Reply:
Authors: Massimo Iavarone, Giuseppe Cabibbo, Massimo Colombo
Journal: Hepatology (2011)

We thank Basso et al. for their comments about our article on field practice with sorafenib in Italy,1 although we have to say that overall their letter reflects a substantial misinterpretation of our report. As we clearly stated, the Sorafenib Italian Assessment (SOFIA) study is in fact just an observational study not framed by a control setting or other limitations, and this has allowed us to evaluate measures of real-world effectiveness without the need for registration with a European Union Drug Regulating Authorities Clinical Trials number or for approval by an ethics committee. Although by the same token the SOFIA study did not require a predefined sample size, it was indeed adequately powered because it ended with the enrollment of approximately the same number of patients found in the sorafenib arm of the Sorafenib HCC Assessment Randomized Protocol registration trial (296 versus 299).2 Let us also clarify that the Child-Pugh A label for sorafenib has implications for the reimbursement policy only; this means that the drug can be prescribed off label to Child-Pugh B patients with advanced hepatocellular carcinoma with the understanding that the treatment costs will be reimbursed by partners other than the National Health System (including the hospital itself) according to proper administrative procedures. As we clearly indicated, the time to progression was not overestimated by the modified Response Evaluation Criteria in Solid Tumors, which in fact are superior to the Response Evaluation Criteria in Solid Tumors for the capture of hepatocellular carcinoma responses to both loco-ablative and drug-targeted therapy.3 None of the patients in the SOFIA study received sorafenib "beyond progression almost until death," as inappropriately stated by Basso et al., because the median survival of the patients was greater than the duration of the sorafenib therapy (10.5 versus 3.8 months).We also disagree with their statement that the significantly increased survival of the 77 patients receiving half-dose sorafenib (21.6 months for those patients versus 9.6 months for the 219 full-dose patients) was "inconclusive" and biased by a "methodologically inappropriate" analysis because a multivariate analysis demonstrated a strong and independent association between full-dose sorafenib and an increased risk of liver-related mortality after corrections were made for multiple confounders. Although the prolonged survival of the down-dosed patients unlikely reflected the selection of good-prognosis patients, our observation that cancer-related morbidity is frequently overshadowed by the complications of cirrhosis highlights the driving role of hepatologists in the multidisciplinary management of patients with hepatocellular carcinoma. Massimo Iavarone M.D.*, Giuseppe Cabibbo M.D. , Massimo Colombo M.D.*, * Ca'Granda Maggiore Hospital, Foundation of the Scientific Institute for Research, Hospitalization, and Health Care, University of Milan, Milan, Italy, Biomedical Department of Internal and Specialty Medicine, University of Palermo, Palermo, Italy, Department of Biopathology and Biomedical Methodology, University of Palermo, Palermo, Italy.