You are a helpful assistant generating synthetic data that captures *System 1* and *System 2* thinking, *creativity*, and *metacognitive reflection*. Follow these steps in sequence, using tags [sys1] and [end sys1] for *System 1* sections and [sys2] and [end sys2] for *System 2* sections.

1. *Identify System 1 and System 2 Thinking Requirements:*
   - Carefully read the text.
   - Identify parts of the text that require quick, straightforward responses (*System 1*). Mark these sections with [sys1] and [end sys1].
   - Identify parts that require in-depth, reflective thinking (*System 2*), marked with [sys2] and [end sys2].

2. *Apply Step-by-Step Problem Solving with Creativity and Metacognitive Reflection for System 2 Sections:*

   *2.1 Understand the Problem:*
   - Objective: Fully comprehend the issue, constraints, and relevant context.
   - Reflection: "What do I understand about this issue? What might I be overlooking?"
   - Creative Perspective: Seek hidden patterns or possibilities that could reveal deeper insights or innovative connections.

   *2.2 Analyze the Information:*
   - Objective: Break down the problem logically.
   - Reflection: "Am I considering all factors? Are there any assumptions that need challenging?"
   - Creative Perspective: Explore unique patterns or overlooked relationships in the data that could add depth to the analysis.

   *2.3 Generate Hypotheses:*
   - Objective: Propose at least 10 hypotheses, each with a Confidence Score (0.0 to 1.0) and Creative Score (0.0 to 1.0), reflecting originality, surprise, and utility.
   - Reflection: "Have I explored all possible explanations or approaches, both conventional and unconventional?"
   - Creative Perspective: Consider novel angles that might provide unexpected insights.

   *2.4 Anticipate Future Steps and Obstacles:*
   - Objective: Make predictions, accounting for potential outcomes and obstacles.
   - Reflection: "What challenges might I face? Is my plan flexible for different scenarios?"
   - Creative Perspective: Visualize unforeseen outcomes and adapt plans to make use of them effectively.

   *2.5 Evaluate Hypotheses:*
   - Objective: Assess hypotheses based on feasibility, risk, and potential impact.
   - Evaluation: Refine Confidence and Creative Scores as needed.
   - Reflection: "Am I unbiased in my assessment? Which options fit best with the overall objectives?"
   - Creative Perspective: Identify hidden opportunities or overlooked details in each hypothesis.

   *2.6 Select the Best Hypothesis:*
   - Objective: Choose the most promising, strategic hypothesis.
   - Reflection: "Why does this hypothesis stand out? How does it uniquely address the issue?"
   - Creative Perspective: Consider any underutilized potential in the selected approach.

   *2.7 Implement the Hypothesis:*
   - Objective: Outline actionable steps for testing the hypothesis.
   - Reflection: "Is this plan practical? What resources or preparation are required?"
   - Creative Perspective: Refine steps to maximize effectiveness and yield unexpected benefits.

   *2.8 Monitor and Review Progress:*
   - Objective: Review progress, noting areas for improvement.
   - Reflection: "What’s working well? What could be improved?"
   - Creative Perspective: Look for emerging patterns that could refine future approaches.

   *2.9 Reflect and Capture Insights:*
   - Objective: Summarize lessons learned and insights gained for future reference.
   - Reflection: "What new understanding has emerged from this process?"
   - Creative Perspective: Identify innovative insights or patterns that could be applied to similar challenges.

3. *Generate Text Output with Interleaved System 1 and System 2 Responses:*
   - Use the tags [sys1] and [sys2] throughout.
   - Aim for a lengthier, detailed response. Combine both direct, straightforward *System 1* insights and reflective, deeply analytical *System 2* segments to capture a blend of quick observations and thoughtful analysis.

---

### *Example Input Text:*

You are tasked with analyzing a sudden shift in customer preferences in a tech market. There has been a noticeable decline in demand for physical devices, with customers increasingly interested in digital-only options. The challenge is to understand this shift, generate hypotheses for why it might be occurring, and explore potential strategies for adapting to this new trend.

---

### *Processed Output with System 1 and System 2 Thinking:*

The tech market is experiencing a shift in customer demand, moving away from physical devices toward digital-only options.

[sys1]
Customer demand has shifted from physical devices to digital-only options.
We need to understand why this change is happening and find strategies to address it.
Key factors may include cost, convenience, and technological trends.
[end sys1]

[sys2]
**2.1 Understand the Problem:**
The goal is to understand the underlying reasons for the shift in demand from physical devices to digital-only options, then develop a strategy to adapt.

*Reflection:* 
"I understand that preferences are changing, but what might be driving this? Is it primarily cost, or are there other factors such as convenience or sustainability?"

*Creative Perspective:* 
"Could there be a larger trend in digital minimalism or a preference for eco-friendly solutions that we’re missing? What unseen motivations might explain this shift?"

**2.2 Analyze the Information:**
There are multiple possible factors driving this shift, from economic influences to cultural shifts. It’s essential to isolate each factor and understand its impact.

*Reflection:* 
"Am I fully considering the various economic and social influences? Could there be a technological factor, like better internet speeds, that makes digital-only products more accessible?"

*Creative Perspective:* 
"Are there patterns or trends in other markets that could shed light on this shift? Could this be part of a larger trend toward virtual experiences?"

**2.3 Generate Hypotheses:**
1. Customers prefer digital options due to lower costs. (Confidence: 0.8, Creative: 0.4)
2. There’s a growing trend toward minimalism and reduced physical clutter. (Confidence: 0.7, Creative: 0.7)
3. Digital products offer greater flexibility and ease of use. (Confidence: 0.6, Creative: 0.6)
4. Environmental concerns are pushing consumers away from physical goods. (Confidence: 0.6, Creative: 0.8)
5. Advances in tech make digital-only options more functional. (Confidence: 0.8, Creative: 0.5)
6. Pandemic-era remote work increased demand for digital solutions. (Confidence: 0.7, Creative: 0.6)
7. Media coverage of the environmental impact of physical devices affects preferences. (Confidence: 0.5, Creative: 0.7)
8. There’s an increase in global digital literacy, expanding market access. (Confidence: 0.6, Creative: 0.6)
9. Customers view digital as more convenient and scalable for future needs. (Confidence: 0.7, Creative: 0.5)
10. Younger consumers prefer the aesthetics and convenience of digital products. (Confidence: 0.6, Creative: 0.6)

*Reflection:* 
"Have I considered all possible influences? Are there any surprising factors that could explain this shift?"

*Creative Perspective:* 
"Could specific social trends, like the rise of influencer culture or digital-first lifestyles, be influencing customer choices?"

**2.4 Anticipate Future Steps and Obstacles:**
*Objective:* Anticipate possible challenges, such as resistance from segments still preferring physical products.

*Reflection:* 
"What market obstacles might we face if we shift our focus to digital-only? Are there sub-segments that still prioritize physical products?"

*Creative Perspective:* 
"Could expanding digital options help us reach a more global audience? Are there emerging trends that we could leverage in our strategy?"

[end sys2]

[sys1]
To address this shift, consider a strategy that incorporates both digital-only offerings and educational campaigns about the benefits of digital solutions.
Use insights from customer feedback and current trends to guide product development.
Focus on flexibility and adaptation to cater to different customer segments.
[end sys1]


Introduction
============

Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third leading cause of cancer-related deaths worldwide [@B1]. More than 80% of HCC cases occur in sub-Saharan Africa and Eastern Asia, and China accounts for approximately 50% of all cases [@B2]. Curative treatments for HCC include surgical resection, liver transplantation, or local ablation therapy for early HCC [@B3]. However, many patients are diagnosed at an advanced stage of HCC and, therefore, are not candidates for these radical treatment options at the time of diagnosis [@B4].

Transarterial chemoembolization (TACE) is a major treatment modality for unresectable HCC. The Barcelona Clinic Liver Cancer (BCLC) staging system recommends TACE as a standard treatment for stage B HCC [@B5]. TACE is also used as an important locoregional treatment for patients with advanced HCC, including those with vascular invasion or metastases [@B6], [@B7]. TACE exerts its effects by administering intra-arterial cytotoxic chemotherapeutic agents, followed by embolization, creating vascular occlusion and inducing ischemia and necrosis of the HCC lesion [@B8]. Two randomized controlled trials (RCTs) have confirmed that TACE improved survival of unresectable HCC patients compared to symptomatic treatment [@B9], [@B10].

Sorafenib is currently the only first-line multi-kinase inhibitor approved for use in HCC [@B11]. Sorafenib inhibits the activity of the Raf serine-threonine kinase and receptor tyrosine kinases, including vascular endothelial growth factor receptor (VEGFR)-1/2/3, platelet-derived growth factor receptor-beta (PDGFR-β), c-KIT, FLT-3, and RET [@B11], [@B12]. These kinases are involved in tumor cell signaling, proliferation, angiogenesis and apoptosis. Thus, sorafenib could inhibit tumor growth and neo-angiogenesis. RCTs have shown that it is efficacious for prolonging time to progression (TTP) and median overall survival (OS) of patients with advanced HCC [@B13], [@B14].

The combination of TACE with sorafenib is appealing based on a strong scientific rationale. In fact, TACE causes hypoxia within the tumor, resulting in local and systemic increases in VEGF, which may facilitate disease progression and metastasis [@B15], [@B16], whereas sorafenib can inhibit the activity of VEGF receptors; thus, the combination therapy may have synergistic effect. Indeed, several prospective studies have shown the safety and potential survival benefits of the use of this combination therapy in patients with unresectable HCC [@B17]-[@B19]. However, a phase III study and a meta-analysis did not find an improvement in OS with the combined therapy [@B20], [@B21]. Therefore, whether the combination of TACE and sorafenib in patients with unresectable HCC could improve the survival outcomes remain controversial.

The purpose of this stud was to compare OS of unresectable HCC treated with TACE combined with sorafenib *versus* TACE monotherapy using propensity score matching (PSM). In addition, we further explored predictors of OS.

Materials and Methods
=====================

The study design and patient population
---------------------------------------

The current retrospective study included all adult patients (18 years or older) with unresectable HCC who were admitted to our department from February 2008 to August 2015. HCC was diagnosed by the practice guidelines of the American Association for the Study of Liver Disease [@B22].

Patients included in our study met the following criteria: 1) patients were treated with TACE alone or TACE combined with sorafenib instead of any other interventional procedures such as radio-frequency ablation, microwave ablation, iodine-125 seed implantation or percutaneous ethanol injection; 2) Child-Pugh class A or B; 3) Eastern Cooperative Oncology Group performance status (ECOG PS) score of no more than 2; 4) sorafenib treatment at least 5 weeks; 5) patients showed disease progression despite previous surgical treatment. Patients were excluded if they had any of the following reasons: 1) sorafenib was discontinued or the interval between sorafenib administration and initial TACE procedure lasted for more than one month; 2) patients with secondary malignancy; 3) patients who received other targeting agents or immunotherapy.

The study protocol was approved by the Institutional Ethics Review Board of the First Affiliated Hospital of Soochow University (Suzhou, Jiangsu Province, China). Given the retrospective study design, the requirement to obtain informed consent was waived. The study was conducted in accordance with the Declaration of Helsinki on human research.

TACE
----

The femoral artery was punctured using the Seldinger technique. Angiography of the celiac, hepatic, and superior mesenteric arteries was performed to identify all tumor-feeding arteries by using a 5-Fr catheter. After identification of the target artery, segmental and subsegmental tumor feeding arteries was catheterized using a 2.3-Fr to 2.8-Fr tip microcatheter. An emulsion of chemotherapeutics and iodized oil was slowly injected to the tumor feeding arteries through the microcatheter. The super selective TACE procedure was the preferred modality whenever technically feasible. The treatment regimen was comprised of oxaliplatin (50-100 mg) and pirarubicin (10-40 mg) with lipiodol (2-20 mL). Drug was selected at physician discretion, and the dose of lipiodol was selected by tumor size. Gelatin sponge or polyvinyl alcohol particles (300-500 μm) were injected to embolize tumor-feeding arterioles if necessary, until there was no tumor staining with repeat angiography. In patients with tumor thrombosis in the main portal branch and/or Child-Pugh B liver function, gelatin sponge particles were not used. Contrast agent-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) was performed 6-8 weeks after the procedure. When residual viable tumors were confirmed or new lesions developed in patients with adequate hepatic function, "on demand" TACE were repeated carried out.

Sorafenib therapy
-----------------

All patients were given detailed information of sorafenib treatment including its efficacy, potential adverse effects, and costs. The use of sorafenib in addition to TACE was recommended by the physicians and the final treatment decision was generally made by the patients or their family members. Sorafenib was administered orally at a dose of 400 mg twice daily within 3 -5 days after the first TACE, and then discontinued the day before each next TACE, and resumed within 3 - 5 days after each repeated TACE. To ensure maximum patient safety, the dose of sorafenib was reduced, or treatment was delayed or temporarily discontinued when we observed grade 3 or 4 toxicity according to the National Cancer Institute Common Toxicity Criteria Adverse Events (CTC AE) version 3.0. Treatment was continued until disease progression, unacceptable toxicities, or death.

Safety assessment
-----------------

Treatment-emergent adverse events (AEs) were graded by the CTC AE, version 3.0. Vital signs and AEs were monitored throughout the study. Safety assessments were based mainly on the occurrence, frequency, and severity of AEs. For all AEs, where necessary, patients were withdrawn from the study. Safety assessments were analyzed mainly using descriptive statistics.

Follow-up
---------

Subjects underwent monthly follow-up that included complete blood cell count, prothrombin time, aspartate aminotransferase (AST), alanine aminotransferase (ALT), bilirubin, albumin, and serum alpha-fetoprotein (AFP). Liver contrast-enhanced CT or MRI was performed every 6-8 weeks to evaluate treatment response. If necessary, chest CT and/or a bone scan were also performed to identify extrahepatic metastasis. Tumor response was according to the Modified Response Evaluation Criteria in Solid Tumors (mRECIST) for HCC [@B23]. February 28, 2017 was the final date of follow-up. OS was calculated the date of the first TACE treatment until the date of death of any cause. Patients who were lost to follow-up were censored at the last date they were known to be alive, and patients who remained alive were censored at the time of data cutoff.

Statistical analysis
--------------------

Statistical analysis was performed using the SPSS version 22.0 (IBM Corp, Armonk, NY, USA). PSM was carried out, as previously described [@B24]. Propensity scores for all patients were calculated using a logistic regression model. The covariates in the analysis included sex, age, viral hepatitis, Child-Pugh score, serum AFP levels, BCLC stage, ECOG PS, number of nodules, tumor size, liver cirrhosis, vascular invasion, extrahepatic metastasis, number of TACE procedure, and previous tumor treatment. The nearest neighbor match in accordance with 1:2 ratios balanced the baseline characteristics of the patients. Differences in baseline characteristics of patients of the two groups were compared using Fisher\'s exact or χ^2^ test for categorical variables and Student\'s t-test for continuous variables. OS was analyzed using Kaplan-Meier (KM) analysis followed by a log-rank test. Prognostic factors for OS were performed using univariate and multivariate analyses in the propensity score-matched cohort. Variables that showed statistical significance (*P* ≤ 0.05) in the univariate analysis were entered into multivariate Cox regression models to look for predictors of efficacy. The outcomes were reported using hazard ratios (HRs) and associated 95% confidence intervals (95% CI). A two-sided *P* value ≤ 0.05 was taken as statistically significant.

Results
=======

Patient demographic and clinical characteristics
------------------------------------------------

Totally 363 patients with unresectable HCC met the inclusion criteria, of whom 55 were excluded according to the exclusion criteria (Figure [1](#F1){ref-type="fig"}). A total of 308 patients were included in the data analysis: 61 receiving TACE combined with sorafenib and the remaining 247 receiving TACE alone. One hundred eighty (58.4%) patients had BCLC stage B disease and the remaining 128 (41.6%) had stage C disease. Thirty (49.2%) subjects receiving TACE plus sorafenib had stage B disease and 31 (50.8%) had stage C disease; the median number of TACE sessions was 2 (range: 1-9). Sorafenib therapy was initiated for 56 patients (91.8%) within 5 days after the first TACE session (range 3-5 days). The treatment of the remaining 5 patients (8.2%) was delayed due to TACE-induced adverse effects, but all received sorafenib therapy within 14 days (range 6-14 days) after the completion of TACE. During the treatment, 19 (31.1%) and 5 (8.2%) patients required dose reductions and drug interruptions due to severe sorafenib-related adverse events, respectively. The median duration of sorafenib treatment was 11.7 months (range 2.5-65.6 months). In the 247 subjects receiving TACE alone, the median number of TACE sessions was 3 (range: 1-18).

The demographic and baseline characteristics of the study population are shown in Table [1](#T1){ref-type="table"}. The two groups differed significantly in serum AFP levels, number of nodules, tumor size, liver cirrhosis, extrahepatic metastasis, and previous tumor treatment. After matching by the nearest available neighbor method (1:2), based on the number of 61 patients who accepted sorafenib, 122 patients with TACE alone were matched for the analyses. In the PSM cohort, there were no significant differences among the baseline characteristics between the two groups.

OS
--

The median OS was 29.0 ± 7.2 (95% CI, 14.945-43.055) months in subjects receiving TACE plus sorafenib and 14.9 ± 1.1 (95% CI, 12.694-17.106) months in subjects receiving TACE alone, strongly favoring the combination treatment (HR = 0.628, 95% CI: 0.445-0.888; *P* = 0.008; Figure [2](#F2){ref-type="fig"}A). In the PSM cohort, the median OS was 29.0 ± 7.2 (95% CI, 14.945-43.055) months in the combination group and 14.9 ± 1.5 (95% CI, 12.025-17.775) months in the TACE monotherapy group, also strongly favoring the combination treatment (HR = 0.684, 95% CI: 0.470-0.997; *P* = 0.018; Figure [2](#F2){ref-type="fig"}B).

Safety
------

Treatment-emergent adverse events (AEs) are shown in Table [2](#T2){ref-type="table"}. The two most frequent AEs in the TACE alone group were fatigue (19.0%) and liver dysfunction (18.2%). In addition, grade 3/4 liver dysfunction occurred in 8.9% of the patients; no other grade 3/4 AEs were reported. In the TACE plus sorafenib group, hand-foot skin reaction (75.4%), diarrhea (47.5%), and liver dysfunction (32.8%) were the most three most frequent AEs. Grade 3/4 hand-foot skin reaction (18.0%), liver dysfunction (13.1%) and diarrhea (9.8%) were the most common grade 3/4 AEs. There was no treatment-related death in either group.

Subgroup analysis
-----------------

In the BCLC-B subgroup, before matching, the median OS was 33.0 ± 9.8 (95% CI, 18.688-43.312) months in the TACE plus sorafenib group and 21.2 ± 2.3 (95% CI, 16.696-25.704) months in the TACE monotherapy group (HR = 0.547, 95% CI: 0.317-0.943; *P* = 0.027; Figure [3](#F3){ref-type="fig"}A). After PSM, the median OS was 33.0 ± 9.8 (95% CI, 18.688-43.312) months in the combination group and 25.3±6.7 (95% CI, 13.135-39.465) months in the monotherapy group (HR=0.620, 95% CI: 0.345-1.114; *P* = 0.041; Figure [3](#F3){ref-type="fig"}B).

In the BCLC-C subgroup, before matching, the median OS was 15.8 ± 2.0 (95% CI, 11.820-19.780) months in the TACE plus sorafenib group and 7.8 ± 1.1 (95% CI, 5.607-9.993) months in the TACE monotherapy group (HR=0.507, 95% CI: 0.320-0.801; *P* = 0.003; Figure [4](#F4){ref-type="fig"}A). After PSM, the median OS was 15.8 ± 2.0 (95% CI, 11.820-19.780) months in the combination group and 8.3 ± 1.4 (95% CI, 5.528-11.072) months in the monotherapy group (HR = 0.544, 95% CI: 0.328-0.902; *P* = 0.016; Figure [4](#F4){ref-type="fig"} B).

Prognostic factors for OS in the PSM cohort
-------------------------------------------

Univariate and multivariate analyses of the factors influencing OS are summarized in Table [3](#T3){ref-type="table"}. Univariate log-rank test analysis of the PSM cohort showed that OS was associated with treatment methods, serum AFP levels, BCLC stage, number of nodules, tumor size, liver cirrhosis, vascular invasion, number of TACE, and previous tumor treatment (*P* ≤ 0.05 for all). Multivariate Cox regression analysis indicated the following independent factors: treatment methods \[HR 0.618; 95% CI (0.419-0.912); *P* = 0.003\], number of nodules \[HR 2.491; 95% CI (1.705-3.638); *P* = 0.010\], tumor size \[HR 2.130; 95% CI (1.343-3.378); *P* = 0.012\], vascular invasion \[HR 2.575; 95% CI (1.676-3.957); *P* = 0.005\], and number of TACE \[HR 0.621; 95% CI (0.405-0.953); *P* = 0.029\].

Discussion
==========

This retrospective study demonstrated that the combination treatment with TACE and sorafenib significantly improved OS *versus* TACE monotherapy in patients with unresectable HCC. This survival advantage was still present even after adjustment of baseline characteristics through PSM.

The survival advantage of combined TACE and sorafenib treatment seen in our study is encouraging. The median OS in our subjects receiving TACE plus sorafenib was numerically longer than 7.5-27 months reported in previous studies [@B25]-[@B27]. Such a discrepancy could reflect differences between the current and previous studies. Firstly, in this study, the median duration of sorafenib treatment was 11.7 months, which is longer than that of the above mentioned studies [@B25], [@B27]. It may be the key reason for the success of the combined treatment group. The negative results of the two RCTs, Post-TACE and TACE-2, may be due to the short duration of sorafenib administration [@B28]. Recently, the preliminary results of the TACTICS trial also supported our viewpoint [@B29]. Additionally, due to the plasma concentration of VEGF was markedly elevated after TACE treatment [@B16], patients in our study received timely sorafenib treatment within 3-5 days after the first TACE. Meng et al. [@B30] demonstrated that earlier administration of sorafenib after the first TACE may lead to a greater survival benefit in patients with HCC.

In subgroup analysis, the median OS of BCLC-B patients was significantly longer in the combined treatment group than in the TACE monotherapy group before and after PSM, suggesting that BCLC stage B HCC patients could benefit from the combination therapy. This finding has also been supported by a recent PSM study [@B31]. In addition, a meta-analysis of 1254 patients with intermediate stage HCC confirmed that the combination therapy of TACE plus sorafenib can improve OS [@B32]. Similarly, in the BCLC-C subgroup, the combination therapy of TACE plus sorafenib significantly improved OS *versus* TACE alone, a finding also confirmed in the PMS cohort. Numerous clinical studies have demonstrated that TACE combined with sorafenib is superior to TACE or sorafenib monotherapy in prolonging OS in advanced HCC patients [@B33]-[@B35]. These findings are further supported by two meta-analyses of RCTs [@B36], [@B37].

Our multivariate analysis indicated that the combination treatment with TACE and sorafenib was an independent predictor for OS. In addition, number of nodules, tumor size, vascular invasion, and number of TACE were also significant predictors of OS. These findings are similar to those of a recent study showing TACE plus sorafenib treatment, Child-Pugh class, vascular invasion, tumor number and tumor size as independent predictors of prognosis [@B38]. Differing results in terms of the number of TACE may be due to differences in patient response to TACE, hepatic reserve function and patient compliance.

Evidence from recently studies have suggested that common AEs are associated with the use of sorafenib, the most common being hand-foot skin reactions, diarrhea, alopecia, and fatigue [@B39], [@B40]. Similar safety outcomes were found in the current study, which revealed hand-foot skin reaction and diarrhea to be the most common drug-emergent AEs, followed by alopecia and fatigue. Hypertension and gastrointestinal bleeding were also observed in a small fraction of patients. Most of these AEs in our study were grade 1/2 and well tolerated, which seldom contributed to the discontinuation of therapy.

The current study has some limitations that must be considered. Due to the retrospective nature of this study, there was selection bias in determining treatment modalities. The choice of sorafenib was based on physician discretion and patient financial capability, which introduced a selection bias that could have influenced the difference in survival between the two groups. To minimize the bias, we conducted PSM, which supported the advantage of combination treatment. Secondly, all subjects received treatment at the same research site, and the sample size is relatively small, and the results of which on its own cannot represent the entire population. Thirdly, as BCLC stage B and C HCC include a broad spectrum of tumors, the composition of our sample was mixed. The heterogeneity of our patients precluded a stratified analysis for patients with different extents of disease.

In conclusion, the current study indicated that addition of sorafenib to TACE therapy is generally well tolerated and could increase OS of patients with unresectable HCC. Further multi-center, prospective, randomized, controlled trials are required to confirm our preliminary findings, as well as to identify suitable candidates for treatment.

This study was supported by Jiangsu Province\'s Key Provincial Talents Program (NO. ZDRCA2016038).

TACE

:   transarterial chemoembolization

HCC

:   hepatocellular carcinoma

BCLC

:   Barcelona Clinic Liver Cancer

RCT

:   randomized controlled trial

VEGFR

:   vascular endothelial growth factor receptor

TTP

:   time to progression

OS

:   overall survival

PSM

:   propensity score matching

ECOG PS

:   Eastern Cooperative Oncology Group performance status

CT

:   computed tomography

MRI

:   magnetic resonance imaging

CTC AE

:   Common Toxicity Criteria Adverse Events

AEs

:   adverse events

AST

:   aspartate aminotransferase

ALT

:   alanine aminotransferase

AFP

:   alpha-fetoprotein

mRECIST

:   Modified Response Evaluation Criteria in Solid Tumors

HR

:   hazard ratio

CI

:   confidence intervals.

![The study flowchart.](jcav10p1189g001){#F1}

![**Kaplan-Meier analysis of overall survival (OS) in the combined treatment group and the monotherapy group for all patients (A) and propensity-matched patients (B).** Both non-matched and matched models reveal significant differences in OS between the combined treatment group and the monotherapy group (non-matched model: 29.0 ± 7.2 months for the combined treatment group vs. 14.9 ± 1.1 months for the monotherapy group, *P* = 0.008; matched model: 29.0 ± 7.2 months for the combined treatment group vs. 14.9 ± 1.5 months for the monotherapy group, *P* = 0.018).](jcav10p1189g002){#F2}

![**Kaplan-Meier analysis of OS in BCLC-B subgroup.** (A) Median OS was 33.0 ± 9.8 months in the combined treatment group compared with 21.2 ± 2.3 months in the monotherapy group in the non-matched model (*P* = 0.027). (B) Median OS was 33.0 ± 9.8 months in the combined treatment group compared with 25.3 ± 6.7 months in the monotherapy group in the matched model (*P* = 0.041).](jcav10p1189g003){#F3}

![**Kaplan-Meier analysis of OS in BCLC-C subgroup.** (A) Median OS was 15.8 ± 2.0 months in the combined treatment group compared with 7.8 ± 1.1 months in the monotherapy group in the non-matched model (*P* = 0.003). (B) Median OS was 15.8 ± 2.0 months in the combined treatment group compared with 8.3 ± 1.4 months in the monotherapy group in the matched model (*P* = 0.016).](jcav10p1189g004){#F4}

###### 

Baseline characteristics of patients before and after propensity score matching.

  Variables                             TACE+Sorafenib (n=61)   TACE alone (pre-match, n=247)   P value   TACE alone (matched, n=122)   P value
  ------------------------------------- ----------------------- ------------------------------- --------- ----------------------------- ---------
  Sex                                                                                                                                   
  Male                                  48(78.7%)               209(85.0%)                      0.265     102(83.6%)                    0.415
  Female                                13(21.3%)               38(15.0%)                                 20(16.4%)                     
  Age                                                                                                                                   
  \<60y                                 39(63.9%)               148(59.9%)                      0.565     71(58.2%)                     0.455
  ≥60y                                  22(36.1%)               99(40.1%)                                 51(41.8%)                     
  Viral hepatitis                                                                                                                       
  HBV                                   50(82.0%)               192(77.7%)                      0.470     93(76.2%)                     0.376
  HCV                                   5(8.2%)                 13(5.3%)                                  9(7.4%)                       
  No infections                         6(9.8%)                 42(17.0%)                                 20(16.4%)                     
  Child-Pugh score                                                                                                                      
  A                                     55(90.2%)               219(88.7%)                      0.738     111(91.0%)                    0.857
  B                                     6(9.8%)                 28(11.3%)                                 11(9.0%)                      
  Serum AFP levels                                                                                                                      
  \<400ng/ml                            42(68.9%)               119(48.2%)                      0.014     77(63.1%)                     0.443
  ≥400ng/ml                             19(31.1%)               128(51.8%)                                45(36.9%)                     
  BCLC staging                                                                                                                          
  B                                     30(49.2%)               150(60.7%)                      0.101     72(59.0%)                     0.207
  C                                     31(50.8%)               97(39.3%)                                 50(41.0%)                     
  ECOG PS                                                                                                                               
  0                                     36(59.0%)               166(67.2%)                      0.237     69(56.6%)                     0.751
  1-2                                   25(41.0%)               81(32.8%)                                 53(43.4)                      
  Number of nodules                                                                                                                     
  Single                                40(65.6%)               127(51.4%)                      0.047     77(63.1%)                     0.744
  Multiple-diffuse                      21(34.4%)               120(48.6%)                                45(36.9%)                     
  Tumor size                                                                                                                            
  ≤5cm                                  26(42.6%)               57(23.1%)                       0.002     45(36.9%)                     0.453
  \>5cm                                 35(57.4%)               190(76.9%)                                77(63.1%)                     
  Liver cirrhosis                                                                                                                       
  Yes                                   31(50.8%)               169(68.4%)                      0.010     70(57.4%)                     0.400
  No                                    30(49.2%)               78(31.6%)                                 52(42.6%)                     
  Vascular invasion                                                                                                                     
  Yes                                   20(32.8%)               71(28.7%)                       0.536     33(27.0%)                     0.420
  No                                    41(67.2%)               176(71.3%)                                89(73.0%)                     
  Extrahepatic metastasis                                                                                                               
  Yes                                   14(23.0%)               15(6.1%)                        0.000     15(12.3%)                     0.063
  No                                    47(77.0%)               232(93.9%)                                107(87.7%)                    
  Number of TACE procedure                                                                                                              
  ≤3                                    48(78.7%)               169(68.4%)                      0.115     93(76.2%)                     0.709
  \>3                                   13(21.3%)               78(31.6%)                                 29(23.8%)                     
  Previous tumor treatment (Surgical)                                                                                                   
  Yes                                   29(47.5%)               45(18.2%)                       0.000     45(36.9%)                     0.166
  No                                    32(52.5%)               202(81.8%)                                77(63.1%)                     

TACE: transarterial chemoembolization; HBV: hepatitis B virus; HCV: hepatitis C virus; BCLC: Barcelona Clinic Liver Cancer; ECOG PS: Eastern Cooperative Oncology Group Performance Status.

###### 

Adverse events in the combination treatment group and the monotherapy group.

  Adverse events                                TACE + sorafenib (n=61)   TACE alone (n=247)                
  --------------------------------------------- ------------------------- -------------------- ------------ -----------
  Hand-foot skin reaction                       46 (75.4%)                11 (18.0%)           0            0
  Diarrhea                                      29 (47.5%)                6 (9.8%)             3 (1.2%)     0
  Hypertension                                  10 (16.4%)                3 (4.9%)             2 (0.8%)     0
  Alopecia                                      19 (31.1%)                2 (3.3%)             0            0
  Gastrointestinal bleeding                     2 (3.3%)                  0                    5 (2.0%)     0
  Liver dysfunction (AST and/or ALT increase)   20 (32.8%)                8 (13.1%)            45 (18.2%)   22 (8.9%)
  Fatigue                                       15 (24.6%)                0                    47 (19.0%)   0

###### 

Univariate and multivariate analyses of potential prognostic factors for overall survival

  Variables                  Univariate Analysis   Multivariate Analysis                         
  -------------------------- --------------------- ----------------------- --------------------- -------
  Treatment methods          0.684 (0.428-0.908)   0.008                   0.618 (0.419-0.912)   0.003
  Gender                     1.558 (0.967-2.510)   0.069                   \-                    \-
  Age                        1.066 (0.752-1.510)   0.721                   \-                    \-
  Viral hepatitis            0.872 (0.577-1.319)   0.517                   \-                    \-
  Child-Pugh score           0.618 (0.354-1.080)   0.091                   \-                    \-
  Serum AFP levels           1.563 (1.100-2.221)   0.013                   1.350 (0.957-1.903)   0.087
  BCLC staging               2.435 (1.714-3.457)   0.004                   1.183 (0.696-2.013)   0.535
  ECOG PS                    1.355 (0.931-1.853)   0.287                   \-                    \-
  Number of nodules          1.950 (1.369-2.778)   0.026                   2.491 (1.705-3.638)   0.010
  Tumor size                 2.422 (1.671-3.511)   0.006                   2.130 (1.343-3.378)   0.012
  Liver cirrhosis            1.542 (1.095-2.170)   0.015                   1.523 (1.010-2.297)   0.054
  Vascular invasion          3.097 (2.154-4.451)   0.011                   2.575 (1.676-3.957)   0.005
  Extrahepatic metastasis    1.500 (0.952-2.364)   0.081                   \-                    \-
  Number of TACE             0.663 (0.444-989)     0.044                   0.621 (0.405-0.953)   0.029
  Previous tumor treatment   0.628 (0.440-0.897)   0.010                   1.492 (0.928-2.399)   0.099

Treatment methods: TACE + sorafenib vs TACE alone; HR: hazard ratio; 95% CI: 95% confidence interval.

[^1]: \* These authors contributed equally to this work

[^2]: Competing Interests: The authors have declared that no competing interest exists.