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ORIGINAL ARTICLE
Year : 2018  |  Volume : 14  |  Issue : 1  |  Page : 196-200

Effectiveness and the strategy to treat the side effects of sorafenib administration after transarterial chemoembolization in advanced hepatocellular carcinoma patients


Department of Radiology, Qilu Hospital of Shandong University, Jinan, China

Date of Web Publication8-Mar-2018

Correspondence Address:
Prof. Caixia Li
Wenhuaxilu #107, Jinan, Shandong Province, PS 250012
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_1175_16

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 > Abstract 

Objective: The aim is to study the effectiveness and side effects of sorafenib administration after transarterial chemoembolization (TACE) in advanced hepatocellular carcinoma (HCC) patients. To evaluate the safety of the combination of sorafenib and TACE to treat HCC.
Materials and Methods: A total of 36 unresectable HCC patients were enrolled. After TACE, administration of sorafenib was carried out. Follow-up was taken for every 4 weeks. Liver and renal function and alpha-fetoprotein were tested. Modified response evaluation criteria in solid tumors (mRECIST) was used to evaluate the clinical effect. The side effects were recorded.
Results: The median overall survival (mOS) and the median time to progress were 12.5 and 8 months with the range from 6 to 32 and 4–30 months, respectively. The mOS of patients with single tumor was 18 months while that of multiple tumors in liver was 10 months (χ2 = 4.1639, P = 0.0413). According to mRECIST, there were no complete response patients, 2 partial response patients, 10 stable disease patients, and 24 progressive disease patients. Response rate was 5.5% (2/36). Disease control rate (DCR) was 33% (12/36). The main adverse events were hand-foot skin reaction and diarrhea. The frequency of Grade II, III hand-foot-skin reaction was 39%. After treatment, it decreased to 5.6%. Forty-four percentage patients suffered from diarrhea of Grades I and II. After treatment, it decreased to 28%. The mean interval of TACE was 45 days before combination therapy and 120 days after combination therapy.
Conclusion: Administration of sorafenib after TACE could prolong overall survival of advanced HCC patients, keep the stable status longer and extend the interval between TACEs. The side effects are usually treatable, which proves the safety of this combination.

Keywords: Hepatocellular carcinoma, molecular targeted therapy, sorafenib, transarterial chemoembolization


How to cite this article:
Zhang K, Sun X, Xie F, Jian W, Li C. Effectiveness and the strategy to treat the side effects of sorafenib administration after transarterial chemoembolization in advanced hepatocellular carcinoma patients. J Can Res Ther 2018;14:196-200

How to cite this URL:
Zhang K, Sun X, Xie F, Jian W, Li C. Effectiveness and the strategy to treat the side effects of sorafenib administration after transarterial chemoembolization in advanced hepatocellular carcinoma patients. J Can Res Ther [serial online] 2018 [cited 2019 Nov 18];14:196-200. Available from: http://www.cancerjournal.net/text.asp?2018/14/1/196/214513


 > Introduction Top


Hepatocellular carcinoma (HCC) is one of the most frequently malignant tumors in China.[1] In recent years, therapeutic strategies of HCC have developed rapidly, but the morbidity and mortality are still high.[2] In clinical application, most HCC patients could not be diagnosed until the lesions have been in the advanced stage when they were not a suitable candidate of hepatectomy. Transarterial chemoembolization (TACE) is suggested as the first choice to the treat the Stage B patient in Barcelona Clinic Liver Cancer (BCLC) group classification of HCC. However, the long-term therapeutic efficacy is still not satisfactory.[3],[4] The main problems are relapse and metastasis. Furthermore, after several sessions patients could tend to become refractory and resistant to TACE, eventually leading to therapy failure or no response.[5],[6] In recent years, promising results have been shown in BCLC Stage C HCC patients treated by molecular targeted therapy. The combination of TACE and sorafenib to treat unresectable HCC has suggested primary effectiveness in clinical research both at home and abroad.[7],[8]

The research continuously enrolled 36 cases of patients suffering advanced HCC which were unresectable between February 2010 and June 2015 at Qilu Hospital of Shandong University. Combination therapy of TACE and sorafenib, TACE first then administration of sorafenib, were carried out. Then, therapeutic and side effects were observed to explore the optimal treatment strategy and how to alleviate the side effects. The value of combination therapy was evaluated.


 > Materials and Methods Top


Patients

Entry criteria: Diagnosis was made according to the experts consensus of guideline of diagnosis and therapy in HCC (2011 version) or pathologic results. The patients should be in BCLC B or C stage. According to modified response evaluation criteria in solid tumors (mRECIST), there was at least one measurable tumor. The patient is not suitable for hepatectomy, 3 months life expectancy at least. Eastern Cooperative Oncology Group (ECOG) score was <2. The informed consent was signed.

Exclusion criteria included progressed or died patients, administration of sorafenib <3 months, ceasing to the administration of sorafenib more than 1 month due to intolerable side effects or other reasons.

This retrospective study was approved by the Institutional Review Board of Shandong University, Qilu Hospital (Jinan, China).

The baseline characteristics of 36 patients are listed in [Table 1].
Table 1: Baseline characteristics of 36 patients

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Transarterial chemoembolization

All the procedures were taken using Philips FD20 or Siemens Artis Z digital angiographic system. 5F RF catheter was selectively catherized into superior mesenteric artery, celiac trunk, and common hepatic artery to make an angiography. 3F microcatheter was superselectively catherized into branches of hepatic artery to make it clear the location, size, and supply artery of the tumor. The chemotherapy protocol we used was duramycin (30–50 mg), lipoplatin (50 mg) or oxaliplatin (100–150 mg), 5-fluorouracil (FU) (0.75–1.0 g) and calcium folinate (0.3–0.4 g). The embolization materials were lipidol (8–20 ml) and gelfoam particles. 5-FU and calcium folinate were infused into the tumor, whereas duromycin, platin drugs, and lipidol were mixed together to embolize the feeding arteries. After embolization, angiography was made to evaluate the effectiveness of the procedure. Then, the catheter and sheath were withdrawn and pressed bandage was done. After the procedure, hydration and protection of liver function were carried out for 3–5 days. The interval between TACEs depended on the follow-up results. There were two ways for the administration of sorafenib. The first one is beginning to take sorafenib within 1 week after the first TACE with the initial dose of 200 mg qn, increased to 200 mg q12h. The second one was used for patients after several sessions of TACEs. After TACEs, the patients could choose a proper time to begin taking sorafenib using the same dosage adjustment as the first one.

Follow-up

After administration of sorafenib, all patients were routinely followed-up every 4 weeks until death or June 2015. The hepatic and renal function, side effects were recorded, and the therapeutic effect was evaluated according to mRECIST during each follow-up. The side effects were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0.

Statistical analysis: All analyses were performed using statistical software SAS version 9.2 (SAS Institute, Cary, N.C.). Results were expressed as mean ± standard deviation. Difference between different survival curve was compared using log-rank test. Differences were considered to be statistically significant at P < 0.05 on two-tailed test.


 > Results Top


Therapeutic effects

In this cohort of 36 patients, the mean overall survival (mOS) was 12.5 months (6–32 months) [95% confidence interval (CI): 9–15 months, [Figure 1], the mean time to progress (mTTP) was 8 months (4–30 months) [95% CI: 7–13 months, [Figure 2]. The mOS of Child–Pugh A patients was 13 months (95% CI: 9–18 months). That of Child–Pugh B patients was 10 months (95% CI: 6–23 months). There was no significant difference between them (χ2 = 0.0741, P = 0.7855). The mOS of patients without vessel invasion was 13 months (95% CI: 9–18 months). That of patients with vessel invasion was 10 months (95% CI: 9–14 months). There was no significant difference between them (χ2 = 1.4793, P = 0.2239). As far as the patients with single or multiple liver focal lesions, the mOS was 18 months (95% CI: 6–32 months) and 10 months (95% CI: 9–13 months), respectively, and the difference was significant (χ2 = 4.163, P = 0.0413).
Figure 1: Overall survival curve (month)

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Figure 2: Time to progress curve (month)

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Evaluation of short-term effect

According to mRECIST, there was no complete response patients, 2 partial response patients, 10 stable disease (SD) patients, and 24 progressive disease (PD) patients. Response rate was 5.5% (2/36) and disease control rate (DCR) was 33% (12/36).

Side effects

The main side effects of this cohort included the TACE associated postembolization effects, such as fever, nausea, vomiting, and abdominal pain or distension., which were usually disappeared or alleviated after 3–5 days of symptomatic treatment. Sorafenib associated side effects included hand-foot-kin reaction (22 cases, 61%), diarrhea (16 cases, 44%), fatigue (14 cases, 39%), hypertension (6 cases, 17%), hair loss (1 case, 2.8%), and oral ulceration (2 cases, 5.6%). Four patients did not suffer any discomfort. The onset of side effects of sorafenib was usually 5–10 days after beginning. After dosage adjustment and symptomatic treatment, most of them could be alleviated [Table 2].
Table 2: Side effects of 36 patients after administration of sorafenib

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Frequency of transarterial chemoembolization

Before administration of sorafenib, 28 patients received totally 112 TACE procedures with a mean level of four TACEs per patient (3–8 times). The mean interval between TACEs was 45 days. Eight patients began to take sorafenib within 1 week after first TACE. After combination therapy, all the 36 patients received 77 TACE procedures with a mean level of two TACEs per patient (1–6 times). The mean interval between TACEs prolonged to 120 days.


 > Discussion Top


HCC is one of the most common malignant tumors worldwide. Due to the well-verified short-term effect, TACE has been accepted as the standard palliative treatment strategy of unresectable HCC. However, the long-term effect is unsatisfactory, especially for multiple lesions, tumors with ill-defined margin, because TACE could not embolize the feeding vessels completely so that 100% necrosis could not been achieved. Xiao reported that only 16.1% HCC were necrotic thoroughly after TACE.[9] Hypoxia caused by embolization will stimulate high expression of vascular endothelial growing factor (VEGF), which could cause neovascularization of the lesion. Then, relapse and/or metastasis will occur. The remnant of tumor and neovascularization are the key factor to weaken the long-term effect of TACE to treat HCC. In recent years, much work has been done to find effective ways to inhibit high expression of VEGF and neovascularization to suppress tumor growth. The associated achievements have become the key factor to improve the long-term effect of TACE to treat HCC.[10] Sorafenib is the first and exclusive molecular target medicine which has been approved to treat medium and late stage HCC in many countries. Sorafenib is a small molecular inhibitor of several tyrosine protein (VEGFR and platelet-derived growth factor receptor) and Raf kinases (more avidly C-Raf than B-Raf).[3],[4] Sorafenib also inhibits some intracellular serine/threonine kinases. The two well-known phase III clinical studies, SHARP and oriental have approved that administration of sorafenib in advanced stage HCC patient could prolong overall survival (OS) 44% and 47%, time to progress (TTP) 74% and 73% and decrease the mortality risk 31% and 32%, respectively.[11],[12] Sorafenib has been recommended as the standard choice to treat late stage HCC in many guidelines.[13],[14] However in clinical application, it has been found that taking sorafenib alone could only achieve limited effects. Combination therapy has attracted increasing attention of many researchers. Hypoxia caused by TACE could cause high expression of VEGF, which could be exactly well-inhibited by sorafenib. Then, relapse and metastasis could be decreased so that a better long-term therapeutic effect could be expected. Huang et al. reported their finding of treatment of advanced stage HCC.[15] In their study, combination therapy of TACE and sorafenib was carried out in 18 patients. The other 27 patients were treated by sorafenib alone. The OS and TTP of combination group and single agent group were 16 months and 5.3 months, 11 months and 4.5 months, respectively. The difference were both statistically significant (P< 0.01) The results suggested that combination therapy of TACE and sorafenib to treat advanced stage HCC could elongate the patient's survival. The Asian Pacific study START showed that the therapeutic effect of combination TACE and sorafenib to treat HCC is encouraging with the overall TTP 9.3 months and Chinese cohort TTP 10.6 months.[16] The other global multicenter RCT study SPACE showed that combination therapy could decrease disease progression risk of 20.3% in the whole group and 28% in Asian group. Moreover, the mortality risk of Asian group decreased 32.3%.[17] In this study, the DCR was 33%, mOS was 12.5 months, mTTP was 8 months, which were coincident with other domestic study.[8] Some studies showed even better results.[18] The results of this study was not so promising. We think the possible reason is most patients in this cohort were in late stage. Eighty-nine percentage of them were in BCLC C stage. Only eight patients began to take sorafenib within 1 week after first TACE. Seventy-eight percentage of patients began to take sorafenib after three TACEs because being refractory to TACE. For them, the combination therapy was only remedial treatment. Even though, the combination therapy brought them fairly good DCR. The mOS of Child–Pugh Stage A and Stage B patients was 13 months and 10 months, respectively. The mOS of the single hepatic lesion and multiple hepatic lesion patients was 18 months and 10 months, respectively (χ2 = 4.1639, P = 0.0413). The results suggest that combination therapy of TACE and sorafenib could inhibit tumor growth effectively, improve the life quality of patients, elongate the survival time, especially for the single lesion patients. In this group, even before combination therapy, some patients were evaluated as PD, they could become SD after sorafenib administration and maintain the SD status for a fairly long time. Meanwhile, the ECOG score improved during combination therapy, and better life quality was achieved. The study of Ye et al. has showed promising results of combination therapy of TACE and sorafenib.[18] The patients in their study were in the early stage of HCC, which means the earlier combination therapy starts the better therapeutic effect could be achieved. It had better take sorafenib within 1 week after TACE. Otherwise, the optimal time window of sorafenib to inhibit the expression of VEGF will be missed.

In this group, the mean interval between TACE before combination therapy was 45 days. After the combination, it was elongated to 120 days, which was consistent with the results of START. Elongating the interval could decrease the side effects of agents to the liver, release the psychological and economic burden of patients. In this group, hand-foot skin reaction and diarrhea were the common side effects that most patients suffered from. To alleviate hand-foot skin reaction wearing cotton gloves and smearing lesion with Vaseline cream frequently are helpful. Before go to bed, the patient could smear hand and foot with Vaseline cream then wearing gloves and socks to keep moisture and avoid rubbing the skin. For the patients suffering from diarrhea, it is suggested that to avoid drinking much water and high-fat diet within 2 h before taking sorafenib and do not eat raw, cold, and irritative food. It would better steam fruits before eating. Following the above advices, the symptoms of most patients could be alleviated or disappeared. In this group, the hand-foot skin reaction dropped from 61% to 55% after treatment, especially the severe reaction (II, III grade) dropped from 39% to 5.6%. Diarrhea, which were all I, II grade, dropped from 44% to 28%. To treat fatigue, we have not found effective ways to alleviate it until now. Stratified analysis and the influence of side effects to the therapeutic effect of combination therapy of TACE and sorafenib needs further investigation.


 > Conclusion Top


Administration of sorafenib after TACE could prolong overall survival of advanced HCC patients, keep the stable status longer and extend the interval between TACEs. The side effects are usually treatable. So the combination therapy is effective and safe.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
 > References Top

1.
Li L, Lan X. Association between hepatitis B virus/hepatitis C virus infection and primary hepatocellular carcinoma risk: A meta-analysis based on Chinese population. J Cancer Res Ther 2016;12:284-7.  Back to cited text no. 1
    
2.
Li W, Man W, Guo H, Yang P. Clinical study of transcatheter arterial chemoembolization combined with microwave ablation in the treatment of advanced hepatocellular carcinoma. J Cancer Res Ther 2016;12:217-20.  Back to cited text no. 2
    
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Kudo M, Matsui O, Izumi N, Kadoya M, Okusaka T, Miyayama S, et al. Transarterial chemoembolization failure/refractoriness: JSH-LCSGJ criteria 2014 update. Oncology 2014;87 Suppl 1:22-31.  Back to cited text no. 5
    
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Xiao EH. The molecular and biological change of primary liver cancer treated by transartrial chemoembolization. Modern Med 2008;2:132-5.  Back to cited text no. 9
    
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Chan SL, Mok T, Ma BB. Management of hepatocellular carcinoma: Beyond sorafenib. Curr Oncol Rep 2012;14:257-66.  Back to cited text no. 10
    
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Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359:378-90.  Back to cited text no. 11
    
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Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, 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.  Back to cited text no. 12
    
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Kudo M, Matsui O, Izumi N, Iijima H, Kadoya M, Imai Y, et al. JSH consensus-based clinical practice guidelines for the management of hepatocellular carcinoma: 2014 update by the Liver Cancer Study Group of Japan. Liver Cancer 2014;3:458-68.  Back to cited text no. 14
    
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Pericleous M, Caplin ME, Tsochatzis E, Yu D, Morgan-Rowe L, Toumpanakis C. Hepatic artery embolization in advanced neuroendocrine tumors: Efficacy and long-term outcomes. Asia-Pac J Clin Oncol 2016;12:61-9.  Back to cited text no. 15
    
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Tan X, Xie P, Liu J, Wu H, Xie Y. Therapeutic value of transcatheter arterial chemoembolization combined with portal vein embolization for primary hepatocellular carcinoma with portal vein tumor thrombus: A pilot study. Asia-Pac J Clin Oncol 2015;11:e6-e12.  Back to cited text no. 17
    
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Rapicetta C, Lococo F, Levrini G, Ricchetti T, Sgarbi G, Paci M. Asymptomatic air-embolism following percutaneous radiofrequency ablation of lung tumor: Rare or underestimated complication?. Thoracic Cancer 2015;6:227-9.  Back to cited text no. 18
    


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