LETTERS TO THE EDITOR Down-Staging of Hepatocellular Carcinoma Before Liver Transplantation: Should We Change Our Clinical Practice? To the Editor: W e enjoyed the article by Chapman et al published in the October 2008 issue of Annals of Surgery, 1 where they report an ex- cellent outcome for liver transplantation (LT) following preoperative down-staging of hepa- tocellular carcinoma (HCC). They reported a comparable outcome after LT among patients meeting the Milan criteria 2 before any preop- erative treatments and among those beyond these criteria but meeting them after down- staging procedures. These results confirm the efficacy of chemoembolization procedures (TACE) recently reported by 2 other studies 3,4 ; these procedures seem able to satisfactorily select tumors with more favorable biology, even beyond the Milan criteria. In accordance with the study 3 from the University of California, most cases met the UCSF criteria, namely a single lesion 6.5 cm or 2–3 lesions 4.5 cm with total tumor diameter 8 cm. 5 There were only 4 (23.5%) of 17 patients beyond the Milan criteria with more than 3 HCC nodules, who received a LT. Remarkably, we were able to show that LT also achieves good results in a European population including many cases of multifocal (n  3) HCCs (58.3%). 4 The different study populations (involv- ing more cases with only 1–3 nodules in the American series in comparison to ours) may explain why they 1–3 were able to obtain higher rates of complete tumor necrosis of HCCs following the down-staging procedures: close to 40% compared with 20% in our data. 4 The information we were unable to understand from the study by Chapman et al was the feasibility of their protocol and the intention-to treat analysis. They reported that only 17 of 76 cases (22%) who were outside of the Milan criteria before down-staging procedure actually received a LT, but they did not give details for the reasons for not enlisting or not transplanting the other cases. How many patients were able to com- plete down-staging, or had, instead, disease progression, or were excluded even from first TACE or from transplantation for other clinical conditions? In the other 2 studies, 3,4 a much higher proportion of patients reached LT (close to 60%) confirming not only the safety of the selection that can be achieved with down-stag- ing procedures on final outcome but also its feasibility. Summing the patients from these 3 studies, 1,3,4 84 HCC cases, initially, out of the conventional selection criteria for LT were transplanted following a down-staging procedure and, after a median postoperative follow-up of more than 2 years, these pa- tients had an outcome comparable to that of patients selected according to the conven- tional tumor stage criteria. We believe that these data should be the starting point for the set-up of an inter- national registry where standardized vari- ables are collected and other ongoing expe- riences may be included. If the results reported by the 3 pioneer- ing studies are confirmed in a large series of down-staged cases registered in an interna- tional database, we believe that the criteria currently used in clinical practice to select HCC patients for LT will change in the future. Matteo Ravaioli, MD Gian Luca Grazi, MD Matteo Cescon, MD Giorgio Ercolani, MD Antonio Daniele Pinna, MD Department of Liver and Multi-organ Transplantation Sant’Orsola-Malpighi Hospital University of Bologna Bologna, Italy Fabio Piscaglia, MD Franco Trevisani, MD Department of Digestive Diseases and Internal Medicine Sant’Orsola-Malpighi Hospital University of Bologna Bologna, Italy REFERENCES 1. Chapman WC, Majella Doyle MB, Stuart JE, et al. Outcome of neoadjuvant transarterial chemoemboli- zation to downstage hepatocellular carcinoma before liver transplantation. Ann Surg. 2008;248:617– 625. 2. Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepato- cellular carcinomas in patients with cirrhosis. N Engl J Med. 1996;334:693– 699. 3. Yao FY, Kerlan RK, Hirose R, et al. Excellent outcome following down-staging of hepatocellular carcinoma prior to liver transplantation: an intention- to-treat analysis. Hepatology. 2008;48:819 – 827. 4. Ravaioli M, Grazi GL, Piscaglia F, et al. Liver transplantation for hepatocellular carcinoma: re- sults of down-staging in patients initially outside the Milan selection criteria. Am J Transplant. 2008;8:2547–2557. 5. Yao FY, Xiao L, Bass NM, et al. Liver transplan- tation for hepatocellular carcinoma: validation of the UCSF-expanded criteria based on preoperative imaging. Am J Transplant. 2007;7:2587–2596. Reply: W e would like to thank the authors for their excellent questions and insightful comments regarding our experience with downstaging hepatocellular carcinoma (HCC) to allow for liver transplantation. Our recent report is a retrospective look at patients who were able to undergo TACE for HCC during the study period (bilirubin 3 and reason- ably well compensated chronic liver dis- ease). We consider all patients with HCC beyond Milan criteria (American Liver Tu- mor Study Group TNM 1 T-2 stage) as po- tential down-staging candidates and did not exclude a priori any patient based on the size, number, T-stage, or vascular invasion as long as their disease was confined to the liver. During the time of the current study, there were no approved and effective sys- temic agents available for HCC so TACE was the preferred treatment option in both our transplant and nontransplant candidates. We did not perform routine transplant eval- uations prior to considering TACE-down- staging in such patients and on this basis we do not feel it is appropriate to consider our outcomes on an “intention to treat” basis. In our protocol, unless patients achieved tumor downstaging to meet Milan criteria and had an observation period of 3 to 6 months with no evidence of metastatic disease on restag- ing, then there was little reason to complete a full transplant evaluation. Thus, there were some patients subjected to downstaging treatment who would not have met transplant criteria based on advanced age, medical co- morbidities, or psychosocial factors. The author’s question why other re- ports suggest a higher rate of tumor down- staging than we were able to achieve and this most likely relates to patient selection for consideration of downstaging. In the first report, Yao et al 2 restricted down-staging eligibility criteria to one lesion 5 cm and up to 8 cm, or 2 to 3 tumors with at least one lesion 3 cm and not exceeding 5 cm, with total tumor diameter up to 8 cm; or 4 to 5 lesions with none 3 cm, with total tumor diameter up to 8 cm. These “downstaging criteria” are only slightly beyond standard UCSF criteria (1 lesion 6.5 cm, 2–3 lesions each 4.5 cm with total tumor diameter 8 cm), for which this group has previously advocated as acceptable for transplantation without a requirement for pretransplant tu- mor downstaging. 3 Using these criteria 2 as a restriction for consideration for potential downstaging (and subsequent transplanta- tion), 57.4% (35/61) of their patients were successfully downstaged and transplanted. Ravaioli et al 4 prospectively included pa- tients with a single HCC 5 to 6 cm or 2 HCCs 5 cm or less than 6 HCCs 4 cm and sum diameter 12 cm, and achieved a Annals of Surgery • Volume 250, Number 2, August 2009 348 | www.annalsofsurgery.com