Comparative efficacy and safety of postoperative adjuvant therapies after curative resection for hepatocellular carcinoma: a network meta-analysis

Abstract

Purpose

Hepatocellular carcinoma (HCC) has a high risk of recurrence even after curative-intent hepatic resection. Although several postoperative adjuvant therapies have been investigated, the optimal strategy remains uncertain because direct head-to-head comparisons are limited. This study aimed to compare and rank the efficacy and safety of adjuvant therapies for HCC using a network meta-analysis (NMA).

Methods

A systematic search of MEDLINE via PubMed, Embase, CENTRAL, Web of Science, Scopus, regional databases, clinical trial registries, and conference proceedings was conducted to identify randomized controlled trials evaluating postoperative adjuvant therapies after curative-intent hepatic resection for HCC. The primary outcome was recurrence-free survival (RFS); secondary outcomes included overall survival (OS) and safety. A frequentist NMA was performed to estimate pooled hazard ratios (HRs) with 95% confidence intervals (CIs). Treatments were ranked using P-scores.

Results

Twenty-eight randomized controlled trials involving 4,830 participants were included. Most patients had hepatitis B virus-related HCC and preserved liver function (Child–Pugh A). For OS, adjuvant ¹²⁵I-brachytherapy (HR = 0.36, 95%CI 0.17–0.78), IMRT (HR = 0.44, 95%CI 0.23–0.86), and ¹³¹I-metuximab (HR = 0.46, 95%CI 0.28–0.77) were associated with the greatest reductions in mortality compared with observation. For RFS, autologous formalin-fixed tumor vaccine (AFTV) ranked highest (P-score = 0.92), followed by adjuvant Cidan capsule plus TACE (0.90), ¹²⁵I-brachytherapy (0.84), and IMRT (0.80). Most therapies showed manageable toxicity. Immune checkpoint inhibitors demonstrated a favorable benefit-risk profile, while locoregional therapies were associated with expected procedure-related adverse events.

Conclusion

Internal radiation and brachytherapy approaches (¹²⁵I-brachytherapy, IMRT, and ¹³¹I-metuximab) were associated with the greatest OS benefit, whereas AFTV and adjuvant Cidan capsule plus TACE showed the strongest RFS in the network. However, this finding is based on limited evidence (single small trial) and should be considered hypothesis-generating rather than definitive. These findings support risk-adapted integration of radiotherapy and immunotherapy after resection, although further large-scale head-to-head trials are needed.

Keywords

Hepatocellular carcinoma / Network meta-analysis / Postoperative adjuvant therapy / Overall survival / Recurrence-free survival

References

[1] McGlynn KA, Petrick JL, El-Serag HB. Epidemiology of hepatocellular carcinoma. Hepatology, 2021, 73(S1): 4-13

[2] Rumgay H, Arnold M, Ferlay J, et al. . Global burden of primary liver cancer in 2020 and predictions to 2040. J Hepatol, 2020, 77(6): 1598-1606

[3] Bray F, Laversanne M, Sung H, et al. . Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2022, 74(3): 229-263

[4] Llovet JM, Kelley RK, Villanueva A, et al. . Hepatocellular carcinoma Nat Rev Dis Primers, 2021, 7: 6

[5] Villanueva A. Hepatocellular carcinoma. N Engl J Med, 2019, 380(15): 1450-1462

[6] Huang DQ, Singal AG, Kono Y, et al. . Changing global epidemiology of liver cancer from 2010 to 2019: NASH is the fastest growing cause of liver cancer. Cell Metab, 2010, 34(7): 969-77.e2

[7] Reig M, Forner A, Rimola J, et al. . BCLC strategy for prognosis prediction and treatment recommendation: the 2022 update. J Hepatol, 2022, 76(3): 681-693

[8] Galle PR, Forner A, Llovet JMEuropean Association for the Study of the Liver, et al. . EASL clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol, 2018, 69(1): 182-236

[9] Tabrizian P, Jibara G, Shrager B, et al. . Recurrence of hepatocellular cancer after resection: patterns, treatments, and prognosis. Ann Surg, 2015, 261(5): 947-955

[10] Poon RT, Fan ST, Ng IO, et al. . Different risk factors and prognosis for early and late intrahepatic recurrence after resection of hepatocellular carcinoma. Cancer, 2000, 89(3): 500-507

[11] Portolani N, Coniglio A, Ghidoni S, et al. . Early and late recurrence after liver resection for hepatocellular carcinoma: prognostic and therapeutic implications. Ann Surg, 2006, 243(2): 229-235

[12] Cheng ZJ, Yang PH, Qu SP, et al. . Risk factors and management for early and late intrahepatic recurrence of solitary hepatocellular carcinoma after curative resection. HPB, 2015, 17(5): 422-427

[13] Li L, Li ZZ, Pan LX, et al. . Adjuvant therapy for hepatocellular carcinoma after curative treatment: several unanswered questions. J Clin Transl Hepatol, 2024, 12(5): 525-533

[14] Bruix J, Takayama T, Mazzaferro V, et al. . Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation (STORM): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Oncol, 2015, 16(13): 1344-1354

[15] Qin SK, Chen MS, Cheng AL, et al. . Atezolizumab plus bevacizumab versus active surveillance in patients with resected or ablated high-risk hepatocellular carcinoma (IMbrave050): a randomised, open-label, multicentre, phase 3 trial. Lancet, 2023, 402(10415): 1835-1847

[16] Takayama T, Sekine T, Makuuchi M, et al. . Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomised trial. Lancet, 2000, 356(9232): 802-807

[17] Sun JX, Yang L, Shi J, et al. . Postoperative adjuvant IMRT for patients with HCC and portal vein tumor thrombus: an open-label randomized controlled trial. Radiother Oncol, 2019, 140: 20-25

[18] Shi CY, Li Y, Geng L, et al. . Adjuvant stereotactic body radiotherapy after marginal resection for hepatocellular carcinoma with microvascular invasion: a randomised controlled trial. Eur J Cancer, 2022, 166: 176-184

[19] Ishizuka M, Kubota K, Nemoto T, et al. . Administration of adjuvant oral tegafur/uracil chemotherapy post hepatocellular carcinoma resection: a randomized controlled trial. Asian J Surg, 2016, 39(3): 149-154

[20] Dong H, Li Q, Wang J, et al. . A randomized, controlled trial of postoperative adjuvant cytokine-induced killer cells immunotherapy after radical resection of hepatocellular carcinoma. Dong Hui et al. Dig Liver Dis, 2009, 41(1): 36-41

[21] Zhai XF, Chen Z, Li B, et al. . Traditional herbal medicine in preventing recurrence after resection of small hepatocellular carcinoma: a multicenter randomized controlled trial. J Integr Med, 2013, 11(2): 90-100

[22] Wang Z, Ren ZG, Chen Y, et al. . Adjuvant transarterial chemoembolization for HBV-related hepatocellular carcinoma after resection: a randomized controlled study. Clin Cancer Res, 2018, 24(9): 2074-2081

[23] Ma T, Bai XL, Zhang Q, et al. . Adjuvant transarterial chemoembolization for hepatocellular carcinoma following curative resection: a randomized, open-label, phase 3 trial. Hepatology, 2025, 82(5): 1112-1121

[24] Lo CM, Liu CL, Chan SC, et al. . A randomized, controlled trial of postoperative adjuvant interferon therapy after resection of hepatocellular carcinoma. Ann Surg, 2007, 245(6): 831-842

[25] Lau WY, Lai ECH, Leung TWT, et al. . Adjuvant intra-arterial iodine-131-labeled lipiodol for resectable hepatocellular carcinoma: a prospective randomized trial—update on 5-year and 10-year survival. Ann Surg, 2008, 247(1): 43-48

[26] Chen KY, Xia Y, Wang HN, et al. . Adjuvant iodine-125 brachytherapy for hepatocellular carcinoma after complete hepatectomy: a randomized controlled trial. PLoS ONE, 2013, 8(2): e57397

[27] Chen Q, Shu C, Laurence AD, et al. . Effect of Huaier granule on recurrence after curative resection of HCC: a multicentre, randomised clinical trial. Gut, 2018, 67(11): 2006-2016

[28] Hasegawa K, Takayama T, Ijichi M, et al. . Uracil-tegafur as an adjuvant for hepatocellular carcinoma: a randomized trial. Hepatology, 2006, 44(4): 891-895

[29] Kwok PC, Lam TW, Lam PW, et al. . Randomized controlled trial to compare the dose of adjuvant chemotherapy after curative resection of hepatocellular carcinoma. J Gastroenterol Hepatol, 2003, 18(4): 450-455

[30] Yu WB, Wang WH, Rong WQ, et al. . Adjuvant radiotherapy in centrally located hepatocellular carcinomas after hepatectomy with narrow margin (<1 cm): a prospective randomized study. J Am Coll Surg, 2014, 218(3): 381-392

[31] Chen LT, Chen MF, Li LA, et al. . Long-term results of a randomized, observation-controlled, phase Ⅲ trial of adjuvant interferon alfa-2b in hepatocellular carcinoma after curative resection. Ann Surg, 2012, 255(1): 8-17

[32] Liu CJ, Lee PH, Lin DY, et al. . Heparanase inhibitor PI-88 as adjuvant therapy for hepatocellular carcinoma after curative resection: a randomized phase Ⅱ trial for safety and optimal dosage. Chun-Jen Liu et al. J Hepatol, 2009, 50(5): 958-68

[33] Matsui HM, Hazama S, Nakajima M, et al. . Novel adjuvant dendritic cell therapy with transfection of heat-shock protein 70 messenger RNA for patients with hepatocellular carcinoma: a phase Ⅰ/Ⅱ prospective randomized controlled clinical trial. Cancer Immunol Immunother, 2021, 70(4): 945-957

[34] Zhong C, Guo RP, Li JQ, et al. . A randomized controlled trial of hepatectomy with adjuvant transcatheter arterial chemoembolization versus hepatectomy alone for stage ⅢA hepatocellular carcinoma. J Cancer Res Clin Oncol, 2009, 135(10): 1437-1445

[35] Li J, Xing JL, Yang YF, et al. . Adjuvant ¹³¹I-metuximab for hepatocellular carcinoma after liver resection: a randomised, controlled, multicentre, open-label, phase 2 trial. Lancet Gastroenterol Hepatol, 2020, 5(6): 548-560

[36] Xia Y, Qiu YH, Li J, et al. . Adjuvant therapy with capecitabine postpones recurrence of hepatocellular carcinoma after curative resection: a randomized controlled trial. Ann Surg Oncol, 2010, 17(12): 3137-3144

[37] Li SH, Mei J, Wang QX, et al. . Postoperative adjuvant transarterial infusion chemotherapy with FOLFOX could improve outcomes of hepatocellular carcinoma patients with microvascular invasion: a preliminary report of a phase Ⅲ, randomized controlled clinical trial. Ann Surg Oncol, 2020, 27(13): 5183-5190

[38] Hirokawa F, Komeda K, Taniguchi K, et al. . Is postoperative adjuvant transcatheter arterial infusion therapy effective for patients with hepatocellular carcinoma who underwent hepatectomy A prospective randomized controlled trial. Ann Surg Oncol, 2020, 27(11): 4143-4152

[39] Zheng DH, Yang JM, Wu JX, et al. . Cidan capsule in combination with adjuvant transarterial chemoembolization reduces recurrence rate after curative resection of hepatocellular carcinoma: a multicenter, randomized controlled trial. Chin J Integr Med, 2023, 29(1): 3-9

[40] Wei W, Jian PE, Li SH, et al. . Adjuvant transcatheter arterial chemoembolization after curative resection for hepatocellular carcinoma patients with solitary tumor and microvascular invasion: a randomized clinical trial of efficacy and safety. Cancer Commun, 2018, 38(1): 61

[41] Wang K, Xiang YJ, Yu HM, et al. . Adjuvant sintilimab in resected high-risk hepatocellular carcinoma: a randomized, controlled, phase 2 trial. Nat Med, 2024, 30(3): 708-715

[42] Chung AY, Ooi LL, Machin D, et al. . Adjuvant hepatic intra-arterial iodine-131-lipiodol following curative resection of hepatocellular carcinoma: a prospective randomized trial. World J Surg, 2013, 37(6): 1356-1361

[43] Kuang M, Peng BG, Lu MD, et al. . Phase Ⅱ randomized trial of autologous formalin-fixed tumor vaccine for postsurgical recurrence of hepatocellular carcinoma. Clin Cancer Res, 2004, 10(5): 1574-1579

RIGHTS & PERMISSIONS

The Author(s)