In their study, Iavarone et al.1 found a prolonged time to progression (TTP) in comparison with the Sorafenib HCC Assessment Randomized Protocol study, and they speculated that it was probably related to the utilization of the modified Response Evaluation Criteria in Solid Tumors.2 Moreover, they hypothesized that down-dosing sorafenib allowed a high percentage of the patients to retain the benefits of the drug and achieve improved survival. If TTP was so remarkably improved only because of the accuracy of the modified Response Evaluation Criteria in Solid Tumors (published in the year of the study's start), it seems strange that the median overall survival was comparable to that of phase 3 trials.2 The most unusual observation was the very short postprogression survival (1 month versus 5 months in the Sorafenib HCC Assessment Randomized Protocol study). As a rule, a median TTP approaching the median overall survival occurs because of undiagnosed progression. In our opinion, this means that the interval between computed tomography scans was longer than 2 months in actual daily practice.
Another issue was the high rate of liver function deterioration, which the authors attributed to drug-related adverse events.1 It is not clear how they distinguished this from clinical tumor progression. The analysis suggesting longer survival for patients receiving half-dose sorafenib was not preplanned, and this means that the patients were not stratified according to prognostic factors and that the sample size was not calculated in advance for the hypothesis that the authors intended to demonstrate. For this reason, the aforementioned analysis was methodologically inappropriate for an observational study; it was also inconclusive because the patients' survival might simply have depended on the selection of a good-prognosis cohort.
Finally, two other aspects deserve careful consideration. First, the study lacked formal approval by an ethics committee, which implies the generation of a European Union Drug Regulating Authorities Clinical Trials number according to Italian rules. Second, a cohort of Child B patients was treated, but sorafenib approval in Italy is restricted to Child A patients.
Taken together, our observations suggest the following: (1) the design of this prospective study had potentially serious limitations, (2) sorafenib was used in field practice outside the approved indication, (3) computed tomography scans were not scheduled on a bimonthly basis, and (4) TTP was largely overestimated. In addition, this article subliminally conveys a somewhat hazardous and not adequately supported message about both the arbitrary acceptance of the physician's judgment in deciding the likelihood of benefits without radiological confirmation and the continuation of sorafenib beyond progression almost until death.