatment surgery alone in patients with 1332 Correspondence resectable hepatocellular carcinoma the event-free survival definition itself liver disease is becoming the leading (42·1 months [95% CI 23·2 to not contains a subjective component, cause of hepatocellular carcinoma.7 estimable] vs 19·4 months [14·9 to as it includes “disease progression Additionally, about 50% of patients not estimable]).1 While these findings that precluded surgical resection” as received adjuvant transarterial represent an important advance, an event.1 However, the protocol did chemoembolisation, a practice far several methodological concerns not prespecify operational criteria more common in Asia than elsewhere.8 warrant further discussion. for determining when progression This co-intervention complicates CARES-009 lacks an adjuvant-only precludes surgery, allowing for interpretation of the systemic control group, making it difficult to variability between surgeons therapy’s independent contribution disentangle the specific contribution and centres. Beyond definitional and could limit its applicability to of the neoadjuvant component. This subjectivity, the clinical relevance settings where adjuvant transarterial distinction is particularly relevant of event-free survival as a surrogate chemoembolisation is standard care. because two treatment-related deaths for overall survival remains debated Despite these limitations, the occurred during neoadjuvant therapy. in patients with hepatocellular CARES-009 trial provides valuable The IMbrave050 trial showed that carcinoma. Although event-free evidence supporting perioperative adjuvant atezolizumab–bevacizumab survival or progression-free survival immunotherapy in resectable alone could improve recurrence-free have been proposed as potential hepatocellular carcinoma. However, survival (hazard ratio [HR] 0·72), surrogates,4,5 improvements in these further confirmation through rigor- albeit with diminishing benefit over intermediate measures have not ously designed and more inclusive time.2,3 Therefore, without a direct consistently translated into overall studies remains warranted. comparison between perioperative survival benefits.5 In CARES-009, We declare no competing interests. This and adjuvant-only approaches, the 25% of patients in the control group Correspondence was supported by the Natural incremental value of preoperative received immunotherapy after Science Foundation of Shanghai Municipality (grant number 25ZR1402578) awarded to SL. systemic therapy remains unknown. recurrence, which could further The adaptive design modification attenuate differences in overall Wenyi Jin, Mingyang Xue, *Susu Luo during trial conduct warrants caution. survival, and no prespecified method tingluo@wustl.edu An interim analysis, originally intended (eg, a rank-preserving structural failure Department of Biomedical Sciences, City University for sample size re-estimation, was time model) was applied to account of Hong Kong, Hong Kong Special Administrative Region, China (WJ); Sydney University, Sydney, repurposed for efficacy assessment for treatment switching, which hinders NSW, Australia (MX); Moores Cancer Center, School after observing 119 events (70% of interpretation of long-term outcomes. of Medicine, University of California San Diego, target) in the CARES-009 trial. This The trial population (99% Han La Jolla, CA 92093, USA (SL) change was justified by “emerging Chinese, 76–78% positive for hepatitis 1 Wang Z, Fan J, Zhou S, et al. Perioperative camrelizumab plus rivoceranib versus surgery external evidence and ethical B virus) mirrors the epidemiology alone in patients with resectable considerations” without prespecified of hepatocellular carcinoma in hepatocellular carcinoma at intermediate or high risk of recurrence (CARES-009): a alpha spending adjustment.1 Such China but hinders generalisability. randomised phase 2/3 trial. Lancet 2025; post-hoc changes could inflate type 1 Emerging evidence suggests that 406: 4089–99. error, particularly when the observed responses to immunotherapy depend 2 Qin S, Chen M, Cheng AL, et al, and the IMbrave050 investigators. Atezolizumab plus HR (0·59) exceeded the anticipated on aetiology, with tumours related bevacizumab versus active surveillance in effect size (0·65) used for sample to metabolic dysfunction-associated patients with resected or ablated high-risk hepatocellular carcinoma (IMbrave050): a size calculation. The absence of steatohepatitis showing resistance randomised, open-label, multicentre, phase 3 clearly prespecified alpha adjustment to checkpoint inhibitors compared trial. Lancet 2023; 402: 1835–47. procedures makes the reported p value with viral-related tumours.6 Pfister 3 Yopp A, Kudo M, Chen M, et al. LBA39 updated efficacy and safety data from IMbrave050: (0·0040) crossing the efficacy boundary and colleagues reported no overall phase III study of adjuvant atezolizumab + (0·0148) challenging to interpret with survival benefit from immunotherapy bevacizumab vs active surveillance in patients with resected or ablated high-risk full statistical confidence. in non-viral hepatocellular carcinoma, hepatocellular carcinoma. Ann Oncol 2024; The use of investigator-assessed in contrast to hepatitis B and C related 35: S1230. event-free survival as the primary hepatocellular carcinoma.6 The large 4 Christensen E. Choosing the best endpoint. J Hepatol 2008; 49: 672–73. endpoint in an open-label trial improvement in event-free survival 5 Llovet JM, Montal R, Villanueva A. Randomized is inherently vulnerable to bias. observed in the CARES-009 trial, in trials and endpoints in advanced HCC: role of Although the concordant estimate a predominantly hepatitis B virus- PFS as a surrogate of survival. J Hepatol 2019; 70: 1262–77. from the masked independent positive cohort, might therefore 6 Pfister D, Núñez NG, Pinyol R, et al. NASH review committee (HR 0·63, not be reproducible in other limits anti-tumour surveillance in immunotherapy-treated HCC. Nature 2021; 95% CI 0·44–0·90) lends support to populations, for which metabolic 592: 450–56. the robustness of the primary finding, dysfunction-associated steatotic Correspondence 7 Chan SL, Zhou J, Wang L, et al. Article. The interim efficacy analysis and the Asian-Pacific Association for the Study of The Lancet Commission on addressing the was conducted in accordance with the Liver (APASL); has received travel support from global hepatocellular carcinoma burden: the Beijing Life Oasis Public Service Center, the comprehensive strategies from prevention to a protocol amendment approved Beijing Medical Award Foundation, the Chronic treatment. Lancet 2025; 406: 731–78. approximately 1 year before database Disease Prevention and Treatment of Traditional 8 Park JW, Chen M, Colombo M, et al. Global lock. The Lan–DeMets alpha spending Chinese Medicine Promotion Association, and the patterns of hepatocellular carcinoma Beijing Health Alliance Charitable Foundation; has management from diagnosis to death: the function was used to control served on data safety monitoring boards or advisory BRIDGE study. Liver Int 2015; 35: 2155–66. type 1 error. Although the originally boards for AstraZeneca and Merck Sharp & Dohme; planned sample size re-estimation and holds leadership or fiduciary roles in boards, Authors’ reply was retained, it ultimately became societies, committees, or advocacy organisations, including the Chinese Society of Oncology, the We read the Correspondence by unnecessary as the predefined Chinese Medical Association, APPLE, the Chinese Zhenli Lu and Yufu Tang in response efficacy boundary was crossed. All College of Surgeons, and APASL. All other authors to our Article,1 and welcome the procedures were prespecified to declare no competing interests. opportunity to respond. The maintain statistical rigour. Although Fei Liang, Shaolai Zhou, Zheng Wang, discrepancy in hepatocellular event-free survival includes subjective Jia Fan, *Jian Zhou, on behalf of the carcinoma resectability criteria reflects surgical judgement on resectability CARES-009 investigators inherent regional variations in health- (reflecting real-world clinical practice), zhou.jian@zs-hospital.sh.cn care infrastructure, epidemiological concordance between masked Department of Hepatobiliary Surgery and Liver profiles, and therapeutic frameworks. independent review committee and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China Recent updates to major international investigator assessments confirms (FL, SZ, ZW, JF, JZ) guidelines (eg, the Japan Society its robustness. Event-free survival 1 Wang Z, Fan J, Zhou S, et al. Perioperative of Hepatology’s 2021 version,2 the offers a more direct measure of initial camrelizumab plus rivoceranib versus surgery Korean Liver Cancer Association’s treatment efficacy than overall survival, alone in patients with resectable hepatocellular carcinoma at intermediate or 2022 version,3 and the American which is confounded by subsequent high risk of recurrence (CARES-009): a Association for the Study of Liver therapies.6–8 Overall survival follow- randomised phase 2/3 trial. Lancet 2025; Diseases’ 2023 version4) are actively up is ongoing (with final analysis 406: 4089–99. 2 Hasegawa K, Takemura N, Yamashita T, et al. re-evaluating surgery-centred scheduled at 70% of prespecified Clinical practice guidelines for hepatocellular multidisciplinary management for events), and exploratory sensitivity carcinoma: the Japan Society of Hepatology 2021 version (5th JSH-HCC Guidelines). advanced disease—an alignment that analyses (including rank-preserving Hepatol Res 2023; 53: 383–90. reinforces our study’s conceptual structural failure time models) are 3 Korean Liver Cancer Association and National framework. As mentioned, we planned to mitigate the effect of post- Cancer Center Korea. 2022 KLCA-NCC Korea practice guidelines for the management of urgently need the validation of recurrence crossover. We acknowledge hepatocellular carcinoma. Clin Mol Hepatol cross-sectional studies to promote that our trial was conducted exclusively 2022; 28: 583–705. the implementation of strategies in China, where approximately 80% 4 Singal AG, Llovet JM, Yarchoan M, et al. AASLD practice guidance on prevention, diagnosis, proposed in the future. With regard of cases of hepatocellular carcinoma and treatment of hepatocellular carcinoma. to the absence of an adjuvant- are related to hepatitis B virus Hepatology 2023; 78: 1922–65. 5 Zhou J, Sun H, Wang Z, et al. China Liver Cancer only control group (a limitation (ie, the leading cause of hepatocellular Guidelines for the diagnosis and treatment of acknowledged in our Article1), we carcinoma, responsible for 39% of hepatocellular carcinoma (2024 edition). plan to incorporate this comparator cases worldwide in 2022).8 Because Liver Cancer 2025; 14: 779–835. 6 Broglio KR, Berry DA. Detecting an overall in future trials to quantitatively assess this aetiological profile differs survival benefit that is derived from the independent contribution of from many non-endemic regions, progression-free survival. J Natl Cancer Inst 2009; 101: 1642–49. adjuvant treatment. We appreciate generalisability might be difficult. 7 Cabibbo G, Celsa C, Enea M, et al. Progression- Lu and Tang’s insightful feedback This limitation is acknowledged in free survival early assessment is a robust on our selection criteria, and on the Article. Confirmatory trials in surrogate endpoint of overall survival in immunotherapy trials of hepatocellular defining patients at intermediate to diverse geographical and aetiological carcinoma. Cancers (Basel) 2020; 13: 90. high recurrence risk. Our eligibility populations are needed. Finally, 8 Chan SL, Sun HC, Xu Y, et al. The Lancet criteria (ie, China Liver Cancer Staging although adjuvant transarterial Commission on addressing the global hepatocellular carcinoma burden: stage Ib–IIIa, endorsed by China’s chemoembolisation could complicate comprehensive strategies from prevention to National Health Commission5) were interpretation, its near-identical use treatment. Lancet 2025; 406: 731–78. validated across Barcelona Clinic Liver (ie, 86% in the perioperative group Cancer subgroups (figure 3 in the vs 87% in the surgery alone group) original Article1), supporting its broad makes confounding of the observed applicability. treatment effect unlikely. We also thank Wenyi Jin and JZ has received honoraria from the Asia–Pacific colleagues for their interest in our Primary Liver Cancer Expert Association (APPLE) 1334 --- [PDF原文](https://sci-net.xyz/storage/7932541/fe9947d37e8a06d64a92f1c659ce99b659ee4d5623a9ad3b5161a89eceeddce0/Perioperative-immunotherapy-for-resectable-hepatocellular-carcinoma.pdf) DOI: 10.1016/S0140-6736(26)00142-X