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Page 6 of 8 Wada et al. Hepatoma Res 2018;4:8 I http://dx.doi.org/10.20517/2394-5079.2017.39

during sorafenib treatment is very important. A decrease in liver function or a worsening in the patients’
general condition during sorafenib treatment should be detected early as these patients should be referred
for second-line treatment as early as possible.

Our data revealed that an impairment in the Child-Pugh score of ≥ +2 points (and not ≥ +1 points) but was
associated with a worse PPS. In previous studies, liver function impairment was defined as Child-Pugh score
B or C. However, using this definition, an impairment in the Child-Pugh score of +1 point would be only
defined as liver function impairment in patients with a Child-Pugh score of A6 at baseline, but not for those
with a Child-Pugh score of A5 at baseline. Furthermore, the Child-Pugh score at the confirmation of PD
may not accurately represent the development of the condition. In this study, we therefore focused on the
changes in Child-Pugh scores over time to evaluate the effect on PPS of a change in the score of +1 point.

PS has been shown to correlate strongly with both, tumor and cirrhotic factors, and may predict survival
outcomes in patients with advanced HCC [21,22] . In previous studies, liver function impairment was defined as
a PS > 2 [19,20] . In contrast, this study showed that even an impairment in PS of ≥ +1 point was associated with
a worse PPS.

[19]
A recent study by Reig et al. showed that the radiologic progression pattern affected both, OS and PPS in
HCC patients receiving sorafenib treatment. The radiologic progression pattern in previous studies included
intrahepatic growth, new intrahepatic lesion, extrahepatic growth, or new extrahepatic lesion. Patients
with a new extrahepatic lesion, in particular, had a worse PPS [19,20] . When estimating a tumor response,
radiologic examinations show a certain progression pattern in some patients; however, many patients have a
complicated combination of progression patterns. Estimated all combination of these progression patterns,
complicated combination may be difficult to comprehend. In this study, we adopted the progression pattern
of target lesion growth and/or the emergence of a new lesion for a convenient and easily available approach
in clinical practice.

Interestingly, a TTP of < 4 months was identified as an independent prognostic predictor in this study. A
[20]
recent study reported that a TTP of < 4 months was an independent predictor of OS and PPS . Earlier PD
development predicts a poorer PPS after adjusting for other survival predictors. These patients should be
referred for second-line treatment. It has been reported that continuous sorafenib treatment was a useful
treatment option at the time of radiologic confirmation of PD. Moreover, our previous study showed that
continuing sorafenib treatment after radiologic confirmation of PD may be a useful treatment strategy,
[23]
especially in patients with a TTP of ≥ 4 months . On the other hand, for patients with rapid PD, as defined
[24]
by a TTP of < 4 months, alternative second-line treatments should be considered .
This study had some limitations. First, this study was a retrospective study. However, all patients
underwent tumor evaluation by contrast-enhanced CT or MRI every 2 months during sorafenib treatment.
Furthermore, no patient was lost to follow-up. Second, the study only enrolled patients with a Child-Pugh
score of ≤ 7. Clinical trials of sorafenib showed the drug’s efficacy in patients with a Child-Pugh score of ≤ 6.
[26]
[25]
However, global and Japanese observational studies revealed that sorafenib treatment was often initiated
in patients with a Child-Pugh score of 7 in clinical practice. Third, the target population of this study was
heterogenous and included patients with BCLC-B and -C. However, sorafenib treatment is often used for
HCC patients with BCLC-B who are refractory to TACE in clinical practice. Furthermore, predictors of
PPS were analyzed after adjusting for BCLC staging. Fourth, 17 patients treated with TACE as a second-line
treatment after the confirmation of radiologic PD were included in this study, as it is common practice to
use a combination therapy of TACE and sorafenib to control disease progression. However, the efficacy of a
combination therapy of TACE and sorafenib is still controversial and should be confirmed in a randomized
[27]
clinical trial . Fifth, radiologic progression pattern, as mentioned before. Finally, the size of the study