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Contemporary Oncology/Współczesna Onkologia
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vol. 22
 
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Original paper

Efficacy of sequential sorafenib plus hepatic arterial infusion chemotherapy in patients with Barcelona Clinic Liver Cancer stage B and C hepatocellular carcinoma: a retrospective single-institution study

Shinichi Ikuta
,
Tsukasa Aihara
,
Naoki Yamanaka

Contemp Oncol (Pozn) 2018; 22 (3): 165-171
Online publish date: 2018/09/30
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Introduction

Hepatocellular carcinoma (HCC) is one of the major causes of cancer death worldwide [1]. Despite recent progress in the surveillance and management of HCC, potentially curative treatments such as surgical resection, liver transplantation, or radiofrequency ablation are still only suitable for a limited number of patients due to impaired hepatic reserve, advanced disease stage, or frequent metachronous recurrence [2, 3]. Patients with advanced HCC are only candidates for palliative therapy, and they have a dismal prognosis with a median survival time of less than one year [4, 5].
Sorafenib is an oral multikinase inhibitor that blocks tumour cell proliferation and angiogenesis, and it represents the current standard therapy for improving the overall survival (OS) of patients with advanced HCC [4, 5]. Sorafenib is strictly indicated for HCC patients in Barcelona Clinic Liver Cancer (BCLC) stage C or patients with progressive disease after locoregional therapy provided that they have preserved liver function [6]. In two international, randomised, controlled trials reported in 2008–2009, about half of the patients receiving sorafenib achieved disease control [4, 5]. However, the benefit of sorafenib monotherapy in actual clinical practice has been more modest with low response rates, relatively frequent adverse effects, and high costs [4, 5, 7, 8].
As an alternative or complementary therapy to sorafenib, hepatic arterial infusion chemotherapy (HAIC) is a regional cytotoxic chemotherapy for advanced or unresectable HCC. HAIC directly delivers chemotherapy agents to the feeding vessels of liver tumours, thereby increasing the local drug concentration and minimising systemic toxicity [9]. However, the position of HAIC in the treatment of HCC has not yet been established due to the lack of well-conducted randomised trials, although a number of studies have found benefits of HAIC in relation to response and survival [9–15].
HCC generally consists of a complex and heterogeneous tumour cell population [16, 17]. Furthermore, patients with advanced HCC show diverse clinical presentations associated with multifocal tumour spread, large vessel invasion, and/or extrahepatic metastasis. Multimodal treatment strategies may therefore be required to improve disease control and survival, even though management guidelines for HCC recommend monotherapy as a treatment option. In a recent randomised phase II trial, sorafenib plus HAIC with cisplatin yielded favourable OS when compared with sorafenib alone in patients with advanced HCC [18]. By contrast, addition of HAIC with cisplatin and 5-fluorouracil to sorafenib failed to significantly improve OS according to phase III trial results [19]. The reasons underlying the discrepancy between these clinical trials remain unclear but warrant further studies, given the potential of combination therapy to extend the survival of advanced HCC patients.
While the above-mentioned studies [18, 19] incorporated continuous sorafenib administration protocol concurrently with HAIC, sequential combination of HAIC with interrupted dosing of sorafenib would be an alternative treatment to reduce toxicity and costs without significant loss in efficacy. In the appropriate clinical setting, we have administered planned sequential therapy with sorafenib and HAIC to eligible patients with BCLC stage B or stage C HCC. We analysed retrospectively patients who had received sequential combination therapy and compared these individuals with patients who received sorafenib monotherapy, to observe differences in the therapeutic effects and survival between these groups.

Material and methods

Patients

We analysed retrospectively data from 141 HCC patients who received sorafenib at our institute between September 2009 and March 2017. Twenty-nine patients were excluded because the duration of sorafenib treatment was less than four weeks (n = 28) or because of Child-Pugh class C liver function (n = 1). Patients were also excluded if they had received HAIC as subsequent therapy after failure of sorafenib monotherapy (n = 14), leaving 98 patients for final analysis. Among them, 64 patients (65.3%) were BCLC stage C and 34 patients (34.7%) were stage B. Of the 98 patients, 26 received planned sequential sorafenib-HAIC combination and were allocated to the combination group. Combination therapy was chosen at the discretion of the treating physician but generally based on the following characteristics: presence of multiple intrahepatic tumours; absence of rapidly progressive, extensive multiorgan or numerous extrahepatic metastases; lack of renal insufficiency that contraindicated cisplatin; Child-Pugh class A or B ≤ 7; Eastern Cooperative Oncology Group performance status (ECOG-PS) ≤ 1; and technical feasibility of HAIC, which depends on the following factors occasionally making catheter placement difficult, e.g. celiac axis stenosis or occlusion, tortuous small hepatic arteries, postsurgical changes or variations in vascular anatomy, and reflux of chemotherapy agents into the gastrointestinal tract and out of the liver. The remaining 72 patients who received sorafenib monotherapy were allocated to the control group. Baseline clinical characteristics and treatment outcomes were compared retrospectively between the groups. Written, informed consent was obtained from each patient. This study was approved by the Institutional Review Board of Meiwa Hospital (permission number: 29–34) and was performed in accordance with the ethical guidelines of the World Medical Association Declaration of Helsinki.

Treatment

Eighty-five patients (86.7%) started sorafenib at a reduced dosage of 400 mg/day according to their age, body weight, and co-morbidities, at the physician’s discretion. If the starting dose was tolerated, it was increased stepwise to 600 or 800 mg/day. In the combination group, sorafenib was administered for 1–2 months based on tolerability, after which HAIC was performed sequentially. Briefly, on day 1 of HAIC, 50 mg of cisplatin in 5–10 ml of lipiodol was injected through a subcutaneously implanted port system (Fig. 1) with adequate systemic hydration. Then 5 fluorouracil (5-FU) (250 mg/day) was continuously infused using a syringe pump for 10 days (on days 1–5 and 8–12) with two days off treatment. This sequential sorafenib-HAIC regimen was repeated every 2–3 months (Fig. 2). The interval between sorafenib treatment and HAIC was not specified but did not exceed two weeks. We reduced the dose of cisplatin by 25–50% in patients with pre-existing or new-onset renal insufficiency, but the dose of 5 FU was fixed in principle. Dose reduction or interruption of sorafenib in response to toxicity was performed in all subjects according to the general recommendations. If the tumour became refractory or there was intolerance to combination therapy or sorafenib monotherapy, patients were considered for subsequent therapy providing that survival or quality of life benefit was expected. Tumour response and disease progression were evaluated by using the modified Response Evaluation Criteria in Solid Tumours criteria [20], and adverse effects were graded according to Common Terminology Criteria for Adverse Events (version 4.03).

Statistical analysis

The Mann-Whitney U test was used to compare paired independent continuous variables, while categorical variables were compared by the chi-square test or Fisher’s exact test. OS was calculated from the date of initiating sorafenib therapy until the patient died of any cause or until the finish of follow-up. Kaplan-Meier curves were drawn, and the log-rank test was performed to compare OS between the two treatment groups. Univariate and stepwise multivariate Cox proportional hazard models were employed to detect factors with an influence on OS. To reduce selection bias and better assess the effect of the different treatment modalities, the two groups were balanced by performing inverse probability weighing (IPW) with propensity scores. All statistical analyses were performed with R Statistical Software (Foundation for Statistical Computing, Vienna, Austria), and p < 0.05 was considered significant.

Results

The baseline characteristics of the patients are summarised in Table 1. There were no significant differences between the two groups with respect to variables such as age, gender, Child-Pugh score, aetiology, previous treatment for HCC, maximum tumour size, macrovascular invasion, and serum -fetoprotein (AFP) level. The combination group was significantly less likely to have extrahepatic metastasis and BCLC stage C disease, but was more likely to have numerous intrahepatic tumours (≥ 10) than patients in the control group. Moreover, a good ECOG-PS was significantly more frequent in the combination group than in the control group. After IPW adjustment, baseline characteristics were balanced and the two groups showed no significant differences.

Response and adverse effects

In the combination group, the median number of sorafenib plus HAIC treatment cycles was three (range: 1–9 cycles). The median duration of sorafenib treatment was 5.9 months (range: 1.7–27.3 months) in the combination group and 4.7 months (range: 1.0–32.8 months) in the control group (p = 0.07). The best responses to each treatment are summarised in Table 2. In the combination group, 1 (3.8%), 5 (19.2%), and 12 (46.2%) patients showed a complete response, a partial response, and stable disease, respectively. The overall response rate tended to be higher in the combination group compared with the control group (23.1 vs. 6.9%, p = 0.06), although the difference was not significant. The disease control rate was significantly better in the combination group compared with the control group (69.2 vs. 44.4%, p = 0.04). The incidence of severe treatment-related adverse effects (grades 3–4) was similar in the two groups.

Overall survival and prognostic factors

The median follow-up period after initiation of sorafenib was 9.7 (1.2–58.8) months. The crude median OS was 17.1 months (95% confidence interval [CI]: 14.3–25.6 months) in the combination group compared with 9.7 months (95% CI: 7.0–15.1 months) in the control group, with one-year survival rates of 74.2% (95% CI: 51.2–87.6%) and 44.2% (95% CI: 31.7–56.0%), respectively (p = 0.01) (Fig. 3A). Univariate analysis revealed that OS was significantly associated with the ECOG-PS, BCLC stage, baseline AFP level (≥ 400 ng/ml), and combination therapy, while neither macrovascular invasion nor extrahepatic metastasis showed significant association with OS. According to multivariate regression analysis, combination therapy (hazard ratio [HR]: 0.521, 95% CI: 0.297–0.915, p = 0.02) and the AFP level (≥ 400 ng/ml) (HR: 2.221, 95% CI: 1.338–3.685, p = 0.002) were significant determinants of OS (Table 3). After adjustment by IPW, the combination group still showed significantly better OS than the control group (p = 0.04) (Fig. 3B).

Discussion

In the previous two largest studies, the SHARP trial [4] and the Asia-Pacific trial [5], the objective partial response rate to sorafenib monotherapy was only 2–3.3%, and no complete responses were obtained. Furthermore, sorafenib only extended the median OS by three months. Because of such limited efficacy, many studies have focused on combining sorafenib with other treatments, including transarterial chemoembolisation (TACE) [21], systemic chemotherapy [22, 23], and other molecular targeting agents [24]. However, no combination therapy has yet been shown to have a clear survival benefit.
HAIC has been widely used in Asian countries to treat advanced HCC, with favourable response rates ranging from 14.3% to 86.3% [9–15]. The Japanese guidelines for management of HCC recommend HAIC for the same patients as those indicated for sorafenib [25]. Among numerous HAIC regimens, cisplatin alone [10, 11], 5-FU plus cisplatin [12–14], and 5-FU plus interferon [15] are used most frequently in Japan. 5-FU and cisplatin combination have been shown to produce a synergistic antitumour effect [14, 26]. Cisplatin has both time-dependent and concentration-dependent features; however, 5-FU exerts a time-dependent antitumour effect with continuous infusion [26]. In 2010, Nagamatsu et al. reported on the efficacy of HAIC using cisplatin suspended in lipiodol and 5-FU in 51 HCC patients with portal vein tumour thrombus [14], achieving a very high response rate of 86.3% and long median OS of 33 months. Based on these promising results, we modified their HAIC regimen for our combination group.
A recent study investigating sorafenib combined with HAIC suggested that combining systemic therapy and regional cytotoxic chemotherapy could enhance antitumour activity. In a prospective multicentre phase II trial, a total of 108 patients with advanced HCC were randomised to treatment with sorafenib monotherapy or sorafenib plus HAIC with cisplatin. The response rate was 21.7% with sorafenib plus HAIC vs. 7.3% with sorafenib monotherapy (p = 0.09), and the median OS was significantly longer with sorafenib plus HAIC compared to sorafenib monotherapy (10.6 vs. 8.8 months, p = 0.031) [18]. In another multicentre, openlabel, randomised, phase III trial of sorafenib plus HAIC (low-dose cisplatin and 5-FU) vs. sorafenib monotherapy performed in 206 patients with advanced HCC, sorafenib plus HAIC failed to significantly improve survival (median OS was 11.8 months in both groups), but it improved OS for the subgroup of patients with portal vein involvement [19]. The response rate of 17.5% in the sorafenib arm observed in this phase III trial was higher than the observed response rates in the sorafenib arm in other studies, and OS was significantly better in patients who responded to sorafenib monotherapy than in non-responders. It is speculated that the difference in the efficacy of combining HAIC with sorafenib could be attributed to patient population differences, specifically related to sorafenib sensitivity.
It is noteworthy that we combined sorafenib with HAIC sequentially every 2–3 months, while HAIC was administered concomitantly with sorafenib every 4–6 weeks in the previous trials [18, 19]. Our results suggest that sequential HAIC can enhance antitumour activity even when delivered at relatively long intervals, while sorafenib acts as a disease stabiliser. In preclinical studies, sorafenib was shown to exert a synergistic anticancer effect with cisplatin [27], but antagonism between platinum drugs and sorafenib was also found at the cellular level [28]. Therefore, the optimal regimen for combining sorafenib and HAIC (sequential or concomitant) should be investigated further at the clinical level.
The influence of sorafenib on the prognosis partly depends on the duration of treatment [29, 30], rather than the daily dosage [31, 32]. In the present study, the duration of sorafenib treatment tended to be longer in the combination group than in the control group. In addition, although the difference was not significant, there was a lower rate of severe adverse effects related to sorafenib with combination therapy compared to sorafenib monotherapy. One possible advantage of sequential combination is that interruption of sorafenib administration during HAIC may prolong the total treatment period with this agent by reducing the risk of, or promoting recovery from, adverse effects such as hand-foot syndrome.
The present study had some limitations. First, the sample size was small. Second, this study was performed retrospectively, and selection bias could not be avoided. The IPW adjustment did not eliminate completely the between-group differences, for example with regard to the incidence of extrahepatic metastasis and BCLC stage C disease. However, these differences were not an independent prognostic factor in multivariate analysis; therefore, the difference did not significantly influence OS. Since a phase III trial [19] has already demonstrated limited value of combining sorafenib and HAIC, we should be conservative in interpreting our results. Third, the time to progression was not evaluated because this study was based on data obtained during routine clinical practice, and radiological assessment was performed at the discretion of each physician.

Conclusions

In conclusion, this study suggests that the sequential sorafenib-HAIC combination is a feasible and promising treatment option for selected patients with BCLC stage B/C HCC. Because a considerable proportion of HCC patients are unable to receive curative treatment, it is important to explore multimodal strategies for such patients. Further studies will be required to convincingly establish the efficacy of sequential combination therapy with HAIC and sorafenib.

The authors declare no conflict of interest.

References

1. Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015; 136: E359-386.
2. Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet 2003; 362: 1907-1917.
3. Bruera G, Cannita K, Giordano AV, et al. Multidisciplinary management of hepatocellular carcinoma in clinical practice. Biomed Res Int 2014; 2014: 806391.
4. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008; 359: 378-390.
5. Cheng AL, Kang YK, Chen Z, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol 2009; 10: 25-34.
6. Forner A, Reig ME, de Lope CR, Bruix J. Current strategy for staging and treatment: the BCLC update and future prospects. Semin Liver Dis 2010; 30: 61-74.
7. Colagrande S, Regini F, Taliani GG, Nardi C, Inghilesi AL. Advanced hepatocellular carcinoma and sorafenib: diagnosis, indications, clinical and radiological follow-up. World J Hepatol 2015; 7: 1041-1053.
8. Cammà C, Cabibbo G, Petta S, et al. Cost-effectiveness of sorafenib treatment in field practice for patients with hepatocellular carcinoma. Hepatology 2013; 57: 1046-1054.
9. Song MJ. Hepatic artery infusion chemotherapy for advanced hepatocellular carcinoma. World J Gastroenterol 2015; 21: 3843-3849.
10. Furuse J, Ikeda M, Okusaka T, et al. A phase II trial of hepatic arterial infusion chemotherapy with cisplatin for advanced HCC with portal vein tumor thrombosis. J Clin Oncol 2008; 26: abstr 15556.
11. Court WS, Order SE, Siegel JA, et al. Remission and survival following monthly intraarterial cisplatinum in nonresectable hepatoma. Cancer Invest 2002; 20: 613-625.
12. Nouso K, Miyahara K, Uchida D, et al. 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: 1904-1907.
13. Yamasaki T, Sakaida I. Hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma and future treatments for the poor responders. Hepatol Res 2012; 42: 340-348.
14. Nagamatsu H, Hiraki M, Mizukami N, et al. Intra-arterial therapy with cisplatin suspension in lipiodol and 5-fluorouracil for hepatocellular carcinoma with portal vein tumour thrombosis. Aliment Pharmacol Ther 2010; 32: 543-550.
15. Yamashita T, Arai K, Sunagozaka H, et al. Randomized, phase II study comparing interferon combined with hepatic arterial infusion of fluorouracil plus cisplatin and fluorouracil alone in patients with advanced hepatocellular carcinoma. Oncology 2011; 81: 281-290.
16. Lu LC, Hsu CH, Hsu C, Cheng AL. Tumor heterogeneity in hepatocellular carcinoma: Facing the challenges. Liver Cancer 2016; 5: 128-138.
17. Friemel J, Rechsteiner M, Frick L, et al. Intratumor heterogeneity in hepatocellular carcinoma. Clin Cancer Res 2015; 21: 1951-1961.
18. Ikeda M, Shimizu S, Sato T, et al. Sorafenib plus hepatic arterial infusion chemotherapy with cisplatin versus sorafenib for advanced hepatocellular carcinoma: randomized phase II trial. Ann Oncol 2016; 27: 2090-2096.
19. Kudo M, Ueshima K, Yokosuka O, et al. Prospective randomized controlled phase III trial comparing the efficacy of sorafenib versus sorafenib in combination with low-dose cisplatin/fluorouracil hepatic arterial infusion chemotherapy in patients with advanced hepatocellular carcinoma. J Hepatol 2016; 64: S209-210 (abstr LB04).
20. Lencioni R, Llovet JM. Modified RECIST (mRECIST) Assessment for hepatocellular carcinoma. Semin Liver Dis 2010; 30: 52-60.
21. Meyer T, Fox R, Ma YT, et al. Sorafenib in combination with transarterial chemoembolisation in patients with unresectable hepatocellular carcinoma (TACE 2): a randomised placebo-controlled, double-blind, phase 3 trial. Lancet Gastroenterol Hepatol 2017; 2: 565-575.
22. Abou-Alfa GK, Niedzwieski D, Knox JJ, et al. Phase III randomized study of sorafenib plus doxorubicin versus sorafenib in patients with advanced hepatocellular carcinoma (HCC): CALGB 80802 (Alliance). J Clin Oncol 2016; 34: abstr 192.
23. Assenat E, Boige V, Thézenas S, et al. Sorafenib alone versus sorafenib combined with gemcitabine and oxaliplatin (GEMOX) in first-line treatment of advanced hepatocellular carcinoma (HCC): final analysis of the randomized phase II GONEXT trial (UNICANCER/FFCD PRODIGE 10 trial). J Clin Oncol 2013; 31: abstr 4028.
24. Zhu AX, Rosmorduc O, Evans TR, et al. SEARCH: A phase III, randomized, double-blind, placebo-controlled trial of sorafenib plus erlotinib in patients with advanced hepatocellular carcinoma. J Clin Oncol 2015; 33: 559-566.
25. Kudo M, Izumi N, Kokudo N, et al. Management of hepatocellular carcinoma in Japan: consensus-based clinical practice guidelines proposed by the Japan society of hepatology (JSH) 2010 updated version. Dig Dis 2011; 29: 339-364.
26. Obi S, Sato S, Kawai T. Current status of hepatic arterial infusion chemotherapy. Liver Cancer 2015; 4: 188-199.
27. Yang Q, Zhang S, Kang M, Dong R, Zhao J. Synergistic growth inhibition by sorafenib and cisplatin in human osteosarcoma cells. Oncol Rep 2015; 33: 2537-2544.
28. Schneider V, Chaib S, Spanier C, et al. Transporter-mediated interaction between platinum drugs and sorafenib at the cellular level. AAPS J 2017; 20: 9.
29. Nakano M, Tanaka M, Kuromatsu R, et al. Efficacy, safety, and survival factors for sorafenib treatment in Japanese patients with advanced hepatocellular carcinoma. Oncology 2013; 84: 108-114.
30. Nakano M, Tanaka M, Kuromatsu R, et al. Sorafenib for the treatment of advanced hepatocellular carcinoma with extrahepatic metastasis: a prospective multicenter cohort study. Cancer Med 2015; 4: 1836-1843.
31. Morimoto M, Numata K, Kondo M, et al. Field practice study of half-dose sorafenib treatment on safety and efficacy for hepatocellular carcinoma: a propensity score analysis. Hepatol Res 2015; 45: 279-287.
32. Reiss KA, Yu S, Mamtani R, et al. Starting dose of sorafenib for the treatment of hepatocellular carcinoma: a retrospective, multiinstitutional study. J Clin Oncol 2017; 35: 3575-3581.

Address for correspondence

Shinichi Ikuta
Department of Surgery
Meiwa Hospital
4-31 Agenaruo, Nishinomiya
Hyogo 663-8186, Japan
e-mail: g2s1002@gmail.com

Submitted: 24.06.2018
Accepted: 15.07.2018
Copyright: © 2018 Termedia Sp. z o. o. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0) License (http://creativecommons.org/licenses/by-nc-sa/4.0/), allowing third parties to copy and redistribute the material in any medium or format and to remix, transform, and build upon the material, provided the original work is properly cited and states its license.
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