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Accepted Manuscript
Predictors of Sorafenib Benefit in Patients with Hepatocellular Carcinoma
Jordi Bruix, Ann Lii Cheng, Josep Llovet
To appear in:
Journal of Hepatology
Received Date:
Accepted Date:
9 October 2017
10 October 2017
Please cite this article as: Bruix, J., Cheng, A.L., Llovet, J., Predictors of Sorafenib Benefit in Patients with
Hepatocellular Carcinoma, Journal of Hepatology (2017), doi:
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Predictors of Sorafenib Benefit in Patients with Hepatocellular
Answer to the letter by Jackson et al.
We were surprised to receive the letter by Jackson et al. stating that sorafenib does not
benefit patients with hepatocellular carcinoma associated to hepatitis B virus infection. This
statement is based on an inherently problematic meta-analysis recently published by the
same authors (1) and based on an incorrect interpretation of our own study which pooled the
databases of the two seminal sorafenib trials in HCC comparing sorafenib vs placebo (2).
The two problematic aspects of the metanalysis are as follows: First, it did not include the
pivotal trials that demonstrated the benefit of sorafenib vs placebo (3,4), and second, the
three phase 3 trials that constituted the basis of the meta-analysis were not placebocontrolled, but had active agents (sunitinib, brivanib and linifanib) that were compared to
sorafenib. While these three trials were negative, it cannot be concluded that these agents
are equivalent to placebo.
Jackson et al neglect the fact that in the RCT of sorafenib vs placebo by Cheng et al (4) the
majority of the patients were HBV positive and the results were unequivocally positive. While
this Asia-Pacific trial results should be enough to accept the survival benefit of sorafenib in
HBV patients, his understanding of the results of our study pooling the two sorafenib vs
placebo trials (2) is not correct. We did not explore if sorafenib was effective in a subgroup of
patients, but rather if in a given subgroup the results were significantly better using the “p for
interaction” statistical test. Thus, we demonstrated that sorafenib was significantly more
effective in patients with HCV infection and in those with liver only disease. For HBV patients
we did not identify that the benefit was more or less intense than in the global population.
We hope that these comments help to explain the flaws of the metanalysis and the letter by
Jackson et al and that his misleading suggestions will not prevent the effective treatment
with sorafenib for HBV patients that develop hepatocellular carcinoma and are in need of
systemic treatment.
References.1.- Jackson R, Psarelli EE, Berhane S, et al. Impact of Viral Status on Survival in Patients
Receiving Sorafenib for Advanced Hepatocellular Cancer: A Meta-Analysis of Randomized
Phase III Trials. J Clin Oncol 2017;35:622-628.
2.- Bruix J, Cheng AL, Meinhardt G, et al. Prognostic Factors and Predictors of Sorafenib
Benefit in Patients With Hepatocellular Carcinoma: Analysis of Two Phase 3 Studies. J
Hepatol 2017.
3.- Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Sorafenib in
advanced hepatocellular carcinoma. N Engl J Med 2008;359:378-390.
4.- Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, et al. Efficacy and safety of
sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a
phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol 2009;10:25-34.
Jordi Bruix. BCLC Hospital Clínic Barcelona, IDIBAPS, University of Barcelona CIBERehd,
Barcelona, Spain.
Ann Lii Cheng. Department of Oncology, National Taiwan University Hospital, Taipei,
Josep Llovet. BCLC Hospital Clínic Barcelona, IDIBAPS, University of Barcelona CIBERehd,
Barcelona, Spain; Mount Sinai Liver Cancer Program, Icahn School of Medicine at Mount
Sinai, New York, NY, USA; Institució Catalana de Recerca i Estudis Avançats (ICREA),
Barcelona, Catalonia, Spain.
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