LIVER TRANSPLANTATION 21:1117–1119, 2015

EDITORIAL

Downstaging: Looking for Answers, Generating More Questions? Laura Kulik and Riad Salem Department of Medicine, Northwestern University, Chicago, IL Received June 4, 2015; accepted June 28, 2015.

See Article on Page 1142 Downstaging of hepatocellular carcinoma (HCC) has become an important strategy to allow liver transplantation in patients outside Milan criteria. Downstaging attempts to redefine the “biological stage” of a tumor, beyond strict size and number, using response to liverdirected therapy (LDT), including tumor markers (alphafetoprotein [AFP] and/or des-gamma-carboxyprothrombin [DCP]) and durability of response for a specified period of time. The literature contains successful downstaging rates ranging from 24% to 90% with significant heterogeneity reflecting different criteria for downstaging protocols, type of LDT employed, 6 incorporation of biological markers, definition of successful downstaging (European Association for the Study of the Liver [EASL], Response Evaluation Criteria in Solid Tumors, modified Response Evaluation Criteria in Solid Tumors, and World Health Organization [WHO]), and predetermined time period of stability before listing.1 Parikh et al.2 performed a systematic review of downstaging to within the Milan criteria and posttransplant outcomes. The overall downstaging rate was 48%, which increased to 54% after excluding 2 studies with tumor thrombus. The overall HCC recurrence after orthotopic liver transplantation (OLT) was 16%. The authors found no significant difference in successful downstaging and postOLT recurrence comparing transarterial chemoembolization (TACE), to transarterial radioembolization with Yttrium 90 (Y90). Both prospective studies and multimodal therapy were associated with significantly higher

downstaging rates, compared to retrospective studies and TACE/Y90, respectively. There are several key points that warrant comment. Downstaging was a radiographic endpoint. Therefore, not all the patients included in this systematic review were necessarily considered OLT candidates. This may have had an impact on aggressiveness of the therapeutic approach as well as a willingness to perform OLT if hepatic decompensation complicated downstaging in contrast to patients treated with a palliative intent. Hence, this may have impacted results and limited the ability to determine important endpoints such as dropout rates and post-OLT outcomes. Baseline tumor burden is an important factor affecting the success of downstaging. The heterogeneity of reporting among the studies did not allow the authors to specifically examine tumor burden influence on ability to downstage, other than a subanalysis excluding those with portal vein involvement. The superior results noted among the 2 prospective trials included in the downstaging analysis were most likely related to a defined baseline tumor burden inclusion criteria and use of multimodal therapy. No differences in HCC recurrence rates were noted comparing retrospective and prospective studies (P 5 0.09), despite a defined waiting time of 3 months before listing after downstaging in 2 of the 3 prospective trials. The prospective trial with the highest recurrence rate, 30%, included 67% with stage IVa disease and defined >50% tumor reduction for OLT candidacy regardless of Milan downstaged.3 Additionally, in Ravaioli et al.,4 radiographic understaging was significantly higher among those downstaged compared to the non-downstaged group. Therefore, it is not clear if radiographic underestimation of tumor burden could

Abbreviations: AFP, alpha-fetoprotein; cTACE, conventional transarterial chemoembolization; DCP, des-gamma-carboxyprothrombin; DDLT, deceased donor liver transplantation, DEB, drug-eluting bead; EASL, European Association for the Study of the Liver; HCC, hepatocellular carcinoma; LDLT, living donor liver transplantation; LDT, liver-directed therapy; OLT, orthotopic liver transplantation; OS, overall survival; RCT, randomized controlled trials; TACE, transarterial chemoembolization; TARE, transarterial radioembolization; WHO, World Health Organization; Y90, Yttrium 90. Address reprint requests to Laura Kulik, M.D., Department of Medicine, Northwestern University, 675 North Saint Clair Street, Galter Pavilion 15, Chicago, IL 60611. Telephone: 312-695-6110; FAX: 312-695-0036; E-mail: [email protected] DOI 10.1002/lt.24209 View this article online at wileyonlinelibrary.com. LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases

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offer an explanation because pathologic tumor stage was not analyzed and should be included in reporting criteria for future downstaging studies. Absence of a significant difference in TACE versus transarterial radioembolization (TARE) in successful downstaging may be related to patient differences in each group and the limited number of patients treated with Y90, which represented 9.2% of the entire population, 7.5% after exclusion of portal vein thrombosis patients, a contraindication for OLT. There is also a potential bias against Y90 in that the largest of the 4 studies comprising the experience in downstaging used the strictest criteria for downstaging to Milan—WHO criteria, which measures the entire lesion as opposed to only the viable portion of the tumor.5 In this study, Y90 administration was significantly more likely to lead to successful downstaging compared to TACE, particularly in a solitary lesion exceeding 5 cm. Furthermore, radiographic endpoints favored Y90. The median time to achieve radiographic response (EASL/WHO) was shorter, and the time to progression was significantly longer in the Y90 group compared to TACE, which could translate into a lower dropout rate, especially if the designated time period of observation after initiation of downstaging therapy is longer. The retrospective nature of this study did not allow such an analysis. Lastly, in 1 of the 4 included trials, patients had either progressed after TACE or were determined to not be candidates for TACE, highlighting perceived differences of applicability of TACE versus Y90. Conventional TACE was used in most of the included trials with only 1 study using drug-eluting beads (DEBs).6 Higher necrosis rates on explant and improved 3-year posttransplant recurrencefree survival have been reported with DEB over conventional transarterial chemoembolization (cTACE).7 Although it is unlikely that a particular form of LDT changes the biology of the tumor and more probable that tumor biology dictates response to the selective pressure of a cytotoxic therapy, only well-designed prospective randomized trials comparing TACE (defining cTACE or DEBs) to Y90 will address biases to determine if the 2 therapies can be applied similarly and are indeed equivalent. If the transplant community accepts downstaging as a viable strategy, what should be the expected results after OLT: the benchmark of 50% overall survival (OS) at 5 years? An international consensus conference suggested that results should be equivalent to those meeting the Milan criteria without downstaging.8 Others have suggested a 5-year OS in those exceeding Milan should be at a minimum 61% in order to not disadvantage non-HCC patients on the waiting list by further increasing competition for organ access.9 The authors were unable to determine pooled data on post-OLT OS because of significant heterogeneity in the data. However, Yao et al.10 met this criteria (good survival) with a 5-year post-OLT OS of 78% among the downstaged patients which was not significantly different from those listed who met Milan (81%; P 5 0.69). Additionally, recurrence-free survival was also comparable between the 2 groups. These are essential endpoints that will require additional scrutiny

LIVER TRANSPLANTATION, September 2015

within prospective multicenter trials. This analysis focused on downstaging before OLT. Hepatic resection is another important curative option, which realistically may increase in the future as less toxic direct antiviral agents for hepatitis C virus lessen progression to overtly decompensated cirrhosis. Unlike the Milan criteria for OLT, there is no upper limit of tumor size for resection.11 However, tumor location/size as well as concern about an inadequate future liver remnant can render resection anatomically unfeasible. On the basis of randomized controlled trials (RCTs), TACE is not routinely recommended as a neo-adjuvant therapy before resection because of reported increased mortality and an estimated 10% dropout associated with a delay in surgery after TACE.12 There are no RCTs that have been performed to evaluate the role of LDT downstaging to resection. Retrospective data on radiation lobectomy have shown simultaneous treatment of the tumor and hypertrophy of the future remnant liver, occurring within 1 month after therapy, enabling resection in those who may have not been deemed candidates otherwise because of an inadequate liver remnant.13 Another area that will require additional research is downstaging before living donor liver transplantation (LDLT) specifically to “what” criteria because the availability of an organ is not dependent on a granted prioritization for meeting the Milan criteria as it is in deceased donor liver transplantation (DDLT). This study was predominantly composed of DDLT.2 Various criteria beyond the Milan criteria have been proposed and have reported excellent 5-year OS in LDLT.14 In addition to tumor biomarkers (AFP/DCP), markers of inflammation may provide insight into tumor biology beyond size or number. Serum neutrophil to lymphocyte ratio >4 has been reported to correlate with the presence of tumor-associated macrophages within the tumor microenvironment leading to higher post-OLT HCC recurrence.15 As pointed out by the authors, standard methods are desperately needed across studies to gather comparable data input to ultimately determine the role of downstaging in OLT.2 Future studies using standard methods will hopefully also lend insight into additional questions such as if there is an upper limit on the number of lesions without negatively impacting results and if progression with development of new lesions in those still within Milan criteria (based on exclusion of lesions with complete radiographic response) have similar outcomes to those without progression. Only with such data will clinicians be able to properly inform patients with HCC beyond the Milan criteria of the best option for potential cure.

REFERENCES 1. Toso C, Mentha G, Kneteman NM, Majno P. The place of downstaging for hepatocellular carcinoma. J Hepatol 2010;52:930-936. 2. Parikh ND, Waljee AK, Singal AG. Downstaging hepatocellular carcinoma: a systematic review and pooled analysis. Liver Transpl 2015;21:1142-1152. 3. Graziadei IW, Sandmueller H, Waldenberger P, Koenigsrainer A, Nachbaur K, Jaschke W, et al. Chemoembolization followed

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by liver transplantation for hepatocellular carcinoma impedes tumor progression while on the waiting list and leads to excellent outcome. Liver Transpl 2003;9:557-563. Ravaioli M, Grazi GL, Piscaglia F, Trevisani F, Cescon M, Ercolani G, et al. Liver transplantation for hepatocellular carcinoma: results of down-staging in patients initially outside the Milan selection criteria. Am J Transplant 2008;8:2547-2557. Lewandowski RJ, Kulik LM, Riaz A, Senthilnathan S, Mulcahy MF, Ryu RK, et al. A comparative analysis of transarterial downstaging for hepatocellular carcinoma: chemoembolization versus radioembolization. Am J Transplant 2009;9:1920-1928. Green TJ, Rochon PJ, Chang S, Ray CE Jr, Winston H, Ruef R, et al. Downstaging disease in patients with hepatocellular carcinoma outside of Milan criteria: strategies using drug-eluting bead chemoembolization. J Vasc Interv Radiol 2013;24:1613-1622. Nicolini D, Svegliati-Baroni G, Candelari R, Mincarelli C, Mandolesi A, Bearzi I, et al. Doxorubicin-eluting bead vs conventional transcatheter arterial chemoembolization for hepatocellular carcinoma before liver transplantation. World J Gastroenterol 2013;19:5622-5632. Clavien PA, Lesurtel M, Bossuyt PM, Gores GJ, Langer B, Perrier A; for OLT for HCC Consensus Group. Recommendations for liver transplantation for hepatocellular carcinoma: an international consensus conference report. Lancet Oncol 2012;13:e11-e22.

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9. Volk ML, Vijan S, Marrero JA. A novel model measuring the harm of transplanting hepatocellular carcinoma exceeding Milan criteria. Am J Transplant 2008;8:839-846. 10. 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. 11. Llovet JM, Fuster J, Bruix J. Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: resection versus transplantation. Hepatology 1999;30: 1434-1440. 12. Samuel M, Chow PK, Chan Shih-Yen E, Machin D, Soo KC. Neoadjuvant and adjuvant therapy for surgical resection of hepatocellular carcinoma. Cochrane Database Syst Rev 2009;21:CD001199. 13. Vouche M, Lewandowski RJ, Atassi R, Memon K, Gates VL, Ryu RK, et al. Radiation lobectomy: time-dependent analysis of future liver remnant volume in unresectable liver cancer as a bridge to resection. J Hepatol 2013;59: 1029-1036. 14. Chan SC, Fan ST. Selection of patients of hepatocellular carcinoma beyond the Milan criteria for liver transplantation. Hepatobiliary Surg Nutr 2013;2:84-88. 15. Motomura T, Shirabe K, Mano Y, Muto J, Toshima T, Umemoto Y, et al. Neutrophil-lymphocyte ratio reflects hepatocellular carcinoma recurrence after liver transplantation via inflammatory microenvironment. J Hepatol 2013;58:58-64.

Downstaging: Looking for answers, generating more questions?

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