Post liver transplant recurrence in patients with hepatocellular carcinoma: not necessarily the end of the road!

Abstract

Aim: We analysed outcomes using multimodality therapy in patients with hepatocellular carcinoma (HCC) recurrence post living donor liver transplantation (LDLT).

Methods: Of 2363 LDLT’s performed between 2005 to mid 2018, 435 (18.4%) were for HCC within our expanded selection criteria (absence of extrahepatic disease and vascular invasion, irrespective of tumor size and number). Survival after recurrence, and prognostic factors for these patients were studied.

Results: Of 435 LDLT patients, 51% had HCC beyond Milan and 43% beyond UCSF criteria at the time of LDLT. pre-LT AFP > 100 ng/mL and tumour FDG-18 PET avidity predicted overall survival (OS), whereas pre-LT AFP > 100 ng/mL, UCSF criteria, and FDG-18 PET avidity predicted recurrence-free survival. Hundred patients (23%) developed HCC recurrence at a median time of 16 months (range 2-108 months) post LDLT. Lungs (53%), liver (37%), and bone (21%) were the most common sites of recurrence. Ninety-five patients received tyrosine kinase inhibitors (TKI) after recurrence and 62 received mTOR inhibitors (protocol-based after LDLT, or post recurrence). Surgical resection of metastases was performed in 14 patients, 15 received stereotactic body radiotherapy, and 18 underwent ablation (radiofrequency, microwave ablation, transarterial chemoembolisation, or percutaneous ethanol injection). One- and 3-yr OS after recurrence were 57%, and 24% respectively, with a maximum post recurrence survival of 7.5 years. HCC recurrence within one year after LDLT (P = 0.004, HR = 2.38, 95%CI: 1.325-4.276), AFP > 200 ng/mL at the time of recurrence (P =0.02, HR = 2.075, 95%CI: 1.121-3.841), and recurrence at multiple sites (P = 0.047, HR = 1.831, 95%CI: 1.009-3.321) were poor prognostics factors for post recurrence survival. Multimodality management of recurrence using combined medical, surgical, ablative treatments and radiotherapy significantly improved survival compared to the use of TKI’s or mTORi’s alone, or in combination.

Conclusion: In patients accepted for LDLT beyond the conventional size-number criteria, even after HCC recurrence, an aggressive approach using multimodality therapy, when possible, aids in further prolongation of survival.

Keywords

Living donor liver transplantation / hepatocellular carcinoma recurrence / multimodality treatment / outcomes / prognostic factors

References

[1] European Association for the Study of the LiverCorrigendum to “EASL Clinical Practice Guidelines: management of hepatocellular carcinoma”..J Hepatol2018;69:182-236

[2] Mazzaferro V,Doci R,Pulvirenti A.Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis..N Engl J Med1996;334:693-9

[3] Yao FY,Bass NM,Ascher NL.Liver transplantation for hepatocellular carcinoma: validation of the UCSF expanded criteria based on pre-operative imaging..Am J Transpl2007;7:2587-96

[4] Herrero JI,Quiroga J,Herraiz M.Influence of tumor characteristics on the outcome of liver transplantation among patients with liver cirrhosis and hepatocellular carcinoma..Liver Transpl2001;7:631-6

[5] Duffy JP,Benjamin E,Farmer DG.Liver transplantation criteria for hepatocellular carcinoma should be expanded. A 22-year experience with 467 patients at UCLA..Ann Surg2007;246:502-11 PMCID:PMC1959350

[6] Mazzaferro V,Miceli R,Schiavo M.Predicting survival after liver transplantation in patients with hepatocellular carcinoma beyond the Milan criteria: a retrospective, exploratory analysis..Lancet Oncol2009;10:35-43

[7] D’Amico F,Vitale A,Roayaie S.Predicting recurrence after liver transplantation in patients with hepatocellular carcinoma exceeding the up-to-seven criteria..Liver Transpl2009;15:1278-87

[8] Sugawara Y,Makuuchi M.Living donor liver transplantation for hepatocellular carcinoma: Tokyo University series..Dig Dis2007;25:310-2

[9] Lee SG,Moon DB,Kim KH.Expanded indication criteria of living donor liver transplantation for hepatocellular carcinoma at one large-volume center..Liver Transpl2008;14:935-45

[10] Duvoux C,Decaens T,Badran H.Liver transplantation for hepatocellular carcinoma: a model including α-fetoprotein improves the performance of Milan criteria..Gastroenterology2012;143:986-94

[11] Kaido T,Mori A,Ito T.Usefulness of the Kyoto criteria as expanded selection criteria for liver transplantation for hepatocellular carcinoma..Surgery2013;154:1053-60

[12] Taketomi A,Soejima Y,Uchiyama H.Impact of des-gamma-carboxy prothrombin and tumor size on the recurrence of hepatocellular carcinoma after living donor liver transplantation..Transplantation2009;87:531-7

[13] Ito T,Ueda M,Maetani Y.Expansion of selection criteria for patients with hepatocellular carcinoma in living donor liver transplantation..Liver Transpl2007;13:1637-44

[14] Clavien PA,Bossuyt PM,Langer B.Recommendations for liver transplantation for hepatocellular carcinoma: an international consensus conference report..Lancet Oncol2012;13:e11-22 PMCID:PMC3417764

[15] Alshahrani AA,Hwang S,Kim KH.Clinical features and surveillance of very late hepatocellular carcinoma recurrence after liver transplantation..Ann Transplant2018;23:659-65 PMCID:PMC6255332

[16] Chok KS,Cheung TT,Fan ST.Late recurrence of hepatocellular carcinoma after liver transplantation..World J Surg2011;35:2058-62 PMCID:PMC3152711

[17] Foerster F,Vollmar J,Weinmann A.Long-term observation of hepatocellular carcinoma recurrence after liver transplantation at a European transplantation centre..United European Gastroenterol J2019;7:838-49 PMCID:PMC6620871

[18] Soin AS,Kataria T,Piplani T.Experience with LDLT in patients with hepatocellular carcinoma and portal vein tumor thrombosis postdownstaging..Transplantation2020;

[19] de’Angelis N,Carra MC.Managements of recurrent hepatocellular carcinoma after liver transplantation: a systematic review..World J Gastroenterol2015;21:11185-98 PMCID:PMC4607916

[20] Mazzaferro V,Zhou J,De Carlis L.Metroticket 2.0 model for analysis of competing risks of death after liver transplantation for hepatocellular carcinoma..Gastroenterology2018;154:128-39

[21] Liang W,Ling X,Ju W.Living donor liver transplantation versus deceased donor liver transplantation for hepatocellular carcinoma: a meta-analysis..Liver Transpl2012;18:1226-36

[22] Fernandez-Sevilla E,Selten J,Vibert E.Recurrence of hepatocellular carcinoma after liver transplantation: Is there a place for resection?.Liver Transpl2017;23:440-7

[23] Sapisochin G,Astete S,Davidson D.Benefit of treating hepatocellular carcinoma recurrence after liver transplantation and analysis of prognostic factors for survival in a large Euro-American series..Ann Surg Oncol2015;22:2286-94

[24] Kornberg A,Tannapfel A,Thrum K.Long-term survival after recurrent hepatocellular carcinoma in liver transplant patients: clinical patterns and outcome variables..Eur J Surg Oncol2010;36:275-80

[25] Valdivieso A,Gastaca M,Ventoso A.Management of hepatocellular carcinoma recurrence after liver transplantation..Transplant Proc2010;42:660-2

[26] Escartin A,Bilbao I,Bueno J.Recurrence of hepatocellular carcinoma after liver transplantation..Transplant Proc2007;39:2308-10

[27] Kim HR,Rha SY,Han KH.Treatment of recurrent hepatocellular carcinoma after liver transplantation..Asia Pac J Clin Oncol2011;7:258-69

[28] Wang Y,Washburn WK.Sirolimus plus sorafenib in treating HCC recurrence after liver transplantation: a case report..World J Gastroenterol2010;16:5518-22 PMCID:PMC2988248

[29] Bhoori S,Sposito C,Pellegrinelli A.Personalized molecular targeted therapy in advanced, recurrent hepatocellular carcinoma after liver transplantation: a proof of principle..J Hepatol2010;52:771-75

[30] Gomez-Martin C,Castroagudin JF,Garralda E.Efficacy and safety of sorafenib in combination with mammalian target of rapamycin inhibitors for recurrent hepatocellular carcinoma after liver transplantation..Liver Transpl2012;18:45-52

[31] Sposito C,Germini A,Bongini M.Comparative efficacy of sorafenib versus best supportive care in recurrent hepatocellular carcinoma after liver transplantation: a case-control study..J Hepatol2013;59:59-66

[32] Weinmann A,Koch S,Heise M.Sorafenib for recurrence of hepatocellular carcinoma after liver transplantation..Dig Liver Dis2012;44:432-37

[33] Yoon DH,Ryu MH,Hwang S.Sorafenib for recurrent hepatocellular carcinoma after liver transplantation..Jpn J Clin Oncol2010;40:768-73

[34] Geissler EK,Zülke C,Proneth A.Sirolimus use in liver transplant recipients with hepatocellular carcinoma: a randomized, multicenter, open- label phase 3 trial..Transplantation2016;100:116-25 PMCID:PMC4683033

[35] Zhang ZH,Li P,Pan B.Sirolimus in liver transplant recipients with hepatocellular carcinoma: an updated meta-analysis..J Invest Surg2019;32:632-41

[36] Jeng LB,Soin AS,Suh KS.Efficacy and safety of everolimus with reduced tacrolimus in living-donor liver transplant recipients: 12-month results of a randomized multicenter study..Am J Transplant2018;18:1435-46

[37] Cholongitas E,Rodríguez-Castro KI.Mammalian target of rapamycin inhibitors are associated with lower rates of hepatocellular carcinoma recurrence after liver transplantation: a systematic review..Transpl Int2014;27:1039-49

[38] Vivarelli M,Zanello M,Cescon M.Effect of different immunosuppressive schedules on recurrence-free survival after liver transplantation for hepatocellular carcinoma..Transplantation2010;89:227-31

[39] Zhou J,Wu ZQ,Yu Y.Sirolimus-based immunosuppression therapy in liver transplantation for patients with hepatocellular carcinoma exceeding the Milan criteria..Transplant Proc2008;40:3548-53

[40] Iavarone M,Czauderna C,Bhoori S.Preliminary experience on safety of regorafenib after sorafenib failure in recurrent hepatocellular carcinoma after liver transplantation..Am J Transplant2019;19:3176-84

[41] Kittai AS,Cetnar J.Immune checkpoint inhibitors in organ transplant patients..J Immunother2017;40:277-81

[42] Roayaie S,Sung MW,Miller C.Recurrence of hepatocellular carcinoma after liver transplant: patterns and prognosis..Liver Transpl2004;10:534-40

[43] Regalia E,Valente U,Damilano I.Pattern and management of recurrent hepatocellular carcinoma after liver transplantation..J Hepatobiliary Pancreat Surg1998;5:29-34

[44] Bodzin AS,Markovic D,Busuttil RW.Predicting mortality in patients developing recurrent hepatocellular carcinoma after liver transplantation: impact of treatment modality and recurrence characteristics..Ann Surg2017;266:118-25

[45] Invenizzi F,Donato MF,Torre M.Pulmonary resection for metastasis of hepatocellular carcinoma recurring after liver transplant: an Italian multicenter experience..Front Oncol2020;10:381 PMCID:PMC7175841

[46] Tomimaru Y,Yamada T,Takami K.The significance of surgical resection for pulmonary metastasis from hepatocellular carcinoma..Am J Surg2006;192:46-51

[47] Bates MJ,Taylor D.Pulmonary resection of metastatic hepatocellular carcinoma after liver transplantation..Ann Thorac Surg2008;85:412-5

[48] Hwang S,Kim DK,Moon DB.Resection of pulmonary metastases from hepatocellular carcinoma following liver transplantation..World J Surg2012;36:1592-602

[49] Nakajima J,Matsumoto J,Fukami T.Appraisal of surgical treatment for pulmonary metastasis from hepatocellular carcinoma..World J Surg2005;29:715-8

[50] Poon RT,O’Suilleabhain CB.Aggressive management of patients with extrahepatic and intrahepatic recurrences of hepatocellular carcinoma by combined resection and locoregional therapy..J Am Coll Surg2002;195:311-8

[51] O’Suilleabhain CB,Lau CW.Repeated resections of extrahepatic metastases after hepatic resection: an aggressive approach to hepatocellular carcinoma..Hepatogastroenterology2004;51:825-9

[52] Gwak GY,Sung SW.Long-term survival after pulmonary metastatectomy of hepatocellular carcinoma; treatment outcome or natural history?.Hepatogastroenterology2004;51:1428-33

[53] Han KN,Yoon JH,Song JY.Role of surgical resection for pulmonary metastasis of hepatocellular carcinoma..Lung Cancer2010;70:295-300

[54] Aoki M,Kawaguchi H,Sato M.Stereotactic body radiotherapy for lung metastases as oligo-recurrence: a single institutional study..J Radiat Res2016;57:55-61 PMCID:PMC4708917

[55] Zhai H,Yu XL,Han ZY.Microwave ablation in treating intrahepatic recurrence of hepatocellular carcinoma after liver transplantation: an analysis of 11 cases..Int J Hyperthermia2015;31:863-8

[56] Ko HK,Yoon HK.Tumor response to transcatheter arterial chemoembolization in recurrent hepatocellular carcinoma after living donor liver transplantation..Korean J Radiol2007;8:320-7 PMCID:PMC2627154

[57] Rivera L,Miller W,Hillebrand DJ.Hepatic intra-arterial infusion of yttrium-90 microspheres in the treatment of recurrent hepatocellular carcinoma after liver transplantation: a case report..World J Gastroenterol2006;12:5729-32 PMCID:PMC4088179

[58] Huang J,Wu H,Liao M.Is radiofrequency ablation applicable for recurrent hepatocellular carcinoma after liver transplantation?.J Surg Res2016;200:122-30

[59] Zhou B,Zhu KS,Guan SH.Chemoembolization with lobaplatin mixed with iodized oil for unresectable recurrent hepatocellular carcinoma after orthotopic liver transplantation..J Vasc Interv Radiol2010;21:333-8

[60] Toso C,Majno P.Integrating sorafenib into an algorithm for the management of post-transplant hepatocellular carcinoma recurrence..J Hepatol2013;59:3-5

[61] Sanuki N,Kunieda E.Role of stereotactic body radiation therapy for hepatocellular carcinoma..World J Gastroenterol2014;20:3100-11 PMCID:PMC3964382

[62] Sharabi AB,Kochel CM,Francica BJ.Stereotactic radiation therapy augments antigen-Specific PD-1-mediated antitumor immune responses via cross-presentation of tumor antigen..Cancer Immunol Res2015;3:345-55 PMCID:PMC4390444

[63] Parker JJ,Strober S.Characterization of direct radiation-induced immune function and molecular signalling changes in an antigen presenting cell line..Clin Immunol2013;148:44-55 PMCID:PMC4045494

[64] Gupta A,Vuong V,Muth S.Radiotherapy promotes tumor-specific effector CD8+ T cells via dendritic cell activation..J Immunol2012;189:558-66

[65] Pfiffer TEF,Nicolaou A,Riess H.Recurrent hepatocellular carcinoma in liver transplant recipients: parameters affecting time to recurrence, treatment options and survival in the sorafenib era..Tumori2011;97:436-41

[66] Roh YN,Song S,Man Kim J.The prognosis and treatment outcomes of patients with recurrent hepatocellular carcinoma after liver transplantation..Clin Transplant2014;28:141-8

[67] Guerrini GP,Tarantino G,Pecchi A.Multimodal oncological approach in patients affected by recurrent hepatocellular carcinoma after liver transplantation..Eur Rev Med Pharmacol Sci2017;21:3421-35