Hepatectomy combined with apatinib and camrelizumab for CNLC stage IIIb hepatocellular carcinoma: a phase II trial protocol

Jun Tao Huang, Jian-Hong Zhong, Jie Zhang, Wen Feng Gong, Liang Ma, Le Qun Li, Bang-De Xiang, Jun Tao Huang, Jian-Hong Zhong, Jie Zhang, Wen Feng Gong, Liang Ma, Le Qun Li, Bang-De Xiang

Abstract

Introduction: Current clinical guidelines recommend systematic antitumour therapy as the primary treatment option for patients with stage IIIb hepatocellular carcinoma (HCC) based on the China liver cancer (CNLC) staging criteria. Several different targeted therapeutics have been applied in combination with immunotherapeutic regimens to date in patients with advanced HCC. The present study was developed to evaluate the relative safety and efficacy of hepatectomy of HCC in combination with targeted apatinib treatment and immunotherapeutic camrelizumab treatment CNLC-IIIb stage HCC patients with the goal of providing evidence regarding the potential value of this therapeutic regimen in individuals diagnosed with advanced HCC.

Methods and analysis: This is a multicentre phase II trial with single-arm in which patients undergo hepatectomy in combination with targeted treatment (apatinib) and immunotherapy (camrelizumab). Patients will undergo follow-up every 2-3 months following treatment initiation to record any evidence of disease progression and adverse event incidence for a minimum of 24 months following the discontinuation of treatment until reaching study endpoint events or trial termination. The primary endpoint for this study is patient mortality.

Ethics and dissemination: This study protocol was approved by the Ethics Committee of the Guangxi Medical University Cancer Hospital (KS2022[124]). The results of this study will be submitted for publication in a peer-reviewed journal.

Trial registration number: NCT05062837.

Keywords: health & safety; hepatology; protocols & guidelines.

Conflict of interest statement

Competing interests: Jiangsu Hengrui Pharmaceutical Company Limited provided both the camrelizumab and apatinib used in the trial free of charge, with the patients covering all other expenditures.

© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1
Figure 1
Study flow. DCR, disease control rate; DoR, duration of response; ORR, objective response rate; PFS, progression-free survival;TTR, time to response.

References

    1. Sung H, Ferlay J, Siegel RL, et al. . Global cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021;71:209–49. 10.3322/caac.21660
    1. Zhong J-H, Peng N-F, You X-M, et al. . Tumor stage and primary treatment of hepatocellular carcinoma at a large tertiary hospital in China: A real-world study. Oncotarget 2017;8:18296–302. 10.18632/oncotarget.15433
    1. Yau T, Tang VYF, Yao T-J, et al. . Development of Hong Kong liver cancer staging system with treatment stratification for patients with hepatocellular carcinoma. Gastroenterology 2014;146:1691–700. 10.1053/j.gastro.2014.02.032
    1. Farinati F, Vitale A, Spolverato G, et al. . Development and validation of a new Prognostic system for patients with hepatocellular carcinoma. PLoS Med 2016;13:e1002006. 10.1371/journal.pmed.1002006
    1. Chan SL, Chong CCN, Chan AWH, et al. . Management of hepatocellular carcinoma with portal vein tumor thrombosis: review and update at 2016. World J Gastroenterol 2016;22:7289–300. 10.3748/wjg.v22.i32.7289
    1. Xiang X, Lau W-Y, Wu Z-Y, et al. . Transarterial Chemoembolization versus best supportive care for patients with hepatocellular carcinoma with portal vein tumor Thrombus：A multicenter study. Eur J Surg Oncol 2019;45:1460–7. 10.1016/j.ejso.2019.03.042
    1. Zhou J, Sun H, Wang Z, et al. . Guidelines for the diagnosis and treatment of hepatocellular carcinoma (2019 edition). Liver Cancer 2020;9:682–720. 10.1159/000509424
    1. Galle PR, Forner A, Llovet JM, et al. . EASL clinical practice guidelines: management of hepatocellular carcinoma. Journal of Hepatology 2018;69:182–236. 10.1016/j.jhep.2018.03.019
    1. Heimbach JK, Kulik LM, Finn RS, et al. . AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology 2018;67:358–80. 10.1002/hep.29086
    1. Vogel A, Cervantes A, Chau I, et al. . Hepatocellular carcinoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2018;29:iv238–55. 10.1093/annonc/mdy308
    1. Omata M, Cheng A-L, Kokudo N, et al. . Asia-Pacific clinical practice guidelines on the management of hepatocellular carcinoma: a 2017 update. Hepatol Int 2017;11:317–70. 10.1007/s12072-017-9799-9
    1. Korean Liver Cancer Association K, National Cancer Center NCC. Korean liver cancer Association-National cancer center Korea practice guidelines for the management of hepatocellular carcinoma. Gut and Liver 2019;13:227–99. 10.5009/gnl19024
    1. Shao Y-Y, Wang S-Y, Lin S-M, et al. . Management consensus guideline for hepatocellular carcinoma: 2020 update on surveillance, diagnosis, and systemic treatment by the Taiwan liver cancer Association and the Gastroenterological society of Taiwan. J Formos Med Assoc 2021;120:1051–60. 10.1016/j.jfma.2020.10.031
    1. Llovet JM, Ricci S, Mazzaferro V, et al. . Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359:378–90. 10.1056/NEJMoa0708857
    1. Cheng A-L, Kang Y-K, Chen Z, et al. . Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol 2009;10:25–34. 10.1016/S1470-2045(08)70285-7
    1. Kudo M, Finn RS, Qin S, et al. . Lenvatinib versus sorafenib in first-line treatment of patients with Unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet 2018;391:1163–73. 10.1016/S0140-6736(18)30207-1
    1. Casadei-Gardini A, Scartozzi M, Tada T, et al. . Lenvatinib versus sorafenib in first-line treatment of Unresectable hepatocellular carcinoma: an inverse probability of treatment weighting analysis. Liver Int 2021;41:1389–97. 10.1111/liv.14817
    1. Facciorusso A, Tartaglia N, Villani R, et al. . Lenvatinib versus sorafenib as first-line therapy of advanced hepatocellular carcinoma: a systematic review and meta-analysis. Am J Transl Res 2021;13:2379–87.
    1. Qin S, Bi F, Gu S, et al. . Donafenib versus sorafenib in first-line treatment of Unresectable or metastatic hepatocellular carcinoma: A randomized, open-label, parallel-controlled phase II-III trial. J Clin Oncol 2021;39:3002–11. 10.1200/JCO.21.00163
    1. El-Khoueiry AB, Sangro B, Yau T, et al. . Nivolumab in patients with advanced hepatocellular carcinoma (Checkmate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet 2017;389:2492–502. 10.1016/S0140-6736(17)31046-2
    1. Finn RS, Ikeda M, Zhu AX, et al. . Phase IB study of Lenvatinib plus Pembrolizumab in patients with Unresectable hepatocellular carcinoma. J Clin Oncol 2020;38:2960–70. 10.1200/JCO.20.00808
    1. Finn RS, Qin S, Ikeda M, et al. . Atezolizumab plus Bevacizumab in Unresectable hepatocellular carcinoma. N Engl J Med 2020;382:1894–905. 10.1056/NEJMoa1915745
    1. Lee MS, Ryoo B-Y, Hsu C-H, et al. . Atezolizumab with or without Bevacizumab in Unresectable hepatocellular carcinoma (Go30140): an open-label, Multicentre, phase 1B study. Lancet Oncol 2020;21:808–20. 10.1016/S1470-2045(20)30156-X
    1. Ren Z, Xu J, Bai Y, et al. . Sintilimab plus a Bevacizumab Biosimilar (Ibi305) versus sorafenib in Unresectable hepatocellular carcinoma (ORIENT-32): a randomised, open-label, phase 2-3 study. Lancet Oncol 2021;22:977–90. 10.1016/S1470-2045(21)00252-7
    1. Chen K, Wei W, Liu L, et al. . Lenvatinib with or without immune Checkpoint inhibitors for patients with Unresectable hepatocellular carcinoma in real-world clinical practice. Cancer Immunol Immunother 2022;71:1063–74. 10.1007/s00262-021-03060-w
    1. Deng Z-J, Li L, Teng Y-X, et al. . Treatments of hepatocellular carcinoma with portal vein tumor thrombus: Current status and controversy. J Clin Transl Hepatol 2022;10:147–58. 10.14218/JCTH.2021.00179
    1. Qin S, Li Q, Gu S, et al. . Apatinib as second-line or later therapy in patients with advanced hepatocellular carcinoma (AHELP): a Multicentre, double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Gastroenterol Hepatol 2021;6:559–68. 10.1016/S2468-1253(21)00109-6
    1. Xu J, Shen J, Gu S, et al. . Camrelizumab in combination with Apatinib in patients with advanced hepatocellular carcinoma (RESCUE): A Nonrandomized, open-label, phase II trial. Clin Cancer Res 2021;27:1003–11. 10.1158/1078-0432.CCR-20-2571
    1. Lam CM, Lo CM, Yuen WK, et al. . Prolonged survival in selected patients following surgical resection for pulmonary metastasis from hepatocellular carcinoma. Br J Surg 1998;85:1198–200. 10.1046/j.1365-2168.1998.00846.x
    1. Chan K-M, Yu M-C, Wu T-J, et al. . Efficacy of surgical resection in management of isolated extrahepatic metastases of hepatocellular carcinoma. World J Gastroenterol 2009;15:5481–8. 10.3748/wjg.15.5481
    1. Yang T, Lu J-H, Lin C, et al. . Concomitant lung metastasis in patients with advanced hepatocellular carcinoma. World J Gastroenterol 2012;18:2533–9. 10.3748/wjg.v18.i20.2533
    1. Kow AWC, Kwon CHD, Song S, et al. . Clinicopathological factors and long-term outcome comparing between lung and peritoneal Metastasectomy after hepatectomy for hepatocellular carcinoma in a tertiary institution. Surgery 2015;157:645–53. 10.1016/j.surg.2014.07.024
    1. Llovet JM, De Baere T, Kulik L, et al. . Locoregional therapies in the era of molecular and immune treatments for hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 2021;18:293–313. 10.1038/s41575-020-00395-0
    1. Galluzzi L, Buqué A, Kepp O, et al. . Immunogenic cell death in cancer and infectious disease. Nat Rev Immunol 2017;17:97–111. 10.1038/nri.2016.107
    1. Cheng A-L, Hsu C, Chan SL, et al. . Challenges of combination therapy with immune Checkpoint inhibitors for hepatocellular carcinoma. Journal of Hepatology 2020;72:307–19. 10.1016/j.jhep.2019.09.025
    1. Ngwa W, Irabor OC, Schoenfeld JD, et al. . Using Immunotherapy to boost the Abscopal effect. Nat Rev Cancer 2018;18:313–22. 10.1038/nrc.2018.6
    1. Reig M, Forner A, Rimola J, et al. . BCLC strategy for prognosis prediction and treatment recommendation: the 2022 update. J Hepatol 2022;76:681–93. 10.1016/j.jhep.2021.11.018
    1. Zhong J-H, Xiang B-D, Gong W-F, et al. . Comparison of long-term survival of patients with BCLC stage B hepatocellular carcinoma after liver resection or Transarterial Chemoembolization. PLoS ONE 2013;8:e68193. 10.1371/journal.pone.0068193
    1. Zheng Y, Zhu M, Li M. Effects of alpha-Fetoprotein on the occurrence and progression of hepatocellular carcinoma. J Cancer Res Clin Oncol 2020;146:2439–46. 10.1007/s00432-020-03331-6
    1. Wong RJ, Ahmed A, Gish RG. Elevated alpha-Fetoprotein: differential diagnosis - hepatocellular carcinoma and other disorders. Clin Liver Dis 2015;19:309–23. 10.1016/j.cld.2015.01.005
    1. Yamamoto K, Imamura H, Matsuyama Y, et al. . DCP, and Gp73 as markers for monitoring treatment response and recurrence and as Surrogate markers of Clinicopathological variables of HCC. J Gastroenterol 2010;45:1272–82. 10.1007/s00535-010-0278-5
    1. Tayob N, Kanwal F, Alsarraj A, et al. . The performance of AFP, Afp-3, Dcp as biomarkers for detection of hepatocellular carcinoma (HCC): a phase 3 biomarker study in the United States. Clin Gastroenterol Hepatol 2023;21:415–23. 10.1016/j.cgh.2022.01.047
    1. Chalasani NP, Ramasubramanian TS, Bhattacharya A, et al. . A novel blood-based panel of Methylated DNA and protein markers for detection of early-stage hepatocellular carcinoma. Clin Gastroenterol Hepatol 2021;19:2597–605. 10.1016/j.cgh.2020.08.065
    1. So JBY, Kapoor R, Zhu F, et al. . Development and validation of a serum microRNA biomarker panel for detecting gastric cancer in a high-risk population. Gut 2021;70:829–37. 10.1136/gutjnl-2020-322065
    1. Zhang W, Wang Y, Dong X, et al. . Elevated serum Ca19-9 indicates severe liver inflammation and worse survival after curative resection in hepatitis B-related hepatocellular carcinoma. Biosci Trends 2022;15:397–405. 10.5582/bst.2021.01517
    1. Nomura F, Ishijima M, Kuwa K, et al. . Serum des-gamma-Carboxy prothrombin levels determined by a new generation of sensitive immunoassays in patients with small-sized hepatocellular carcinoma. Am J Gastroenterol 1999;94:650–4. 10.1111/j.1572-0241.1999.00930.x

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