Page 17 - Read Online

Daniele et al. Hepatoma Res 2021;7:61 https://dx.doi.org/10.20517/2394-5079.2021.58 Page 5 of 14

Baseline tumor measurement, with abdominal and pelvic computed tomography scan or magnetic
resonance, was planned for all patients, before the randomization, and in the sorafenib arm only, every eight
weeks during treatment, until disease progression. PFS, defined as the time between the date of
randomization and the date of disease progression [according to the modified Response Evaluation Criteria
in Solid Tumors (RECIST 1.1)] or death, whichever occurred first, was described only in the sorafenib
[14]
arm. For this purpose, patients who did not progress or die were censored at the date of the last available
information on vital status.

Statistical analysis
Sample size calculation was based on an expected median survival of 4.5 months in the control arm and an
auspicated 6.5-month median survival in the sorafenib arm, corresponding to a hazard ratio (HR) of death
of 0.70. With a two-tailed alpha error of 0.05, and 80% power, 234 events were required, and it was planned
to enroll 320 patients in two years (EAST 3.1, Cytel Software, Cambridge, MA, USA).

In March 2017, the study was stopped due to slow enrolment, with 35 patients randomized. Due to low
study power, only descriptive analyses are reported.

[15]
Median follow-up was calculated according to the Schemper’s reverse Kaplan-Meier technique .
Survival curves were drawn with the Kaplan-Meier product-limit method, and the HR of death was
calculated with the Cox proportional hazard model.

Toxicity was described for all the patients with available toxicity information. Side-effects were grouped
either as any grade (Grade ≥ 1) or as severe (Grade ≥ 3).

Only baseline QoL was descripted due to the high number of missing QoL data through the follow up.

Analyses were performed using STATA MP 14.1 (StataCorp LP, College Station, TX, USA).

RESULTS
Patients’ characteristics
From 27 November 2012 to 2 February 2017, 13 Italian centers enrolled 35 patients (18 were assigned to the
experimental and 17 to the control arm). One patient in the control arm withdrew consent immediately
after randomization [Figure 2].

Notwithstanding the small number of patients, the baseline characteristics were well balanced between
study arms [Table 1]. Median age was 64.8 years [interquartile range (IQR): 59.2-71.3 years]; 85.3% of
patients were male, and 73.0% had an ECOG PS 0-1. Child-Pugh scores 7, 8, and 9 were similarly
represented in the study population; only few patients (8.8%) were in the lowest CLIP score category, the
majority of the patients (64.7%) being in the CLIP 2-3 category. Chronic hepatitis C virus infection was the
predominant cause of liver disease (67.7% of the cases), followed by alcohol consumption, and HBV
infection. Overall, 16 patients (47.1%) had been previously treated with locoregional therapy.

Treatment compliance
Data on compliance to sorafenib are missing for one patient. The median duration of sorafenib treatment
was 28 days (IQR: 20-60 days). The profile of dosing per day across the first two cycles is reported in
Figure 3. There were three violations regarding the sorafenib initial dose, with a starting dose of 400 mg