Response to Letter to the Editors

Abstract

TO THE EDITORS:We thank dos Santos Schraiber et al. 1 and Lai and Lerut 2 for their interest and comments regarding our study on applying alpha-fetoprotein (AFP) >1000 ng/ mL as an exclusion criterion for liver transplantation (LT) for hepatocellular carcinoma (HCC).3 dos Santos Schraiber et al.1 reported their experience with 206 patients receiving transplants for HCC and found that an AFP threshold of 200 ng/mL was predictive of HCC recurrence. They believed that the higher AFP >1000 ng/mL used in our study was restrictive and that our results were based on a small number of patients. We recognize the small number of patients with AFP >1000 ng/mL to be a limitation, but our results are entirely consistent with those reported from a recent large study published by the Liver Transplantation French Study Group in the subgroup of patients meeting Milan criteria. 4 The key question of our study is how many patients would have to be excluded from LT at a specific AFP threshold to prevent 1 HCC recurrence. We found that applying an AFP level >1000 ng/mL as the cutoff would have resulted in the exclusion of approximately 5% of patients for LT and a 20% reduction in the rate of HCC recurrence. The 5-year survival without HCC recurrence was 80% after excluding those with pre-LT AFP >1000 ng/mL. Applying a lower AFP threshold (>300 ng/mL to >500 ng/mL) would have resulted in a slightly greater reduction in the HCC recurrence rate but at the expense of excluding more patients from LT who did not have tumor recurrence and would have benefited from LT. We also found AFP >1000 ng/mL to have the highest specificity in predicting vascular invasion as well as post-LT HCC recurrence compared with a lower AFP.We agree with Lai and Lerut's 2 comments about the complexity of using AFP as a variable in exclusion of candidates for LT. We should point out that, among the 211 patients in our study cohort, 12 patients had an initial AFP >1000 ng/mL at LT listing who showed a decrease in AFP to <1000 ng/mL by the time of LT as a result of local regional therapy (LRT), and only 1 of these 12 patients suffered from HCC recurrence after LT. Although the numbers are small, this observation highlights the importance of change in AFP in the context of LRT while on the LT waiting list as Lai et al. 5 have indicated from their recent multicenter study. We agree that there should be a "dynamic" approach to using AFP in the selection guidelines for LT that are readily adoptable in clinical practice. At our center, we have implemented a policy in which those with an initial AFP >1000 ng/ mL are required to show a decrease in AFP to <500 ng/ mL with LRT before they can undergo LT.

Contribution of alpha-fetoprotein in liver transplantation for hepatocellular carcinoma

“…In France, Duvoux's algorithm is currently in use and an AFP value of 1000 ng/mL is recognized as a limit over which a LT should not be performed. The UCSF team now applies a similar policy [62] . What about the values in between 15 and 1000 ng/mL?…”

“…These studies enabled AFP to be part of the definition of a successful downstaging, along with radiological features. In fact, Yao et al [62] in California require that patients with an initial AFP > 1000 ng/mL have AFP decreased to < 500 ng/mL after loco regional therapy, before undergoing LT. Similarly, in Yamashiki et al [43] 2004 93 United States Prospective 100 ng/mL Drop-out from list Shetty et al [42] 2004 109 United States Retrospective 300 ng/mL Recurrence, death Todo et al [54] 2007 653 Japan Retrospective 200 ng/mL Recurrence 1000 ng/mL Parfitt et al [61] 2007 75 Canada Retrospective 1000 ng/mL Recurrence Pérez-Saborido et al [44] 2007 95 Spain Retrospective 200 ng/mL Recurrence Onaca et al [10] 2007 902 United States Retrospective 200 ng/mL Recurrence Adler et al [86] 2008 226 Belgium Retrospective 100 ng/mL Recurrence Zou et al [45] 2008 303 China Retrospective 1000 ng/mL Fatal recurrence Ioannou et al [50] 2008 5028 United States Retrospective 455 ng/mL Death Xu et al [46] 2009 97 China Retrospective 400 ng/mL Recurrence Toso et al [49] 2009 6478 Canada Retrospective 400 ng/mL Death Lao et al [55] 2009 124 United States Prospective 1000 ng/mL Recurrence Xiao et al [87] 2009 224 China Retrospective 800 ng/mL Death McHugh et al [47] 2010 101 United States Retrospective 100 ng/mL Recurrence, death Levi et al [88] 2010 244 United States Retrospective 100 ng/mL Recurrence Merani et al [66] 2011 6817 United States Retrospective 400 ng/mL Death Lai et al [89] 2011 153 Italy Retrospective 210 ng/mL Recurrence Mailey et al [48] 2011 2253 United States Retrospective 400 ng/mL Death Muscari et al [28] 2012 122 France Retrospective 500 ng/mL Recurrence, death Ciccarelli et al [65] 2012 137 Belgium Retrospective 400 ng/mL Recurrence Wong et al [59] 2013 211 United States Retrospective 400 ng/mL Recurrence Harimoto et al [90] 2013 167 Japan Retrospective 300 ng/mL Recurrence Abdel-Wahab et al [68] 2013 170 Egypt Retrospective 200 ng/mL Recurrence, death Grąt et al [67] 2014 121 Poland Retrospective 100 ng/mL Recurrence Hameed et al [30] 2014 211 United States Retrospective 1000 ng/mL Microvascular invasion Lee et al [91] ...…”

Delta‐slope of alpha‐fetoprotein improves the ability to select liver transplant patients with hepatocellular cancer

“…Such datum is not in line with other experiences, in which the adoption of specific models based on AFP values showed a reduction in transplantable patients ranging from 4.7% to 6.2% . In the latter cases, a very high AFP cut‐off (>1000 ng/ml) was used, with the obvious intent to simultaneously reduce the HCC recurrence rate and to avoid excluding too many patients from LT without post‐LT recurrence …”

“…23,24 In the latter cases, a very high AFP cut-off (>1000 ng/ml) was used, with the obvious intent to simultaneously reduce the HCC recurrence rate and to avoid excluding too many patients from LT without post-LT recurrence. 25 Another confirmation of the fact that AFP should be used in combination with imaging derives from the sub-analysis focused on the impact of the AFP delta-slope in different subgroups of patients according to the mRECIST status after LRT. The higher AFP discriminative ability was observed in patients with tumour progression: this can be explained by the consideration that AFP levels are strongly influenced by successful or unsuccessful LRTs.…”

Selection tool alpha-fetoprotein for patients waiting for liver transplantation: How to easily manage a fractal algorithm

“…Starting from this statement, different equations able to define AFP modification have been proposed. The San Francisco transplant center underlined the recent implementation in their inclusion policy for LT to include patients with AFP levels > 1000 ng/mL only if LRT enabled to decrease this level beneath 500 ng/mL [21] . A Canadian study including 48 patients showed by 1901 July 28, 2015|Volume 7|Issue 15| WJH|www.wjgnet.com McHugh et al [12] 2010 101 United States 100 Grąt et al [13] 2014 121 Poland 100 Abdel-Wahab et al [14] 2013 170 (LDLT) Egypt 200 Lai et al [15] 2011 153 Italy 210 Harimoto et al [16] 2013 167 (LDLT) Japan 300 Merani et al [6] 2011 6817 United States 400 Toso et al [7] 2009 6478 United States 400 Zheng et al [8] 2008…”