Supplementary webappendix

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1 Supplementary webappendix This webappendix formed part of the original submission and has been peer reviewed. We post it as supplied by the authors. Supplement to: Clavien P-A, Lesurtel M, Bossuyt PMM, et al, on behalf of the OLT for HCC Consensus Group. Recommendations for liver transplantation for hepatocellular carcinoma: an international consensus conference report. Lancet Oncol 2011; published online Nov 1. DOI: /S (11)

2 Recommendations for Liver Transplantation for HCC: an International Consensus Conference Report WEBAPPENDIX Expert panels: M. Abecassis, USA, C. Balabaud, France, S. Bhoori, Italy, S. Breitenstein, Switzerland, C. Broelsch, Germany, P. Burra, Italy, D. Cherqui, France, M. Colombo, Italy, C. d'albuquerque, Brazil, A. D'Alessandro, USA, E. de Santibanes, Argentina, JF. Dufour, Switzerland, F. Durand, France, P. Dutkowski, Switzerland, H. El-Serag, USA, ST. Fan, Hong Kong, R. Fisher, USA, A. Forner, Spain, J. Fung, USA, A. Geier, Switzerland, G. Germani, UK, ASH. Gouw, the Netherlands, K. Gurusamy, UK, N. Heaton, UK, M. Heim, Switzerland, A. Hemming, USA, S. Hubscher, UK, T. Ichida, Japan, D. Kahn, South Africa, M. Kew, South Africa, Y. Kita, Japan, T. Kiuchi, Japan, M. Kudo, Japan, SG. Lee, Korea, R. Lencioni, Italy, T. Livraghi, Italy, P. Lodge, UK, G. McCaughan, Australia, D. Madoff, USA, J. Marrero, USA, H. Mergental, UK, P. Merle, France, R. Miksad, USA, F. Mornex, France, V. Paradis, France, B. Pestalozzi, Switzerland, R. Poon, Hong Kong, R. Porte, the Netherlands, KR. Prasad, UK, T. Roskams, Belgium, M. Rossi, Italy, H. Schlitt, Germany, A. Shaked, USA, M. Sherman, Canada, M. Siegler, USA, K. Suh, South Korea, S. Todo, Japan, C. Toso, Switzerland, F. Trevisani, Italy, JCG. Valdecasas, Spain, JN. Vauthey, USA, V. Vilgrain, France, F. Villamil, Argentina, C. Wald, USA, A. Weber, Switzerland, R. Wiesner, USA, L. Wright, Canada, S. Zheng, China, J. Zucman-Rossi, France. Local organising committee (Zurich, Switzerland): V. Bertschi, P.A. Clavien, M. Meyer, B. Müllhaupt, A. Munson, M. Lesurtel, D. Raptis and R. Vonlanthen. Writing committee selected by the organizing committee: A. Perrier, Switzerland, B. Langer, Canada, P. Bossuyt, The Netherlands, G Gores, USA, M. Lesurtel, Switzerland, PA Clavien, Switzerland, FULL SEARCH CRITERIA OF THE LITERATURE FROM THE 19 WORKING GROUPS Group 1: What is the goal that LT should achieve? (Samuel et al.) An English language literature review was performed including PubMed, Embase databases and the Cochrane central register of controlled trials. The search was limited to the period from January 1985 to December Text, keywords and medical subject heading terms were used for titles and abstracts. Manual cross-referencing was also used to find further relevant articles. Search terms included: hepatocellular carcinoma, liver cancer, cirrhosis complications, liver transplantation, liver resection, hepatectomy, MELD allocation system. Group 2: Is a tumor biopsy necessary? (Müllhaupt et al.) To answer these questions an electronic search was carried out by an information specialist who included MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials (CENTRAL) into the search algorythm. The search was limited to the period between January 1995 and February 2010, mainly to take into considerations that the quality of the imaging procedures has dramatically changed of the last few decades. The detailed search strategy is available from the authors. The reference list of included articles and reviews were also scrutinized for relevant articles and if appropriate studies were identified, they were manually added to the electronic search results Group 3: What is the best staging system of HCC? (Olthoff et al.) Electronic searches of Medline and Pubmed were performed using specific relevant keywords (hepatocellular carcinoma, staging system, liver transplantation) and articles were retrieved and reviewed. The authors critically reviewed all original descriptions of the various HCC staging systems and recent literature on comparison of 1

3 various HCC staging systems, including reviews and papers describing single center and multicenter analyses, and summary reports from recent consensus conferences and societies. Group 4: What is the optimal imaging modality to stage HCC? (Lee et al.) A systematic review of the relevant literature and synthesis of available evidence with later phases of peer group appraisal and the expert review was performed. The consensus statements consist of recommendations and scientific comments based on comprehensive review of the literature on each topic. The quality of existing evidence and strength of recommendations were ranked from 1 (highest) to 5 (lowest) and from A (strongest) to D (weakest), respectively according to the Oxford system of evidence-based approach for developing the consensus statements. Group 5: Milan criteria, where are we? (Mazzaferro et al.) An English language literature review was performed using the search terms outlined below. The following PubMed, Embase and Scopus-based search strategy, combining text, keywords and MESH terms was used for the title and abstract of medical subject headings. Manual cross-referencing was also used to find further relevant articles. This part of the search strategy was not restricted by date. Search Terms used in various combinations were: Milan Criteria, Primary Liver Cancer, Primary Liver Tumor, Hepatoma, Hepatocellular Carcinoma, HCC, BCLC A, T1-T2, Tumor Size, Tumor Number, Tumor Burden, Metastatic Disease and Metastases of HCC, Transplantation, Liver Transplantation, Liver Substitution, Orthotopic Liver Transplantation, OLT, LT, Living Donor Liver Transplantation, Deceased Donor Liver Transplantation, Survival, Overall Survival, Recurrence Free Survival, RFS, Disease Free Survival, DFS, Prognosis, Death, Recurrence, Tumor Relapse, Time To Recurrence, Time To Relapse and TTR. Due to the large quantity of reports including the use of Milan Criteria in the setting of management of HCC, case-studies and reviews not focused specifically on MC were not considered Group 6: What matters: number of tumor, size of larger tumor, total volume of tumor? (Burroughs et al.) MEDLINE, Cochrane Controlled trial Register (CENTRAL), EMBASE and Science Citation Index databases were searched until April Comparative studies were identified using the following key words: carcinoma, hepatocellular and liver transplantation and using validated search filters to identify only prognostic studies. Equivalent free text terms were used. There were no language restrictions. Only studies reporting hazard ratio (HR) or Kaplan-Meier curves for death and/or HCC recurrence according to: a) selection criteria (i.e. Milan, UCSF, TNM) or b) tumour size and volume and c) tumour number were included. Studies identified by the search were screened independently by G.G. and M.G., and then verified reciprocally. Any disagreements were arbitrated by A.K.B. Group 7: Markers for microvascular invasion, where do we stand? (Gouw et al.) We searched Medline database from 2002 to 2010 to identify the significance of microvascular invasion in outcome after LT for HCC using the search keywords hepatocellular carcinoma, HCC, microvascular invasion, liver transplantation, liver resection. We also performed a full manual search from bibliographies of selected papers and included 4 additional papers from earlier years. Papers were included based on the presence of data regarding MVI and its relation with tumor characteristics and/or prognostic data. The search resulted in a total of 55 relevant papers. Group 8: What information molecular markers may bring? (Llovet et al.) A review of the English language literature was performed including PubMed, Embase, Scopus databases and the Cochrane central register of controlled trials. The search was limited to the period between January 1990 to was also used to find further relevant articles. Search terms included: Biomarkers, prognosis, diagnosis, HCC, Liver Cancer, Markers, gene signatures, targeted therapies, signalling. Group 9: What are the criteria for OLT? (Freeman et al.) the Cochrane central register of controlled trials. The search was limited to the period between January 1995 to hepatocellular carcinoma, criteria, indications. Group 10: Should the enlisting criteria be different for HCC in an otherwise normal liver? (Lerut et al.) A review of the literature on resection and LT for HCC in patients with non cirrhotic livers was undertaken using MEDLINE, SCIENCE CITATION, EMBASE, COCHRANE databases and the MESH keywords hepatocellular 2

4 carcinoma, hepatocellular cancer and liver transplantation and liver resection and normal liver. Limit search was set to human studies, English language and the period January 1995-May One exception to the English language limit consisted of the inclusion in this analysis of the 2006 yearly report of the Association Française de Chirurgie (AFC or French Surgical Society) related to hepatocellular cancer. Full texts were consulted after abstract review. Duplication, registries and repeated series from the same centre were excluded from this review. Only patients with description of tumour characteristics; recurrence and outcome data were finally included in this study. Group 11: Is treatment of HCC on the waiting list necessary? (Majno et al.) the Cochrane central register of controlled trials. The search was limited to the period between January 1995 to hepatocellular carcinoma, downstafing, monitoring, follow-up, radiotherapy, chemotherapy. Group 12: Does a patient qualify for OLT after downstaging? (Yao et al.) We searched the MEDLINE (PubMed) citations and the Cochrane Library to identify studies evaluating down-staging and loco-regional therapy of hepatocellular carcinoma (HCC) before liver transplantation. The search was restricted to those published in the English language and during the period from 1990 to The key words for the search included: Down-staging, liver transplantation, hepatocellular carcinoma, loco-regional therapy, staging, treatment outcomes, radiofrequency ablation, and transarterial chemoembolization. All published articles and Abstracts were reviewed and screened by two members of the working group independently, and relevant articles and abstracts were selected for further review by the group. Group 13: Tools to monitor HCC on the waiting list (αfp, size, biopsy, ) and monitoring after liver transplantation. (Kneteman et al.) The keywords used in the searches varied with each question. For electronic searches, we concentrated on MEDLINE, but we also reviewed the Cochrane database. For imaging strategies, we performed a search of the MEDLINE database with the medical subject headings hepatocellular carcinoma, primary liver cancer, liver cell carcinoma, and liver cancer as free text words in combination with liver transplantation, waiting list, and imaging for January 2002 to March All titles and abstracts were reviewed, and appropriate studies were further assessed. We further reviewed the reference sections of all these publications to identify studies that may have been missed during the primary search. The main analysis concentrated on randomized controlled trials, controlled studies, and meta-analysis reviews. A second analysis concentrated on case-control analytical studies. Different concordant clinical studies and studies reporting the opinions of respected experts were also considered for inclusion. Group 14: Should we use living donor graft for HCC? (E Pomfret et al.) Literature searches were conducted with additional references provided by Committee members. Conference calls and exchange were used to debate the relevant issues as there is a paucity of relevant published data. Group 15: Should the LT criteria be different between deceased and living donation? (Grant et al.) Literature searches were conducted of PubMed and Embase using the following keywords: 1) livingand liver AND donation AND transplantation AND hepatocellular AND cancer; and 2) living AND liver AND donation AND ethics. 201 references were identified. A literature search was conducted of PubMed using the following search terms: hepatocellular AND cancer AND transplantation. An additional 1590 references were obtained. The Cochrane Collection was searched using the following terms: hepatobiliary; hepatocellular; transplantation; donation. No relevant articles were identified. The information above was supplemented with additional references provided by Committee members. Group 16: Should we use deceased LT after transplant failure from a LDLT? (Greig et al.) Electronic literature searches were performed on Ovid Medline, Embase, and Cochrane databases in English, German and French. The following key-words were used in various combinations: liver transplant, live donor liver transplant, retransplant, rejection, loss, failure, survival, primary non function, hepatic artery thrombosis, mortality, UNOS, Eurotransplant. The Medline search yielded 49 papers, Embase yielded 68, and Cochrane yielded 46. These were reviewed and relevant studies were supplemented with additional studies and have been referenced in the literature review. Group 17: What is the role of adjuvant therapy after LT for HCC? (Duvoux et al.) 3

5 We searched the MEDLINE (PubMed) citations, the Cochrane Hepato-Biliary Group Controlled Trials Register, and the Cochrane Library until 2010 to identify trials testing for the impact of adjuvant therapy after liver transplantation for HCC. The identified single arm and controlled trials were reviewed by 3 co-workers independently and discrepancies were resolved by consensus. The key words used for the search were hepatocellular carcinoma, liver transplantation and adjuvant therapy. Studies testing for both neodjuvant and adjuvant therapy were not excluded. We also searched for prognostic models of recurrence after liver transplantation for HCC, using prognostic model, hepatocellular carcinoma and liver transplantation as key words. Group 18: What is the impact of immunosuppression on HCC recurrence? Should we adapt it? (Trotter et al.) An English language literature review was performed including PubMed. The search was limited to the period from January 1990 to September Text, keywords and medical subject heading terms were used for titles and abstracts. Manual cross-referencing was also used to find further relevant articles. Search terms included: sirolimus, rapamycin, immunosuppression, cyclosporine, tacrolimus, mycophenolate mofetil, azathioprine, liver transplantation, hepatoma, hepatocellular carcinoma. Group 19: Should patient be retransplanted because of HCC recurrence? (Schwartz et al.) the Cochrane central register of controlled trials. The search was limited to the period between January 1990 to hepatocellular carcinoma, recurrence, treatment. 4