Page 14 - Read Online

Academic Editor: Guang-Wen Cao Copy Editor: Yue-Yue Zhang Production Editor: Yue-Yue Zhang

Abstract
Aim: Only patients with good liver function {[Child-Pugh (CP)] A class} were eligible for trials testing sorafenib as
first-line treatment of hepatocellular carcinoma (HCC); nevertheless, the drug was authorized without restrictions
based on liver function. Therefore, we planned to test sorafenib efficacy and safety in patients with HCC and
deteriorated liver function (CP-B).

Methods: This was an open-label, multicenter, randomized phase 3 trial. Patients with HCC, no previous systemic
therapy, and CP-B score 7-9 were assigned 1:1 to best supportive care alone (control arm) or with standard dose
sorafenib (experimental arm). Overall survival (OS) was the primary endpoint. To detect a 0.70 HR of death, with
80% power, and two-tailed α error 0.05, 234 events were required. The study closed prematurely because of slow
accrual. Descriptive analyses are reported.

Results: From 2012 to 2017, 13 Italian centers randomized 35 patients. In total, 28 deaths were recorded, 12
without and 16 with sorafenib; median OS was 4.9 (95%CI: 1.2-5.6) and 3.5 months (95%CI: 1.3-5.3), respectively.
At least one severe adverse event was reported in 2/15 (13.3%) without and 9/17 (52.9%) patients with sorafenib.
Conclusions: This trial failed its planned enrolment goal, showing the difficulty in performing clinical trials with
drugs already registered with a label broader than what available evidence supports.

Keywords: Hepatocellular carcinoma, Child-Pugh B class, sorafenib

INTRODUCTION
In 2018, hepatocellular carcinoma (HCC) represented the 6th most common human cancer (over 840,000
new cases) and the fourth most common cause of cancer-related death (780,000 estimated deaths),
according to the International Agency for Research on Cancer database . Estimated ranking of incidence
[1]
and mortality in 2019 in the United States suggests that incidence is going to decrease as compared to other
types of cancer, but mortality remains significant . Prognosis depends on both the tumor characteristics
[2]
and the liver failure due to concomitant cirrhosis; thus, Child-Pugh score and other markers of liver
[3-5]
function are included in several HCC staging systems .

In patients with advanced untreated HCC, the prognosis is extremely poor, yielding a median survival of 4-
[6]
7 months .

Sorafenib is an oral multi-kinase inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, the
[7]
platelet-derived growth factor receptor, and the RAF pathways . In two randomized phase 3 trials (SHARP
and Asia-Pacific), it prolonged overall survival and time to progression compared to placebo in patients
[8,9]
with advanced HCC who had not received prior systemic therapy .

In both trials, only patients with good liver function (Child-Pugh A) were eligible and few Child-Pugh B