REVIEW
Hepatocellular carcinoma downstaging for liver transplantation in the era of systemic combined therapy with anti-VEGF/TKI and immunotherapy
Nguyen H. Tran,
Sergio Muñoz,
Scott Thompson,
Christopher L. Hallemeier,
Jordi Bruix,
Corresponding Author
Nguyen H. Tran
Division of Medical Oncology, Department of Oncology, Mayo Clinic, Rochester, Minnesota, USA
Correspondence
Nguyen H. Tran, Division of Medical Oncology, Department of Oncology, Mayo Clinic, 200 First St SW, Rochester, MN 55905 USA.
Email: [email protected]
Jordi Bruix, BCLC Group, Liver Unit, Hospital Clínic, University of Barcelona, IDIBAPS, CIBEREHD, Villarroel 170, Barcelona, 08036, Spain.
Email: [email protected]
Search for more papers by this authorSergio Muñoz
BCLC Group, Liver Unit, Hospital Clinic Barcelona, IDIBAPS, CIBEREHD, University of Barcelona, Barcelona, Spain
Search for more papers by this authorScott Thompson
Division of Vascular and Interventional Radiology, Department of Radiology, Mayo Clinic, Rochester, Minnesota, USA
Search for more papers by this authorChristopher L. Hallemeier
Division of Radiation Oncology, Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota, USA
Search for more papers by this authorCorresponding Author
Jordi Bruix
BCLC Group, Liver Unit, Hospital Clinic Barcelona, IDIBAPS, CIBEREHD, University of Barcelona, Barcelona, Spain
Correspondence
Nguyen H. Tran, Division of Medical Oncology, Department of Oncology, Mayo Clinic, 200 First St SW, Rochester, MN 55905 USA.
Email: [email protected]
Jordi Bruix, BCLC Group, Liver Unit, Hospital Clínic, University of Barcelona, IDIBAPS, CIBEREHD, Villarroel 170, Barcelona, 08036, Spain.
Email: [email protected]
Search for more papers by this authorNguyen H. Tran,
Sergio Muñoz,
Scott Thompson,
Christopher L. Hallemeier,
Jordi Bruix,
Corresponding Author
Nguyen H. Tran
Division of Medical Oncology, Department of Oncology, Mayo Clinic, Rochester, Minnesota, USA
Correspondence
Nguyen H. Tran, Division of Medical Oncology, Department of Oncology, Mayo Clinic, 200 First St SW, Rochester, MN 55905 USA.
Email: [email protected]
Jordi Bruix, BCLC Group, Liver Unit, Hospital Clínic, University of Barcelona, IDIBAPS, CIBEREHD, Villarroel 170, Barcelona, 08036, Spain.
Email: [email protected]
Search for more papers by this authorSergio Muñoz
BCLC Group, Liver Unit, Hospital Clinic Barcelona, IDIBAPS, CIBEREHD, University of Barcelona, Barcelona, Spain
Search for more papers by this authorScott Thompson
Division of Vascular and Interventional Radiology, Department of Radiology, Mayo Clinic, Rochester, Minnesota, USA
Search for more papers by this authorChristopher L. Hallemeier
Division of Radiation Oncology, Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota, USA
Search for more papers by this authorCorresponding Author
Jordi Bruix
BCLC Group, Liver Unit, Hospital Clinic Barcelona, IDIBAPS, CIBEREHD, University of Barcelona, Barcelona, Spain
Correspondence
Nguyen H. Tran, Division of Medical Oncology, Department of Oncology, Mayo Clinic, 200 First St SW, Rochester, MN 55905 USA.
Email: [email protected]
Jordi Bruix, BCLC Group, Liver Unit, Hospital Clínic, University of Barcelona, IDIBAPS, CIBEREHD, Villarroel 170, Barcelona, 08036, Spain.
Email: [email protected]
Search for more papers by this authorAbstract
Hepatocellular carcinoma remains a global health challenge affecting close to 1 million cases yearly. Liver transplantation provides the best long-term outcomes for those meeting strict criteria. Efforts have been made to expand these criteria, whereas others have attempted downstaging approaches. Although locoregional approaches to downstaging are appealing and have demonstrated efficacy, limitations and challenges exists including poor imaging modality to assess response and appropriate endpoints along the process. Recent advances in systemic treatments including immune checkpoint inhibitors alone or in combination with tyrosine kinase inhibitors have prompted the discussion regarding their role for downstaging disease prior to transplantation. Here, we provide a review of prior locoregional approaches for downstaging, new systemic agents and their role for downstaging, and finally, key and critical considerations of the assessment, endpoints, and optimal designs in clinical trials to address this key question.
CONFLICT OF INTEREST
Jordi Bruix consults for, is on the speakers' bureau for, and received grants from Bayer and BTG. He consults for and is on the speakers' bureau for Eisai, Terumo, Sirtex, and Ipsen. He consults for Arqule, Novartis, BMS, Nerviano, Sanofi, Kowa, Gilead, Bio-Alliance, Roche, AbbVie, MSD, AstraZeneca, Incyte, and Lilly. Nguyen H. Tran consults for QED and Helsinn. She received grants from Exact Science. Sergio Muñoz received speakers fee and grants from Bayer. He received grants from Eisai, BMS, and Celgene.
REFERENCES
- 1Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, 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.
- 2Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med. 1996; 334(11): 693–9.
- 3Yao FY, Ferrell L, Bass NM, Bacchetti P, Ascher NL, Roberts JP. Liver transplantation for hepatocellular carcinoma: comparison of the proposed UCSF criteria with the Milan criteria and the Pittsburgh modified TNM criteria. Liver Transpl. 2002; 8: 765–74.
- 4Mazzaferro V, Bhoori S, Sposito C, Bongini M, Langer M, Miceli R, et al. Milan criteria in liver transplantation for hepatocellular carcinoma: an evidence-based analysis of 15 years of experience. Liver Transpl. 2011; 17(Suppl 2): S44–57.
- 5Kaido T, Ogawa K, Mori A, Fujimoto Y, Ito T, Tomiyama K, et al. Usefulness of the Kyoto criteria as expanded selection criteria for liver transplantation for hepatocellular carcinoma. Surgery. 2013; 154(5): 1053–60.
- 6Mazzaferro V, Llovet JM, Miceli R, Bhoori S, Schiavo M, Mariani L, et al. Predicting survival after liver transplantation in patients with hepatocellular carcinoma beyond the Milan criteria: a retrospective, exploratory analysis. Lancet Oncol. 2009; 10(1): 35–43.
- 7Sapisochin G, Goldaracena N, Laurence JM, Dib M, Barbas A, Ghanekar A, et al. The extended Toronto criteria for liver transplantation in patients with hepatocellular carcinoma: A prospective validation study. Hepatology. 2016; 64(6): 2077–88.
- 8Yao FY, Ferrell L, Bass NM, Watson JJ, Bacchetti P, Venook A, et al. Liver transplantation for hepatocellular carcinoma: Expansion of the tumor size limits does not adversely impact survival. Hepatology. 2001; 33(6): 1394–403.
- 9Yao FY, Mehta N, Flemming J, Dodge J, Hameed B, Fix O, et al. Downstaging of hepatocellular cancer before liver transplant: long-term outcome compared to tumors within Milan criteria. Hepatology. 2015; 61(6): 1968–77.
- 10Yao FY, Xiao L, Bass NM, Kerlan R, Ascher NL, Roberts JP. Liver transplantation for hepatocellular carcinoma: validation of the UCSF-expanded criteria based on preoperative imaging. Am J Transplant. 2007; 7(11): 2587–96.
- 11Ferrer-Fàbrega J, Sampson-Dávila J, Forner A, Sapena V, Díaz A, Vilana R, et al. Limited tumour progression beyond Milan criteria while on the waiting list does not result in unacceptable impairment of survival. J Hepatol. 2021; 75(5): 1154–63.
- 12Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008; 359(4): 378–90.
- 13Kudo M, Finn RS, Qin S, Han KH, Ikeda K, Piscaglia F, 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(10126): 1163–73.
- 14Abou-Alfa GK, Meyer T, Cheng AL, El-Khoueiry AB, Rimassa L, Ryoo BY, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. N Engl J Med. 2018; 379(1): 54–63.
- 15Bruix J, Qin S, Merle P, Granito A, Huang YH, Bodoky G, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017; 389: 56–66.
- 16Zhu AX, Kang YK, Yen CJ, Finn RS, Galle PR, Llovet JM, et al. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased α-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019; 20: 282–96.
- 17Foerster F, Gairing SJ, Ilyas SI, Galle PR. Emerging immunotherapy for HCC: A guide for hepatologists. Hepatology. 2022; 75(6): 1604–26.
- 18Yau T, Kang YK, Kim TY, El-Khoueiry AB, Santoro A, Sangro B, et al. Efficacy and safety of nivolumab plus ipilimumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib: the CheckMate 040 randomized clinical trial. JAMA Oncol. 2020; 6(11):e204564.
- 19Zhu AX, Finn RS, Edeline J, Cattan S, Ogasawara S, Palmer D, et al. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol. 2018; 19: 940–52.
- 20Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, et al. IMbrave150: Updated overall survival (OS) data from a global, randomized, open-label phase III study of atezolizumab (atezo) + bevacizumab (bev) versus sorafenib (sor) in patients (pts) with unresectable hepatocellular carcinoma (HCC). J Clin Oncol. 2021; 39(3 suppl):267.
- 21Abou-Alfa GK, Chan SL, Kudo M, Lau G, Kelley RK, Furuse J, et al. Phase 3 randomized, open-label, multicenter study of tremelimumab (T) and durvalumab (D) as first-line therapy in patients (pts) with unresectable hepatocellular carcinoma (uHCC): HIMALAYA. J Clin Oncol. 2022; 40(4 suppl):379.
- 22Bizollon T, Rode A, Bancel B, Gueripel V, Ducerf C, Baulieux J, et al. Diagnostic value and tolerance of Lipiodol-computed tomography for the detection of small hepatocellular carcinoma: correlation with pathologic examination of explanted livers. J Hepatol. 1998; 28: 491–6.
- 23Kulik L, Abecassis M. Living donor liver transplantation for hepatocellular carcinoma. Gastroenterology. 2004; 127(5 suppl 1): S277–82.
- 24Bruix J, Sherman M, Llovet JM, Beaugrand M, Lencioni R, Burroughs AK, et al. Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. European Association for the Study of the Liver. J Hepatol. 2001; 35: 421–30.
- 25Navasa M, Bruix J. Multifaceted perspective of the waiting list for liver transplantation: the value of pharmacokinetic models. Hepatology. 2010; 51(1): 12–5.
- 26Tabrizian P, Holzner M, Halazun K, Agopian VG, Busuttil RW, Yao F, et al. A US multicenter analysis of 2529 HCC patients undergoing liver transplantation: 10-year outcome assessing the role of down-staging to within Milan criteria [abstract 15]. Hepatology. 2019; 70: 1A–187A.
- 27Kim CG, Kim C, Yoon SE, Kim KH, Choi SJ, Kang B, et al. Hyperprogressive disease during PD-1 blockade in patients with advanced hepatocellular carcinoma. J Hepatol. 2021; 74: 350–9.
- 28Marrero JA, Kulik LM, Sirlin CB, Zhu AX, Finn RS, Abecassis MM, et al. Diagnosis, staging, and management of hepatocellular carcinoma: 2018 Practice Guidance by the American Association for the Study of Liver Diseases. Hepatology. 2018; 68: 723–50.
- 29 OPTN/UNOS Liver and Intestinal Organ Transplantation Committee. Organ procurement and transplantation network. Accessed: September 4, 2021. Available from: https://optn.transplant.hrsa.gov/governance/public-comment/hcc-auto-approval-criteria-changes/
- 30Mehta N, Guy J, Frenette CT, Dodge JL, Osorio RW, Minteer WB, et al. Excellent outcomes of liver transplantation following down-staging of hepatocellular carcinoma to within milan criteria: a multicenter study. Clin Gastroenterol Hepatol. 2018; 16: 955–64.
- 31Sinha J, Mehta N, Dodge JL, Poltavskiy E, Roberts J, Yao F. Are there upper limits in tumor burden for down-staging of hepatocellular carcinoma to liver transplant? Hepatology. 2019; 70: 1185–96.
- 32Mehta N, Dodge JL, Grab JD, Yao FY. National experience on down-staging of hepatocellular carcinoma before liver transplant: influence of tumor burden, alpha-fetoprotein, and wait time. Hepatology. 2020; 71: 943–54.
- 33Mehta N, Frenette C, Tabrizian P, Hoteit M, Guy J, Parikh N, et al. Downstaging outcomes for hepatocellular carcinoma: results from the multicenter evaluation of reduction in tumor size before liver transplantation (MERITS-LT) consortium. Gastroenterology. 2021; 161(5): 1502–12.
- 34Gabr A, Abouchaleh N, Ali R, Vouche M, Atassi R, Memon K, et al. Comparative study of post-transplant outcomes in hepatocellular carcinoma patients treated with chemoembolization or radioembolization. Eur J Radiol. 2017; 93: 100–6.
- 35Shi F, Wu M, Lian SS, Mo ZQ, Gou Q, Xu RD, et al. Radiofrequency ablation following downstaging of hepatocellular carcinoma by using transarterial chemoembolization: long-term outcomes. Radiology. 2019; 293: 707–15.
- 36Shi F, Lian S, Mai Q, Mo Z, Zhuang W, Cui W, et al. Microwave ablation after downstaging of hepatocellular carcinoma: outcome was similar to tumor within Milan criteria. Eur Radiol. 2020; 30: 2454–62.
- 37Lu DS, Yu NC, Raman SS, Limanond P, Lassman C, Murray K, et al. Radiofrequency ablation of hepatocellular carcinoma: treatment success as defined by histologic examination of the explanted liver. Radiology. 2005; 234: 954–60.
- 38Serra C, Cucchetti A, Felicani C, Mosconi C, de Cinque A, Golfieri R, et al. Assessment of radiofrequency ablation efficacy for hepatocellular carcinoma by histology and pretransplant radiology. Liver Transpl. 2019; 25: 88–97.
- 39Crocetti L, Scalise P, Bozzi E, Campani D, Rossi P, Cervelli R, et al. Microwave ablation of very-early- and early-stage HCC: efficacy evaluation by correlation with histology after liver transplantation. Cancers (Basel). 2021; 13(14):3420.
- 40Brillet PY, Paradis V, Brancatelli G, Rangheard AS, Consigny Y, Plessier A. Percutaneous radiofrequency ablation for hepatocellular carcinoma before liver transplantation: a prospective study with histopathologic comparison. AJR Am J Roentgenol. 2006; 186: S296–305.
- 41Bale R, Schullian P, Eberle G, Putzer D, Zoller H, Schneeberger S, et al. Stereotactic radiofrequency ablation of hepatocellular carcinoma: a histopathological study in explanted livers. Hepatology. 2019; 70: 840–50.
- 42Sapisochin G, Barry A, Doherty M, Fischer S, Goldaracena N, Rosales R, et al. Stereotactic body radiotherapy vs. TACE or RFA as a bridge to transplant in patients with hepatocellular carcinoma. An intention-to-treat analysis. J Hepatol. 2017; 67: 92–9.
- 43Wong TC, Lee VH, Law AL, Pang HH, Lam KO, Lau V, et al. Prospective study of stereotactic body radiation therapy for hepatocellular carcinoma on waitlist for liver transplant. Hepatology. 2021; 74: 2580–94.
- 44Bush DA, Smith JC, Slater JD, Volk ML, Reeves ME, Cheng J, et al. Randomized clinical trial comparing proton beam radiation therapy with transarterial chemoembolization for hepatocellular carcinoma: results of an interim analysis. Int J Radiat Oncol Biol Phys. 2016; 95: 477–82.
- 45Reig M, Forner A, Rimola J, Ferrer-Fàbrega J, Burrel M, Garcia-Criado Á, et al. BCLC strategy for prognosis prediction and treatment recommendation: the 2022 update. J Hepatol. 2022; 76(3): 681–93.
- 46Bruix J, Chan SL, Galle PR, Rimassa L, Sangro B. Systemic treatment of hepatocellular carcinoma: an EASL position paper. J Hepatol. 2021; 75(4): 960–74.
- 47Nanda R, Liu MC, Yau C, Shatsky R, Pusztai L, Wallace A, et al. Effect of pembrolizumab plus neoadjuvant chemotherapy on pathologic complete response in women with early-stage breast cancer: an analysis of the ongoing phase 2 adaptively randomized I-SPY2 trial. JAMA Oncol. 2020; 6: 676–84.
- 48Powles T, Kockx M, Rodriguez-Vida A, Duran I, Crabb SJ, van der Heijden M, et al. Clinical efficacy and biomarker analysis of neoadjuvant atezolizumab in operable urothelial carcinoma in the ABACUS trial. Nat Med. 2019; 25: 1706–14.
- 49Menzies AM, Amaria RN, Rozeman EA, Huang AC, Tetzlaff MT, van de Wiel B, et al. Pathological response and survival with neoadjuvant therapy in melanoma: a pooled analysis from the International Neoadjuvant Melanoma Consortium (INMC). Nat Med. 2021; 27: 301–9.
- 50Conroy T, Bosset JF, Etienne PL, Rio E, François É, Mesgouez-Nebout N, et al. Neoadjuvant chemotherapy with FOLFIRINOX and preoperative chemoradiotherapy for patients with locally advanced rectal cancer (UNICANCER-PRODIGE 23): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2021; 22: 702–15.
- 51Raphael MJ, Booth CM. Neoadjuvant chemotherapy for muscle-invasive bladder cancer: Underused across the 49(th) parallel. Can Urol Assoc J. 2019; 13(2): 29–31.
- 52Mamtani A, Barrio AV, King TA, van Zee K, Plitas G, Pilewskie M, et al. How often does neoadjuvant chemotherapy avoid axillary dissection in patients with histologically confirmed nodal metastases? Results of a prospective study. Ann Surg Oncol. 2016; 23: 3467–74.
- 53Yoo EJ, Shin HS, Kim SU, Joo DJ, Park JY, Choi GH, et al. Orthotopic liver transplantation after the combined use of locoregional therapy and sorafenib for advanced hepatocellular carcinoma. Onco Targets Ther. 2013; 6: 755–9.
- 54Vagefi PA, Hirose R. Sorafenib combined with locoregional therapy prior to liver transplantation for hepatocellular carcinoma: an update on a previous case report. J Gastrointest Cancer. 2013; 44(2): 246–7.
- 55Saidi RF, Shah SA, Rawson AP, Grossman S, Piperdi B, Bozorgzadeh A. Treating hepatocellular carcinoma with sorafenib in liver transplant patients: an initial experience. Transplant Proc. 2010; 42: 4582–4.
- 56Frenette CT, Boktour M, Burroughs SG, Kaseb A, Aloia TA, Galati J, et al. Pre-transplant utilization of sorafenib is not associated with increased complications after liver transplantation. Transpl Int. 2013; 26: 734–9.
- 57Adair A, Wigmore SJ. Sorafenib for hepatocellular carcinoma before liver transplantation. Transpl Int. 2013; 26: e100–1.
- 58Golse N, Radenne S, Rode A, Ducerf C, Mabrut JY, Merle P. Liver transplantation after neoadjuvant sorafenib therapy: preliminary experience and literature review. Exp Clin Transplant. 2018; 16: 227–36.
- 59Rimola J, Díaz-González Á, Darnell A, Varela M, Pons F, Hernandez-Guerra M, et al. Complete response under sorafenib in patients with hepatocellular carcinoma: Relationship with dermatologic adverse events. Hepatology. 2018; 67: 612–22.
- 60Hoffmann K, Ganten T, Gotthardtp D, Radeleff B, Settmacher U, Kollmar O, et al. Impact of neo-adjuvant Sorafenib treatment on liver transplantation in HCC patients - a prospective, randomized, double-blind, phase III trial. BMC Cancer. 2015; 15:392.
- 61Eilard MS, Andersson M, Naredi P, Geronymakis C, Lindnér P, Cahlin C, et al. A prospective clinical trial on sorafenib treatment of hepatocellular carcinoma before liver transplantation. BMC Cancer. 2019; 19:568.
- 62Tomonari T, Sato Y, Tanaka H, Tanaka T, Taniguchi T, Sagobe M, et al. Conversion therapy for unresectable hepatocellular carcinoma after lenvatinib: three case reports. Medicine. 2020; 99(42):e22782.
- 63Liu Z, Fu Z, Li G, Lin D. Downstaging of recurrent advanced hepatocellular carcinoma after lenvatinib treatment: opportunities or pitfalls? Onco Targets Ther. 2020; 13: 10267–73.
- 64Sato N, Beppu T, Kinoshita K, Yuki H, Suyama K, Chiyonaga S, et al. Conversion hepatectomy for huge hepatocellular carcinoma with arterioportal shunt after chemoembolization and lenvatinib therapy. Anticancer Res. 2019; 39(10): 5695–701.
- 65Bruix J, Takayama T, Mazzaferro V, Chau GY, Yang J, Kudo M, 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: 1344–54.
- 66Lizaola-Mayo BC, Mathur AK, Borad MJ, Jadlowiec CC, Lam-Himlin DM, Corey RL, et al. Immunotherapy as a downstaging tool for liver transplantation in hepatocellular carcinoma. Am J Gastroenterol. 2021; 116(12): 2478–80.
- 67Nordness MF, Hamel S, Godfrey CM, Shi C, Johnson DB, Goff LW, et al. Fatal hepatic necrosis after nivolumab as a bridge to liver transplant for HCC: Are checkpoint inhibitors safe for the pretransplant patient? Am J Transplant. 2020; 20: 879–83.
- 68Schwacha-Eipper B, Minciuna I, Banz V, Dufour JF. Immunotherapy as a downstaging therapy for liver transplantation. Hepatology. 2020; 72: 1488–90.
- 69Dehghan Y, Schnickel GT, Hosseini M, Burgoyne AM, Ajmera VH, Morris GP, et al. Rescue liver re-transplantation after graft loss due to severe rejection in the setting of pre-transplant nivolumab therapy. Clin J Gastroenterol. 2021; 14: 1718–24.
- 70Chen Z, Hong X, Wang T, Guo Y, Huang C, Li M, et al. Prognosis after liver transplantation in patients treated with anti- PD-1 immunotherapy for advanced hepatocellular carcinoma: case series. Ann Palliative Med. 2021; 10: 9354–61.
- 71Kaseb AO, Hasanov E, Cao HST, Xiao L, Vauthey JN, Lee SS, et al. Perioperative nivolumab monotherapy versus nivolumab plus ipilimumab in resectable hepatocellular carcinoma: a randomised, open-label, phase 2 trial. Lancet Gastroenterol Hepatol. 2022; 7(3): 208–18.
- 72Marron TU, Fiel MI, Hamon P, Fiaschi N, Kim E, Ward SC, et al. Neoadjuvant cemiplimab for resectable hepatocellular carcinoma: a single-arm, open-label, phase 2 trial. Lancet Gastroenterol Hepatol. 2022; 7(3): 219–29.
- 73Kumar V, Shinagare AB, Rennke HG, Ghai S, Lorch JH, Ott PA, et al. The safety and efficacy of checkpoint inhibitors in transplant recipients: a case series and systematic review of literature. Oncologist. 2020; 25: 505–14.
- 74Tabrizian P, Florman SS, Schwartz ME. PD-1 inhibitor as bridge therapy to liver transplantation? Am J Transpl. 2021; 21: 1979–80.
- 75 Opdivo [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2021.
- 76 KEYTRUDA [package insert]. Accessed: February, 2022. Available from: https://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf
- 77Brahmer JR, Drake CG, Wollner I, Powderly JD, Picus J, Sharfman WH, et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol. 2010; 28: 3167–75.
- 78Friend BD, Venick RS, McDiarmid SV, Zhou X, Naini B, Wang H, et al. Fatal orthotopic liver transplant organ rejection induced by a checkpoint inhibitor in two patients with refractory, metastatic hepatocellular carcinoma. Pediatr Blood Cancer. 2017; 64(12):e26682.
- 79Gassmann D, Weiler S, Mertens JC, Reiner CS, Vrugt B, Nägeli M, et al. Liver allograft failure after nivolumab treatment-a case report with systematic literature research. Transplant Direct. 2018; 4(8):e376.
- 80Haber PK, Torres-Martin M, Dufour JF, Verslype C, Marquardt J, Galle PR, et al. Molecular markers of response to anti-PD1 therapy in advanced hepatocellular carcinoma. J Clin Oncol. 2021; 39(15 suppl):4100.
- 81Ueshima K, Kudo M, Yamanaka T, Aikata H, Yamashita T, Ikeda M, et al. REPLACEMENT trial in progress: combination therapy with atezolizumab plus bevacizumab for TACE unsuitable patients with beyond up-to-seven criteria in intermediate stage hepatocellular carcinoma: a phase II study. J Clin Oncol. 2021; 39(15 suppl):TPS4162.
- 82Xia Y, Wang P, Pu L, Qian X, Cheng F, Wang K, et al. Preliminary efficacy and safety of perioperative treatment of camrelizumab combined with apatinib in resectable hepatocellular carcinoma (HCC): a prospective phase II study. J Clin Oncol. 2021; 39(15 suppl):4082.
- 83Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020; 382: 1894–905.
- 84Finn RS, Ikeda M, Zhu AX, Sung MW, Baron AD, Kudo M, et al. Phase Ib study of lenvatinib plus pembrolizumab in patients with unresectable hepatocellular carcinoma. J Clin Oncol. 2020; 38: 2960–70.
- 85Chen X, Zhang Y, Zhang N, Ge Y, Jia W. Lenvatinib combined nivolumab injection followed by extended right hepatectomy is a feasible treatment for patients with massive hepatocellular carcinoma: a case report. Onco Targets Ther. 2019; 12: 7355–9.
- 86Huang C, Zhu XD, Shen YH, Wu D, Ji Y, Ge NL, et al. Organ specific responses to first-line lenvatinib plus anti-PD-1 antibodies in patients with unresectable hepatocellular carcinoma: a retrospective analysis. Biomark Res. 2021; 9(1): 19.
- 87Zhu XD, Huang C, Shen YH, Ji Y, Ge NL, Qu XD, et al. Downstaging and resection of initially unresectable hepatocellular carcinoma with tyrosine kinase inhibitor and anti-PD-1 antibody combinations. Liver Cancer. 2021; 10: 320–9.
- 88Zhang W, Hu B, Han J, Wang Z, Ma G, Ye H, et al. Surgery after conversion therapy with PD-1 inhibitors plus tyrosine kinase inhibitors are effective and safe for advanced hepatocellular carcinoma: a pilot study of ten patients. Front Oncol. 2021; 11:747950.
- 89Kaseb AO, Vence L, Blando J, Yadav SS, Ikoma N, Pestana RC, et al. Immunologic correlates of pathologic complete response to preoperative immunotherapy in hepatocellular carcinoma. Cancer Immunol Res. 2019; 7(9): 1390–5.
- 90He M, Ming S, Lai Z, Li Q. A phase II trial of lenvatinib plus toripalimab and hepatic arterial infusion chemotherapy as a first-line treatment for advanced hepatocellular carcinoma (LTHAIC study). J Clin Oncol. 2021; 39(15 suppl):4083.
- 91Ho WJ, Zhu Q, Durham J, Popovic A, Xavier S, Leatherman J, et al. Neoadjuvant cabozantinib and nivolumab convert locally advanced hepatocellular carcinoma into resectable disease with enhanced antitumor immunity. Nat Cancer. 2021; 2: 891–903.
- 92Bruix J, Reig M, Sangro B. Assessment of treatment efficacy in hepatocellular carcinoma: response rate, delay in progression or none of them. J Hepatol. 2017; 66(6): 1114–7.
- 93Bruix J. Endpoints in clinical trials for liver cancer and their value in evidence-based clinical decision making: an unresolved Gordian knot. J Hepatol. 2021; 74(6): 1483–8.
- 94Finn RS, Ryoo BY, Merle P, Kudo M, Bouattour M, Lim HY, et al. Pembrolizumab as second-line therapy in patients with advanced hepatocellular carcinoma in KEYNOTE-240: a randomized, double-blind. Am Society Clin Oncol Meeting Proce. 2020; 38: 193–202.
- 95Thompson SM, Suman G, Torbenson MS, ZME C, Jondal DE, Patra A, et al. PSMA as a theranostic target in hepatocellular carcinoma: immunohistochemistry and (68) Ga-PSMA-11 PET using cyclotron-produced (68) Ga. Hepatol Commun. 2022; 6(5): 1172–85.
- 96Tran NH, Kisiel J, Roberts LR. Using cell-free DNA for HCC surveillance and prognosis. JHEP Rep. 2021; 3(4):100304.
- 97Yao FY, Fidelman N, Mehta N. The key role of staging definitions for assessment of downstaging for hepatocellular carcinoma. Semin Liver Dis. 2021; 41(2): 117–27.
- 98Kardashian A, Florman SS, Haydel B, Ruiz RM, Klintmalm GB, Lee DD, et al. Liver transplantation outcomes in a U.S. multicenter cohort of 789 patients with hepatocellular carcinoma presenting beyond milan criteria. Hepatology. 2020; 72: 2014–28.
- 99Murali AR, Romero-Marrero C, Miller C, Aucejo F, Levitin A, Gill A, et al. Predictors of successful downstaging of hepatocellular carcinoma outside milan criteria. Transplantation. 2016; 100: 2391–7.
- 100Londoño MC, Reig M, RETOINMUNO Multidisciplinary Group. Multidisciplinary clinical approach to cancer patients with immune-related adverse events induced by checkpoint inhibitors. Cancers (Basel). 2020; 12(11):3446.
- 101Champiat S, Ferrara R, Massard C, Besse B, Marabelle A, Soria JC, et al. Hyperprogressive disease: recognizing a novel pattern to improve patient management. Nat Rev Clin Oncol. 2018; 15: 748–62.
- 102Ally A, Balasundaram M, Carlsen R, Chuah E, Clarke A, Dhalla N, et al. Comprehensive and integrative genomic characterization of hepatocellular carcinoma. Cell. 2017; 169: 1327–41.e23.
- 103Monga SP. Β-catenin signaling and roles in liver homeostasis, injury, and tumorigenesis. Gastroenterology. 2015; 148(7): 1294–310.
- 104Pez F, Lopez A, Kim M, Wands JR, Caron de Fromentel C, Merle P. Wnt signaling and hepatocarcinogenesis: Molecular targets for the development of innovative anticancer drugs. J Hepatol. 2013; 59: 1107–17.
- 105Adebayo Michael AO, Ko S, Tao J, Moghe A, Yang H, Xu M, et al. Inhibiting glutamine-dependent mTORC1 activation ameliorates liver cancers driven by β-catenin mutations. Cell Metabolism. 2019; 29: 1135–50.e6.
- 106Ruiz de Galarreta M, Bresnahan E, Molina-Sánchez P, Lindblad KE, Maier B, Sia D, et al. β-catenin activation promotes immune escape and resistance to anti-PD-1 therapy in hepatocellular carcinoma. Cancer Discov. 2019; 9: 1124–41.
- 107Harding JJ, Nandakumar S, Armenia J, Khalil DN, Albano M, Ly M, et al. Prospective genotyping of hepatocellular carcinoma: clinical implications of next-generation sequencing for matching patients to targeted and immune therapies. Clin Cancer Res. 2019; 25: 2116–26.
- 108Rimola J, Da Fonseca LG, Sapena V, Perelló C, Guerrero A, Simó MT, et al. Radiological response to nivolumab in patients with hepatocellular carcinoma: a multicenter analysis of real-life practice. Eur J Radiol. 2021; 135:109484.
- 109Pfister D, Núñez NG, Pinyol R, Govaere O, Pinter M, Szydlowska M, et al. NASH limits anti-tumour surveillance in immunotherapy-treated HCC. Nature. 2021; 592: 450–6.
