J Liver Cancer.  2024 Sep;24(2):171-177. 10.17998/jlc.2024.08.30.

Multidisciplinary approaches to downstaging hepatocellular carcinoma: present and future

• Hwang SY
• Choi H
• Jeon W
• Kim RG

• KMID: 2559464
• DOI: http://doi.org/10.17998/jlc.2024.08.30

Abstract

Downstaging of hepatocellular carcinoma (HCC) is typically defined as the reduction in size or number of viable tumors through locoregional therapy (LRT), aiming to meet the established criteria for liver transplantation (LT). According to the Barcelona Clinic Liver Cancer (BCLC) staging system, a subgroup of patients with BCLC-B may benefit most from downstaging therapies. The United Network Organ Sharing downstaging protocol identifies potential candidates for downstaging by setting out ‘inclusion criteria’ and defining ‘successful downstaging.’ Additionally, the protocol considers factors related to tumor biology, such as an alphafetoprotein level <500 ng/mL after LRT. Reports indicate that successful downstaging rates following LRT are about 50%, with post- LT recurrence rates comparable to those of patients within the Milan criteria. A comprehensive multicenter US study on 10-year outcomes post-LT after downstaging showed 10-year post-LT survival and recurrence rates of 52.1% and 20.6%, respectively, for patients whose disease was downstaged; this compares to 61.5% and 13.3% for those consistently within the Milan criteria. Recently, the development of effective systemic treatments for HCC, such as immuno-oncologic agents, has provided additional opportunities for downstaging. Numerous clinical trials are exploring a multidisciplinary approach (MDA) combining LRT and systemic therapy. Although concrete evidence of the superiority of MDA for HCC downstaging is lacking, some retrospective studies and phase I and II trials have shown promising results regarding the efficacy and safety of MDA for this purpose. In this review, we will also discuss the future of MDA protocols in downstaging for improved clinical outcomes.

Keyword

Carcinoma, hepatocellular; Multidisciplinary approach; Downstaging; Immunotherapy

Figure

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  Figure 1. Treatment algorithm for patients with intermediate stage of hepatocellular carcinoma. BCLC, Barcelona Clinic Liver Cancer; LT, liver transplantation; AFP, alpha fetoprotein; TACE, trans-arterial chemoemolization.

Reference

References

1. Villanueva A. Hepatocellular carcinoma. N Engl J Med. 2019; 380:1450–1462.

2. Su GL, Altayar O, O’Shea R, Shah R, Estfan B, Wenzell C, et al. AGA clinical practice guideline on systemic therapy for hepatocellular carcinoma. Gastroenterology. 2022; 162:920–934.

3. Reig 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; 76:681–693.

4. Matevish L, Patel MS, Vagefi PA. Downstaging techniques for hepatocellular carcinoma in candidates awaiting liver transplantation. Surg Clin North Am. 2024; 104:145–162.

5. Finn 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; 382:1894–1905.

6. Abou-Alfa GK, Lau G, Kudo M, Chan SL, Kelley RK, Furuse J, et al. Tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. NEJM Evid. 2022; 1:EVIDoa2100070.

7. Ivanics T, Claasen MPAW, Samstein B, Emond JC, Fox AN, Pomfret E, et al. living donor liver transplantation for hepatocellular carcinoma within and outside traditional selection criteria: a multicentric North American experience. Ann Surg. 2024; 279:104–111.

8. Yao 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; 61:1968–1977.

9. Mehta N, Dodge JL, Grab JD, Yao FY. National experience on downstaging of hepatocellular carcinoma before liver transplant: influence of tumor burden, alpha-fetoprotein, and wait time. Hepatology. 2020; 71:943–954.

10. Tabrizian P, Holzner ML, Mehta N, Halazun K, Agopian VG, Yao F, et al. Ten-year outcomes of liver transplant and downstaging for hepatocellular carcinoma. JAMA Surg. 2022; 157:779–788.

11. Mehta 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; 16:955–964.

12. Mazzaferro V, Citterio D, Bhoori S, Bongini M, Miceli R, De Carlis L, et al. Liver transplantation in hepatocellular carcinoma after tumour downstaging (XXL): a randomised, controlled, phase 2b/3 trial. Lancet Oncol. 2020; 21:947–956.

13. Tan DJH, Lim WH, Yong JN, Ng CH, Muthiah MD, Tan EX, et al. UNOS down-staging criteria for liver transplantation of hepatocellular carcinoma: systematic review and meta-analysis of 25 studies. Clin Gastroenterol Hepatol. 2023; 21:1475–1484.

14. Mehta 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; 161:1502–1512.

15. Natarajan B, Tabrizian P, Hoteit M, Frenette C, Parikh N, Ghaziani T, et al. Downstaging hepatocellular carcinoma before liver transplantation: a multicenter analysis of the “all-comers” protocol in the multicenter evaluation of reduction in tumor size before liver transplantation (MERITS-LT) consortium. Am J Transplant. 2023; 23:1771–1780.

16. Yu J, Zhuang L, Liu P, Liu Z, Ling S, Deng Y, et al. Long-term outcomes of deceased donor liver transplantation in hepatocellular carcinoma patients with portal vein tumor thrombus: a multicenter study. Eur J Surg Oncol. 2022; 48:121–132.

17. Soin AS, Bhangui P, Kataria T, Baijal SS, Piplani T, Gautam D, et al. Experience with LDLT in patients with hepatocellular carcinoma and portal vein tumor thrombosis postdownstaging. Transplantation. 2020; 104:2334–2345.

18. Serenari M, Cappelli A, Cucchetti A, Mosconi C, Strigari L, Monari F, et al. Deceased donor liver transplantation after radioembolization for hepatocellular carcinoma and portal vein tumoral thrombosis: a pilot study. Liver Transpl. 2021; 27:1758–1766.

19. El Dahan KS, Reczek A, Daher D, Rich NE, Yang JD, Hsiehchen D, et al. Multidisciplinary care for patients with HCC: a systematic review and meta-analysis. Hepatol Commun. 2023; 7:e0143.

20. Sinn DH, Choi GS, Park HC, Kim JM, Kim H, Song KD, et al. Multidisciplinary approach is associated with improved survival of hepatocellular carcinoma patients. PLoS One. 2019; 14:e0210730.

21. Kim DH. Combination of interventional oncology local therapies and immunotherapy for the treatment of hepatocellular carcinoma. J Liver Cancer. 2022; 22:93–102.

22. Kudo M, Aoki T, Ueshima K, Tsuchiya K, Morita M, Chishina H, et al. Achievement of complete response and drug-free status by atezolizumab plus bevacizumab combined with or without curative conversion in patients with transarterial chemoembolization-unsuitable, intermediate-stage hepatocellular carcinoma: a multicenter proof-of-concept study. Liver Cancer. 2023; 12:321–338.

23. Ding M, Wang Y, Chi J, Wang T, Tang X, Cui D, et al. Is adjuvant cellular immunotherapy essential after TACE-predominant minimally-invasive treatment for hepatocellular carcinoma? A systematic meta-analysis of studies including 1774 patients. PLoS One. 2016; 11:e0168798.

24. Yeo YH, Liang J, Lauzon M, Luu M, Noureddin M, Ayoub W, et al. Immunotherapy and transarterial radioembolization combination treatment for advanced hepatocellular carcinoma. Am J Gastroenterol. 2023; 118:2201–2211.

25. Tai D, Loke K, Gogna A, Kaya NA, Tan SH, Hennedige T, et al. Radioembolisation with Y90-resin microspheres followed by nivolumab for advanced hepatocellular carcinoma (CA 209-678): a single arm, single centre, phase 2 trial. Lancet Gastroenterol Hepatol. 2021; 6:1025–1035.

26. Lee YB, Nam JY, Cho EJ, Lee JH, Yu SJ, Kim HC, et al. A phase I/IIa trial of yttrium-90 radioembolization in combination with durvalumab for locally advanced unresectable hepatocellular carcinoma. Clin Cancer Res. 2023; 29:3650–3658.

27. Hwang SY, Woo HY, Heo J, Kim HJ, Park YJ, Yi KY, et al. Outcome of atezolizumab plus bevacizumab combination therapy in high-risk patients with advanced hepatocellular carcinoma. Cancers (Basel). 2024; 16:838.

28. Chiang CL, Chiu KWH, Chan KSK, Lee FAS, Li JCB, Wan CWS, et al. Sequential transarterial chemoembolisation and stereotactic body radiotherapy followed by immunotherapy as conversion therapy for patients with locally advanced, unresectable hepatocellular carcinoma (START-FIT): a single-arm, phase 2 trial. Lancet Gastroenterol Hepatol. 2023; 8:169–178.

29. Wang T, Chen Z, Liu Y, Jia Y, Ju W, Chen M, et al. Neoadjuvant programmed cell death 1 inhibitor before liver transplantation for HCC is not associated with increased graft loss. Liver Transpl. 2023; 29:598–606.

30. Rezaee-Zavareh MS, Yeo YH, Wang T, Guo Z, Tabrizian P, Ward SC, et al. Impact of pre-transplant immune checkpoint inhibitor use on post-transplant outcomes in HCC: a systematic review and individual patient data meta-analysis. J Hepatol. 2024; Jul. 10. doi: 10.1016/j.jhep.2024.06.042 [Epub ahead of print].