ORIGINAL ARTICLE. Abstract. Introduction

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1 ORIGINAL ARTICLE Early Decreases in α-fetoprotein and Des-γ-carboxy Prothrombin Predict the Antitumor Effects of Hepatic Transarterial Infusion Chemotherapy with Cisplatin (CDDP) Powder in Patients with Advanced Hepatocellular Carcinoma Takeshi Hatanaka 1, Satoru Kakizaki 2, Yasushi Shimada 1, Daichi Takizawa 1, Kenji Katakai 3, Yuichi Yamazaki 2,KenSato 2, Motoyasu Kusano 2 and Masanobu Yamada 2 Abstract Objective We retrospectively investigated the relationship between the tumor response and serial changes in α-fetoprotein (AFP) and des-γ-carboxy prothrombin (DCP) during hepatic arterial infusion of a cisplatin powder formulation (CDDP powder) in patients with advanced hepatocellular carcinoma (HCC). Methods Seventy-six advanced HCC patients were analyzed. All HCC patients received high-concentration cisplatin (1.43 mg/ml) via the haptic artery at a dose of 65 mg/m 2. AFP and DCP were measured at baseline and four to eight weeks after treatment, and the antitumor responses were evaluated according to the response evaluation criteria in solid tumours (RECIST) criteria after one or two courses of treatment. The patients were classified into two groups, a decreased group and a non-decreased group, according to the change in the serum levels of AFP and DCP at four to eight weeks compared to baseline. Results The response to treatment of the decreased group (n=16) and non-decreased group (n=60) was complete response/partial response/stable disease/progressive disease (CR/PR/SD/PD) in 4/4/5/3 and 1/11/8/40 patients, respectively. The response rate and disease control rate of the decreased group were significantly higher than those of the non-decreased group (p=0.016 and p<0.001, respectively). The median survival time (MST) of the decreased/non-decreased groups were 25.9/10.6 months, respectively. The cumulative survival rates for the decreased group were significantly higher than those of the non-decreased group (p=0.042). In the multivariate analysis, vascular invasion and the decreased group were significant factors that affected the therapeutic efficacy. Conclusion A decrease in the levels of AFP and DCP after the first treatment with CDDP powder is a good predictor for the antitumor effect and the prognosis. Key words: hepatocellular carcinoma, cisplatin, transarterial infusion chemotherapy () () Introduction Hepatocellular carcinoma (HCC) is one of the most common malignant tumors. HCC ranks fifth as the cause of death for men and eighth as the cause of death for women worldwide (1-3). When the disease is detected at early stages or at Barcelona Clinic Liver Cancer stage A, a fiveyear survival rate of 60% to 70% can be achieved in select patients who undergo surgery (liver resection or transplantation) or loco-regional procedures (e.g., radiofrequency ablation) (4). However, HCC is often diagnosed at an advanced Department of Internal Medicine, Isesaki Municipal Hospital, Japan, Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Japan and Department of Internal Medicine, Katakai Clinic, Japan Received for publication October 12, 2015; Accepted for publication December 15, 2015 Correspondence to Dr. Satoru Kakizaki, kakizaki@showa.gunma-u.ac.jp 2163

2 stage, when such curative therapy is unlikely to be effective. Therefore, most patients with advanced HCC are considered to be candidates for non-curative treatment, which includes sorafenib or hepatic artery infusion therapy (5). Cisplatin is widely used for the treatment of various malignancies, including HCC. Cisplatin has been administered for transarterial chemotherapy in combination with Lipiodol and/or embolic material, with favorable results for HCC patients (6-9). In 2004, a fine powder formulation of cisplatin (DDP-H, IA call ; Nippon Kayaku, Tokyo, Japan) was developed for use in the treatment of HCC. The cisplatin powder is administered through the transarterial approach without Lipiodol or embolic material. Transarterial chemotherapy using cisplatin (CDDP) powder was shown to be potentially beneficial for patients with advanced HCC, and the cumulative survival rates for complete response/partial response (CR/PR) patients were significantly higher than those of stable disease/progressive disease (SD/PD) patients (10, 11). However, little is known about the early predictive factors for the response to transarterial chemotherapy using CDDP powder. Several regimens have been reported as hepatic arterial infusion chemotherapy (HAIC) using cisplatin. For patients with portal vein tumor thrombosis, HAIC using low-dose cisplatin and 5-fluorouracil (5-FU) achieved a response rate of 48% (12) and a cisplatin-lipiodol emulsion and 5-FU achieved a response rate of 86.3% (13). Although these two retrospective regimens achieved high response rates, they require catheter placement and a continuous infusion of anticancer agents. On the other hand, there were no differences in the response rate between low-dose cisplatin plus 5-FU and cisplatin monotherapy in a prospective study of FAIT (5-FU arterial infusion + interferon therapy) (14). As a result, there is currently no definitive regimen and the selection of the regimen remains controversial. We chose HAIC using CDDP powder in this study because this regimen does not require catheter placement or a continuous infusion of anti-cancer agents. In this study, we investigated the relationship between the antitumor effects and the changes in α-fetoprotein (AFP) and des-γ-carboxy prothrombin (DCP) during the first course of administration in patients with advanced HCC. Patient eligibility Materials and Methods From March 2007 to July 2014, 130 patients with HCC were consecutively treated by transarterial chemotherapy using CDDP powder at Isesaki Municipal Hospital. HCC was diagnosed either by a histological examination or according to the diagnostic criteria of the American Association for the Study of Liver Diseases (AASLD) (2). The HCC stage was diagnosed according to the criteria of the Liver Cancer Study Group of Japan (15). Patients were included if they met the following criteria: a measurable lesion according to the Response Evaluation Criteria in Solid Tumors (RECIST) (16), advanced HCC not eligible for surgical or loco-regional therapies, Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0-2, life expectancy 12 weeks from the initial date of the first treatment, follow-up by dynamic computed tomography (CT) and/or magnetic resonance imaging (MRI) after one to two months of treatment, measured serum levels of AFP and DCP within four to eight weeks after treatment, adequate liver function (Child-Pugh class A or B, total bilirubin 3 mg/dl, transaminases within five times the upper limit of the normal range), adequate renal function (creatinine <1.5 mg/dl), hemoglobin (Hb) 8.5 g/dl, white blood count 2,000/μL, platelets 50,000/μL and no active malignancy other than HCC. Hepatic arterial infusion chemotherapy (HAIC) of CDDP powder The femoral artery was catheterized under local anesthesia and a 3-, 4- or 5- French (Fr) catheter was inserted. All patients underwent angiography of the celiac artery and superior mesenteric artery to confirm the feeding artery. CDDP powder was solubilized in saline at a concentration of 100 mg/70 ml (1.42 mg/ml) immediately before use and infused into the liver through the proper, right or left hepatic artery over 30 minutes. The maximum dose of CDDP powder was 65 mg/m 2. The treatment was repeated every four to eight weeks until the appearance of tumor progression and/ or unacceptable toxicity. In principle, the dose of CDDP powder was reduced if the patient s creatinine clearance was decreased or if the patient s liver function was poor. The severity of any toxicity and adverse events were evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Serum tumor markers The serum levels of AFP and DCP were measured at baseline and four to eight weeks after treatment. The cut-off values of AFP and DCP were 10 ng/ml and 40 mau/ml, respectively. Because the DCP levels are influenced by vitamin K and warfarin, patients who were administered these agents were excluded from the DCP analysis. Response The therapeutic responses were assessed according to the findings of dynamic CT and/or MRI at one to two months after one or two courses of HAIC of CDDP powder according to the RECIST. The best overall response was recorded for each patient. The overall survival rates were measured from the day of initial treatment to the day of death or the last follow-up examination. Classification according to the changes in the AFP and DCP levels at four or eight weeks after treatment The patients were classified into two groups, a decreased 2164

3 Figure 1. A flow chart showing the patient selection. HCC: hepatocellular carcinoma, CDDP: cisplatin, CT: computed tomography, AFP: α-fetoprotein, DCP: des-γ-carboxy prothrombin group and a non-decreased group, according to the change in the serum levels of AFP and DCP at four to eight weeks compared to baseline. Patients who had decreases in the serum levels of both AFP and DCP were defined as the decreased group. Patients who had an increase in either AFP or DCP four to eight weeks after treatment were defined as the non-decreased group. When either the AFP or DCP level at baseline was within the normal limits, and the other tumor marker was elevated, we only analyzed the elevated tumor marker. When both AFP and DCP were within the normal limits, we defined these patients as the non-decreased group. Four patients with HCC had AFP and DCP levels both within the normal limits. Three patients who were administered vitamin K and warfarin were excluded from the DCP analysis, and we analyzed only AFP for these patients. Statistical analyses Statistical analyses were performed using the EZR graphical interface (17). Student s t-test was used to compare continuous data. Fisher s exact probability test was used to compare categorical data. Univariate and multivariate analyses were performed using a logistic regression model and the Cox regression analysis. The Kaplan-Meier method was used to calculate the survival curves. A value of p <0.05 was considered to be statistically significant. Results Out of 130 patients with HCC, we excluded 23 patients who died within 12 weeks, six patients who did not receive suitable follow-up, eight patients who were not assessed by CT or MRI, seven patients who did not undergo measurement of the serum AFP and DCP levels within four to eight weeks after treatment, two patients who were in Child Pugh class C, six patients who had a low platelet count (<50,000/ μl) and two patients who were anemic (<8.5 g/dl) (Fig. 1). The remaining 76 patients were included in this study. The characteristics of the 76 patients are summarized in Table 1. The median age of the patients was 71.5 years old (range: 44-88). The etiology of HCC was hepatitis B virus (HBV), hepatitis C virus (HCV) and others in two, 62 and Table 1. The Characteristics of the Patients and Tumors. Case (n) 76 Age 71.5 (48-99) years Sex Male / Female ECOG PS 0 / 1 / 2 Previous treatment Absent/ Present Etiology HBV / HCV / others Child-Pugh classification A / B Disease stage I / II / III / IVA / IVB Vascular invasion Positive / Negative AFP DCP 60 / / 38 / 1 18 / 58 2 / 62 / / 29 0 / 7 / 41 / 20 / 8 26 / (1-303,500) ng/ml 338 (6-53,258) mau/ml ECOG PS: Eastern Cooperative Group Performance Status, HBV: hepatitis B virus, HCV: hepatitis C virus, AFP: -fetoprotein, DCP: des- -carboxy prothrombin 13 patients, respectively. The Child-Pugh class was A/B in 47/29 patients. The stage of the tumor was stage I/II/III/IVA/ IVB in 0/7/41/20/8 patients. Twenty-six of the 76 patients (34.2%) had vascular or biliary invasion. The best radiological response to treatment was a CR/PR/ SD/PD in 5/15/13/43 patients, respectively. The overall response rate was 26.3%, and the disease control rate was 43.4%. The median survival times (MST) of the overall patient cohort was 13.9 months (Table 2). The overall one-, two- and three-year survival rates were 56.9%, 29.8% and 19.9%, respectively (Fig. 2). The MST for responders (CR/ PR) and non-responders (SD/PD) were 25.9 and 10.6 months, respectively. The survival rate of responders was significantly longer than that of non-responders (p=0.0015, Fig. 3). For additional therapy after HAIC using CDDP powder, nothing/sorafenib/transarterial chemoembolization (TACE)/radiofrequency ablation (RFA)/hepatic resection/radiation therapy were selected in 38/11/18/5/0/3 patients, respectively (Table 2). The relationship between the therapeutic response and the decreased group The baseline characteristics of the decreased group and non-decreased group were not significantly different except for the dose of CDDP powder per session, which was significantly lower in the decreased group (Table 3). The response to treatment of the decreased group (n=16) and nondecreased group (n=60) was CR/PR/SD/PD in 4/4/5/3 and 1/ 11/8/40 patients, respectively. The response rate of the decreased group was significantly better than that of the nondecreased group (p=0.016). The disease control rate of the decreased group was significantly higher than that of the non-decreased group (p<0.001). The MST of the decreased/ 2165

4 Table 2. The Characteristics of the Treatment. Case (n) 76 Number of sessions 2 (1-14) times Dose of CDDP powder per session Follow-up period Response to treatment 48.8 ( ) mg/m ( ) months 5 (6.6%) / 15 (19.7%) / 13 (17.1%) / 43 (56.6%) CR/PR/SD/PD Response rate 26.3% Disease control rate 43.4% MST of overall patients 13.9 months Stage II 10.2 months Stage III 16.1 months Stage IVA 19.0 months Stage IVB 7.1 months Additional therapy after HAIC using CDDP powder Nothing / sorafenib / TACE / RFA / hepatic resection / 38/11/18/5/0/3 radiation therapy CDDP: Cisplatin, CR: complete response, PR: partial response, SD: stable disease, PD: progressive disease, MST: median survival time, HAIC: hepatic arterial infusion chemotherapy, TACE: transarterial chemoembolization, RFA: radiofrequency ablation Survival me(months) Figure 2. The cumulative survival rate illustrating the overall survival for all patients in this study. The overall one-, twoand three-year survival rates were 56.9%, 29.8% and 19.9%, respectively. Figure 3. The results of a prognostic analysis according to the therapeutic effects of HAIC using cisplatin powder. The median survival times (MST) for responders (CR/PR) and nonresponders (SD/PD) were 25.9 and 10.6 months, respectively. The survival rate of the responders was significantly higher than that of the non-responders (p=0.0015). HAIC: hepatic arterial infusion chemotherapy, MST: median survival time, CR: complete response, PR: partial response, SD: stable disease, PD: progressive disease non-decreased groups were 25.9/10.6 months, respectively. The cumulative survival rate for the decreased group were significantly higher than those of the non-decreased group (p=0.042, Fig. 4). Previous treatment, vascular invasion and the decreased group were found to be significantly associated with a good therapeutic response in the univariate analysis (Table 4). In the multivariate analysis, vascular invasion and the decreased group were significant factors that affected the therapeutic efficacy (Table 5). Analyses of the survival according to the prognostic factors are shown in Tables 6 and 7. The patient age, HCV infection, Child-Pugh classification, extrahepatic metastasis, total amount of CDDP powder, number of sessions, and both decreased AFP and DCP levels were significant factors according to the univariate analysis (Table 6). The patient age, Child-Pugh classification, extrahepatic metastasis, number of sessions, and both decreased AFP and DCP levels were also identified to be significant factors that affected the 2166

5 Table 3. The Characteristics of Patients Categorized according to Variations in the AFP and DCP Levels at Four to Eight Weeks after HAIC Using CDDP Treatment. Characteristic Sex Male/Female Age (years) median (range) ECOG PS 0 / 1 / 2 Previous treatment Absent/ Present Etiology HBV / HCV / others Child-Pugh classification A / B Disease stage I / II / III / IVA / IVB Vascular invasion Positive / Negative Number of sessions Dose of CDDP powder per session Mean ± SD (range) Decreased group (n=16) Non-decreased group (n=60) 12/4 48/ (50-88) 70.5 (48-83) /10/1 32/28/ /12 14/ /12/3 1/50/ /7 38/ /2/10/4/0 0/5/31/16/ /11 21/ (1-7) times 2 (1-14) times ± 7.7 ( ) mg/m ± 7.2 (39-65) mg/m Response to treatment CR/PR/SD/PD 4 /4/5/3 1/11/8/40 <0.001 Response rate 50.5% 20.0% Disease control rate 81.3% 33.3% <0.001 AFP: -fetoprotein, DCP: des- -carboxy prothrombin, ECOG PS: Eastern Cooperative Group Performance Status, HBV: hepatitis B virus, HCV: hepatitis C virus, HAIC: hepatic arterial infusion chemotherapy, CDDP: Cisplatin, CR: complete response, PR: partial response, SD: stable disease, PD: progressive disease p survival according to the multivariate analysis (Table 7). Table 8 shows the adverse events of HAIC using CDDP. Grade 3 nausea was observed in 8 of 76 patients (10.5%). Grade 3 elevation of AST/ALT was observed in 4 of 76 patients (5.3%). There were no grade 4 adverse events. These adverse effects were all controlled by medical treatment or conservative therapy. None of the deaths were related to HAIC using CDDP powder. Discussion Figure 4. The cumulative survival rate illustrating the overall survival for the decreased and non-decreased groups. The cumulative survival rates of the decreased group were significantly higher than those of the non-decreased group (p=0.042). In the present study, we investigated the relationships between the changes in tumor markers, such as AFP and DCP, and antitumor responses in the early period following HAIC using CDDP powder. The response rate, disease control rate and MST of the decreased group were significantly higher than those of the non-decreased group. In the multivariate analysis, vascular invasion and the decreased group were significant factors that affected the therapeutic efficacy. These results suggest that an early decrease in the serum levels of AFP and DCP was a good predictor of the response after the first course of treatment with HAIC using CDDP powder. Tumor markers are substances that are produced by the tumor or secreted by the tissues due to malignancy. Measurements of tumor markers such as AFP and DCP are simple and already widely used for the surveillance and diagnosis of HCC. They are also used to monitor recurrence and serve as prognostic factors following treatments such as curative hepatic resetion (18, 19), loco-regional therapy (20) and TACE procedures (21, 22). Although numerous studies have reported the relationships between the changes in tu- 2167

6 Table 4. Analysis of the Response to Treatment according to the Results of the Univariate Analysis. Variable OR (95% CI) a p Sex Male 1.09 ( ) 1.00 Female 1.00 Age (years) < ( ) HCV infection Positive 0.87 ( ) 1.00 Negative 1.00 Previous treatment Yes 0.33 ( ) 0.07 No 1.00 Child-Pugh classification A 1.11 ( ) 1.00 B 1.00 Vascular invasion Present 4.39 ( ) Absent 1.00 Extrahepatic metastasis Present 0.37 ( ) 0.67 Absent 1.00 Dose of CDDP powder at first session 48.8 mg/m ( ) <48.8 mg/m Both AFP and DCP decreased at four to Decreased group 3.91 ( ) eight weeks Non-decreased group 1.00 OR: odds ratio, CI: confidence interval, HCV: hepatitis C virus, CDDP: Cisplatin, AFP: -fetoprotein, DCP: des- -carboxy prothrombin a ; The ORs were calculated using Fisher s exact test. Table 5. Analysis of the Response to Treatment according to the Results of the Multivariate Analysis. Variable OR (95% CI) a p Vascular invasion Present 5.73 ( ) <0.001 Absent 1.00 Both AFP and DCP decreased at four to eight Decreased group 5.45 ( ) <0.001 weeks Non-decreased group 1.00 CI: confidence interval, AFP: -fetoprotein, DCP: des- -carboxy prothrombin a ; The ORs were calculated using Fisher s exact test. Previous treatment, vascular invasion, and both AFP and DCP decreased were included as covariates in the multivariate logistic regression analysis. mor markers during treatment and the antitumor response, there have been no comprehensive reports that have evaluated the relationship between the tumor response and serial changes in AFP and DCP during HAIC using CDDP powder. To the best of our knowledge, this is the first report to evaluate the relationship between the tumor response and changes in tumor markers during HAIC using CDDP powder. In this study, 4 patients with HCC had AFP and DCP levels both within the normal limits and were defined as the non-decreased group. All 4 patients exhibited increased AFP or DCP levels after treatment within or out of the normal limits. In 2 of 4 patients, the DCP levels were elevated over the normal limit during the follow-up periods. Because there were no cases in which the tumor marker was decreased within the normal range in this study, the importance of the change in the tumor markers within the normal limits remains unclear. There were 3 PD patients in the decreased group. As a result, the decrease of AFP and DCP could not predict the response in these 3 patients. Although the decrease in the tumor markers was slight after one course of treatment in these 3 patients, these patients were defined as the decreased group according to the decrease of both AFP and DCP. In this study, we simply defined the decreased group as patients who had decreased serum levels of both AFP and DCP. The amount or rate of change in the AFP and DCP levels was not determined. A simple classification is convenient for users, however, this simple definition may be a limitation of this study. On the other hand, there were 1 CR and 11 PR patients in the non-decreased group. These patients showed a good response in the AFP or DCP after the first session. However, the other tumor marker was slightly elevated and therefore the patients were classified as the nondecreased group. After two courses of treatment, both the AFP and DCP markedly decreased in these patients. We could not predict the responses of 15 patients (19.7%), including 3 PD patients in the decreased group and 12 responders in the non-decreased group. Because we simply defined the groups according to the titer of tumor markers, slight decreases or increases in the tumor markers occasionally biased the results. These are several potential reasons for the discrepancy between the group category and the re- 2168

7 Table 6. Analysis of the Survival according to the Results of the Univariate Analysis for Prognostic Factors. Variable n=76 Median 95% CI p (log rank test) Sex Male Female Age (years) < HCV infection Positive NA Negative Previous treatment Yes No Child-Pugh classification A <0.001 B Vascular invasion Present Absent Extrahepatic metastasis Absent Present Total amount of CDDP powder 170 mg/body <170 mg/body Number of sessions 3 sessions <3 sessions Both AFP and DCP decreased Decreased group NA Non-decreased group CI: confidence interval, HCV: hepatitis C virus, NA: not available, CDDP: Cisplatin, AFP: -fetoprotein, DCP: des- -carboxy prothrombin Table 7. Analysis of the Survival according to the Results of the Multivariate Analysis for Prognostic Factors. Variable OR (95% CI) p Age (years) < ( ) < Child-Pugh A 2.98 ( ) <0.001 B 1.00 Extrahepatic metastasis Absent 4.05 ( ) <0.001 Present 1.00 Number of sessions 3 sessions 2.14 ( ) <0.001 <3 sessions 1.00 Both AFP and DCP decreased Decreased group 2.35 ( ) <0.001 Non-decreased group 1.00 OR: odds ratio, CI: confidence interval, AFP: -fetoprotein, DCP: des- -carboxy prothrombin Age, HCV infection, Child-Pugh classification, extrahepatic metastasis, total amount of CDDP powder, number of sessions, and both AFP and DCP decreased were included as covariates in the Cox regression analysis. sponses. For early prediction and simple classification, we defined the decreased group as patients who had decreases in the serum levels of both AFP and DCP. However, the time at prediction and the range of tumor marker change should be considered in future investigations. Modification of the time at prediction and the range of tumor marker change may be reduced by the discrepancy between the group category and the responses. On the other hand, a simple prediction formula may be useful for reducing the discrepancy of prediction. In a previous study, the efficacy of systemic chemotherapy with cisplatin for HCC patients was 9.3% (23). Therefore, the efficacy of intravenous infusion of cisplatin is limited. The activity of cisplatin is concentration- and timedependent, and the drug is mainly excreted by the kidneys (24). Court et al. (25) revealed that the first-pass uptake by liver tumors was 48.4% of the cisplatin administered into the hepatic artery. Kajanti et al. (26) showed that the response rate to cisplatin (50 mg/m 2 ) administered via the hepatic artery over 1.5 hours in 10 HCC patients was 40%. However, the number of cases was small. CDDP powder, a fine powder formulation of cisplatin, was developed for use in the treatment of HCC via a transarterial approach without Lipiodol or any embolic materi- 2169

8 Table 8. Adverse Events of HAIC Using CDDP. Number of patients (n=76) Event Grade 3 Grade 4 Abdominal pain 2(2.6%) - Nausea 8 (10.5%) - Vomiting 1(1.3%) 0 Fever 0 0 Leukopenia 4(5.3%) 0 Anemia 0 0 Thrombocytopenia 3(3.9%) 0 Elevated AST 4(5.3%) 0 Elevated ALT 4(5.3%) 0 Elevated total bilirubin 0 0 Elevated creatinine level 0 0 HAIC: hepatic arterial infusion chemotherapy, CDDP: Cisplatin, AST: aspartate aminotransferase, ALT: alanine aminotransferase Adverse events were evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. als in Japan (10). CDDP powder represents an improvement over the standard liquid cisplatin formulation for intraarterial administration. CDDP powders are highly soluble and can provide higher concentration solutions (1.42 mg/ ml) than conventional cisplatin formulations (0.5 mg/ml). As a result, the solubility of CDDP powder is approximately 3 times higher than that of standard cisplatin without the need of an implanted port and catheter. Therefore, HAIC using CDDP powder was expected to increase the local drug concentration in HCC and to have a higher therapeutic efficacy. Yoshikawa et al. (10) reported a favorable response rate (33.8%) and 1- and 2-year survival rates (67.5% and 50.8%, respectively) in 80 advanced HCC patients. Kondo et al. (11) treated 24 HCC patients with portal vein tumor thrombosis and reported that the overall median survival time and objective response rate were 7.0 months and 20.8%, respectively. On the other hand, Iwasa et al. (27) reported only modest activity with a 3.6% overall response rate in patients with transcatheter arterial chemoembolization-refractory HCC. The baseline characteristics of the decreased group and non-decreased group did not differ in any of the categories except for the dose of CDDP powder per session. The doses of CDDP powder per session used in the decreased group were significantly lower than those used in the nondecreased group. This suggests that the sensitivity to CDDP may be important to the response. In the univariate analyses, the dose of CDDP per session did not influence the response. Osaki et al. (28) also reported that there was no correlation between the administration dose of CDDP and the area reduction rate of HCC either with normalization or without normalization of the body surface area in 15 CDDPresponded nodules. Additionally, there were no significant differences in the CDDP dose between the sensitive and resistant cases (28). Thus, the sensitivity to CDDP may be an important factor in the response in comparison with the CDDP dose. The current standard therapy for advanced HCC is sorafenib (4, 29). Sorafenib is an oral, small-molecule tyrosine kinase inhibitor that blocks the synthesis of several intracellular proteins considered to be important for tumor progression, including platelet-derived growth factor receptor-beta, raf kinase and vascular endothelial growth factor receptor. The SHARP study (30) and the Asia-Pacific Study (31), two large-scale, phase III clinical studies, demonstrated that sorafenib significantly prolonged the time to progression and improved the overall survival. However, the response rate in the sorafenib group was only 2.3%, and only Child-Pugh class A patients were eligible for sorafenib treatment. Therefore, additional treatments applicable to a larger population of patients are needed. The candidates for HAIC using CDDP powder are at an advanced stage and speculated to have a poor prognosis. If the response to HAIC using CDDP powder is bad, then the patients do not have much time to receive additional treatments. As a result, it is important to recognize the response to therapy immediately and determine the therapeutic strategy. Patients who do not achieve an early decrease in the serum tumor markers should be switched to sorafenib or another chemotherapy regimen. There are some limitations associated with the present study. First, this study was a retrospective study. To validate the efficacy of HAIC using CDDP powder, prospective analyses are needed. Second, four-fifths of the patients received various treatments, such as liver resection, radiofrequency ablation, transarterial chemoembolization and/or sorafenib, before and after the administration of CDDP powder. These treatments could have influenced the results. In conclusion, our findings suggested that changes in the tumor markers are a good predictor and can serve as prognostic factors for the therapeutic effects of CDDP powder against advanced HCC. If the serum levels of both AFP and DCP decrease after HAIC using CDDP treatment, then patients should continue to receive HAIC using CDDP. However, if the serum levels of both AFP and DCP do not decrease, then the treatment should be changed to sorafenib or another regimen of chemotherapy. In addition, the multivariate analysis in the present study showed that HCC patients with vascular invasion are good candidates for treatment with HAIC using CDDP powder. The authors state that they have no Conflict of Interest (COI). References 1. Ferenci P, Fried M, Labrecque D, et al. Hepatocellular carcinoma (HCC): a global perspective. J Clin Gastroenterol 44: , Bruix J, Sherman M. Practice Guidelines Committee, American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma. Hepatology 42: , Parkin DM, Bray F, Ferlay J, Pisani P. 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