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Daniele et al. Hepatoma Res 2021;7:61 https://dx.doi.org/10.20517/2394-5079.2021.58 Page 3 of 14

cases (20 and 6 patients in SHARP and Asia Pacific, respectively) were enrolled as protocol violations.
Nevertheless, the Food and Drug Administration and European Medicines Agency approved sorafenib for
the treatment of patients with advanced HCC regardless of liver function. However, the cost-benefit ratio is
unknown in patients with highly compromised liver function, and sorafenib is reimbursed only for Child-
Pugh A patients in several countries (Australia, Belgium, Canada, France, Italy, South Korea, Taiwan, and
[10]
Switzerland) .
In 2011, we planned the BOOST (B Child-Pugh HCC patients - Optimization Of Sorafenib Treatment)
randomized phase 3 trial to assess the efficacy and safety of sorafenib plus best supportive care (BSC) vs.
BSC alone in Child-Pugh B advanced HCC patients.

PATIENTS AND METHODS
Study management and design
BOOST (NCT:01405573, EudraCT number: 2009-013870-42) was an open-label, multicenter, randomized
phase 3 trial promoted by the Istituto Nazionale per lo Studio e la Cura dei Tumori - IRCCS Fondazione G.
Pascale, Napoli, Italy. The study was supported by the Italian Drug Agency (AIFA) in May 2011 (code
FARM84SA2X) for trial coordination activities. A request to the pharmaceutical company for gratuitous
drug supply was unsuccessful. Therefore, only 15 centers, willing to pay for the experimental drug, accepted
to participate, but the enrolment was quite null. In August 2014, AIFA agreed on further funding to buy the
experimental drug. The number of centers willing to participate increased to 36, but only 13 actually
enrolled at least one patient. Figure 1 summarizes time dynamics of the trial.

Patients were randomly assigned, in a 1:1 ratio, to receive BSC alone (control arm) or combined with
sorafenib (experimental arm) until disease progression, occurrence of unacceptable toxicity, or progression
of the underlying cirrhosis.

Participants provided written informed consent before any study procedures.

Eligibility criteria
Eligible patients had liver function classified as Child-Pugh B and advanced HCC (according to the
American Association for the Study of Liver Diseases and the European Association for the Study of the
[11]
Liver criteria) , were not eligible for loco-regional treatment, and had not received previous systemic
treatment. Other inclusion criteria were age ≥ 18 years, Eastern Cooperative Oncology Group (ECOG)
performance status (PS) score 0-2, life expectancy longer than 2 months, adequate hematologic (platelet
9
count ≥ 60.0 × 10 /L; hemoglobin > 9 g/dL) and renal function (serum creatinine < 1.5 times the upper limit
of normal range), and signed informed consent.

Key exclusion criteria were the presence of any unstable systemic disease or medical contraindication to
sorafenib and any grade encephalopathy or gastrointestinal hemorrhage within 30 days before the
randomization.

Treatment and study procedures
Sorafenib, at the starting dose of 800 mg (two 200 mg tablets every 12 h), was assumed orally on a
continuous daily basis; for convenience, the treatment period was divided into 4-week cycles. Based on the
occurrence and the severity of side effects (diarrhea, skin toxicity, hematologic, or other non-hematologic
adverse events) or Child-Pugh deterioration, sorafenib was allowed to be stepwise reduced to 400 mg daily
(200 mg bid) or 400 mg every other day. After such reductions, in case of persistent toxicity, treatment had