Liver Resection Confers Survival Advantage over TACE for Hepatocellular Carcinoma Modestly Beyond Milan Criteria: A Multicenter Propensity-Matched Analysis

Liver Resection Confers Survival Advantage over TACE for Hepatocellular Carcinoma Modestly Beyond Milan Criteria: A Multicenter Propensity-Matched Analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Liver Resection Confers Survival Advantage over TACE for Hepatocellular Carcinoma Modestly Beyond Milan Criteria: A Multicenter Propensity-Matched Analysis Xiaoyan Fan, Guobin Sun, Xiaodong Liu, Yong Meng, Linyin Zhang, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8974789/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 7 You are reading this latest preprint version Abstract Background and Aim: Liver transplantation (LT) is the optimal treatment option for hepatocellular carcinoma (HCC) meeting the Extended Liver Transplant Criteria (ELTC), but it is only offered for the minority. The optimal alternative strategy for HCCs beyond the Milan criteria (BMC) but meeting the ELTC, which is defined as modestly beyond the Milan criteria (MBMC) here, is a matter of concern. The aim of this study was to evaluate the survival benefits of LR compared with transarterial chemoembolization (TACE) for MBMC-HCCs. Methods From January 2010 to October 2021, from fifteen Chinese hepatobiliary centres, 1110 MBMC-HCC patients with Child‒Pugh A who underwent LR (n = 424) or TACE (n = 686) were included. Overall survival benefit of LR versus TACE in the MBMC-HCC cohort was compared based on a propensity matching and was further validated in addition BMC-HCC cohorts selected according to other extended LT criteria (Asan criteria, up-to-7 criteria, French alpha-foetoprotein model and Metroticket 2.0 model). Results Survival analyses in the MBMC-HCC cohort as well as other 4 BMC-HCC cohorts demonstrated that overall survival was significantly longer in the LR group than that in the TACE group (all log-rank P < 0.001). After a 1:1 propensity score matching in the MBMC-HCC cohort, multivariate analysis and subsequent subgroup analyses based on tumour burden and other important covariates further confirmed the robust survival advantage of LR compared to TACE. Conclusions LR rather than TACE is highly recommended as the preferred alternative for potential LT candidates with MBMC-HCC regardless of tumor burden. Biological sciences/Cancer Health sciences/Gastroenterology Health sciences/Oncology Hepatocellular carcinoma (HCC) beyond the Milan criteria liver transplantation (LT) liver resection (LR) transarterial chemoembolization (TACE) Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Hepatocellular carcinoma (HCC) is one of the most common malignancies with increasing incidence worldwide 1 . Liver transplantation (LT) is currently thought as the best oncologic treatment for HCC since it replaces the diseased liver and restores normal hepatic function 2 . The Milan criteria (1 lesion ≤ 5 cm or 2–3 lesions each ≤ 3 cm combined with the absence of extrahepatic lesions or macrovascular invasion) 3 have remained the benchmark in selecting candidates with HCC eligible for transplantation over the last two decades 4 , 5 . To increase patient access to LT, several expanded selection criteria have been advocated for HCC beyond the Milan criteria (BMC) with an appropriate overall tumour burden 6 – 10 . Among them, the University of California, San Francisco (UCSF) downstaging protocol has recently been adopted as the standardized criteria, with initial selection criteria as 1 lesion ≤ 8 cm, 2–3 lesions each < 5 cm or 4–5 lesions all < 3 cm with total tumour diameter < 8 cm 6 . Substantial evidence has reported the noninferiority of these modest expansions 11 , 12 , although post-LT survival incrementally decreases with increasing tumour burden 13 . However, regardless of whether the initial tumour meets or exceeds Milan criteria, LT is only offered to a minority of these candidates owing to limited availability of donor organs and drop-out due to tumour progression 14 . Therefore, it is essential to provide effective alternative strategies for candidates who failed to receive LT. Undoubtedly, liver resection (LR) is recommended as the preferred alternative treatment for HCCs meeting the Milan criteria 15 , 16 with decent long-term survival in studies completed after 2010 and cohorts who underwent enhanced surveillance 17 . However, whether LR can be performed for BMC-HCCs remains controversial 18 . According to the Barcelona Clinic Liver Cancer (BCLC) classification 19 , 20 , single and multinodular BMC-HCCs are categorized as early-stage and intermediate-stage, respectively. For the former, LR should be preferred for single larger nodules followed by TACE if LR is infeasible 19 . For the latter, transcatheter arterial chemoembolization (TACE), instead of LR, was once recommended for most intermediate HCCs according to the 2018 BCLC version 15 . However, the intermediate stage is stratified into three subgroups according to tumour burden and liver function according to the latest 2022 BCLC version. Patients meeting the Extended Liver Transplant criteria (ELTC; i.e., inclusion criteria of UCSF down-staging protocol) could be candidates for LT, whereas patients without the option of transplant or matching transplant-failure but with preserved portal flow and defined tumour burden are candidates for TACE 19 . Unfortunately, currently there have been few reports concerning whether LR could offer better survival for patients beyond Milan criteria but meeting ELTC. Herein, we aimed to identify the optimal alternative option for BMC-HCC patients meeting ELTC based on a large-scale, Chinese nationwide, multicentre retrospective survey. Based on the above considerations, a particular HCC population was screen according to the following criteria: single lesion > 5 cm and up to 8 cm; or 2–3 lesions with at least one > 3 cm and up to 5 cm; or 4–5 lesions with none > 3 cm, which were defined as modestly beyond Milan criteria (MBMC) in the present study. The survival benefit of LR versus TACE in the MBMC-HCC cohort was compared based on a propensity score matching analysis and was further validated in other BMC-HCC cohorts selected according to other extended criteria for LT including the Asan criteria 7 , up-to-7 criteria 10 , French alpha-foetoprotein (AFP) model 8 and Metroticket 2.0 model 9 , respectively. We hope that our research will provide reliable guidance on treatment decisions for patients with MBMC-HCC who fail to receive a LT. Methods Study design Between January 2010 and October 2021, 5,073 patients diagnosed with HCC who underwent LR or TACE from fifteen Chinese hepatobiliary centres were enrolled. Patients beyond the Milan criteria but within ELTC were included into this study: (I) single lesion > 5 cm and up to 8 cm; (II) 2–3 lesions with at least one > 3 cm and up to 5 cm; (III) 4–5 lesions with none > 3 cm 6 . Patients were excluded if they met any of the following criteria: (I) Child-Pugh B or C; (II) insufficient available data; (III) radiological evidence of extrahepatic metastasis, portal vein or other major vascular involvement 21 ; (IV) receiving treatment other than LR or TACE; (V) without informed consent. Ultimately, 1,110 MBMC-HCC patients (LR, 424; TACE, 686) were included in this cohort study (Fig. 1 ). In addition, 4 specifical BMC-HCC cohorts meeting other extended criteria for LT were established based on the exclusion criteria described above and their respective inclusion criteria as presented in Table S1 for further verification. The study was approved by the Ethics Committee of the Army Medical Center of PLA on human research (No: 2022 − 233) and Institutional Review Board of Tang Du Hospital, Air Force Medical University (No: TDLL-202303-11), and individual consent for this retrospective analysis was waived. Diagnosis and definitions HCC diagnosis was proposed preoperatively based on at least two imaging examinations (magnetic resonance imaging, sonography, contrast-enhanced dynamic computed tomography or hepatic arterial angiography) or single imaging technique together with serum AFP level > 400 ng/mL, and was confirmed by histopathological examination of resection specimens in the LR group and needle biopsy in the TACE group 22 . The severity of cirrhosis was determined according to the Child-Pugh classification. Performance status was determined by using the ECOG-PS of 0 (asymptomatic) to 4 (restricted to bed). Vascular invasion was defined by the presence of thrombus adjacent to the tumour in the portal vein with vague boundaries. Tumour size was defined as the maximum radial diameter of the largest invasive tumour based on the results of imaging tests. Treatment The criteria for LR were based on comprehensive assessment including serum total bilirubin (TBIL) levels, indocyanine green clearance, residual liver volume estimated by volumetric computed tomography, as well as absence of ascites and hepatic encephalopathy. Multiple lesions were removed by en bloc excision or multiple excisions when patients had an adequate functional liver remnant with good liver function. TACE was performed after tumour vascularity was investigated by hepatic arteriography. During TACE, the catheter tip was inserted selectively into the tumour-feeding artery under image guidance. An injection of a mixture containing anticancer agent (doxorubicin, cisplatin, mitomycin C, epirubicin and 5-fluorouracil) and lipiodol, followed by arterial embolization using 300–500 micron gelatine sponge particles was then performed. The doses of the anticancer agent lipiodol and embolic particles were determined based on both the size and extent of the lesions. Follow-up Post-treatment follow-up, including ultrasonography, enhanced computed tomography or magnetic resonance imaging of the abdomen, serum biochemistry and AFP levels, was performed every three months in the first year and twice a year in subsequent years. The prognosis of these patients was confirmed at each follow-up. Patients with tumour recurrence were treated with re-resection, radiofrequency ablation, TACE, conservative treatment, or sorafenib depending on the tumour site, liver function, and the general condition 19 . Follow-up treatment for those receiving TACE included repeated TACE, local ablative treatment, or conservative treatment which was determined by the general condition and liver functional status 18 . The median follow-up time was computed with censored observations only. The primary outcome was overall survival (OS) measured from the date of diagnosis to death or last follow-up (for censored patients). Statistical analysis Quantitative data were analyzed using the Mann-Whitney U-test, and categorical data with the chi-square test or Fisher’s exact test as appropriate. Survival curves were generated using the Kaplan-Meier method and compared using the log-rank test. Univariate and multivariate analyses were performed using the Cox proportional hazards model. To overcome patient selection bias, a PSM analysis was performed using a logistic regression model according to a 1:1 nearest-neighbour method between the LR and TACE groups. The following covariates were selected in this model: age, sex, hepatitis virus infection, ECOG-PS, Child‒Pugh score, tumour number, tumour size, AFP, TBIL, aspartate transaminase (AST), alanine aminotransferase (ALT), platelets, albumin, haemoglobin, international normalized ratio (INR), blood urea nitrogen (BUN), and serum creatinine (Scr). The absolute standardized mean difference (ASMD) up to 0.1 indicating successful balance. All tests were two-tailed, and P value < 0.05 was considered statistically significant. All statistical analyses were performed using SPSS software (version 22.0) and R software (version 3.3.1). Results Characteristics of all study patients The patient enrolment scheme and research design were illustrated in Fig. 1 . 1110 MBMC (i.e. beyond the Milan criteria within the ELTC criteria) patients were identified. And additional cohorts that beyond the Milan criteria but meeting the Asan criteria, the up-to-7 criteria, the French AFP model or the Metroticket 2.0 model were respectively established ( Table S1 ). Baseline demographics and clinical characteristics of MBMC-HCC patients who underwent LR (n = 424) or TACE (n = 686) were demonstrated in Table 1 . Patients in the TACE group were significantly older, had more lesions as well as higher Child‒Pugh scores, and were less likely to have hepatitis virus infection (all P < 0.001). Patients in the LR group had significantly higher ALT levels ( P < 0.05), platelet counts (P < 0.001), albumin ( P = 0.041) and haemoglobin ( P < 0.001) levels, but had lower INR ( P = 0.001) and Scr levels ( P = 0.041). No significant difference in other covariates was seen between the two groups. Survival analysis of all study patients The median follow-up time of patients in the MBMC-HCC cohort was 43.2 months (95% confidence interval [CI], 40.8–45.7), and the median OS was 51.9 months (95% CI, 44.5–59.3). The median follow-up times were 51.0 months (95% CI, 47.6–54.5) and 35.1 months (95% CI, 32.3–37.9) for the LR and TACE groups, respectively ( P < 0.001). As shown in Fig. 2 A, OS in the LR group was significantly better than that in the TACE group (log-rank P < 0.001). Consistent results in other BMC-HCC cohorts (Fig. 2 B-E, all log-rank P < 0.001) demonstrated that LR does provide significantly better survival outcomes than TACE in potential LT candidates who beyond the Milan criteria even if distinct extended criteria for LT was applied. Since patients with different tumor burden were included together, we further compared the 1-, 3-, and 5-year survival rates following LR and TACE in patients with single lesion or multiple lesions ( Figure S1 ). LR and TACE for multiple lesions both offered a survival outcome comparable with that for single lesion, and LR exhibited consistently a better overall survival benefit versus TACE. Moreover, survival analyses based on the lesion number indicated that single lesion offered only a slight survival advantage over multiple lesions in BMC patients within the up-to-7 criteria (log-rank P = 0.030; Figure S2A ) and BMC patients within the French AFP model (log-rank P = 0.025; Figure S2B ). While no statistically significant difference was observed between single lesion and multiple lesions in other 2 BMC cohorts (log-rank P > 0.05; Figure S2C-D ). In summary, BMC-HCC patients exhibited similar prognosis despite different tumor burdens, and this indirectly reflects the homogeneity of LT candidates screened based on distinct extended LT criteria. PSM analysis in the MBMC-HCC cohort In order to exclude any effect of these confounding factors on survival, a PSM analysis was performed to balance the covariates between the two groups. Out of the 686 patients from the TACE group, 374 (54.5%) were successfully matched with an equal number of patients (88.2%) from the LR group. All the covariates were well balanced between the matched groups with an ASMD ≤ 0.1. The distribution of propensity scores per group before and after matching is presented in Figure S3 . When only matched patients were considered, there was no significant difference in any of the clinical covariates between the two groups (Table 1). After PSM, the median follow-up time of all matched patients was 45.4 months (95% CI, 42.9–48.0), and the median OS was 59.6 months (95% CI, 47.0-72.2). The median follow-up time was significantly longer in the LR group (52.2 months; 95% CI, 48.8–55.7) than in the TACE group (36.0 months; 95% CI, 32.2–39.9) (P < 0.001). Notably, the matched MBMC-HCC patients who underwent LR showed significantly improved OS than those who underwent TACE (Fig. 2 F, log-rank P < 0.001), which is consistent with the observations in the entire MBMC-HCC cohort. To identify whether the influence of therapeutic option on survival was affected by other clinical variables, univariate and multivariate analyses were subsequently performed in the entire and PSM matched MBMC-HCC cohorts, respectively. As shown in Fig. 3 A-B, several independent predictors of poor prognosis were identified before PSM, namely, ECOG score = 1 [hazard ratio (HR): 1.431; 95% CI, 1.162–1.764; P = 0.001), serum AFP ≥ 400 ng/mL (HR: 1.452; 95% CI, 1.206–1.749; P < 0.001), INR ≥ 1.1 (HR: 1.375; 95% CI, 1.107–1.706; P = 0.004), and TACE (HR: 2.878; 95% CI, 2.308–3.588; P 400 ng/mL (HR: 1.485; 95% CI, 1.180–1.868; P = 0.001) and TACE (HR: 2.756; 95% CI, 2.166–3.508; P < 0.001) were independent predictors of poor prognosis. Subgroup analyses of patients matched in the propensity model To more deeply explore the survival benefits of LR for MBMC-HCC, subgroup analyses for OS were further performed on the basis of several characteristics. Among patients with single lesion or 2–3 lesions, the OS was significantly better in the LR group than in the TACE group (log-rank P < 0.001), and LR experienced a survival benefit over TACE at 1 year, 3 years, and 5 years (Fig. 4 A-B). Notably, even with a relatively small number of patients with 4–5 lesions, a significant survival benefit for LR over TACE was also observed (log-rank P = 0.027; Fig. 4 C). dditionally, among patients with ECOG-PS 0 or ECOG-PS 1 (Fig. 4 D-E), patients with serum AFP levels < 1000 ng/mL or ≥ 1000 ng/mL (Fig. 4 F-G), and patients with INR < 1.1 or INR ≥ 1.1 (Fig. 4 H-I), LR consistently exhibited a significantly better survival outcome compared to TACE (all log-rank P < 0.001). Discussion In this large-scale multicentre retrospective study, the survival advantage of LR compared with TACE for MBMC-HCC patients with preserved liver function was revealed based on a PSM analysis and further verified in additional BMC-HCC cohorts established according to different extended criteria for LT. Univariate and subsequent multivariate Cox regression models revealed that LR, together with Child‒Pugh score and serum AFP level were independent predictors of OS for these patients. Subgroup analyses based on tumour burden, ECOG-PS, serum AFP level, and INR confirmed the robust survival advantage of LR compared to TACE. These results unambiguously demonstrated that LR rather than TACE should be considered as the preferred alternative treatment strategy for MBMC-HCC patients. According to the latest BCLC guideline, resection or ablation is the first treatment option for single HCCs if the patient has contraindications or no access to LT. TACE is only recommended if resection or ablation is unsuccessful or not feasible 23 . Despite these strategies, current understandings concerning the treatment of single large HCCs are still lacking. Early data have documented that patient with HCC > 5 cm had a worse 5-year survival than those with HCC ≤ 5 cm after LR 24 . However, recent studies reported positive outcomes after resection even in single large HCC (≥ 5 cm) 23 even huge HCC (≥ 10 cm), and demonstrated that LR should not be considered based on solely the tumour burden 25 . However, these studies had limitations, such as small sample sizes, lack of comparison groups, and/or selection bias. Herein, we observed that LR provided a 5-year survival rate of 63.4% in single large HCCs (> 5 cm and up to 8 cm), and exhibited a significant better OS over TACE. In support of prevailing guidelines 15 , 16 , we advocated LR for candidates with large solitary MBMC-HCCs who failed to accept a LT. TACE, as a non-curative option, was once recommended as the first-line treatment for intermediate-stage HCC 19 , 20 . However, clinicians are becoming more aware that TACE should be considered more cautiously in potentially resectable patients. It was reported that LR for intermediate or advanced HCCs were associated with high risks of intraoperative bleeding and postoperative liver failure 26 . Nevertheless, with advances in surgical techniques and perioperative management, LR had been strongly advocated for HCC beyond early-stage in several institutions due to improved long-term survival 18 , 27 , 28 . In the present study, we further investigate the OS of LR versus TACE for multinodular MBMC-HCCs in our large cohort, and demonstrated the significantly better survival benefit of LR. One interesting phenomenon in our results was that no significant difference was observed in OS among patients with different tumour burdens and tumour number or size was not an independent factor for poor prognosis. Subgroup analyses also suggested that LR provides a comparable survival advantage in single or multiple MBMC-HCCs. These data seemed to contradict with prior researches indicating the independent prognostic value of tumour number or size for HCC 29 , 30 . We believe that this discrepancy may be due to the narrow eligibility criteria of our study population. Meanwhile, the comparable prognosis in single or multiple MBMC-HCCs indirectly reflects the rationality of ELTC for screening LT candidates. Considering these, LR should be considered first for MBMC-HCC patients, even for those with multiple lesions. Moreover, our multivariate analyses in MBMC-HCCs revealed several independent prognostic factors for OS, including ECOG-PS, Child score, AFP and INR. Thus, in addition to tumour size and number, many other factors need to be considered when making treatment decisions. Subgroup analyses based on ECOG-PS, AFP and INR indicated that LR led to better survival outcomes than TACE in MBMC-HCC patients regardless of baseline factors. Taken together, LR rather than TACE can serve as a superior alternative option for these potential candidates with MBMC-HCCs who failed to receive a LT, no matter with large solitary or multinodular tumours. This study has several limitations. First, total tumour diameter was not considered in the inclusion criteria because it was not routinely assessed at most centres. Second, there might be differences in surgical technique and perioperative management across centres. The details of TACE and additional therapies after LR or TACE could not be controlled. Finally, despite propensity score matching, our retrospective design could not fully exclude the possibility of residual confounding or unmeasured confounding, and further prospective randomized controlled trials should be considered. In conclusion, LR rather than TACE should be recommended as the preferred alternative for potential LT candidates with MBMC-HCC who have no access to a transplantion regardless of tumor burden, when liver function is well preserved and the estimated volume of the remnant liver is sufficient. Our research will undoubtedly provide guidance for the treatment decisions of MBMC-HCC patients who fail to accept a liver transplantation. Abbreviations LT Liver transplantation HCC hepatocellular carcinoma ELTC Extended Liver Transplant Criteria BMC beyond the Milan criteria MBMC modestly beyond the Milan criteria LR liver resection TACE transarterial chemoembolization OS overall survival PSM propensity score matching UCSF University of California,San Francisco BCLC Barcelona Clinic Liver Cancer AFP alpha-foetoprotein TBIL total bilirubin AST aspartate transaminase ALT alanine aminotransferase INR international normalized ratio BUN blood urea nitrogen Scr serum creatinine ASMD absolute standardized mean difference HR hazard ratio. Declarations Conflict of Interest The authors have no conflict of interests related to this publication. Ethical Statement The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Ethics Committee of the Army Medical Center of PLA on human research (No: 2022 − 233) and Institutional Review Board of Tang Du Hospital, Air Force Medical University (No: TDLL-202303-11), and individual consent for this retrospective analysis was waived. Data Sharing Statement The data used to support the findings of this study are available from the corresponding author upon request. Funding This work was supported by the National Natural Science Foundation of China (82403485) . Author Contribution Study concept and design (CR, ZhuJ), acquisition of data (FXY, SGB, LXD), analysis and interpretation of data (ZhuJ, FXY), drafting of the manuscript (FXY, ZhuJ), critical revision of the manuscript for important intellectual content (MY, ZLY, PY), administrative, technical, or material support (WP, QLP), and study supervision (CR). All authors have made a significant contribution to this study and have approved the final manuscript. 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A snapshot of the effective indications and results of surgery for hepatocellular carcinoma in tertiary referral centers: is it adherent to the EASL/AASLD recommendations?: an observational study of the HCC East-West study group. Ann Surg 2013;257(5):929–937. doi: 10.1097/SLA.0b013e31828329b8 . PMID: 23426336. Tables Table 1 is available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Table1.png Table 1 Supplementarymaterial.docx Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 13 Apr, 2026 Reviewers agreed at journal 01 Apr, 2026 Reviewers agreed at journal 15 Mar, 2026 Reviewers invited by journal 15 Mar, 2026 Editor assigned by journal 03 Mar, 2026 Submission checks completed at journal 02 Mar, 2026 First submitted to journal 26 Feb, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8974789","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":606479156,"identity":"5765a205-9bd8-426f-afc5-8d5b02c5d5a6","order_by":0,"name":"Xiaoyan Fan","email":"","orcid":"","institution":"Xijing Hospital, Air Force Medical University","correspondingAuthor":false,"prefix":"","firstName":"Xiaoyan","middleName":"","lastName":"Fan","suffix":""},{"id":606479157,"identity":"997b6d24-2ae2-4d29-ac0c-b658bf3fae9c","order_by":1,"name":"Guobin Sun","email":"","orcid":"","institution":"People's Hospital of Ningxia","correspondingAuthor":false,"prefix":"","firstName":"Guobin","middleName":"","lastName":"Sun","suffix":""},{"id":606479158,"identity":"6943ea74-4e20-4287-b8da-960009703b77","order_by":2,"name":"Xiaodong Liu","email":"","orcid":"","institution":"the Third Hospital of Xi'an","correspondingAuthor":false,"prefix":"","firstName":"Xiaodong","middleName":"","lastName":"Liu","suffix":""},{"id":606479159,"identity":"92d698dd-7dc3-40c1-93b2-16bba27cbaa9","order_by":3,"name":"Yong Meng","email":"","orcid":"","institution":"the First Hospital of Northwest University","correspondingAuthor":false,"prefix":"","firstName":"Yong","middleName":"","lastName":"Meng","suffix":""},{"id":606479160,"identity":"651cd1fb-737d-4dfb-92f8-cf01142ec587","order_by":4,"name":"Linyin Zhang","email":"","orcid":"","institution":"Air Force Medical University","correspondingAuthor":false,"prefix":"","firstName":"Linyin","middleName":"","lastName":"Zhang","suffix":""},{"id":606479162,"identity":"b2e8599f-01f2-4d2f-a5c8-49d7489c5b0b","order_by":5,"name":"Yan Peng","email":"","orcid":"","institution":"Air Force Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yan","middleName":"","lastName":"Peng","suffix":""},{"id":606479168,"identity":"019c1637-ba7a-4974-b225-5a69a84c36e7","order_by":6,"name":"Pang Wang","email":"","orcid":"","institution":"Air Force Medical University","correspondingAuthor":false,"prefix":"","firstName":"Pang","middleName":"","lastName":"Wang","suffix":""},{"id":606479173,"identity":"2cbc6ed4-e91e-4e76-8210-89929163de47","order_by":7,"name":"Liping Qiao","email":"","orcid":"","institution":"Air Force Medical University","correspondingAuthor":false,"prefix":"","firstName":"Liping","middleName":"","lastName":"Qiao","suffix":""},{"id":606479175,"identity":"38c90181-917c-4d5e-9097-3eba12fe5150","order_by":8,"name":"Jun Zhu","email":"","orcid":"","institution":"The Southern Theater Air Force Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jun","middleName":"","lastName":"Zhu","suffix":""},{"id":606479178,"identity":"383cbf45-8397-4c0b-80ef-392818a20a54","order_by":9,"name":"Rui Chen","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA20lEQVRIie2QoQoCQRCG5xgYy+DVFUSbeVEQg+Cr7CKYFIwbDMLJXZB7F6NREc6yar3oPYLNpmdW3LMZ9kt/mI+ZfwA8nj+EatH+qsyDR4fwVoaFW6lzNpZXi004Qq8MmVtpiWmnUcQ4hAv0G8UKKxzGloSyxEEEE6OXBGGyVo4u6WGgDDMiZLneNkHY08ax5axzZQUTBnGuLYEUM4ciplLoWL7W0FzHWEnplopigURQTXk9WdkdS2Qs/5Cxs0s7ifbF3exGMrTB7W4WrTBJvytv8G/jHo/H4/nIEysKRgOTbbJkAAAAAElFTkSuQmCC","orcid":"","institution":"the First Affiliated Hospital of Northwest University","correspondingAuthor":true,"prefix":"","firstName":"Rui","middleName":"","lastName":"Chen","suffix":""}],"badges":[],"createdAt":"2026-02-26 07:41:34","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8974789/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8974789/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":104878781,"identity":"b53a50e0-db7d-462e-94f5-f6c60e438ffd","added_by":"auto","created_at":"2026-03-18 08:58:24","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":278793,"visible":true,"origin":"","legend":"\u003cp\u003eFlow chart of the study design. Asterisks represent excluded cases. HCC, hepatocellular carcinoma; LR, liver resection; TACE, transarterial chemoembolization. AFP, α-fetoprotein; ELTC, Extended Liver Transplant Criteria.\u003c/p\u003e","description":"","filename":"Figure11.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8974789/v1/4dcb69d6c3749af48c92812f.jpg"},{"id":104878780,"identity":"6df9b476-9689-401e-9f1c-d91e510d82c9","added_by":"auto","created_at":"2026-03-18 08:58:24","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":915681,"visible":true,"origin":"","legend":"\u003cp\u003eOverall survival in BMC-HCC patients within different extended criteria for liver transplantation including (A) the ELTC criteria, (B) the Asan criteria, (C) the up-to-7 criteria, (D) the French AFP model and (E) the Metroticket 2.0 model according to therapy (LR or TACE). (F) Overall survival in BMC-HCC patients within the ELTC criteria after PSM. LR, liver resection; TACE, transarterial chemoembolization; ELTC, Extended Liver Transplant Criteria; AFP, α-fetoprotein; PSM, propensity score matching.\u003c/p\u003e","description":"","filename":"OnlineFigure21.png","url":"https://assets-eu.researchsquare.com/files/rs-8974789/v1/5662e48aae88bbf465d0691b.png"},{"id":104878775,"identity":"8ce98682-d095-4269-b5a3-b89362d8e382","added_by":"auto","created_at":"2026-03-18 08:58:22","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":634120,"visible":true,"origin":"","legend":"\u003cp\u003eUnivariate and multivariate Cox regression analyses of overall survival in MBMC-HCC patients (A-B)\u003cstrong\u003e \u003c/strong\u003ebefore and (C-D) after PSM. * P \u0026lt; 0.05, ** P \u0026lt; 0.01, *** P \u0026lt; 0.001. PSM, propensity score matching; ECOG-PS, Eastern Cooperative Oncology Group performance status; AFP, alpha-fetoprotein; TBIL, total bilirubin; AST, aspartate transaminase; ALT, alanine aminotransferase; PLT, platelet; INR, international normalized ratio; BUN, blood urea nitrogen; Scr, serum creatinine.\u003c/p\u003e","description":"","filename":"OnlineFigure31.png","url":"https://assets-eu.researchsquare.com/files/rs-8974789/v1/9ccb9e834b54beb877a0e06f.png"},{"id":104878810,"identity":"3aae919b-8998-4fc0-b15d-8254f36b03f9","added_by":"auto","created_at":"2026-03-18 08:58:29","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":1204407,"visible":true,"origin":"","legend":"\u003cp\u003eSubgroup Analysis of MBMC-HCC Patients after propensity score matching. Overall survival in patients with (A) single lesion, (B) 2-3 lesions, and (C) 4-5 lesions according to therapy (LR or TACE). Overall survival in patients with (D) ECOG-PS 0 and (E)\u003cstrong\u003e \u003c/strong\u003eECOG-PS 1 according to therapy. Overall survival in patients with (F) AFP \u0026lt; 1000 ng/mL and (G) ≥ 1000 ng/mL according to therapy. Overall survival in patients with (H) INR \u0026lt; 1.1 and (I) INR ≥ 1.1 according to therapy. LR, liver resection; TACE, transarterial chemoembolization; ECOG-PS, Eastern Cooperative Oncology Group performance status; AFP, alpha-fetoprotein; INR, international normalized ratio.\u003c/p\u003e","description":"","filename":"OnlineFigure41.png","url":"https://assets-eu.researchsquare.com/files/rs-8974789/v1/b1acc42c3c49b92362273c2a.png"},{"id":104878872,"identity":"63361c4d-3046-44c6-b5de-c8845fbf5f14","added_by":"auto","created_at":"2026-03-18 08:58:52","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1772355,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8974789/v1/ffa213d1-38dd-4675-80a6-2de16c58252e.pdf"},{"id":104878728,"identity":"a6628e33-8c2b-458d-a34d-771fc1b37ea4","added_by":"auto","created_at":"2026-03-18 08:58:07","extension":"png","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":98567,"visible":true,"origin":"","legend":"\u003cp\u003eTable 1\u003c/p\u003e","description":"","filename":"Table1.png","url":"https://assets-eu.researchsquare.com/files/rs-8974789/v1/2f2948f38ed4da9266c477db.png"},{"id":104878768,"identity":"70c7861f-4eb8-49b5-8b4e-2abb583e7e97","added_by":"auto","created_at":"2026-03-18 08:58:20","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":3230575,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementarymaterial.docx","url":"https://assets-eu.researchsquare.com/files/rs-8974789/v1/e92599740135d9ed489d3848.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Liver Resection Confers Survival Advantage over TACE for Hepatocellular Carcinoma Modestly Beyond Milan Criteria: A Multicenter Propensity-Matched Analysis","fulltext":[{"header":"Introduction","content":"\u003cp\u003eHepatocellular carcinoma (HCC) is one of the most common malignancies with increasing incidence worldwide \u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. Liver transplantation (LT) is currently thought as the best oncologic treatment for HCC since it replaces the diseased liver and restores normal hepatic function \u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. The Milan criteria (1 lesion\u0026thinsp;\u0026le;\u0026thinsp;5 cm or 2\u0026ndash;3 lesions each \u0026le;\u0026thinsp;3 cm combined with the absence of extrahepatic lesions or macrovascular invasion) \u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e have remained the benchmark in selecting candidates with HCC eligible for transplantation over the last two decades \u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. To increase patient access to LT, several expanded selection criteria have been advocated for HCC beyond the Milan criteria (BMC) with an appropriate overall tumour burden \u003csup\u003e\u003cspan additionalcitationids=\"CR7 CR8 CR9\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. Among them, the University of California, San Francisco (UCSF) downstaging protocol has recently been adopted as the standardized criteria, with initial selection criteria as 1 lesion\u0026thinsp;\u0026le;\u0026thinsp;8 cm, 2\u0026ndash;3 lesions each \u0026lt;\u0026thinsp;5 cm or 4\u0026ndash;5 lesions all \u0026lt;\u0026thinsp;3 cm with total tumour diameter\u0026thinsp;\u0026lt;\u0026thinsp;8 cm \u003csup\u003e6\u003c/sup\u003e. Substantial evidence has reported the noninferiority of these modest expansions \u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e,\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e, although post-LT survival incrementally decreases with increasing tumour burden \u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. However, regardless of whether the initial tumour meets or exceeds Milan criteria, LT is only offered to a minority of these candidates owing to limited availability of donor organs and drop-out due to tumour progression \u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. Therefore, it is essential to provide effective alternative strategies for candidates who failed to receive LT.\u003c/p\u003e \u003cp\u003eUndoubtedly, liver resection (LR) is recommended as the preferred alternative treatment for HCCs meeting the Milan criteria \u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e,\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e with decent long-term survival in studies completed after 2010 and cohorts who underwent enhanced surveillance \u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. However, whether LR can be performed for BMC-HCCs remains controversial \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. According to the Barcelona Clinic Liver Cancer (BCLC) classification \u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e,\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e, single and multinodular BMC-HCCs are categorized as early-stage and intermediate-stage, respectively. For the former, LR should be preferred for single larger nodules followed by TACE if LR is infeasible \u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e. For the latter, transcatheter arterial chemoembolization (TACE), instead of LR, was once recommended for most intermediate HCCs according to the 2018 BCLC version \u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. However, the intermediate stage is stratified into three subgroups according to tumour burden and liver function according to the latest 2022 BCLC version. Patients meeting the Extended Liver Transplant criteria (ELTC; i.e., inclusion criteria of UCSF down-staging protocol) could be candidates for LT, whereas patients without the option of transplant or matching transplant-failure but with preserved portal flow and defined tumour burden are candidates for TACE \u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e. Unfortunately, currently there have been few reports concerning whether LR could offer better survival for patients beyond Milan criteria but meeting ELTC.\u003c/p\u003e \u003cp\u003eHerein, we aimed to identify the optimal alternative option for BMC-HCC patients meeting ELTC based on a large-scale, Chinese nationwide, multicentre retrospective survey. Based on the above considerations, a particular HCC population was screen according to the following criteria: single lesion\u0026thinsp;\u0026gt;\u0026thinsp;5 cm and up to 8 cm; or 2\u0026ndash;3 lesions with at least one\u0026thinsp;\u0026gt;\u0026thinsp;3 cm and up to 5 cm; or 4\u0026ndash;5 lesions with none\u0026thinsp;\u0026gt;\u0026thinsp;3 cm, which were defined as modestly beyond Milan criteria (MBMC) in the present study. The survival benefit of LR versus TACE in the MBMC-HCC cohort was compared based on a propensity score matching analysis and was further validated in other BMC-HCC cohorts selected according to other extended criteria for LT including the Asan criteria \u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e, up-to-7 criteria \u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e, French alpha-foetoprotein (AFP) model \u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e and Metroticket 2.0 model \u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e, respectively. We hope that our research will provide reliable guidance on treatment decisions for patients with MBMC-HCC who fail to receive a LT.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design\u003c/h2\u003e \u003cp\u003eBetween January 2010 and October 2021, 5,073 patients diagnosed with HCC who underwent LR or TACE from fifteen Chinese hepatobiliary centres were enrolled. Patients beyond the Milan criteria but within ELTC were included into this study: (I) single lesion\u0026thinsp;\u0026gt;\u0026thinsp;5 cm and up to 8 cm; (II) 2\u0026ndash;3 lesions with at least one\u0026thinsp;\u0026gt;\u0026thinsp;3 cm and up to 5 cm; (III) 4\u0026ndash;5 lesions with none\u0026thinsp;\u0026gt;\u0026thinsp;3 cm \u003csup\u003e6\u003c/sup\u003e. Patients were excluded if they met any of the following criteria: (I) Child-Pugh B or C; (II) insufficient available data; (III) radiological evidence of extrahepatic metastasis, portal vein or other major vascular involvement \u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e; (IV) receiving treatment other than LR or TACE; (V) without informed consent. Ultimately, 1,110 MBMC-HCC patients (LR, 424; TACE, 686) were included in this cohort study (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eIn addition, 4 specifical BMC-HCC cohorts meeting other extended criteria for LT were established based on the exclusion criteria described above and their respective inclusion criteria as presented in \u003cb\u003eTable \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e\u003c/b\u003e for further verification. The study was approved by the Ethics Committee of the Army Medical Center of PLA on human research (No: 2022\u0026thinsp;\u0026minus;\u0026thinsp;233) and Institutional Review Board of Tang Du Hospital, Air Force Medical University (No: TDLL-202303-11), and individual consent for this retrospective analysis was waived.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eDiagnosis and definitions\u003c/h3\u003e\n\u003cp\u003eHCC diagnosis was proposed preoperatively based on at least two imaging examinations (magnetic resonance imaging, sonography, contrast-enhanced dynamic computed tomography or hepatic arterial angiography) or single imaging technique together with serum AFP level\u0026thinsp;\u0026gt;\u0026thinsp;400 ng/mL, and was confirmed by histopathological examination of resection specimens in the LR group and needle biopsy in the TACE group \u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. The severity of cirrhosis was determined according to the Child-Pugh classification. Performance status was determined by using the ECOG-PS of 0 (asymptomatic) to 4 (restricted to bed). Vascular invasion was defined by the presence of thrombus adjacent to the tumour in the portal vein with vague boundaries. Tumour size was defined as the maximum radial diameter of the largest invasive tumour based on the results of imaging tests.\u003c/p\u003e\n\u003ch3\u003eTreatment\u003c/h3\u003e\n\u003cp\u003eThe criteria for LR were based on comprehensive assessment including serum total bilirubin (TBIL) levels, indocyanine green clearance, residual liver volume estimated by volumetric computed tomography, as well as absence of ascites and hepatic encephalopathy. Multiple lesions were removed by en bloc excision or multiple excisions when patients had an adequate functional liver remnant with good liver function. TACE was performed after tumour vascularity was investigated by hepatic arteriography. During TACE, the catheter tip was inserted selectively into the tumour-feeding artery under image guidance. An injection of a mixture containing anticancer agent (doxorubicin, cisplatin, mitomycin C, epirubicin and 5-fluorouracil) and lipiodol, followed by arterial embolization using 300\u0026ndash;500 micron gelatine sponge particles was then performed. The doses of the anticancer agent lipiodol and embolic particles were determined based on both the size and extent of the lesions.\u003c/p\u003e\n\u003ch3\u003eFollow-up\u003c/h3\u003e\n\u003cp\u003ePost-treatment follow-up, including ultrasonography, enhanced computed tomography or magnetic resonance imaging of the abdomen, serum biochemistry and AFP levels, was performed every three months in the first year and twice a year in subsequent years. The prognosis of these patients was confirmed at each follow-up. Patients with tumour recurrence were treated with re-resection, radiofrequency ablation, TACE, conservative treatment, or sorafenib depending on the tumour site, liver function, and the general condition \u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e. Follow-up treatment for those receiving TACE included repeated TACE, local ablative treatment, or conservative treatment which was determined by the general condition and liver functional status \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. The median follow-up time was computed with censored observations only. The primary outcome was overall survival (OS) measured from the date of diagnosis to death or last follow-up (for censored patients).\u003c/p\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eQuantitative data were analyzed using the Mann-Whitney U-test, and categorical data with the chi-square test or Fisher\u0026rsquo;s exact test as appropriate. Survival curves were generated using the Kaplan-Meier method and compared using the log-rank test. Univariate and multivariate analyses were performed using the Cox proportional hazards model.\u003c/p\u003e \u003cp\u003eTo overcome patient selection bias, a PSM analysis was performed using a logistic regression model according to a 1:1 nearest-neighbour method between the LR and TACE groups. The following covariates were selected in this model: age, sex, hepatitis virus infection, ECOG-PS, Child‒Pugh score, tumour number, tumour size, AFP, TBIL, aspartate transaminase (AST), alanine aminotransferase (ALT), platelets, albumin, haemoglobin, international normalized ratio (INR), blood urea nitrogen (BUN), and serum creatinine (Scr). The absolute standardized mean difference (ASMD) up to 0.1 indicating successful balance.\u003c/p\u003e \u003cp\u003eAll tests were two-tailed, and \u003cem\u003eP\u003c/em\u003e value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant. All statistical analyses were performed using SPSS software (version 22.0) and R software (version 3.3.1).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eCharacteristics of all study patients\u003c/h2\u003e \u003cp\u003eThe patient enrolment scheme and research design were illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. 1110 MBMC (i.e. beyond the Milan criteria within the ELTC criteria) patients were identified. And additional cohorts that beyond the Milan criteria but meeting the Asan criteria, the up-to-7 criteria, the French AFP model or the Metroticket 2.0 model were respectively established (\u003cb\u003eTable \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e\u003c/b\u003e).\u003c/p\u003e \u003cp\u003eBaseline demographics and clinical characteristics of MBMC-HCC patients who underwent LR (n\u0026thinsp;=\u0026thinsp;424) or TACE (n\u0026thinsp;=\u0026thinsp;686) were demonstrated in \u003cb\u003eTable\u0026nbsp;1\u003c/b\u003e. Patients in the TACE group were significantly older, had more lesions as well as higher Child‒Pugh scores, and were less likely to have hepatitis virus infection (all \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Patients in the LR group had significantly higher ALT levels (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05), platelet counts (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001), albumin (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.041) and haemoglobin (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) levels, but had lower INR (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001) and Scr levels (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.041). No significant difference in other covariates was seen between the two groups.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eSurvival analysis of all study patients\u003c/h3\u003e\n\u003cp\u003eThe median follow-up time of patients in the MBMC-HCC cohort was 43.2 months (95% confidence interval [CI], 40.8\u0026ndash;45.7), and the median OS was 51.9 months (95% CI, 44.5\u0026ndash;59.3). The median follow-up times were 51.0 months (95% CI, 47.6\u0026ndash;54.5) and 35.1 months (95% CI, 32.3\u0026ndash;37.9) for the LR and TACE groups, respectively (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). As shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA, OS in the LR group was significantly better than that in the TACE group (log-rank P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Consistent results in other BMC-HCC cohorts (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB-E, all log-rank P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) demonstrated that LR does provide significantly better survival outcomes than TACE in potential LT candidates who beyond the Milan criteria even if distinct extended criteria for LT was applied.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eSince patients with different tumor burden were included together, we further compared the 1-, 3-, and 5-year survival rates following LR and TACE in patients with single lesion or multiple lesions (\u003cb\u003eFigure \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e\u003c/b\u003e). LR and TACE for multiple lesions both offered a survival outcome comparable with that for single lesion, and LR exhibited consistently a better overall survival benefit versus TACE. Moreover, survival analyses based on the lesion number indicated that single lesion offered only a slight survival advantage over multiple lesions in BMC patients within the up-to-7 criteria (log-rank P\u0026thinsp;=\u0026thinsp;0.030; \u003cb\u003eFigure S2A\u003c/b\u003e) and BMC patients within the French AFP model (log-rank P\u0026thinsp;=\u0026thinsp;0.025; \u003cb\u003eFigure S2B\u003c/b\u003e). While no statistically significant difference was observed between single lesion and multiple lesions in other 2 BMC cohorts (log-rank P\u0026thinsp;\u0026gt;\u0026thinsp;0.05; \u003cb\u003eFigure S2C-D\u003c/b\u003e). In summary, BMC-HCC patients exhibited similar prognosis despite different tumor burdens, and this indirectly reflects the homogeneity of LT candidates screened based on distinct extended LT criteria.\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003ePSM analysis in the MBMC-HCC cohort\u003c/h2\u003e \u003cp\u003eIn order to exclude any effect of these confounding factors on survival, a PSM analysis was performed to balance the covariates between the two groups. Out of the 686 patients from the TACE group, 374 (54.5%) were successfully matched with an equal number of patients (88.2%) from the LR group. All the covariates were well balanced between the matched groups with an ASMD\u0026thinsp;\u0026le;\u0026thinsp;0.1. The distribution of propensity scores per group before and after matching is presented in \u003cb\u003eFigure S3\u003c/b\u003e. When only matched patients were considered, there was no significant difference in any of the clinical covariates between the two groups (Table\u0026nbsp;1).\u003c/p\u003e \u003cp\u003eAfter PSM, the median follow-up time of all matched patients was 45.4 months (95% CI, 42.9\u0026ndash;48.0), and the median OS was 59.6 months (95% CI, 47.0-72.2). The median follow-up time was significantly longer in the LR group (52.2 months; 95% CI, 48.8\u0026ndash;55.7) than in the TACE group (36.0 months; 95% CI, 32.2\u0026ndash;39.9) (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Notably, the matched MBMC-HCC patients who underwent LR showed significantly improved OS than those who underwent TACE (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eF, log-rank P\u0026thinsp;\u0026lt;\u0026thinsp;0.001), which is consistent with the observations in the entire MBMC-HCC cohort.\u003c/p\u003e \u003cp\u003eTo identify whether the influence of therapeutic option on survival was affected by other clinical variables, univariate and multivariate analyses were subsequently performed in the entire and PSM matched MBMC-HCC cohorts, respectively. As shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA-B, several independent predictors of poor prognosis were identified before PSM, namely, ECOG score\u0026thinsp;=\u0026thinsp;1 [hazard ratio (HR): 1.431; 95% CI, 1.162\u0026ndash;1.764; P\u0026thinsp;=\u0026thinsp;0.001), serum AFP\u0026thinsp;\u0026ge;\u0026thinsp;400 ng/mL (HR: 1.452; 95% CI, 1.206\u0026ndash;1.749; P\u0026thinsp;\u0026lt;\u0026thinsp;0.001), INR\u0026thinsp;\u0026ge;\u0026thinsp;1.1 (HR: 1.375; 95% CI, 1.107\u0026ndash;1.706; P\u0026thinsp;=\u0026thinsp;0.004), and TACE (HR: 2.878; 95% CI, 2.308\u0026ndash;3.588; P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Univariate and multivariate analyses after PSM (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eC-D) revealed that Child-Pugh score\u0026thinsp;=\u0026thinsp;6 (HR: 1.292; 95% CI, 1.010\u0026ndash;1.654; P\u0026thinsp;=\u0026thinsp;0.042), serum AFP\u0026thinsp;\u0026gt;\u0026thinsp;400 ng/mL (HR: 1.485; 95% CI, 1.180\u0026ndash;1.868; P\u0026thinsp;=\u0026thinsp;0.001) and TACE (HR: 2.756; 95% CI, 2.166\u0026ndash;3.508; P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) were independent predictors of poor prognosis.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eSubgroup analyses of patients matched in the propensity model\u003c/h2\u003e \u003cp\u003eTo more deeply explore the survival benefits of LR for MBMC-HCC, subgroup analyses for OS were further performed on the basis of several characteristics. Among patients with single lesion or 2\u0026ndash;3 lesions, the OS was significantly better in the LR group than in the TACE group (log-rank P\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and LR experienced a survival benefit over TACE at 1 year, 3 years, and 5 years (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eA-B). Notably, even with a relatively small number of patients with 4\u0026ndash;5 lesions, a significant survival benefit for LR over TACE was also observed (log-rank P\u0026thinsp;=\u0026thinsp;0.027; Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eC). dditionally, among patients with ECOG-PS 0 or ECOG-PS 1 (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eD-E), patients with serum AFP levels\u0026thinsp;\u0026lt;\u0026thinsp;1000 ng/mL or \u0026ge;\u0026thinsp;1000 ng/mL (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eF-G), and patients with INR\u0026thinsp;\u0026lt;\u0026thinsp;1.1 or INR\u0026thinsp;\u0026ge;\u0026thinsp;1.1 (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eH-I), LR consistently exhibited a significantly better survival outcome compared to TACE (all log-rank P\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this large-scale multicentre retrospective study, the survival advantage of LR compared with TACE for MBMC-HCC patients with preserved liver function was revealed based on a PSM analysis and further verified in additional BMC-HCC cohorts established according to different extended criteria for LT. Univariate and subsequent multivariate Cox regression models revealed that LR, together with Child‒Pugh score and serum AFP level were independent predictors of OS for these patients. Subgroup analyses based on tumour burden, ECOG-PS, serum AFP level, and INR confirmed the robust survival advantage of LR compared to TACE. These results unambiguously demonstrated that LR rather than TACE should be considered as the preferred alternative treatment strategy for MBMC-HCC patients.\u003c/p\u003e \u003cp\u003eAccording to the latest BCLC guideline, resection or ablation is the first treatment option for single HCCs if the patient has contraindications or no access to LT. TACE is only recommended if resection or ablation is unsuccessful or not feasible \u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e. Despite these strategies, current understandings concerning the treatment of single large HCCs are still lacking. Early data have documented that patient with HCC\u0026thinsp;\u0026gt;\u0026thinsp;5 cm had a worse 5-year survival than those with HCC\u0026thinsp;\u0026le;\u0026thinsp;5 cm after LR \u003csup\u003e24\u003c/sup\u003e. However, recent studies reported positive outcomes after resection even in single large HCC (\u0026ge;\u0026thinsp;5 cm) \u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e even huge HCC (\u0026ge;\u0026thinsp;10 cm), and demonstrated that LR should not be considered based on solely the tumour burden \u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e. However, these studies had limitations, such as small sample sizes, lack of comparison groups, and/or selection bias. Herein, we observed that LR provided a 5-year survival rate of 63.4% in single large HCCs (\u0026gt;\u0026thinsp;5 cm and up to 8 cm), and exhibited a significant better OS over TACE. In support of prevailing guidelines \u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e,\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e, we advocated LR for candidates with large solitary MBMC-HCCs who failed to accept a LT.\u003c/p\u003e \u003cp\u003eTACE, as a non-curative option, was once recommended as the first-line treatment for intermediate-stage HCC \u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e,\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. However, clinicians are becoming more aware that TACE should be considered more cautiously in potentially resectable patients. It was reported that LR for intermediate or advanced HCCs were associated with high risks of intraoperative bleeding and postoperative liver failure \u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e. Nevertheless, with advances in surgical techniques and perioperative management, LR had been strongly advocated for HCC beyond early-stage in several institutions due to improved long-term survival \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e,\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e,\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e. In the present study, we further investigate the OS of LR versus TACE for multinodular MBMC-HCCs in our large cohort, and demonstrated the significantly better survival benefit of LR. One interesting phenomenon in our results was that no significant difference was observed in OS among patients with different tumour burdens and tumour number or size was not an independent factor for poor prognosis. Subgroup analyses also suggested that LR provides a comparable survival advantage in single or multiple MBMC-HCCs. These data seemed to contradict with prior researches indicating the independent prognostic value of tumour number or size for HCC \u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e,\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e. We believe that this discrepancy may be due to the narrow eligibility criteria of our study population. Meanwhile, the comparable prognosis in single or multiple MBMC-HCCs indirectly reflects the rationality of ELTC for screening LT candidates. Considering these, LR should be considered first for MBMC-HCC patients, even for those with multiple lesions.\u003c/p\u003e \u003cp\u003eMoreover, our multivariate analyses in MBMC-HCCs revealed several independent prognostic factors for OS, including ECOG-PS, Child score, AFP and INR. Thus, in addition to tumour size and number, many other factors need to be considered when making treatment decisions. Subgroup analyses based on ECOG-PS, AFP and INR indicated that LR led to better survival outcomes than TACE in MBMC-HCC patients regardless of baseline factors. Taken together, LR rather than TACE can serve as a superior alternative option for these potential candidates with MBMC-HCCs who failed to receive a LT, no matter with large solitary or multinodular tumours.\u003c/p\u003e \u003cp\u003eThis study has several limitations. First, total tumour diameter was not considered in the inclusion criteria because it was not routinely assessed at most centres. Second, there might be differences in surgical technique and perioperative management across centres. The details of TACE and additional therapies after LR or TACE could not be controlled. Finally, despite propensity score matching, our retrospective design could not fully exclude the possibility of residual confounding or unmeasured confounding, and further prospective randomized controlled trials should be considered.\u003c/p\u003e \u003cp\u003eIn conclusion, LR rather than TACE should be recommended as the preferred alternative for potential LT candidates with MBMC-HCC who have no access to a transplantion regardless of tumor burden, when liver function is well preserved and the estimated volume of the remnant liver is sufficient. Our research will undoubtedly provide guidance for the treatment decisions of MBMC-HCC patients who fail to accept a liver transplantation.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eLT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eLiver transplantation\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHCC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ehepatocellular carcinoma\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eELTC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eExtended Liver Transplant Criteria\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eBMC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ebeyond the Milan criteria\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMBMC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003emodestly beyond the Milan criteria\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eLR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eliver resection\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eTACE\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003etransarterial chemoembolization\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eOS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eoverall survival\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePSM\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003epropensity score matching\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eUCSF\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eUniversity of California,San Francisco\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eBCLC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eBarcelona Clinic Liver Cancer\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eAFP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ealpha-foetoprotein\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eTBIL\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003etotal bilirubin\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eAST\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003easpartate transaminase\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eALT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ealanine aminotransferase\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eINR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003einternational normalized ratio\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eBUN\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eblood urea nitrogen\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eScr\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eserum creatinine\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eASMD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eabsolute standardized mean difference\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ehazard ratio.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":" \u003ch2\u003eConflict of Interest\u003c/h2\u003e \u003cp\u003eThe authors have no conflict of interests related to this publication.\u003c/p\u003e \u003ch2\u003eEthical Statement\u003c/h2\u003e \u003cp\u003e The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Ethics Committee of the Army Medical Center of PLA on human research (No: 2022\u0026thinsp;\u0026minus;\u0026thinsp;233) and Institutional Review Board of Tang Du Hospital, Air Force Medical University (No: TDLL-202303-11), and individual consent for this retrospective analysis was waived.\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eData Sharing Statement\u003c/strong\u003e \u003cp\u003eThe data used to support the findings of this study are available from the corresponding author upon request.\u003c/p\u003e \u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eThis work was supported by the National Natural Science Foundation of China (82403485) .\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eStudy concept and design (CR, ZhuJ), acquisition of data (FXY, SGB, LXD), analysis and interpretation of data (ZhuJ, FXY), drafting of the manuscript (FXY, ZhuJ), critical revision of the manuscript for important intellectual content (MY, ZLY, PY), administrative, technical, or material support (WP, QLP), and study supervision (CR). All authors have made a significant contribution to this study and have approved the final manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgments\u003c/h2\u003e \u003cp\u003eWe gratefully acknowledge American Journal Experts for their assistance in revising the manuscript.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe data used to support the findings of this study are available from the corresponding author upon request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eLlovet JM, Kelley RK, Villanueva A, Singal AG, Pikarsky E, Roayaie S, \u003cem\u003eet al.\u003c/em\u003e Hepatocellular carcinoma. Nat Rev Dis Primers 2021;7(1):6. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/s41572-020-00240-3\u003c/span\u003e\u003cspan address=\"10.1038/s41572-020-00240-3\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. 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PMID: 30672806.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWada H, Eguchi H, Noda T, Ogawa H, Yamada D, Tomimaru Y, \u003cem\u003eet al.\u003c/em\u003e Selection criteria for hepatic resection in intermediate-stage (BCLC stage B) multiple hepatocellular carcinoma. Surgery 2016;160(5):1227\u0026ndash;1235. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.surg.2016.05.023\u003c/span\u003e\u003cspan address=\"10.1016/j.surg.2016.05.023\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. PMID: 27395761.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTorzilli G, Belghiti J, Kokudo N, Takayama T, Capussotti L, Nuzzo G, \u003cem\u003eet al.\u003c/em\u003e A snapshot of the effective indications and results of surgery for hepatocellular carcinoma in tertiary referral centers: is it adherent to the EASL/AASLD recommendations?: an observational study of the HCC East-West study group. 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PMID: 23426336.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 is available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"npj-gut-and-liver","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [npj Gut and Liver](https://www.nature.com/npjgutliver)","snPcode":"44355","submissionUrl":"https://submission.springernature.com/new-submission/44355/3","title":"npj Gut and Liver","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"NPJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Hepatocellular carcinoma (HCC), beyond the Milan criteria, liver transplantation (LT), liver resection (LR), transarterial chemoembolization (TACE)","lastPublishedDoi":"10.21203/rs.3.rs-8974789/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8974789/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground and Aim:\u003c/h2\u003e \u003cp\u003eLiver transplantation (LT) is the optimal treatment option for hepatocellular carcinoma (HCC) meeting the Extended Liver Transplant Criteria (ELTC), but it is only offered for the minority. The optimal alternative strategy for HCCs beyond the Milan criteria (BMC) but meeting the ELTC, which is defined as modestly beyond the Milan criteria (MBMC) here, is a matter of concern. The aim of this study was to evaluate the survival benefits of LR compared with transarterial chemoembolization (TACE) for MBMC-HCCs.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eFrom January 2010 to October 2021, from fifteen Chinese hepatobiliary centres, 1110 MBMC-HCC patients with Child‒Pugh A who underwent LR (n\u0026thinsp;=\u0026thinsp;424) or TACE (n\u0026thinsp;=\u0026thinsp;686) were included. Overall survival benefit of LR versus TACE in the MBMC-HCC cohort was compared based on a propensity matching and was further validated in addition BMC-HCC cohorts selected according to other extended LT criteria (Asan criteria, up-to-7 criteria, French alpha-foetoprotein model and Metroticket 2.0 model).\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eSurvival analyses in the MBMC-HCC cohort as well as other 4 BMC-HCC cohorts demonstrated that overall survival was significantly longer in the LR group than that in the TACE group (all log-rank P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). After a 1:1 propensity score matching in the MBMC-HCC cohort, multivariate analysis and subsequent subgroup analyses based on tumour burden and other important covariates further confirmed the robust survival advantage of LR compared to TACE.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eLR rather than TACE is highly recommended as the preferred alternative for potential LT candidates with MBMC-HCC regardless of tumor burden.\u003c/p\u003e","manuscriptTitle":"Liver Resection Confers Survival Advantage over TACE for Hepatocellular Carcinoma Modestly Beyond Milan Criteria: A Multicenter Propensity-Matched Analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-18 08:55:56","doi":"10.21203/rs.3.rs-8974789/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2026-04-14T02:54:25+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"286809058009851927685938932120227370078","date":"2026-04-02T01:38:14+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"44924399949267955722879613466865095004","date":"2026-03-15T22:59:43+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-03-15T19:16:39+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-03-03T08:31:29+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-03-02T18:50:31+00:00","index":"","fulltext":""},{"type":"submitted","content":"npj Gut and Liver","date":"2026-02-26T07:30:09+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"npj-gut-and-liver","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [npj Gut and Liver](https://www.nature.com/npjgutliver)","snPcode":"44355","submissionUrl":"https://submission.springernature.com/new-submission/44355/3","title":"npj Gut and Liver","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"NPJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"f78a5059-c565-4c15-a316-c9aefa3c1002","owner":[],"postedDate":"March 18th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":64535518,"name":"Biological sciences/Cancer"},{"id":64535519,"name":"Health sciences/Gastroenterology"},{"id":64535520,"name":"Health sciences/Oncology"}],"tags":[],"updatedAt":"2026-03-18T08:55:57+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-18 08:55:56","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8974789","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8974789","identity":"rs-8974789","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}