Int J Clin Oncol DOI 10.1007/s10147-015-0942-0

ORIGINAL ARTICLE

Effects of sorafenib combined with low‑dose interferon therapy for advanced hepatocellular carcinoma: a pilot study Norio Itokawa1 · Masanori Atsukawa1 · Akihito Tsubota2 · Tomomi Okubo1 · Taeang Arai1 · Ai Nakagawa1 · Chisa Kondo1 · Katsuhiko Iwakiri1 

Received: 30 July 2015 / Accepted: 12 December 2015 © Japan Society of Clinical Oncology 2015

Abstract  Background  Sorafenib is a standard of care for advanced hepatocellular carcinoma (HCC). An in vitro study showed the synergistic effects of sorafenib and interferon for HCC. To clarify the efficacy, combination therapy with sorafenib and interferon was performed for patients with advanced HCC. Methods  Pegylated interferon α-2a was administered every 2 weeks for the initial 4 weeks. Subsequently, it was combined with sorafenib. We evaluated the anti-tumor effect and biomarkers during treatment period. Results  The subjects were 13 patients with advanced HCC complicated by hepatitis C virus (HCV)-related liver cirrhosis. A partial response, stable disease and progressive disease were noted in 4, 6, and 3 patients, respectively. The response rate, the disease control rate, the mean time to progression and the median survival time (MST) were 30.8 % (4/13), 76.9 % (10/13), 12.2 months, and 17.5 months, respectively. In 8 Child-Pugh class A and 5 Child-Pugh class B patients, the MST was 22.0 and 11.0 months, respectively (p = 0.001). In plasma vascular endothelial growth factor (VEGF), serum alpha-fetoprotein (AFP), AFP-L3, a protein induced by vitamin K absence M Atsukawa and A Tsubota contributed equally to the preparation of this manuscript. * Masanori Atsukawa [email protected] 1

Division of Gastroenterology, Department of Internal Medicine, Nippon Medical School Chiba Hokusoh Hospital, 1715 Kamakari, Inzai, Chiba, Japan

2

Core Research Facilities for Basic Science, Research Center for Medical Sciences, Jikei University, School of Medicine, Tokyo, Japan





or antagonist-II (PIVKA II), and hepatocyte growth factor (HGF), there was no pretreatment factor and no biomarker during the combination therapy to predict therapeutic effect in the present study. Conclusions  The results of this study suggest that combination therapy with sorafenib and interferon could be effective and safe in advanced HCC patients with HCV-related liver cirrhosis. Keywords  Hepatocellular carcinoma · Sorafenib · Pegylated interferon · Vascular endothelial growth factor · α-Fetoprotein

Introduction Although the survival rate of patients with HCC in whom radical treatments, such as hepatectomy, liver transplantation, and radiofrequency ablation, can be performed has improved, many patients are diagnosed in the state of advanced cancer for which radical treatment is difficult, and their prognoses are unfavorable [1–3]. Therefore, therapeutic strategies for advanced HCC should be urgently established. In 2005, sorafenib was approved as a drug for advanced renal cell carcinoma by the Food and Drug Administration (FDA). Thereafter, two large-scale, placebo-controlled, randomized, comparative studies involving patients with unresectable HCC (SHARP and Asia–Pacific studies) showed an increase in the disease control rate, the significant prolongation of survival period, and a 30 % decrease in the risk of death [4, 5]. In 2007, FDA approved sorafenib as a drug for advanced HCC. The efficacy of sorafenib in HCC patients who were refractory to transarterial chemoembolization (TACE) was also reported [6]. Currently, sorafenib

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is one of the standards of care for advanced HCC. In the two studies, however, the median survival time (MST) was 10.7 and 6.5 months, respectively [4, 5]. In the GIDEON study, the MST in Child-Pugh class B patients was only 5.2 months [7]. Many clinical trials were conducted to develop new molecule-targeting drugs that could be superior to sorafenib. Comparative studies using sorafenib as a control drug showed that the investigational drugs were less favorable than sorafenib [8–10]. Chronic hepatitis C is one of the major underlying diseases for the development of HCC [11]. Type 1-interferon (IFN), including IFN-α, which is used to treat chronic hepatitis C, exhibits antiviral effects, immunity-activating actions, and anti-tumor effects, such as the suppression of tumor cell proliferation/neovascularization [12–14]. Many studies reported the inhibitory effects of IFN on carcinogenesis in patients with hepatitis C virus (HCV)-related liver cirrhosis [15–18]. A clinical study indicated that renal cell carcinoma patients receiving combination therapy with sorafenib and IFN-α was higher in the response rate than those treated with monotherapy with IFN or sorafenib, suggesting their synergistic effects. It was also reported that the incidence of hand-foot skin reaction (HFSR) in combination therapy was lower than that in monotherapy with sorafenib [19, 20]. Concerning the anti-tumor effects on HCC, an in vitro study showed the synergistic effects of sorafenib and IFN [21, 22]. However, no clinical study has reported the efficacy or safety of combination therapy with sorafenib and IFN in patients with advanced HCC. This pilot study aimed at evaluating the efficacy and safety of combination therapy with sorafenib and IFN in HCV-related cirrhotic patients with advanced HCC.

Patients and methods Subjects Between January 2012 and December 2013, patients were diagnosed as having advanced HCV-related HCC and participated in this pilot study of sorafenib/IFN combination therapy in Nippon Medical School Chiba Hokusoh Hospital. A diagnosis of HCC and an evaluation of the disease stage were made in accordance with the Guidelines for the Management of Liver Cancer prepared by the Japan Society of Hepatology and American Association for the Study of Liver Diseases (AASLD) criteria [23, 24]. Inclusion criteria for this pilot study were as follows: (1) metastasis or marked vascular infiltration (Vp3/4 or Vv3), non-response to TACE therapy, or TACE-untreatable status; (2) Child-Pugh class A or B (score of <8); (3) an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0–1; and (4) laboratory data including a neutrophil count of >1500/μl,

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platelet count of >75 × 103/µl, hemoglobin level of >8.5 g/ dl, serum albumin level of >2.5 g/dl, total bilirubin level of <3.0 mg/dl, and ALT level of
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every 4 weeks. The serum AFP level and L3 fraction were assayed using ARCHITECT AFP EX (Abbott, Illinois, USA) and µTAS Wako i30 (Wako Pure Chemical Industries, Osaka, Japan), respectively. The serum PIVKA II level was assayed using Picolumi PIVKA II MONO (Eisai, Tokyo, Japan). The plasma VEGF level was measured using an ELISA kit (Quantikine Human VEGF immunoassay, R&D SYSTEM, Minneapolis, USA). The serum HGF level was determined using an HGF Otsuka ELISA kit (Otsuka, Tokyo, Japan).

differences between the two patient groups. Differences between two groups in various variables were examined using the Mann–Whitney U-test or Fisher’s exact test, as appropriate. Changes in the biomarkers during treatment were examined using the Wilcoxon signed-rank test. For statistical analysis, SPSS version 20.0 software (IBM Japan, Tokyo, Japan) was used. A p value of <0.05 was regarded as significant.

Results End points Background The main end point in this study was the overall survival (OS). Accessory end points were the response rate defined as CR and PR, disease control rate defined as CR, PR, and SD, association between biomarkers and treatment responses, and incidence of adverse events. Statistical analysis The OS curve was calculated using the Kaplan–Meier method, and the log-rank test was used to analyze Table 1  Baseline clinical and demographic characteristics of 13 patients with advanced hepatocellular carcinoma

A total of 13 patients with advanced HCC and HCV-related liver cirrhosis were enrolled in this study. The patient characteristics are shown in Table 1. The median age was 75 years. They consisted of 11 males and 2 females. Of the 13 patients, 11 had a previous treatment history: TACE were performed twice in 4 patients and three times in 3 patients, and two TACE plus one RFA in 4 patients. The Child-Pugh classification was class A in 8 patients and class B in 5 patients. In one patient, extrahepatic metastasis

Sorafenib/pegylated interferon (n = 13) Age (years)a Gender (male/female) Performance status (0/1) History of prior treatment (none/TACE/RFA+TACE) Stage (III/IVa/IVb) Maximum tumor diameter (mm)a Number of tumors (1–3/≤4) Extrahepatic metastases (yes/no) Major vascular invasion (yes/no) Child-Pugh class (A/B) alpha-fetoprotein (ng/ml)a PIVKA II (mAU/ml)a Plasma VEGF (pg/ml)a Serum HGF (ng/ml)a White blood cell count (/μl)a Hemoglobin (g/dl)a Platelet count (/mm3) × 103 a Alanine aminotransferase (IU/l)a Albumin (g/dl)a Total bilirubin (mg/dl)a Prothrombin time (%)a

75 (62–84) 11/2 10/3 2/7/4 8/4/1 28 (8–70) 7/6 1/12 4/9 8/5 58.8 (5.8–4978) 85.0 (27–25943) 83.3 (30–452) 0.44 (0.24–0.64) 4620 (2890–9080) 13.1 (9.1–17) 96 (77–222) 55 (15–215) 3.5 (2.9–4.4) 0.5 (0.3–1.2) 74 (62–97.3)

HCV RNA (Log IU/ml)a

6 (4.7–6.7)

TACE transcatheter arterial chemoembolization, RFA radiofrequency ablation, PIVKA II a protein induced by vitamin K absence or antagonist-II, VEGF vascular endothelial growth factor, HGF hepatocyte growth factor a

  Median (range)

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was detected in the lung. Portal vein tumor thrombosis (Vp3-4) was found in 4 patients. The median HCV RNA level before the lead-in IFN monotherapy was 6.0 Log IU/ ml. Treatment responses The median administration period of sorafenib was 389 days (range 78–1141). PR was achieved in 4 patients, SD was noted in 6 patients, and PD was observed in 3 patients. Thus, the response rate was 30.8 % (4/13) and the disease control rate was 76.9 % (10/13). The median time to progression was 12.2 months (range 3.0–17.0 months). Of the 13 patients, 10 died between 4.0 and 26.0 months

Fig. 1  Kaplan–Meier survival curves for all patients in this study

Fig. 2  Kaplan–Meier survival curves according to the clinical stage. The MST of patients in stage-IVa/IVb were shorter than those in stage-III, though not statistically significant (19.0 and 6.0 months, p = 0.171)

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after treatment [median survival time (MST) 14.5 months]. All of the 10 patients died of HCC-related death. The MST of the remaining 3 survival patients was 20.0 months (range 19.0–40.0 months). Overall, the MST was 17.5 months (range 4.0–40.0 months) (Fig. 1). We evaluated the MST of patients according to the stage. In 8 stage-III and 5 stage-IVa/IVb patients, the median MST was 19.0 and 6.0 months, respectively (p  = 0.171) (Fig. 2). Furthermore, we also investigated the MST according to the Child-Pugh classification. In 8 Child-Pugh class A and 5 Child-Pugh class B patients, the MST was 22.0 and 11.0 months, respectively (p = 0.001) (Fig. 3). Taken together, patients with advanced stage were shorter in the MST than those with less advanced, though

Int J Clin Oncol Fig. 3  Kaplan–Meier survival curves according to Child-Pugh class. The MST of patients in Child-Pugh class B were significantly shorter in the MST than those in Child-Pugh class A (22.0 and 11.0 months, p = 0.001)

Table 2  Characteristics of patients according to overall survival OS ≥15 months Group A (n = 7)

OS <15 months Group B (n = 6)

p value

alpha-fetoprotein (ng/ml)a alpha-fetoprotein-L3 (%)a PIVKA II (mAU/ml)a Plasma VEGF (pg/ml)a Serum HGF (ng/ml)a HCV RNA (LogIU/ml)a Maximum tumor diameter (mm)a Number of tumors (1–3/≤4) Child-Pugh class (A/B) Stage (III/IV)

48.9 (5.8–4978) 8.4 (1.5–14.2) 70 (27–808) 182.1 (66–452) 0.42 (0.27–0.47) 5.8 (4.7–6.7) 18 (8–45) 4/3 7/0 6/1

64.9 (6.5–103.5) 19.4 (2.2–50.9) 113 (53–2549) 114.7 (30–364) 0.59 (0.24–0.64) 6.1 (4.7–6.6) 32 (18–70) 3/3 1/5 3/3

0.775b 0.144b 0.721b 0.153b 0.198b 0.141b 0.135b 1.0c 0.004c 0.266c

Major vascular invasion (yes/no)

1/6

3/3

0.266c

A p value <0.05 is shown in bold PIVKA II a protein induced by vitamin K absence or antagonist-II, VEGF vascular endothelial growth factor, HGF hepatocyte growth factor a

  Median (range)

b

  Mann–Whitney U-test

c

  Fisher’s exact test

not statistically significant. Patients with decompensated cirrhosis were significantly shorter in the MST than those with compensated status. Comparison of pretreatment factors/biomarkers according to overall survival We divided the subjects into two groups according to the OS period and compared the groups in each baseline factor. Group A was a favorable treatment response group with an OS of 15 months or longer (n = 7), and Group B was an unfavorable treatment response group with an OS of 14 months or shorter (n = 6). The median and range

of biomarkers at baseline in Groups A and B are shown in Table 2. In baseline levels of AFP, AFP-L3, PIVKA II, VEGF, HGF and HCV-RNA, there was no significant difference between two groups. Concerning tumor factors including diameter and number of tumors, there was no significant difference between the two groups. We evaluated treatment responses according to the ChildPugh classification. Interestingly, all of Group A patients were classified into class A, whereas 4 of 5 patients in Group B were in class B (p  = 0.004; Table 2). Only one patient in group A and half of patients in Group B were in advanced stage with major vascular invasion (Table 2).

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Next, we compared some biomarker kinetics during treatment period between the two groups.Median of serum AFP levels in Group A decreased during the initial treatment and thereafter remained at a low level compared with those in Group B. Median of serum AFP-L3 values in Group B were higher throughout treatment period compared to those in Group A, and dramatically increased 3 months after the combination therapy. During the initial IFN monotherapy, plasma VEGF levels decreased in 11 of 13 patients. In Group A, thereafter, plasma VEGF levels remained unchanged. In Group B, however, the plasma VEGF level gradually increased after the combination therapy. Plasma VEGF levels at 3 months of the combination therapy were significantly higher than those at the start of combination therapy. Adverse events The treatment-related adverse events are shown in Table 3. During treatment, the dose of sorafenib was reduced due to adverse events in 5 patients (diarrhea in 3 patients, anorexia in 1, and malaise in 2). Grade 1 hand-foot-skinreaction (HFSR) was noted in 2 patients, who received the combination therapy without HFSR-related dose reduction or treatment discontinuation. The incidence of HFSR was 15.4 %. All of 13 patients received peg-IFN α-2a without dose reduction throughout the treatment period. Eventually, 8 of 13 patients continued to receive the combination therapy without dose reduction. There were no other serious adverse events and no patients who discontinued combination therapy. Table 3  Treatment-related adverse events (n = 13) Adverse events, n

Grade 1

Grade 2

Grade 3–4

Any grade

Malaise Diarrhea Anorexia HFSR Nausea Anemia Neutropenia Thrombocytopenia Liver disfunction Hypertention Dry skin Depression

2 0 1 2 2 2 2 2 2 1 1 1

2 3 1 0 0 0 0 0 0 0 0 0

0 0 0 0 0 0 0 0 0 0 0 0

4 3 2 2 2 2 2 2 2 1 1 1

Fever

1

0

0

1

HFSR hand-foot skin reaction

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Discussion This is the first pilot study to clarify the efficacy and safety of combination therapy with sorafenib and low-dose pegIFN in advanced HCC patients with HCV-related liver cirrhosis. The results of this study encourage us to develop combination therapy, when compared to those of sorafenib monotherapy [4, 5]. IFN-α exhibits antiviral actions, direct/indirect inhibitory effects on tumor cell proliferation, immunity-activating actions, surface antigen-expressing actions, and differentiation-inducing/-promoting actions [12–14]. Previous studies reported the usefulness of IFN-α as an anti-tumor drug for renal cell carcinoma (RCC), melanoma, and chronic myelocytic leukemia [26–28]. Furthermore, several studies indicated that IFN-α inhibited tumor cell proliferation and induced apoptosis in HCC patients [29, 30]. Another study reported the effect of combination with peg-IFN and transarterial infusion chemotherapy using 5-FU [31]. A large number of studies showed that IFN-α prevented carcinogenesis and recurrent carcinoma in patients with chronic hepatitis C [15–18, 32, 33]. Sorafenib is a multi-kinase inhibitor that exhibits actions by suppressing the MAPK/ERK pathway, VEGFR, and PDGFR. It was approved as an anticancer drug for RCC and HCC, and has been widely used for the advanced stage. However, sorafenib monotherapy has some limitations in the anti-tumor and adverse effects. Alternatively, several clinical studies reported the anti-tumor efficacy and high response rate in combination therapy with IFN-α and sorafenib for patients with RCC [19, 20, 34]. With respect to HCC, two in vitro and in vivo experimental studies reported the synergistic anti-tumor effects of sorafenib and IFN-α2a/peg-IFN-α2b by using HCC cell lines [21, 22]. Concerning the anti-tumor mechanism of combination therapy, an in vitro study on RCC showed that in all cell lines except Caki-2, in which cell line JAK-STAT pathway is absence, the combination treatment with IFN-α and sorafenib more inhibited the phosphorylation of MEK and ERK, which exist downstream of the MAPK/ERK system, compared to treatment with each agent alone. Thereby IFN-α-activated JAK-STAT pathway may be necessary to achieve enhancing the anti-tumor effects of the combination with IFN and sorafenib [35]. Another in vivo study on RCC showed that sorafenib alone did not activate splenic natural killer cells or cytotoxic T lymphocytes, whereas combination therapy with IFN-α activated them [36]. However, no clinical study has reported combination therapy with sorafenib and IFN for patients with advanced HCC. The results of this pilot study (MST 17.5 months, TTP

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12.0 months, response rate 30.8 %, and disease control rate 76.9 %) were markedly excellent compared to those of the SHARP (10.7, 5.5 months, 2.3, and 43.0 %, respectively) and Asia–Pacific (6.5, 2.8 months, 3.3, and 35.3 %, respectively) studies using sorafenib monotherapy [4, 5]. The RECIST criteria and modified-RECIST are developed based on intra-tumor blood flow and commonly used to evaluate the effects of sorafenib [25, 37]. However, it is difficult to evaluate treatment responses based on imaging findings alone, because many advanced carcinoma lesions show atypical blood flow patterns. Any other diagnostic tools (e.g. biomarker) are required to monitor the antitumor effect and predict prognosis. Several studies reported that the rapid decline in serum AFP level after treatment was associated with favorable OS and progression-free survival (PFS) [38–40]. In one-half of the SHARP study cohort, serum AFP, HGF, and Ang2 levels were significant pretreatment predictors [41]. Plasma VEGF level was also associated with the prognosis in the SHARP study [41]. VEGF is one of the target molecules for sorafenib. A clinical study reported that the plasma VEGF level increased at 4 weeks of sorafenib monotherapy regardless of treatment responses, and that the decline at 8 weeks was related to good treatment responses [42]. A transient treatmentrelated increase in the plasma VEGF level was observed even after TACE for HCC. This kinetic could be attributable to ischemic changes of tumor cells [43]. We evaluated some baseline factors and biomarkers during treatment to predict outcomes, including plasma VEGF, serum AFP, AFP-L3, PIVKA II and HGF. Unfortunately, in this pilot study, there was no prognostic predictor at baseline and on-treatment factor for therapeutic effect. The difference in VEGF kinetics among studies may reflect the difference in the anti-tumor mechanism between IFN and sorafenib/ TACE. HFSR is a representative sorafenib-related adverse event and the primary cause of treatment discontinuation. The incidence in sorafenib monotherapy was 21 % in the SHARP study and 45 % in the Asia–Pacific study [4, 5]. To avoid discontinuation of sorafenib, close monitoring of HFSR and prompt attention are required. It is noteworthy that the incidence of HFSR in this study was apparently low. Combination therapy for RCC also showed a low incidence of HFSR: 16 % [19] and 10 % [20]. Although the pathogenesis of HFSR remains unclear, concurrent IFN administration with sorafenib may inhibit or palliate HFSR by modifying the differentiation/proliferation of keratinocytes. This study showed that combination therapy with sorafenib and IFN could yield relatively favorable results even for advanced HCC patients with HCV-related liver cirrhosis and suggested that the combination therapy may be more effective and lower in the incidence of HFSR than

sorafenib monotherapy. In sorafenib monotherapy, outcomes of Child-Pugh class B patients were reported to be inferior to those of class A patients [7]. This study clearly demonstrated that outcomes of the combination therapy were extremely poor in patients with Child-Pugh class B as well as those of sorafenib monotherapy. Therefore, the combination therapy for patients with advanced HCC would be advantageous to those with Child-Pugh class A. This study has some limitations. Firstly, the number of patients was small, and there was no comparative control group. Secondly, portal infiltration was noted in 4 of 13 patients, but remote metastasis was detected in 1. The stage was less advanced than that in two large-scale, randomized clinical trials of sorafenib monotherapy [4, 5]. Lastly, images before and after the initial peg-IFN monotherapy were evaluated in only 3 patients. Thus, there was a small amount of comparative data between the anti-tumor effect based on images and biomarker kinetics. However, it is difficult to accurately evaluate its anti-tumor effects, as described above. In conclusion, the results of this pilot study suggest that the combination therapy could be effective compared to sorafenib monotherapy. Compliance with ethical standards  Conflict of interest  There are no conflicts of interest.

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