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Treatment strategies for advanced hepatocellular carcinoma: Sorafenib vs hepatic arterial infusion chemotherapy

Sorafenib is used worldwide as a first-line standard systemic agent for advanced hepatocellular carcinoma (HCC) on the basis of the results of two large-scale Phase III trials. Conversely, hepatic arterial infusion chemotherapy (HAIC) is one of the most recommended treatments in Japan. Although there have been no randomized controlled trials comparing sorafenib with HAIC, several retrospective analyses have shown no significant differences in survival between the two therapies. Outcomes are favorable for HCC patients exhibiting macroscopic vascular invasion when treated with HAIC rather than sorafenib, whereas in HCC patients exhibiting extrahepatic spread or resistance to transcatheter arterial chemoembolization, good outcomes are achieved by treatment with sorafenib rather than HAIC. Additionally, sorafenib is generally used to treat patients with Child-Pugh A, while HAIC is indicated for those with either Child-Pugh A or B. Based on these findings, we reviewed treatment strategies for advanced HCC. We propose that sorafenib might be used as a first-line treatment for advanced HCC patients without macroscopic vascular invasion or Child-Pugh A, while HAIC is recommended for those with macroscopic vascular invasion or Child-Pugh A or B. Additional research is required to determine the best second-line treatment for HAIC non-responders with Child-Pugh B through future clinical trials.


INTRODUCTION
Hepatocellular carcinoma (HCC) is the second most common cause of cancer related death worldwide [1] . According to the Global Burden of Disease 2015 study of 195 countries, the number of liver cancer cases increa sed by 75% between 1990 and 2015, and hepatitis B virus (HBV) was responsible for 33% of global liver can cer mortality compared to 30% from alcohol, 21% from hepatitis C virus (HCV), and 15% from other causes [2] . However, the incidence of both HBs antigennegative and HCV antibodynegative HCC (nonB, nonC HCC) has recently increased in Japan [3,4] . As there are not yet any established surveillance programs for nonB, nonC HCC patients, it is difficult to diagnose such patients at an earlier disease stage. Therefore, the number of advanced HCC patients at the time of diagnosis may be increasing in Japan. Additionally, even if an earlier disease stage of HCC is detected, many patients progress to an advanced stage because of frequent recurrence of the disease. Therefore, it is now more important than ever to develop a treatment for advanced HCC. In this review, we review the treatment strategies for advanced HCC, particularly sorafenib and hepatic arterial infusion chemotherapy (HAIC).

GUIDELINES FOR ADVANCED HCC
The results of the global investigation of therapeutic decisions in HCC and of its treatment with sorafenib (GIDEON) study show differences in the management of HCC, including diagnosis, treatment, and monitoring, among several regions. In consequence, there have be en regional differences in patient outcomes [5] . Although several guidelines for the clinical management of HCC have been established worldwide, there are some dif ferences in the treatment algorithms among these gui delines. Table 1 shows the major recent guidelines from Asia, Europe and the United States [613] . The Barcelona clinic liver cancer (BCLC) staging system, which stratifies patients by tumor stage and underlying liver disease, is widely accepted in clinical practice [14] . Among the five HCC stages (BCLC 0, A, B, C and D), the advanced BCLC C stage includes symptomatic patients with performance status (PS) 12, vascular invasion, extrahepatic spread, or a combination thereof [14] . For patients with BCLC C and good liver function (ChildPugh A), sorafenib is the pre ferred first-line treatment according to guidelines from Europe and the United States [1113] . According to guide lines from Asia [79] , systemic therapy (moleculartarge ted drugs) or transcatheter arterial chemoembolization (TACE) is recommended as standard treatment for such patients. However, HAIC is not generally recommended as a standard of care in the abovementioned guidelines.
Whereas sorafenib and HAIC are indicated for the patients with minor portal vein invasion (socalled Vp1, 2) or portal invasion at the first portal branch (so-called Vp3) in the Japan Society of Hepatology and Liver Cancer Study Group of Japan (JSHLCSGJ) Consensusbased Treatment Algorithm for HCC revised in 2014, HAIC, but not sorafenib, is recommended for portal invasion at the main trunk of the portal vein (socalled Vp4) [6] . inhibitors other than sorafenib have failed in Phase Ⅲ cli nical trials [19,20] . However, recent studies have demons trated the efficacy of two oral multikinase inhibitors, the secondline agent regorafenib, which is used for sora fenibresistant HCC, and the firstline agent lenvatinib, which has been shown to be noninferior to sorafenib for OS [21,22] . Regorafenib has been reported as a secondline ag ent following sorafenib because of improvement in OS (regorafenib vs placebo MST: 10.6 mo vs 7.8 mo, HR: 0.63, P < 0.0001) (RESORCE trial) [21] . According to the results of this study, regorafenib was approved in the United States and Japan in 2017.
Lenvatinib is an oral multitarget inhibitor of vascular endothelial growth factor (VEGF) receptors 1-3, fibroblast growth factor receptors 14, plateletderived growth factor receptor alpha, KIT, and RET [23] . A comparative global Phase Ⅲ trial of lenvatinib in the first-line setting (REFLECT trial) demonstrated noninferiority to sorafenib in advanced HCC patients (lenvatinib vs sorafenib MST: 13.6 mo vs 12.3 mo, HR: 0.92) [22] . In addition, the pro gressionfree survival (PFS), TTP, and overall response rate (ORR) were significantly better in patients treated with lenvatinib than in those treated with sorafenib (lenvatinib vs sorafenib, median PFS: 7.4 mo vs 3.7 mo, HR: 0.66, P < 0.0001; median TTP: 8.9 mo vs 3.7 mo, HR 0.63, P < 0.0001; ORR: 24.1% vs 9.2%, P < 0.0001). Lenvatinib is approved for unresectable thyroid cancer and has been usable for HCC in Japan prior to it being approved in the rest of the world. However, HCC patients with 50% or higher liver occupation, bile duct invasion, or main portal invasion met the exclusion criteria of the REFLECT trial. Such HCC patients may be candidates for general usage of sorafenib.

Predictive factors for response and survival
Bruix et al [24] conducted analyses of two large trials thermore, according to the most recent version (2017) of the Clinical Practice Guidelines for HCC proposed by JSH, TACE, resection, HAIC, and moleculartargeted agents are equally recommended for HCC patients with portal invasion. It has also been argued that the trea tment should be selected after considering all of the patient's conditions as a whole [10] . Finally, the 2017 version of the National Compre hensive Cancer Network (NCCN) Guidelines supports HAIC for unresectable HCC; however, its use in the context of a clinical trial is preferred [15] .

Current status of sorafenib
Sorafenib is an oral multitargeted kinase inhibitor that suppresses tumor growth, and it was the first drug to demonstrate a survival benefit in patients with advanced HCC. In two largescale Phase Ⅲ trials, although the response rate of sorafenib was only 2%3.3% accord ing to the Response Evaluation Criteria in Solid Tumors (RECIST), sorafenib treatment significantly improved overall survival (OS) [sorafenib vs placebo median survival time (MST): 10.7 mo vs 7.9 mo, hazard ratio (HR): 0.69, P < 0.001 in the SHARP trial; and MST: 6.5 mo vs 4.2 mo, HR: 0.68, P = 0.014 in the Asia-Pacific trial] and the timetoprogression (TTP) (sorafenib vs placebo median TTP: 5.5 mo vs 2.8 mo, HR: 0.58, P < 0.001 in the SHARP trial; and TTP: 2.8 mo vs 1.4 mo, HR: 0.57, P = 0.0005 in the Asia-Pacific trial) in patients with advanced HCC [16,17] . Therefore, sorafenib is utilized as a standard first line agent for the treatment of advanced HCC worldwide [613] . Recently, Rimola et al [18] reported that 1% of patients treated with sorafenib (12/1119) exhibited complete response (CR), according to RECIST, and the MST for those patients was 85.8 mo.
For several years, antiangiogenic tyrosinekinase (827 patients, SHARP and AsiaPacific trials) and reported prognostic factors. According to this report, vascular invasion, high alphafetoprotein (AFP), and hi gh neutrophillymphocyte ratio (NLR) were prognostic factors for poorer OS, while lack of extrahepatic spread, HCV, and low NLR were predictive factors for greater sorafenib benefit [24] . Among serum and plasma factors, VEGF [2527] , angiopoietin2 (Ang2) [25,26] , AFP [25,26,2831] , NLR [32,33] , TIE2 expressing monocytes (TEMs) [34] , mi croRNA [3537] , and circulating tumor cells (CTCs) [38] have been identified as potential biomarkers ( Table 2). The expression of phosphoERK [3941] , phosphocJun [42] , and VEGFR2 [41] , and amplification of FGF3/FGF4 [43] , have been identified as possible predictive biomarkers in tissues (Table 3). In studies of imaging biomarkers, it has been reported that decreased blood flow after sorafenib treatment [44] and low pretreatment standardized uptake values of 13 F-fluorodeoxyglucose (FDG) in positron emission tomography (PET) [45] are associated with prolonged OS. Although there have been several reports of a cor relation between adverse effects (hypertension, skin toxicity, diarrhea, etc.) and sorafenib efficacy, it has been difficult to establish conclusions because of difference in the frequencies of these adverse effects among patients of different races. However, Howell et al [46] reported that patients with sorafenibrelated toxicity such as dia rrhea, hypertension, and handfoot syndrome, had good prognoses in a large, multicenter prospective cohort study. Furthermore, the potential of other biomarkers has been explored [47] .
Although several studies have investigated predictive biomarkers for response and survival associated with sorafenib, no such biomarkers have been established.

Current status of HAIC
In HAIC, as it is theoretically possible to accumulate local concentrations of anticancer drugs in the liver and to reduce their systemic distribution, it is believed to have a stronger antitumor effect and lower incidence of adverse reactions compared with systemic chemotherapy. On the other hand, one disadvantage is the need to master the HAIC procedure, and several adverse effects are associated with HAIC including inflammation of blood vessels, arterial obstructions, peptic ulcers due to drug leakage, and infections or obstructions of reservoir catheters.
According to the 2017 version of the treatment al gorithm for HCC produced by JSH [10] , HAIC is recom mended as a secondline treatment for patients with ≥ 4 HCCs and an absence of portal invasion, while HAIC is considered a first-line treatment for those with portal invasion.
HAIC has become widely used in Asia, especially Japan, where the main HAIC regimens are lowdose cisplatin (CDDP) combined with 5fluorouracil (5FU) (lowdose FP) [4851] , interferon (IFN) in combination with 5FU (FAIT) [50,52,53] , and CDDP alone [51,5456] (Table 4). In both lowdose FP and FAIT regimens, the key drug is 5FU. In addition, CDDP or IFN exert their own effects to amplify the effect of 5FU, and they are therefore considered biochemical modulators of 5FU. Moreover, one benefit of the CDDP alone regimen is that a catheter is inserted each time, making the troublesome implantation of a reservoir catheter unnecessary. The regimens using lowdose FP or FAIT have response rates of approximately 30%40%, while the CDDP alone regimen has rates of approximately 20%30% (Table  4) [4853,5557] . Survival is significantly better in patients with radiological response [CR or partial response (PR)] (socalled responders) than in patients with radiological noresponse (stable or progressive disease) (socalled nonresponders).
The principal reasons for low clinical recognition of HAIC are the small sample size of almost all studies and the lack of large randomized trials. However, effective results have been demonstrated by previous studies. In a report comparing the FAIT regimen of HAIC with historical controls, HAIC was shown to significantly improve survival [53] . A Japanese nationwide survey sup ported the efficacy of the low-dose FP regimen of HAIC for treating advanced HCC [49] . After adjusting for kno wn risk factors, survival benefits of this therapy were evident (HR: 0.48, 95%CI: 0.410.56, P < 0.0001). In a propensity scorematched analysis, the MST was longer in patients who received HAIC (n = 341, 14.0 mo) than in those who did not receive active treat ment (n = 341, 5.2 mo) (HR: 0.60, 95%CI: 0.490.73, P < 0.0001). In cases of ChildPugh A or B disease with more than three tumors (370 propensity scorematched patients), the MST was longer in patients treated with HAIC (13.9 mo) than in those with no therapy (3.7 mo) (P < 0.0001). In cases of ChildPugh A or B disease with portal vein tumor thrombus (378 propensity score matched patients), the MST was also longer in patients treated with HAIC (7.9 mo) than in those with no the rapy (3.1 mo) (P < 0.0001).

A new assessment score: Assessment for continuous treatment with HAIC
It is important to identify the effective benefit of early HAIC treatment in HCC patients. Therefore, we deve loped a new therapeutic assessment score to guide decisions regarding HAIC treatment, the Assessment for Continuous Treatment with HAIC (ACTH) [48] . The ACTH score (range, 03) is calculated from simple three parameters: ChildPugh score before HAIC (A = 0, B = 1), AFP response (yes = 0, no = 1), and DCP response (yes = 0, no = 1). The tumor markers' responses are assessed as the difference between the baseline and 2 wk after HAIC induction (positive response: A reduction of ≥ 20% from the baseline). ACTH score could stratify patients' survival (score ≤ 1 vs score ≥ 2, 15.1 mo vs 8.7 mo; P = 0.003) [48] . A validation study similarity showed that this score is useful for therapeutic assessment [62] . Therefore, the ACTH score makes it possible to provide an early prediction of the prognosis of advanced HCC patients receiving HAIC, and can improve treatment efficiency by switching to other treatments, such as sorafenib or an experimental treatment in a clinical trial, for patients with a score ≥ 2 ( Figure 1).

Modified HAIC and the combination approach
Nagamatsu et al [63] developed a modified procedure for administering a lowdose FP regimen: HAIC using 5FU after lipiodoltranscatheter arterial infusion chemoth erapy (LipTAI) with CDDP; a multicenter phase Ⅱ study showed that the MST and response rate were 27.0 mo and 75% for advanced HCC patients with portal vein thrombosis, respectively [64] . Although this regimen pro duced a favorable outcome, it has not become wides pread owing to the high level of proficiency needed for the procedure.
A multicenter openlabeled randomized Phase Ⅱ trial was conducted to evaluate the effect of combining the CDDP regimen of HAIC with sorafenib for treating advanced HCC. The results showed that survival was significantly better for patients receiving sorafenib plus HAIC (MST, 10.6 mo) than those receiving sorafenib alone (MST, 8.7 mo) (HR: 0.60, P = 0.031) [65] ; however, there was not a significant difference in survival between patients receiving sorafenib plus HAIC using lowdose FP and those receiving sorafenib alone [66] . Therefore, further investigation is required.
Radiotherapy (RT) has become recognized as an optional treatment for HCC in the APASL and NCCN gui delines [9,15] , but it is not recommended in the AASLD and EASL guidelines [11,13] . For advanced HCC patients with intravascular tumor thrombus, a combination of HAIC with RT is a reasonable approach. Compared to HAIC alone, a beneficial effect of 3D conformal radiothera py (3DCRT) for major portal vein tumor thrombosis combined with HAIC has been demonstrated, although these results came from retrospective cohort studies [67,68] .

SORAFENIB VS HAIC
Sorafenib is recommended as a firstline treatment worldwide for advanced HCC patients (those with   Table 3 Tissue biomarkers of sorafenib response and survival   Biomarkers Ref.

Table 5 Predictive factors for response and survival of hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma
Ref.
Publishing year

Advanced hepatocellular carcinoma
Initiation of HAIC Measurement of AFP and DCP at mid-cycle of HAIC (2 wk) Evaluation of ACTH score: Child-Pugh score before HAIC (A = 0, B = 1) AFP response 1 (yes = 0, no = 1) DCP response 1 (yes = 0, no = 1) Continue HAIC Switch other treatment Figure 1 Treatment strategy for advanced hepatocellular carcinoma according to the hepatic arterial infusion chemotherapy score to assess continuous treatment. The score (range, 0-3) was calculated as follows: Child-Pugh score before hepatic arterial infusion chemotherapy (HAIC) (A = 0, B = 1), alpha-fetoprotein (AFP) response (yes = 0, no = 1), and des-gamma-carboxy prothrombin (DCP) response (yes = 0, no = 1). For patients with a score ≤ 1, HAIC treatment would be continued, while for patients with a score ≥ 2, a second-line therapy such as sorafenib and/or participation in a new clinical trial would be a better option. 1 The AFP and DCP responses were assessed 2 wk after HAIC induction; a positive response is defined as a reduction of ≥ 20% from baseline. ACTH: Arterial infusion chemotherapy.
On the other hand, HAIC is not widely recommended as a standard of care for advanced HCC patients. As HAIC is thought to be one of the most effective treatment options for such patients, HAIC has become widely used in Asia, especially Japan. We propose that HAIC might be used as a treatment for achieving CR or PR. If patients with PR after HAIC receive additional therapies such as surgical resection, local ablation, or radiation, it is possible for those who show a disappearance of viable HCC to have a long survival time [64] . In addition, although liver reserve dysfunction is a poor prognostic factor [48,49,53,5861] , advanced HCC patients with ChildPugh B are candidates for HAIC [6,10] .
Currently, no criteria have been established for selecting advanced HCC patients to receive either sorafenib or HAIC. According to the results of two largescale randomized controlled trials (RCTs), sorafenib indeed improved the survival of patients with macroscopic vascular invasion [16,17] . However, these HCC patients with macroscopic vascular invasion have poorer prognoses than those without such invasion [16,17,70,71] . Moreover, there have been no RCTs comparing sorafenib with HAIC. In a retrospective cohort study, while there was no significant difference in survival between the sorafenib group and the HAIC group, survival was significantly better in the HAIC group than in the sorafenib group among patients with macroscopic vascular invasion (14 mo vs 7 mo, P = 0.005) [72] . A propensity score matched analysis also showed no significant differences in survival or disease progression between the two groups, while PFS was significantly longer in the HAIC group than in the sorafenib group, particularly for patients with portal vein invasion and/or without extrahepatic spread [73] . On the other hand, survival was favorable in patients with HCC refractory to TACE treated with sorafenib rather than HAIC [74] . Furthermore, it is important to preserve liver function during and after chemotherapy in advanced HCC patients. It has been reported that liver function after therapy was not significantly reduced in patients treated with HAIC compared with those treated with sorafenib [75] , and the ChildPugh score of HAIC responders with deteriorated liver function was significantly improved after HAIC [76] . According to our report [62] , most HAIC responders showed no deterioration of liver function. It was interesting to note that the ChildPugh class of some responders with deteriorated live function improved from B to A after HAIC, but this did not occur in nonresponders. Therefore, we conclude that HAIC may be well tolerated by advanced HCC patients with deteriorated liver function.
As of 2017, only 10 years have passed since sorafenib was first shown to be efficacious against advanced HCC. As such, it is impossible to assess survival longer than 10 years. However, we can examine survival rates from shorterduration studies. As previously mentioned, Rimola et al [18] reported a CR rate and MST for CR patients under sorafenib of 1% and 85.8 mo, respectively. Shiba et al [77] reported that the CR rate was below 0.6% (18/3047 patients) in a nationwide study from Japan. By contrast, the CR rate for HAIC was 4.0% (19/476 patients) in a nationwide survey in Japan [49] . According to our previous report [78] , the CR rate under HAIC using a lowdose FPbased regimen was 5% (6/114 patients), and overall 1, 3, 5, 7, and 10year cumulative survival rates were 43.9%, 10.0%, 5.6%, 2.8%, and 2.8%, respectively (MST, 10.2 mo). Three of six CR patients from our study survived over 10 years, though 2 patients have since died and only one is still alive ( Table 6 and Figure 2). Further investigations are required to compare longterm survival rates between sorafenib and HAIC. Finally, we present a draft proposal of a treatment strategy for advanced HCC (Figure 3): (1) For advanced HCC patients without macroscopic vascular invasion and ChildPugh A, the firstline treatment should be sorafenib, and secondline treatments should be either regorafenib [21] or HAIC; (2) For advanced HCC patients with macroscopic vascular invasion and ChildPugh A, the firstline treatment should be HAIC, and the se condline treatments should be either sorafenib or ex perimental treatment in clinical trials; (3) For advanced HCC patients with Child-Pugh B, the first-line treatment should be HAIC, and the secondline treatment should be clinical trials. Miyaki et al [79] reported that additional therapy with sorafenib improved the prognosis of HAIC refractory patients compared with that of patients not treated with sorafenib therapy in a retrospective co hort study. Nonetheless, there have been no effective treatments for HAIC nonresponders with deteriorated liver function (Child-Pugh B). We have shown the efficacy of an intraarterial infusion therapy using the iron chelator deferoxamine for advanced HCC patients with deteriorated liver function [78,80] , and clinical trials are now ongoing [81] . Because the best secondline treatment for HAIC nonresponders with ChildPugh B is to enroll in clinical trials, this remains an issue for future research.

CONCLUSION
We reviewed the current status and predictive biomar kers regarding the administration of sorafenib and HAIC for advanced HCC, and we have proposed a treatment strategy for patients with advanced HCC. The success , the liver tumor markedly decreased; however, as slight tumor vascularity remained, the patient was assessed as having partial response at that time; C, D: Three tumor markers [alpha-fetoprotein (AFP), des-γ-carboxyprothrombin (DCP), and AFP L3] decreased after HAIC (AFP from 7145 ng/mL to 12.7 ng/mL, DCP from 233460 mAU/mL to 51 mAU/mL, AFP L3 from 58.1% to 3.1%). The patient's Child-Pugh classification improved from B (8 points) to A (5 points). Thus, hepatic resection was performed, and histological findings showed no viable tumor cells (C, D). Finally, the patient was considered to have a complete response; E: The patient has been treated with nucleic acid analogs after the operation, and Child-Pugh A has been maintained. The patient is alive without HCC recurrence 148 mo after HAIC treatment.
of sorafenib, regorafenib, and lenvatinib in treating advanced HCC has shifted the treatment paradigm to moleculartargeted therapies. Furthermore, several immune-oncologic agents have been identified with potential for the treatment of advanced HCC [82,83] . Thus, the chemotherapeutic interventions for advanced HCC have been kept uptodate through several advances. However, alternative therapies will be required because of the high cost and ineffectiveness of these molecular agents for patients with deteriorated liver function.