Background: In patients with advanced hepatocellular carcinoma (HCC), evidence is unclear as to whether hepatic arterial infusion chemotherapy (HAIC) or sorafenib is superior. We performed a prospective, open-label, non-comparative phase II study to assess survival with HAIC or HAIC converted to sorafenib. Methods: Fifty-five patients were prospectively enrolled. Patients received HAIC as a second course if they had complete response, partial response, or stable disease (SD) with an alpha fetoprotein (AFP) ratio < 1 or a des-γ-carboxy prothrombin (DCP) ratio < 1. Patients were switched to sorafenib if they had SD with an AFP ratio > 1 and a DCP ratio > 1 or disease progression. The primary endpoint was the 1-year survival rate. Secondary endpoints were the 2-year survival rate, HAIC response, survival rate among HAIC responders, progression-free survival, and adverse events. Results: Of the 55 patients in the intent-to-treat population, the 1-year and 2-year survival rates were 64.0 and 48.3%, respectively. After the first course of HAIC, one (1.8%) patient showed complete response, 13 (23.6%) showed partial response, 30 (54.5%) had SD, and 10 (18.1%) patients had progressive disease. Twenty-three patients (41.8%) had SD with AFP ratios < 1 or DCP ratios < 1, and 7 (12.7%) had SD with AFP ratios > 1 and DCP ratios > 1. Thirty-seven patients (68.5%) were responders and 17 (30.9%) were non-responders to HAIC. In responders, the 1-year and 2-year survival rates were 78 and 62%, respectively. Conclusion: Given the results of this study, this protocol deserves consideration for patients with advanced HCC. This trial was registered prospectively from December 12. 2012 to September 1. 2016. Keywords: HCC, HAIC, Sorafenib, Tumor marker, RECIST * Correspondence: firstname.lastname@example.org Department of Gastroenterology and Metabolism, Institute of Biomedical & Health Science, Hiroshima University, Hiroshima 734-8551, Japan Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Hatooka et al. BMC Cancer (2018) 18:633 Page 2 of 10 Background or DCP levels increased. Therefore, we considered patients Hepatocellular carcinoma (HCC) is the sixth most common to be HAIC responders in the first course of HAIC when cancer and the second leading cause of cancer-related mor- they showed CR, PR, or SD with decreased levels of AFP or tality in the world. [1, 2]. Advances in technology have con- DCP. We defined HAIC non-responders as either patients tributed to development of new diagnostic techniques such with PD or patients with SD who had increased levels of as ultrasonography, computed tomography, magnetic res- AFP and DCP after the first course of HAIC. onance imaging, and angiography. Similarly, new treatment Few prospective studies of HAIC have been performed. modalities have been developed, including surgical resec- No study protocols have been examined in which HAIC tion, radiofrequency ablation , percutaneous ethanol in- was continued only in responders while non-responders jection, transcatheter arterial chemoembolization (TACE), were switched to sorafenib where the outcome of the first and hepatic arterial infusion chemotherapy (HAIC), course of HAIC was determined by early assessment of resulting in improved prognosis in HCC patients [4–12]. tumor markers and imaging responses. Therefore, we cre- However, the survival rates are still poor for patients with ated a protocol in which HAIC was continued unless the advanced HCC with associated complications such as por- outcome of therapy was non-response, and non-responders tal vein tumor thrombosis, and refractoriness to TACE. were then switched from HAIC to sorafenib. Two phase III clinical trials of sorafenib for advanced HCC showed significant efficacy in terms of overall sur- Methods vival (OS) time compared with placebo [13, 14]. Based Study design on these studies, sorafenib has become the standard of The phase II HICS study (Hepatic Arterial Infusion therapy for advanced HCC. Sorafenib is associated with Chemotherapy followed by Sorafenib) was a single-arm, extension of OS time by 2.3–2.8 months and the im- prospective, open-label trial. In this study, the primary provement of response rate by 2.0–3.3%. However, the endpoint was the survival rate at 1 year. The secondary survival advantage of sorafenib has been described as endpoints were the survival rate at 2 years, overall sur- insufficient. vival (OS), response to HAIC, survival rate according to HAIC is widely used throughout Asia, especially in HAIC response, progression-free survival (PFS), and ad- Japan. Several studies have shown the survival benefits verse events (AEs). The primary endpoint, survival rate of HAIC for advanced HCC free of extrahepatic metas- at 1 year, was defined as the probability of patients being tasis (extrahepatic spread, or EHS), with response rates alive 1 year after their first course of HAIC. OS was de- ranging from 20.8 to 52%, and have shown that the me- fined as the time from the start of the study treatment dian survival time (MST) in responders ranges from to the death due to any reason. PFS was defined as the 17.6–40.7 months [11, 12, 15–18]. In most retrospective time from the start of study treatment to the first docu- studies, the survival time was much better among re- mentation of objective tumor progression or to death sponders than non-responders. Nevertheless, HAIC is not due to any cause. regarded as the standard of care for advanced HCC pa- One month after the first course of HAIC, therapeutic tients as no prospective randomized phase III trials have efficacy was assessed by imaging studies and AFP/DCP. shown survival benefits in patients with advanced HCC. Results of imaging studies were assessed according to Among responders, a better prognosis was expected the Response Evaluation Criteria In Solid Tumors. with HAIC compared with sorafenib, while HAIC Safety assessments of the drugs included recording of non-responders had a poor prognosis at 6 months in AEs, changes in laboratory test results, physical examin- previous studies. Therefore, it is necessary to identify ation, and vital signs. Adverse events associated with the HAIC non-responders as early as possible. drugs were those listed in the Common Terminology In a previous study, we reported that patients showing Criteria for Adverse Events (CTCAE) 4.0. either complete or partial response (CR and PR respect- The study was registered with the University Hospital ively) by the first course of HAIC had good prognoses, Medical Information Network Clinical Trials Registry as whereas patients with progressive disease  by the HICS 55, with the identifier number UMIN 000009094. first course of HAIC had poor prognoses. However, we The study was approved by the ethics committee and con- observed that the majority of patients had stable disease ducted in accordance with the Declaration of Helsinki. (SD) after the first course of HAIC. Furthermore, we Informed consent was obtained from each patient. reported that among patients determined to have SD based on the imaging response to the first course of HAIC, Patients those with alpha fetoprotein (AFP) and des-γ-carboxy pro- Key inclusion criteria were as follows: minimum age of thrombin (DCP) ratios > 1 had significantly poorer survival 20 years; life expectancy of at least 12 weeks at the pre-- times .That is, patients in whom AFP or DCP levels treatment evaluation; advanced HCC based on histological decreased had better prognoses than those in whom AFP evidence via biopsy specimen or dynamic computed Hatooka et al. BMC Cancer (2018) 18:633 Page 3 of 10 tomography or magnetic resonance imaging; not eligible switched from HAIC to sorafenib. The therapeutic efficacy for resection or local ablation therapy or TACE; at least of sorafenib was assessed by imaging studies and AFP/ 4 weeks since the last therapy for HCC; no prior sorafenib DCP one month after starting therapy. TACE was pro- and HAIC treatment; no intrahepatic tumor that could vided to partial and non-responders during this study. affect patient prognosis; Eastern Cooperative Oncology Group performance status of 0 or 1; Child-Pugh score Hepatic arterial infusion chemotherapy of 5, 6, or 7; and adequate bone marrow, liver, and renal Cisplatin was administered at a dose of 20 mg/m /day function, as assessed by the following laboratory re- on days 1 and 8, and fluorouracil was administered at a 3 2 quirements: granulocyte count ≥3000/mm , platelet dose of 330 mg/m /day on days 1–5and 8–12 of every count ≥50,000 /mm ,hemoglobin ≥8.5 g/dL, total serum 28-day cycle, followed by 2 weeks off. HAIC was inter- bilirubin ≤3 mg/dL, serum albumin ≥2.8, serum creatinine rupted in patients who experienced hematologic and ≤1.5 mg/dL, prothrombin consumption test ≥50%, and non-hematologic toxicities attributed to HAIC. amylase ≤ twice the upper limit of normal. Key exclusion criteria were as follows: other malignant disease, preg- Sorafenib nancy or suspected pregnancy, severe infectious disease, Sorafenib 400 mg bid was used for the treatment of patients history of severe allergy, severe renal function disease, se- who switched from HAIC. Sorafenib doses were adjusted, vere allergy to 5-fluorouracil or cisplatin, severe bone mar- by interruption or reduction, in patients who experienced row suppression, esophageal and/or gastric varices with a clinically significant hematologic or non-hematologic toxic- high risk of bleeding and clinically significant gastrointes- ities attributed to sorafenib. Sorafenib doses were reduced tinal bleeding, or serious hypertension. Patients who were stepwise from 400 mg twice daily to 400 mg once daily to unstable or whose safety or compliance in the study could 400 mg every other day to 200 mg every other day as war- be jeopardized based on the investigator’s judgment were ranted. Stepwise increases were allowed after resolution of also excluded. the AE. TACE, radiation therapy, and hepatectomy were allowed as additional therapies. Treatments Figure 1 illustrates the study schema. HAIC was adminis- Statistical analysis tered as the first therapy. Within one month after HAIC We assumed a threshold survival rate at 1 year of 45% with administration, efficacy was assessed by imaging studies an expected survival rate at 1 year of 60% (0.1 α-error and and AFP/DCP. Patients who showed CR or PR or SD with 0.1 β-error). From these, we predicted that 46 patients AFP ratio < 1 or DCP ratio < 1 were defined as responders. would qualify and established a patient enrollment target of Patients who showed SD with AFP ratio > 1 and DCP 55 assuming that 20% would be disqualified. ratio > 1 or PD  were defined as non-responders. Re- Statistical analysis was performed using SPSS (IBM, sponders continued HAIC while non-responders were Armonk, NY, USA). Continuous variables are expressed st HAIC 1 course Evaluation in each course using RECIST and tumor marker ratio HAIC responder HAIC non-responder CR/PR PD SD with AFP > 1 and DCP > 1 nd HAIC 2 course Conversion to sorafenib Fig. 1 Study schema. Abbreviations: AFP alpha fetoprotein, CR complete response, DCP des-gamma-carboxy prothrombin, FP, HAIC hepatic arterial infusion chemotherapy, PD progressive disease, PR partial response, SD stable disease Hatooka et al. BMC Cancer (2018) 18:633 Page 4 of 10 as medians and ranges, while categorical variables are Table 1 Background characteristics of patients who received hepatic arterial infusion chemotherapy expressed as counts or frequencies. Kaplan–Meier survival curves with log-rank tests were used for the analysis of Characteristics Median (range) or patient numbers OS. The statistical analysis was performed in September Age (years) 66 (32–88) 2017. Differences between groups were examined for stat- istical significance using the Mann-Whitney U test, logis- Gender (M/F) 49/6 tic regression test, or chi-square test as appropriate. The ECOG performance status (0/1) 50/5 cumulative survival rate was calculated from the date of Etiology (HBV/HCV/others) 14/24/17 initiation of HAIC and assessed by the Kaplan-Meier Platelet count (/mm ) 15.6 (6.4–41.4) life-table method. Differences between groups were evalu- Total bilirubin (mg/dL) 0.9 (0.3–1.8) ated by the log-rank test. For baseline characteristics such Albumin (g/dL) 3.7 (2.7–5.0) as performance status, age, stage of disease, and history of therapy, we calculated frequencies, averages, and medians Prothrombin consumption test (%) 78 (57.4–118) to assess their distribution. Child-Pugh score (5/6/7) 22/23/10 Variables that achieved statistical significance (P <0.05) Number of liver tumors 5 (1–40) or marginal significance (P < 0.10) in the univariate ana- Size of liver tumors (mm) 85 (18–170) lysis were entered into multiple logistic regression analysis Macroscopic vascular invasion (without/with) 17/38 to identify significant independent predictive responders. Vp (0–2/3–4) 26/29 Multivariate Cox proportional hazards regression was performed to assess the independent prognostic factors. Vv (0–1/2–3) 46/9 For both univariate and multivariate analyses, all inde- Relative tumor size in the liver (< 50%/≥ 50%) 47/8 pendent factors that demonstrated statistical significance TACE refractory (without/with) 42/13 as a predictor were analyzed using stepwise selection in Extrahepatic spread (without/with) 49/6 the model. Hazard ratios and corresponding 95% confi- HCC stage (III/IVa/IVb) 30/22/3 dence intervals are reported. BCLC stage (B/C) 18/37 Results AFP (ng/mL) 1895.2 (2.6–529,500) Baseline characteristics DCP (mAU/mL) 3854 (24–226,990) Between December 2012 and October 2016, 55 patients Abbreviations: AFP alpha-fetoprotein, DCP des-gamma-carboxy prothrombin, with unresectable HCC were enrolled in this study at par- ECOG Eastern Cooperative Oncology Group, HBV hepatitis B virus, HCC hepatocellular carcinoma, HCV hepatitis C virus, Vp portal invasion, Vv ticipating hospitals in the Hiroshima Liver study group. venous invasion The median period of observation was 12.2 months with a Vp0 through Vp4 indicated no, third branch, second branch (segmental invasion), first branch (branch invasion) and main portal vein invasion, range of 2.1 to 54.6 months. The data was last updated on respectively, according to Liver Cancer Study Group of Japan criteria September 2017. b According to the Liver Cancer Group of Japan BCLC: Barcelona Clinic Liver Cancer, Patient characteristics are listed in Table 1. The major- ity of study subjects were male, with a median age of 66 years. Among 29 patients who had Vp 3 and 4, 19 pa- in one(1.8%)patient, PRin13(23.6%),SD in30(54.5%), tients received three-dimensional conformal radiother- and PD in 10 (18.1%) patients. SD patients were classified apy. Patients received HAIC therapy a median of two into two groups: 23 patients (41.8%) had SD with AFP ra- times (range: 0 to 11 times). tio < 1 or DCP ratio < 1, whereas 7 (12.7%) had SD with AFP ratio > 1 and DCP ratio > 1. Efficacy Figure 2 shows the flow of patients through the study. Survival The number of responders was 37 patients (68.5%), and Among 55 patients, 27 patients died of HCC; no patients the number of non-responders was 17 patients (30.9%). died of other diseases. Among the responders, 32 patients received a second In the intent-to-treat population, the 1-year and 2-year course of HAIC. Five patients could not undergo the sec- survival rates were 64.0 and 48.3%, respectively (Fig. 3a). ond course because of angitis, catheter occlusion, or wors- The median survival time was 19.9 months, and the PFS ening of performance status. Among the non-responders, of the responders to HAIC was 5.0 months (Fig. 3b). 7 patients switched to sorafenib, whereas 10 patients were The MST of the responders to HAIC and of the ineligible for sorafenib treatment due to liver dysfunction, non-responders to the first course of HAIC were 30.5 disease progression, or worsening of performance status. and 7.7 months, respectively. MST differed significantly The imaging response by the Response Evaluation Criteria between the responders and non-responders (P < 0.001). In In Solid Tumors to the first course of treatment was CR the responders, the 1-year and 2-year survival rates were 78 Hatooka et al. BMC Cancer (2018) 18:633 Page 5 of 10 Patients who were enrolled in HAIC (n=55) Dislocation of tip of catheter (n=1) 1st course of HAIC HAIC responder HAIC non-responder 67.2% (n=37) 30.9% (n=17) Liver dysfunction Angitis (n=3) (n=4) catheter occlusion (n=1) Disease progression (n=3) Worsening of performance Worsening of status (n=1) performance status (n=3) Second course of HAIC Conversion to sorafenib 41.1% (n=7) 86.5% (n=32) Fig. 2 Patient flow chart. Abbreviations: HAIC hepatic arterial infusion chemotherapy and 62%, respectively. In the non-responders, the 1-year and platelet count decrease, AST/ALT increase and leuco- 2-year survival rates were 28 and 12%, respectively (Fig. 4a). cyte count decrease. However, the frequency of AE ≥ MST differed significantly among the imaging response grade 3 was 21.8%. groups (P < 0.0001): 26.6, 30.5, 12.0, and 6.0 months in patients with PR, SD (AFP ratio < 1 or DCP ratio < 1), Predictive parameters of efficacy and overall survival SD (AFP ratio > 1 and DCP ratio > 1), and PD, respect- The univariate analysis identified three parameters that ively (Fig. 4b). were correlated either significantly or marginally with response: TACE refractory status (without TACE re- Safety profile fractory; P =0.007), and MVI (without MVI; P = 0.018). Adverse events (AE) during the first course of HAIC are TACE refractory status and MVI were entered into the shown in Table 2. The most common AEs were anemia, multiple logistic regression analysis to identify significant Number 55 42 29 18 15 10 7 6 21 0 6 0 Number 55 23 16 10 9 7 6 21 at risk at risk Follow-up period (months) Follow-up period (months) Fig. 3 (a) Overall survival (b) Progression free survival Overall survival Progression-free survival Hatooka et al. BMC Cancer (2018) 18:633 Page 6 of 10 P < 0.001 P < 0.001 CR Responder -- - Non-responder SD with AFP<1 or DCP<1 PR SD with AFP>1 and DCP>1 PD DO Follow-up period (months) Follow-up period (months) Number at risk Number at risk CR 1 PR 13 12 10 5 5 3 3 2 1 0 Responder 37 34 27 17 14 10 7 6 2 1 0 SD with 22 21 16 11 8 6 4 4 1 1 0 AFP<1 or DCP<1 Non-responder 17 9 3 1 1 0 SD with 6 6 3 1 1 0 AFP>1 and DCP>1 PD 9 3 0 DO 1 0 Fig. 4 (a) Overall survival according to response (b) Overall survival according to responder or non-responder status independent predictive factors. The multivariate analysis model analysis. This analysis identified EHS as a significant identified the without-TACE refractory stratus as the only and independent determinant of survival. significant and independent factor that influenced re- Subgroup analysis was performed according to Child-Pugh sponse (Table 3). status, macroscopic vessel invasion, EHS and TACE By means of univariate analysis, we then investigated refractory status. MST (25 months) of Child-Pugh A the relationship between survival after the initiation of patients was significantly longer than that (13 months) HAIC treatment and various clinicopathological vari- of Child-Pugh B patients (P = 0.0007) (Fig. 5a). The MST of ables (Table 4). Child-Pugh A, platelet count, DCP and patients who had HCC with and without macroscopic ves- EHS correlated significantly with OS. The above parameters sel invasion were not significantly different: 25.4 months were then entered into a multiple Cox proportional-hazard and 16.3 months, respectively (Fig. 5b). The MST of Table 2 Adverse events associated with the first course of hepatic arterial infusion chemotherapy No. (%) Grade 1 Grade 2 Grade 3 Grade 4 Total Clinical Nausea/Vomiting 9 (17) 2 (4) 0 0 11(20) Anorexia 10 (19) 7 (13) 1(25) 0 18 (33) Fever 5 (9) 1 (25) 0 0 6 (11) Pain 11 (20) 0 0 0 11 (20) Fatigue 8 (15) 1(25) 0 0 9 (17) Diarrhea 0 1(25) 0 0 1(25) Laboratory abnormalities Leucocyte count decrease 22 (41) 6 (11) 1(25) 0 29 (54) Neutrophil count decrease 10 (19) 2 (4) 0 0 12 (22) Anemia 26 (48) 7 (13) 2 (4) 0 35 (65) Platelet count decrease 22 (41) 9 (17) 4 (7) 0 35 (65) AST/ALT increase 24 (44) 4 (7) 4 (7) 0 32 (59) Creatinine increase 15 (28) 0 0 0 15 (28) Total 12 (21.8) 0 (0) Abbreviations: ALT alanine aminotransferase, AST aspartate aminotransferase Overall survival Overall survival Hatooka et al. BMC Cancer (2018) 18:633 Page 7 of 10 Table 3 Univariate and multivariate analyses of factors associated with response Parameters Univariate analysis Multivariate analysis P value Odds ratio 95% CI P value Age (< 65/≥ 65 years) 0.462 Gender (Male/Female) 0.917 ECOG performance status (0/1) 0.667 4 4 Platelet count (< 14.9 × 10 /> 14.9 × 10 /μL) 0.487 Child-Pugh score (A/B) 0.736 Diameter of main tumor (< 80 mm/≥ 80 mm) 0.52 Macroscopic vascular invasion (without/with) 0.018 TACE refractory (without/with) 0.007 5.689 1.490–21.724 0.011 AFP (< 1895/≥ 1895 ng /mL) 0.149 DCP (< 3854/≥ 3854 mAU/mL) 0.547 Extrahepatic spread (without/with) 0.3 Abbreviations: AFP alpha-fetoprotein, DCP des-gamma-carboxy prothrombin, ECOG Eastern Cooperative Oncology Group, MVI macroscopic vascular invasion, TACE transarterial chemoembolization patients who had HCC without EHS was significantly with advanced HCC. The rate of AEs (grade ≥ 3: 21.8%) longer than that of patients who had HCC with EHS was judged to be acceptable by the investigators. (26.6 vs 6.3 months, respectively) (P < 0.001) (Fig. 5c). Sorafenib is currently the standard first-line therapy The MST of patients without and with TACE refractory for advanced HCC patients. However, the MST and re- status was not significantly different: 25.4 months and sponse rate were almost 10 months and 10% with sorafe- 16.3 months, respectively (Fig. 5d). nib therapy, respectively. In addition, HAIC is not used as a standard therapy for advanced HCC patients due to the lack of clinical trial data supporting its use. Discussion The primary endpoint of the 1-year survival rate was We investigated the efficacy of a protocol in which 64.0%, and the MST was 30.5 months. When we compared HAIC was selected as the first-line therapy for patients our protocol to other treatment protocols for advanced with advanced HCC and sorafenib was selected as the HCC, the 1-year survival rates in the SHARP study and in second-line therapy for patients refractory to HAIC. In the Asia-Pacific study of sorafenib monotherapy were 44 our study, the 1-year and 2-year survival rates were 64.0 and 32%, respectively [13, 14]. HAIC therapy followed by and 48.3%, and the MST was 19.9 months. OS was judged sorafenib was superior to sorafenib monotherapy. In sub- to be favorable with HAIC as first-line therapy for patients group analysis of our study, the MST of patients who had Table 4 Univariate and multivariate analyses for determinants of overall survival Parameters Univariate analysis Multivariate analysis P value Hazard ratio 95% CI P value Age (< 65/≥65 years) 0.304 Gender (Male/Female) 0.325 ECOG performance status (0/1) 0.187 4 4 Platelet count (< 14.9 × 10 /> 14.9 × 10 /μL) 0.07 Child-Pugh score (A/B) 0.008 Diameter of main tumor(< 80 mm/≥ 80 mm) 0.036 Macroscopic vascular invasion (without/with) 0.646 TACE refractory (without/with) 0.101 AFP (< 1895/≥ 1895 ng /mL) 0.515 DCP (< 3854/≥ 3854 mAU/mL) 0.055 Extrahepatic spread (without/with) 0.004 3.905 1.420–10.736 0.008 Abbreviations: AFP alpha-fetoprotein, DCP des-gamma-carboxy prothrombin, ECOG Eastern Cooperative Oncology Group, MVI macroscopic vascular invasion, TACE transarterial chemoembolization Hatooka et al. BMC Cancer (2018) 18:633 Page 8 of 10 Child Pugh A MVI - Child Pugh B MVI + P =0.0007 P =0.548 Follow-up period (months) Follow-up period (months) c d EHS - TACE refractory - EHS + TACE refractory + P =0.004 P =0.162 Follow-up period (months) Follow-up period (months) Fig. 5 (a) Overall survival according to Child Pugh grade (b), macroscopic vessel invasion (MVI), (c) extrahepatic spread (EHS), and (d) transcatheter arterial chemoembolization (TACE) refractory HCC with and without macroscopic vessel invasion was non-responders, avoiding unnecessary AEs associated not significantly different: 25.4 months and 16.3 months, with HAIC. respectively (Fig. 5b). The MST of patients who had HCC In our study, 21.8% of patients had AE ≥ grade 3. without EHS was significantly longer than that of patients Similar to our study, rates of AE ≥ grade 3 were 36 and who had HCC with EHS (26.6 vs 6.3 months, respectively) 23.5% in the SHARP and Asia-Pacific studies, respect- (P < 0.001) (Fig. 5c). Bruix et al. reported that the MST of ively [13, 14]. While occlusion of catheter and angitis as patients who had HCC with and without macroscopic ves- HAIC-specific AEs were observed in our study, the sel invasion were 8.1 months and 14.1 months, respectively, rates of HAIC-specific AEs in this study were similar to in sub-analysis of the SHARP study . Cheng et al. those of previous studies [11, 12]. reported that the MST of patients who had HCC with Our multivariate analysis identified TACE non-refractory macroscopic vessel invasion and/or EHS was 5.6 months, status as the only significant and independent factor and the MST of patients who had HCC without macro- that influenced response. In addition, a multiple Cox scopic vessel invasion or EHS was 14.3 months, respect- proportional-hazard model analysis identified lack of ively, in sub-analysis of the Asia-Pacific trial. Therefore, EHS as a significant and independent determinant for HAIC therapy followed by sorafenib was superior to so- OS. Retrospective studies have shown similar results. In rafenib monotherapy in patients with macroscopic ves- two studies, OS was significantly longer in those treated sel invasion. HAIC therapy followed by sorafenib was with sorafenib compared with HAIC in HCC patients not inferior to sorafenib monotherapy in patients with refractory to TACE. A possible reason is that those studies EHS . Furthermore, we compared our protocol to a involved shorter duration of HAIC and a need to withdraw previous HAIC study. Nouso et al. reported that the thetreatment duetostenosis of hepatic artery by catheter 1-year survival rate of HAIC was 52% in a nationwide therapy, reduced sensitivity to the drug, deterioration of study in Japan . Although, there were few differences liver function, and appearance of collateral arteries [23, 24]. between our protocol and Nouso’s study, results of HAIC Another study reported that EHS was a poor prognosis fac- therapy followed by sorafenib in our study was super- tor in HAIC therapy . Given these results, if our study ior to that of the previous HAIC study. The reason for protocol were to be conducted in patients with TACE our favorable results could be that we continued HAIC non-refractory status and without EHS, favorable results in HAIC responders, who are expected to have good are likely. This protocol should therefore be taken into con- prognoses, and switched to sorafenib therapy in HAIC sideration in the study design of a future clinical trial. Overall survival Overall survival Overall survival Overall survival Hatooka et al. 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All authors read and approved the final manuscript. Santoro A, Raoul JL, Forner A, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359(4):378–90. Ethics approval and consent to participate 14. Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, Luo R, Feng J, Ye S, This study was prospective and approved by the Ethics Review Committee Yang TS, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific of the Hiroshima University. region with advanced hepatocellular carcinoma: a phase III randomised, All participants provided written informed consent to participate. double-blind, placebo-controlled trial. Lancet Oncol. 2009;10(1):25–34. 15. Uka K, Aikata H, Takaki S, Miki D, Kawaoka T, Jeong SC, Takahashi S, Toyota Competing interests N, Ito K, Chayama K. Pretreatment predictor of response, time to The authors declare that they have no competing interests. progression, and survival to intraarterial 5-fluorouracil/interferon combination therapy in patients with advanced hepatocellular carcinoma. J Gastroenterol. 2007;42(10):845–53. 16. Uka K, Aikata H, Takaki S, Miki D, Jeong SC, Hiramatsu A, Kodama H, Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in Shirakawa H, Kawakami Y, Takahashi S, et al. Similar effects of recombinant published maps and institutional affiliations. interferon-alpha-2b and natural interferon-alpha when combined with intra- arterial 5-fluorouracil for the treatment of advanced hepatocellular carcinoma. Liver Int. 2007;27(9):1209–16. Author details Department of Gastroenterology and Metabolism, Institute of Biomedical & 17. Katamura Y, Aikata H, Takaki S, Azakami T, Kawaoka T, Waki K, Hiramatsu A, Health Science, Hiroshima University, Hiroshima 734-8551, Japan. Kawakami Y, Takahashi S, Kenjo M, et al. Intra-arterial 5-fluorouracil/ Department of Diagnostic Radiology, Graduate School of Biomedical interferon combination therapy for advanced hepatocellular carcinoma with Sciences, Hiroshima 734-8551, Japan. Hiroshima City Asa Hospital, Hiroshima, or without three-dimensional conformal radiotherapy for portal vein tumor 4 5 Japan. Kure Medical Center, Hiroshima, Japan. Chugoku Rousai Hospital, thrombosis. J Gastroenterol. 2009;44(5):492–502. 6 7 Hiroshima, Japan. Mazda Hospital, Hiroshima, Japan. Onomichi General 18. Miyaki D, Aikata H, Honda Y, Naeshiro N, Nakahara T, Tanaka M, Nagaoki Y, Hospital, Hiroshima, Japan. Liver Research Project Center, Hiroshima Kawaoka T, Takaki S, Waki K, et al. Hepatic arterial infusion chemotherapy for University, Hiroshima, Japan. Laboratory for Digestive Diseases, RIKEN Center advanced hepatocellular carcinoma according to child-Pugh classification. for Integrative Medical Sciences, Hiroshima, Japan. 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Effect of hepatic arterial infusion chemotherapy of 5-fluorouracil and cisplatin for advanced hepatocellular carcinoma in the Nationwide survey of primary liver Cancer in Japan. Br J Cancer. 2013;109(7): 1904–7. 23. Ikeda M, Mitsunaga S, Shimizu S, Ohno I, Takahashi H, Okuyama H, Kuwahara A, Kondo S, Morizane C, Ueno H, et al. Efficacy of sorafenib in patients with hepatocellular carcinoma refractory to transcatheter arterial chemoembolization. J Gastroenterol. 2014;49(5):932–40. 24. Hatooka M, Kawaoka T, Aikata H, Morio K, Kobayashi T, Hiramatsu A, Imamura M, Kawakami Y, Murakami E, Waki K, et al. Comparison of outcome of hepatic arterial infusion chemotherapy and Sorafenib in patients with hepatocellular carcinoma refractory to Transcatheter arterial chemoembolization. Anticancer Res. 2016;36(7):3523–9. 25. Katamura Y, Aikata H, Kimura Y, Kawaoka T, Takaki S, Waki K, Hiramatsu A, Kawakami Y, Takahashi S, Ishikawa M, et al. 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Published: Jun 4, 2018