EDITORIAL Living Donor Transplantation for : To Expand (Beyond Milan) or Downstage (to Milan)? group report their longterm results up to 10 years fol- SEE ARTICLE ON PAGE 369 lowing LDLT for HCC beyond Milan criteria in a prospectively applied protocol.(6) The study cohort met For patients with hepatocellular carcinoma (HCC) the proposed BCLC extended criteria (1 tumor > 5cm exceeding the Milan criteria, survival after liver trans- but  7 cm, 2-3 tumors at least 1 tumor > 3cm plantation (LT) incrementally decreases with increas- but  5 cm, or 4-5 tumors  3 cm) and other protocol (1) ing tumor size and number. The allocation system eligibility requirements including Eastern Cooperative for deceased donors in the United States is largely Oncology Group performance status 0 and Child- restricted to HCC within Milan criteria and does not Pugh class A/B. Out of 22 patients enrolled between accommodate to even modest expansion of tumor 2001 and 2014, 5 were successfully downstaged with (2) size. Wait-list dropout rates remain substantial even local-regional therapy (LRT) from beyond BCLC for HCC within Milan criteria in long wait-time extended criteria to within Milan criteria. A total of 12 (3) regions. Living donor (LDLT) of the 22 patients received LRT, in whom 10 were has been performed for patients with HCC beyond downstaged to within Milan criteria prior to LDLT. Milan criteria adhering to the principle that the risk to This study was therefore composed of a heterogeneous the donor is justified by the expectation of an accept- group of patients who underwent LDLT either with (4) able outcome for the recipient (double equipoise). extended criteria or after tumor downstaging—2 dif- However, the boundaries of tumor size and number to ferent approaches that should be considered separately. be considered for LDLT have varied widely among Explant tumor stage exceeded BCLC extended cri- centers without a consensus based on reproducible teria in 50% (understaged) and within Milan criteria in (5) data. Furthermore, the minimal acceptable survival 18% (downstaged). Poorly differentiated tumor grade threshold after LDLT has not been well defined. and microvascular invasion were observed in 23% and In this issue of Liver Transplantation, Llovet et al. 46%, respectively. Despite the frequency of unfavorable from the Barcelona Clinic (BCLC) histopathologic characteristics, 5- and 10-year survival rates after LDLT were excellent at 80% and 67%, Abbreviations: AFP, alpha-fetoprotein; BCLC, Barcelona Clinic respectively. The cumulative probability of HCC Liver Cancer; DCP, des-gamma-carboxyprothrombin; HCC, hepato- recurrence was 24% and 44% at 5 and 10 years, respec- cellular carcinoma; LDLT, living donor liver transplantation; LRT, tively. In all but 1 case, HCC recurrence occurred local-regional therapy; LT, liver transplantation. beyond 4 years after LDLT. The reason for the sur- Address reprint requests to Neil Mehta, M.D., Division of Gastroen- prising predominance of late HCC recurrence is terology, Department of Medicine, University of California, San Francisco, 513 Parnassus Avenue, Room S-357, San Francisco, CA unknown. All 7 (32%) patients with HCC recurrence 94143-0538. Telephone: 415-476-2777; FAX: 415-476-0659; had recurrent hepatitis C after LDLT, including 5 E-mail: [email protected] with graft . Some of these cases might there- Received January 16, 2018; accepted January 16, 2018. fore represent de novo HCC development in a graft

Copyright VC 2018 by the American Association for the Study of Liver with advanced fibrosis rather than recurrent tumor. Diseases. An intriguing question raised in the BCLC study is

View this article online at wileyonlinelibrary.com. whether downstaging is preferable to expansion of criteria in LDLT. The proposed BCLC extended cri- DOI 10.1002/lt.25017 teria are very similar to the University of California, Potential conflict of interest: Nothing to report. San Francisco downstaging criteria, which also include an upper limit in the total tumor diameter EDITORIAL | 327 MEHTA AND YAO LIVER TRANSPLANTATION, March 2018

(1 tumor > 5 cm but  8 cm, 2-3 tumors at least 1 receiving a cadaveric graft. The small number of tumor > 3 cm but  5 cm with total tumor diameter patients represents a major limitation, and the results 8 cm, or 4-5 tumors  3 cm and total tumor diameter therefore require confirmation in a larger cohort. This 8cm).(7) The 10 patients in the BCLC study who study also suggests superior outcome with achieved downstaging to within Milan criteria by pre- downstaging to Milan that may prove to be the pre- operative radiographic assessment had a significantly ferred approach over expanded criteria for LDLT. A better 5- and 10-year survival of 90% when compared large, prospective multicenter study applying uniform with that in the other 12 patients who did not receive expanded criteria with and without downstaging and LRT or did not achieve downstaging (70% and 52%, incorporating biomarkers of tumor aggressiveness in respectively). These observations thus provide further candidate selection will take us 1 step closer to devel- (7) support of downstaging as a selection tool, but the oping a consensus approach to LDLT for HCC. small sample size precludes drawing firm conclusions. When compared with the proposed BCLC Neil Mehta, M.D. extended criteria, more liberal upper limits in tumor Francis Y. Yao, M.D. size and number for LDLT have been advocated by Division of Gastroenterology (5) other groups predominantly from Asia. Some of Department of Medicine these proposed criteria have incorporated additional University of California, San Francisco assessments of tumor aggressiveness (histology or bio- San Francisco, CA markers) beyond tumor size and number in candidate selection. Alpha-fetoprotein (AFP) is a well- established biomarker for discriminating prognosis REFERENCES (1,8,9) after LT for HCC. An AFP > 1000 ng/mL is 1) Mazzaferro V, Sposito C, Zhou J, Pinna AD, De Carlis L, Fan associated with particularly poor post-LT outcomes J, et al. Metroticket 2.0 model for analysis of competing risks of and has been implemented as an exclusion criterion in death after liver transplantation for hepatocellular carcinoma. Gastroenterology 2018;154:128-139. the priority system of organ allocation in the United 2) Yao FY, Ferrell L, Bass NM, Watson JJ, Bacchetti P, Venook States (unless AFP decreases to <500 ng/mL with A, et al. Liver transplantation for hepatocellular carcinoma: LRT).(9) None of the patients in the BCLC study had expansion of the tumor size limits does not adversely impact sur- AFP > 1000 ng/mL and only 1 had an AFP > 100 ng/ vival. Hepatology 2001;33:1394-1403. (10) 3) Mehta N, Heimbach J, Lee D, Dodge JL, Harnois D, Burns J, mL before LDLT. The extended Toronto criteria et al. Wait time of less than 6 and greater than 18 months pre- pose no restrictions in tumor size and number but dicts hepatocellular carcinoma recurrence after liver transplanta- require biopsy of the largest tumor to exclude poorly tion: proposing a wait time “sweet spot.” Transplantation 2017; 101:2071-2078. differentiated tumor grade. With this approach, the 5- 4) Pomfret EA, Lodge JP, Villamil FG, Siegler M. Should we use year post-LT survival of 69% was similar to that for living donor grafts for patients with hepatocellular carcinoma? ethi- HCC within Milan criteria.(10) The National Cancer cal considerations. Liver Transpl 2011;17(suppl 2):S128-S132. 5) Sapisochin G, Bruix J. Liver transplantation for hepatocellular Center Korea criteria include total tumor diameter carcinoma: outcomes and novel surgical approaches. Nat Rev 18 <10 cm and negative [ F]fludeoxyglucose positron Gastroenterol Hepatol 2017;14:203-217. emission tomography. In LDLT recipients meeting 6) Llovet JM, Pavel M, Rimola J, Diaz MA, Colmenero J, Saavedra-Perez D, et al. Pilot study of living donor liver trans- these criteria preoperatively, the 5-year survival was plantation for patients with hepatocellular carcinoma exceeding (11) 84% versus 54% in those exceeding these criteria. Milan criteria (Barcelona Clinic Liver Cancer extended criteria). Des-gamma-carboxyprothrombin (DCP) has been Liver Transpl 2018; doi: 10.1002/lt.24977. < 7) Yao FY, Mehta N, Flemming J, Dodge J, Hameed B, Fix O, incorporated into the Kyoto criteria. Those with 10 et al. Downstaging of hepatocellular cancer before liver trans- tumors, largest tumor <5 cm, and DCP of <400 plant: long-term outcome compared to tumors within Milan cri- mAU/mL had a 5-year survival of 88% after LDLT, teria. Hepatology 2015;61:1968-1977. versus only 42% in those exceeding these criteria.(12) 8) Duvoux C, Roudot-Thoraval F, Decaens T, Pessione F, Badran H, Piardi T, et al.; for Liver Transplantation French Study Although these liberal criteria have produced surpris- Group. Liver transplantation for hepatocellular carcinoma: a ingly good 5-year survival after LDLT, they require model including alpha-fetoprotein improves the performance of independent validation. Milan criteria. Gastroenterology 2012;143:986-994. 9) Hameed B, Mehta N, Sapisochin G, Roberts JP, Yao FY. In summary, the results of this pilot study by the Alpha-fetoprotein level > 1000 ng/mL as an exclusion criterion (6) BCLC group highlight a cautious approach to for liver transplantation in patients with hepatocellular carcinoma expanding HCC indications for LDLT, with 5- and meeting the Milan criteria. Liver Transpl 2014;20:945-951. 10-year survival rates comparable to that in patients

328 | EDITORIAL LIVER TRANSPLANTATION, Vol. 24, No. 3, 2018 MEHTA AND YAO

10) Sapisochin G, Goldaracena N, Laurence JM, Dib M, Barbas A, computed tomography for living donor liver transplantation in Ghanekar A, et al. The extended Toronto criteria for liver trans- patients with hepatocellular carcinoma: the National Cancer Cen- plantation in patients with hepatocellular carcinoma: a prospec- ter Korea criteria. World J Transplant 2016;6:411-422. tive validation study. Hepatology 2016;64:2077-2088. 12) Kaido T, Ogawa K, Mori A, Fujimoto Y, Ito T, Tomiyama K, 11) Lee SD, Lee B, Kim SH, Joo J, Kim SK, Kim YK, Park SJ. et al. Usefulness of the Kyoto criteria as expanded selection crite- Proposal of new expanded selection criteria using total tumor size ria for liver transplantation for hepatocellular carcinoma. Surgery and (18)F-fluorodeoxyglucose - positron emission tomography/ 2013;154:1053-1060.

EDITORIAL | 329