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Page 2 of 8 Wada et al. Hepatoma Res 2018;4:8 I http://dx.doi.org/10.20517/2394-5079.2017.39

Conclusion: PPS in patients with advanced HCC can be characterized by using time-dependent dynamic changes
in clinical parameters.

Keywords: Contactin-associated protein-2, Isaac, neuromuscular hyperexcitability, neuromyotonia, voltage-gated
potassium channel

INTRODUCTION
Hepatocellular carcinoma (HCC) is the third common cause of cancer-related deaths worldwide. Surgical
resection, liver transplantation, and ablation therapy are curative therapeutic treatments for early-stage HCC,
and transcatheter arterial chemoembolization (TACE) is recommended for patients with intermediate-stage
[1,2]
HCC who have preserved liver function . However, most HCC patients are diagnosed during the advanced
[1-3]
stage of the disease; their prognosis is poor, and treatment options are limited . In patients who are not
candidates for locoregional therapy, the oral multikinase inhibitor sorafenib has been the only systemic
treatment option. Sorafenib inhibits tumor cell proliferation and tumor angiogenesis by inhibiting multiple
signaling pathways. It has been shown to prolong both, progression-free survival and overall survival (OS) in
[4,5]
patients with advanced HCC . Since the Sorafenib HCC Assessment Randomized Protocol (SHARP) trial
[4]
showed the efficacy of sorafenib for prolonging survival in HCC patients almost 10 years ago , all phase
3 trials of novel systemic drugs have failed to improve outcomes over sorafenib, both, as first-line [6-10] and
second-line treatments (following sorafenib) [10-12] . Predicting the efficacy is difficult in sorafenib treatment,
and no surrogate marker has been identified [11-13] . Since tumor progression is a dynamic process, it may be
difficult to identify predictors for survival by analyzing clinical characteristic at one static data point. Using
dynamic data might help clarify the predictors of survival.

A recent regorafenib for patients with HCC who progressed on sorafenib treatment (RESORCE) study [14]
has revealed that regorafenib prolonged survival in patients with advanced HCC who were refractory to
sorafenib treatment. The inclusion criteria in this study were a Child-Pugh score ≤ 6 and tolerability of
sorafenib (≥ 400 mg daily for at least 20 of the 28 days before discontinuation). Based on this, the number
of candidates for second-line treatment with regorafenib is likely very limited. Analyzing post-progression
survival (PPS) after sorafenib treatment is desired to select candidates for second-line treatment.

In this study, we used dynamic and time-dependent data on the clinical characteristics of patients with
advanced HCC, including progression patterns, impairments in liver function, and performance status
(PS). Importantly, we assessed changes in these parameters by comparing them at the time of radiologic
confirmation of progressive disease (PD) to baseline (the initiation of sorafenib treatment) to evaluate PPS.

METHODS
Patients
We reviewed data that were prospectively collected from 171 consecutive patients who received sorafenib
(Nexavar; Bayer HealthCare Pharmaceuticals, West Haven, CT, USA) for the treatment of advanced HCC
at the Department of Hepato-Biliary-Pancreatic Surgery at the National Hospital Organization Kyushu
Medical Center between June 2009 and July 2016. Of these, 135 patients had radiologic PD, as assessed by
[15]
the modified Response Evaluation Criteria In Solid Tumors (mRECIST) . After excluding 7 patients with a
Child-Pugh score ≥ 8, 128 patients were enrolled in the study.

HCC was diagnosed based on the results of a pathological examination or a combination of specific
radiologic findings obtained via contrast-enhanced computed tomography (CT) or magnetic resonance
[2]
imaging (MRI) according to the criteria of the American Association for the Study of Liver Diseases .