Patient Eligibility

Between December 2007 and February 2012 a total of 318 patients with unresectable HCC who were eligible for sorafenib treatment with or without LRTs were reviewed retrospectively. Among patients who underwent S-LRT or SM, 28 patients were excluded according to the following exclusion criteria; short duration of sorafenib administration (<2 week, n = 21), BCLC stage A/B (n = 5), Child-Pugh class C (n = 2), and Eastern Cooperative Oncology Group (ECOG) performance status ≥3 (n = 0). Finally, 290 patients with BCLC C and Child-Pugh class A or B were analyzed.

This study was performed in accordance with the ethical guidelines of the 1975 Declaration of Helsinki. Written informed consent was obtained from each participant or responsible family member after possible complications of the diagnostic procedures and anti-cancer treatments had been fully explained. This study was approved by the independent institutional review board of Severance Hospital.

Diagnosis of HCC

A diagnosis of HCC was based on histological examination or clinico-radiologic criteria according to guidelines proposed by The Korea Liver Cancer Study Group [21] as follows; a patient is considered positive for HCC if they have one or more risk factors (hepatitis B or C virus infection, cirrhosis) and one of the following: 1) serum α-fetoprotein (AFP) ≥ 400 ng/mL and a positive finding on at least one of three typical imaging studies [dynamic computed tomography (CT), dynamic magnetic resonance imaging (MRI), or hepatic angiography], or 2) serum AFP <400 ng/mL and positive findings on at least two of the three imaging studies. A positive finding for typical HCC on dynamic CT or MRI was defined as increased arterial enhancement followed by decreased enhancement compared with the liver (washout) in the portal or equilibrium phase.

Study Design

Subjects were divided into two groups; 1) patients who were treated with sorafenib monotherapy (referred to as “S-M group”), and 2) patients who were treated by other LRTs in addition to sorafenib (referred to as “S-LRTs group”). Patients in the S-M group received 400 mg oral sorafenib (Nexavar Bayer Health Care AG, Leverkusen, Germany) twice daily on a continuous dosing schedule. In addition to the twice daily 400 mg oral sorafenib, patients in the S-LRTs group also received LRTs that included intra-arterial chemotherapy (either TACE or HAIC), external beam radiotherapy, or both to delay progression of intra-hepatic tumors. The detailed protocols of LRTs performed at our institution, such as TACE using doxorubicin, lipiodol, and gelatin sponge particles, HAIC via implantable port system using 5-fluorouracil and cisplatin, and three-dimensional conformal external beam radiotherapy were described previously [22-25]. S-LRTs were performed in advanced HCC with the tolerable liver function for anti-tumor therapy in Severance. However, S-M has been applied for patients who couldn’t afford S-LRTs because national insurance system didn’t guarantee only one method among chemotherapy and LRTs.

The time interval between LRTs and initiation of sorafenib is less than 14 days (median 4 days, range 0–14 days). In both groups, dose reduction and drug interruption were allowed in the case of significant drug-related adverse effects or poor general condition. Sorafenib was also administered until disease progression, the development of intolerable toxicities, or patient refusal. However, for patients in the S-LRTs group, when intrahepatic tumor progression was observed, an alternative LRTs was allowed to delay intrahepatic disease progression, according to physician discretion and patient eligibility.

Evaluation of Treatment Response and Safety Profile

Clinical examination and laboratory assessments were performed upon the initiation of sorafenib treatment. The response evaluation was carried out with a dynamic CT scan or MRI, if appropriate, every 8 weeks. We adopted the modified Response Evaluation Criteria in Solid Tumors as follows: complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). Objective response was defined as CR or PR, and disease control as CR, PR, or SD. Response was analyzed by intention-to-treat analysis. Toxicity grade was assessed before each treatment cycle using the National Cancer Institute Common Toxicity Criteria version 3.0

Statistical Analyses

Student’s t test or Mann-Whitney U tests, if appropriate, were used to compare continuous variables, and Chi-square or Fisher’s exact tests were used for categorical variables. The primary endpoint was overall survival (OS), whereas the secondary endpoints were progression-free survival (PFS) and treatment-related toxicity. OS was calculated as the time interval from the initiation date of either sorafenib or LRTs (provided that LRTs preceded the administration of sorafenib in the S-LRTs group) until the date of death or final follow-up. Similarly, PFS was calculated as the time interval from the initiation date of sorafenib or LRTs until the date of first progression or death. Survival time was estimated by the Kaplan-Meier method, and the survival difference between groups was assessed by the log-rank test. The Cox proportional hazards model was used for a multivariate analysis of survival. All variables found significant in the univariate analysis were included in the multivariate model. Statistical analyses were performed using SAS version 9.1.3 (SAS, Cary, NC). A two-sided P value < 0.05 was considered statistically significant.

Baseline Characteristics

Table 1 shows the baseline characteristics of the entire population. The median age was 56.7 years and 243 (83.8%) patients were male. Most patients (n = 208, 71.7 %) showed preserved liver function of Child-Pugh class A. The median tumor size was 4.0 cm. Extrahepatic spreading (EHS) was identified in 182 (62.8%) patients, whereas regional lymph nodal involvement (RNI) was noted in 89 (36.0%) patients. The most common site for EHS was lung (n = 132, 45.5%). The median AFP and protein induced by vitamin K absence or antagonist (PIVKA) levels were 110 ng/mL and 112 AU/L, respectively. In S-LRTs group, sorafenib was combined with LRTs as follows; TACE (n = 24), HAIC (n = 5), HAIC with radiotherapy (n = 13), and radiotherapy alone (n = 22). The proportion of patients with a previous history of treatment for HCC and non-viral etiology was higher in the S-M group than in the S-LRTs group (79.6% vs. 67.2%, P = 0.037 and 15.9% vs. 6.2%, P = 0.047, respectively). There was no statistically significant difference in clinical variables between the two groups (Table 1).

Treatment Outcomes and Variables Affecting OS

The median OS in the entire population was 6 months [95% confidence interval (CI) 5.2–6.7]. Subjects in the S-LRTs group had a significantly longer median OS than those in the S-M group [8.5 months (95% CI 6.2–10.7 months) vs. 5.5 months (95% CI 4.7–6.2 months); P = 0.001] (Figure 1). In addition, Child-Pugh class, tumor size, EHS and/or RNI, AFP level ≥400 ng/mL, PIVKA level ≥1,000 AU/L, and the cumulative dose of sorafenib (transformed by natural logarithm) significantly predicted OS in univariate analysis (all P < 0.05) (Table 2). Subsequent multivariate analysis revealed that combined LRTs modality with sorafenib remained as the independent predictor for the better OS [adjusted hazard ratio (HR) 0.5, 95% CI 0.3–0.8, P = 0.002], together with Child-Pugh class (adjusted HR 1.8, 95% CI 1.2–2.5, P < 0.001), tumor size (adjusted HR 1.5, 95% CI 1.1–2.3, P = 0.030), EHS and/or RNI (adjusted HR 1.7, 95% CI 1.2–2.4, P = 0.001), AFP level (adjusted HR 1.6, 95% CI 1.1–2.1, P = 0.002), and the cumulative dose of sorafenib (transformed by natural logarithm) (adjusted HR 0.5, 95% CI 0.4–0.6, P < 0.001 ) (Table 2).

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Figure 1. Kaplan-Meier analysis of overall survival (A) and progression-free survival (B) in patients

Data were stratified by the treatment modalities treated with sorafenib monotherapy (S-M) and sorafenib-based loco-regional treatments (S-LRTs). The thick line indicates S-LRTs and the thin line S-M. Median OS and PFS are significantly longer in S-LRTs than S-M.

https://doi.org/10.1371/journal.pone.0077240.g001

Because lung and/or bone metastasis significantly predicted OS in univariate analysis (P = 0.033), it was entered into multivariate analysis, adjusting other significant covariates such as S-LRTs, Child-Pugh class, tumor size, AFP level ≥400 ng/mL, PIVKA level ≥1,000 AU/L, and the cumulative dose of sorafenib. However, presence of EHS and/or RNI was not incorporated into this analysis since presence of EHS and/or RNI partly included lung and/or bone metastasis. Finally, lung and/or bone metastasis was also selected as one of the independent prognostic factor for OS (adjusted HR 1.2, 95% CI 1.1-1.8, P = 0.031) (Table S1).

Treatment Outcomes and Variables Affecting PFS

The median PFS for the entire population was 3.4 months (95% CI 3.0–3.7). Subjects in the S-LRTs group had a significantly longer median PFS than those in the S-M group [5.3 months (95% CI 4.0–6.5 months) vs. 3.0 months (95% CI 2.7–3.2 months); P = 0.002; Figure 1]. In addition, Child-Pugh class, tumor size, EHS and/or RNI, AFP level ≥400 ng/mL, PIVKA level ≥1,000 AU/L, and the cumulative dose of sorafenib (transformed by natural logarithm) significantly predicted PFS in univariate analysis (all P < 0.05; Table 2). Subsequent multivariate analysis revealed that combined LRTs modality with sorafenib remained as the independent predictor for the better PFS (adjusted HR 0.6, 95% CI 0.4–0.9, P = 0.025), together with Child-Pugh class (adjusted HR 1.4, 95% CI 1.1–1.9, P = 0.029), tumor size (adjusted HR 1.6, 95% CI 1.1–2.4, P = 0.012), EHS and/or RNI (adjusted HR 1.7, 95% CI 1.2–2.4, P < 0.001 ), AFP level (adjusted HR 1.9, 95% CI 1.4–2.5, P < 0.001), and the cumulative dose of sorafenib (transformed by natural logarithm) (adjusted HR 0.6, 95% CI 0.5–0.7, P < 0.001) (Table 2).

Because lung and/or bone metastasis significantly predicted PFS in univariate analysis (P = 0.001), it was entered into multivariate analysis, adjusting other significant covariates such as S-LRTs, Child-Pugh class, tumor size, AFP level ≥400 ng/mL, PIVKA level ≥1,000 AU/L, and the cumulative dose of sorafenib. However, presence of EHS and/or RNI was not incorporated into this analysis since presence of EHS and/or RNI partly included lung and/or bone metastasis. Finally, lung and/or bone metastasis was also selected as one of the independent prognostic factor for PFS (adjusted HR 1.5, 95% CI 1.1-2.1, P = 0.005) (Table S1).

Subgroup Analysis According to EHS or Regional Node Metastasis and AFP

The OS and PFS of subgroups according to the presence of EHS and/or RNI were compared (Table 3). In each subgroup, patients treated with S-LRTs had longer OS compared to those treated with S-M (18.0 months vs. 7.8 months in a subgroup with neither EHS nor RNI and 8.3 months vs. 4.8 months in a subgroup with EHS and/or RNI; all P < 0.05). In addition, patients treated with S-LRTs had longer PFS compared to those treated with S-LRTs in a subgroup with neither EHS nor RNI (9.6 months vs. 3.2 months, P = 0.027). However, the therapeutic benefit of LRTs was only marginal in a subgroup with EHS and/or RNI (4.9 months vs. 2.9 months, P = 0.069).

The OS and PFS of subgroups were also affected by AFP level (<400 ng/mL vs. ≥400 ng/mL). In the subgroup with low AFP level (<400 ng/mL), the therapeutic benefit of LRTs to prolong OS did not reach the statistical significance (P = 0.449). However, in the subgroup with high AFP level (≥400 ng/mL), the LRTs was effective to improve the OS (3.4 months vs. 8.0 months, P = 0.001). Regarding PFS, similar results were obtained. Although the S-LRTs could not increase PFS in the subgroup of low AFP level (<400 ng/mL) (P = 0.225), it extended PFS significantly in the subgroup of high AFP level (≥400 ng/mL) (2.0 months vs. 4.2 months, P = 0.012).

Treatment-Related Toxicity

The treatment-related adverse effects of grade 2 or more are described in Table 4. The most common toxicity related to sorafenib was hand foot-skin reaction (23.0% in S-M group vs. 23.4% in S-LRTs group), followed by diarrhea (16.4% in S-M group vs. 15.6% in S-LRTs group). Grade 3 or 4 toxicities were relatively uncommon and hand foot-skin reaction of grade 3 or more was found in 8 (4.8%) patients in the S-M group and 2 (3.7%) patients in the S-LRTs group. Except anorexia, the addition of LRTs to sorafenib did not increase the occurrence of significant toxicities (all P > 0.05). All adverse events were manageable and there was no significance difference of the sorafenib discontinuation due to adverse effects between two groups.