Clinical Radiology xxx (2014) e1ee9
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Safety and efficacy of transarterial chemoembolization plus sorafenib for hepatocellular carcinoma with portal venous tumour thrombus T. Pan a, X.-S. Li b, Q.-K. Xie a, J.-P. Wang c, W. Li a, P.-H. Wu a, M. Zhao a, * a
Minimally Invasive Interventional Division, Medical Imaging Center, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, PR China b Department of Interventional Radiology, Guangzhou First People’s Hospital, Guangzhou Medical University, Guangzhou, PR China c Minimally Invasive Interventional and Target Treatment Division and Cancer Center, The First People’s Hospital of Foshan City, The Affiliated Foshan Hospital of Sun Yat-sen University, Guangzhou, PR China
art icl e i nformat ion Article history: Received 19 May 2014 Received in revised form 15 August 2014 Accepted 9 September 2014
AIM: To evaluate the safety and efficacy of combined therapy with transarterial chemoembolization (TACE) and sorafenib for hepatocellular carcinoma (HCC) with portal venous tumour thrombus (PVTT). MATERIALS AND METHODS: This study was approved by the institutional review board. From May 2009 to May 2012, 170 consecutive patients were newly diagnosed with advancedstage HCC and treated with TACE plus sorafenib. Among them, 41 patients with PVTT were retrospectively enrolled in the study. The adverse events (AEs), overall survival (OS), time to progression (TTP), and prognostic factors were analysed. Statistical analysis was performed with the KaplaneMeier method using the log-rank test and Cox regression models. RESULTS: The most common AEs were handefoot skin reaction related to sorafenib and fever related to TACE. Procedure-related mortality and grade 4 AEs were not observed. Grade 3 AEs were observed in five patients. During the median follow-up period of 13.5 months (range 1.4e45 months), the 6-month and 1-year survival rates were 87.7% and 53.6%, respectively. The median OS was 13 months (range 1.4e44.8 months), and the median TTP was 7 months (range 1e18.6 months). The ChildePugh class (p ¼ 0.022), extrahepatic metastasis (p ¼ 0.009), and gross morphological type (nodular type versus diffuse type; p ¼ 0.008) were prognostic factors related to OS in the multivariate analysis. CONCLUSION: TACE plus sorafenib in an interrupted therapeutic scheme was well tolerated and might improve OS for HCC patients with PVTT, especially in those with ChildePugh class A, no extrahepatic metastasis, or nodular-type HCC. Ó 2014 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
* Guarantor and correspondent: Ming Zhao, Minimally Invasive Interventional Division, Medical Imaging Center, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, 651 Dongfeng Road East, Guangzhou 510060, PR China. Tel./ fax: þ86 020 87343272. E-mail address: [email protected] (M. Zhao). http://dx.doi.org/10.1016/j.crad.2014.09.007 0009-9260/Ó 2014 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Pan T, et al., Safety and efficacy of transarterial chemoembolization plus sorafenib for hepatocellular carcinoma with portal venous tumour thrombus, Clinical Radiology (2014), http://dx.doi.org/10.1016/j.crad.2014.09.007
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T. Pan et al. / Clinical Radiology xxx (2014) e1ee9
Introduction Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third leading cause of cancer mortality globally.1 Although the development of imaging techniques has improved early HCC diagnosis, portal venous tumour thrombus (PVTT) is still identified in 12.5e39.7% of HCC patients at their initial visits.2 Patients suffering from extremely aggressive HCC with PVTT have a median survival time of only 2.7e4 months if left untreated.2 The current standard of practice recommends sorafenib, a potent multi-kinase inhibitor with anti-angiogenic and anti-proliferative properties that block the Raf/MEK/ERK pathway and the tyrosine kinase receptors VEGFR-2/3, PDGFR-b, c-KIT, and Flt-3.3 This drug has been shown to prolong overall survival (OS) by nearly 3 months in advanced HCC patients and by 1.5e3.2 months in those with PVTT.4e6 Other available therapies including hepatectomy, hepatic arterial infusion, radioembolization with yttrium-90 microspheres and radiotherapy have also been utilized in selected HCC and PVTT patients, yielding acceptable OS periods of 6e14, 4.5e11.8, 4.5e10 and 3.8e10.7 months, respectively.2,7,8 Although transarterial chemoembolization (TACE) is the main treatment modality for unresectable HCC patients, its use in patients with PVTT is controversial. Previous theories suggested that TACE blocks hepatic arterial blood flow, along with the already existing poor blood supply from the portal vein caused by PVTT, which likely worsens hepatic tissue ischaemia and may even lead to hepatic failure. However, some recent prospective studies have demonstrated that TACE can serve as a safe procedure in selected HCC patients with PVTT and proved that hepatic tissue could obtain blood from the incompletely occluded portal vein and collateral circulation around an occluded portal vein.9,10 Moreover, TACE in combination with other treatment modalities, including radiotherapy, radiofrequency ablation, and resection, has been safely applied in HCC patients with PVTT, and its survival benefits were proven to be better than that of TACE alone.2,8,11 Considering the promising efficacy of sorafenib, several clinical trials have tested TACE in combination with sorafenib and proven its safety and efficacy in the treatment of unresectable HCC. However, these studies mainly focused on patients with intermediate-stage HCC12,13; data on advanced-stage HCC are scarce,14 and only one study reported data on HCC patients with PVTT.15 The present study was designed to assess the safety and survival benefit of TACE combined with sorafenib for HCC patients with PVTT. Moreover, suitable candidates were also investigated for the combined treatment with TACE and sorafenib.
treatment. A retrospective review of the electronic medical database from May 2009 to May 2012 revealed that a total of 170 consecutive HCC patients received TACE in combination with sorafenib and 41 patients who also had PVTT were enrolled in the study. The eligibility criteria included the following: (1) newly diagnosed HCC with Vp2, Vp3, and Vp4 type PVTT according to the criteria of the Liver Cancer Study Group of Japan, where PVTT grade was defined as follows: Vp0, no PVTT; Vp1, tumour thrombus in a third or more of peripheral branches of the portal vein; Vp2, tumour thrombus in a second branch of the portal vein; Vp3, tumour thrombus in the first branch of the portal vein; Vp4, tumour thrombus in the trunk of the portal vein16; (2) single tumour with size 5 cm or multiple nodular tumours of >3 cm; (3) Eastern Cooperative Oncology Group (ECOG) performance status of 0e1; (4) ChildePugh class A or B; (5) no history of encephalopathy; (6) adequate haematological, renal function, as indicated by a platelet count >60 109/l; haemoglobin concentration >85 g/l; serum creatinine concentration of 1.5-times the upper limit of the normal range or less; and prothrombin time 6 s above the control. The exclusion criteria were defined as follows: (1) received palliative operative liver transplantation or radiotherapy during the period of combined treatment; (2) suffered from another type of carcinoma (Fig 1). The baseline characteristics of the patients in this study were collected (Table 1). HCC was diagnosed based on histopathology (n ¼ 16, 39%) or clinical features (n ¼ 25, 61%) according to the guidelines of the American Association for the Study of Liver Disease.17 HCC with PVTT was confirmed based on contrastenhanced CT or MRI with the presence of an intraluminal filling defect with generalized enhancement, intrathrombus neovascularity, accompanying portal venous expansion, or direct invasion of the portal vein, as described in previous studies.8,18
Materials and methods Patients The institutional review board approved the study protocol, and informed consent was obtained before
Figure 1 Flow diagram shows patient selection criteria.
Please cite this article in press as: Pan T, et al., Safety and efficacy of transarterial chemoembolization plus sorafenib for hepatocellular carcinoma with portal venous tumour thrombus, Clinical Radiology (2014), http://dx.doi.org/10.1016/j.crad.2014.09.007
T. Pan et al. / Clinical Radiology xxx (2014) e1ee9 Table 1 Univariate analysis by log-rank test for prognostic clinicopathological and procedure-related factors for overall survival (n ¼ 41). Characteristic Gender Male Female Age (years) >75 55e75 30e54 400 Total bilirubin (mg/dl) 2 >2 Albumin (g/l) 35 >35
n (%)
p-Value 0.390
38 (92.7) 3 (7.3) 0.388 2 15 21 3
(4.9) (36.6) (51.2) (7.3) 0.151
40 (97.6) 1 (2.4) 0.031 35 (85.4) 6 (14.6) 0.900 20 (48.8) 21 (51.2) 0.221 13 (31.7) 2 (4.9) 26 (63.4) 0.389 25 (61.0) 16 (39.0) 0.045 8 (19.5) 23 (56.0) 10 (24.4) 0.019 14 (34.1) 27 (65.9) 0.003 11 5 1 1
(26.8) (12.2) (2.4) (2.4) 0.112
4 (9.8) 37 (90.2) 0.650 22 (53.7) 19 (46.3) 0.310 26 (63.4) 15 (36.6) 0.120 5 (12.2) 36 (87.8)
ECOG, Eastern Cooperative Oncology Group. a Tumour size, the maximum diameter of the largest target index lesion.
Treatment procedure The treatment modality of each patient was decided in consensus during a multidisciplinary HCC conference with hepatobiliary surgeons, medical oncologists, interventional radiologists, and diagnostic radiologists. Detailed information regarding TACE and sorafenib treatment, including the efficacy and potential adverse effects (AEs), was explained to all patients. The patients selected their treatment, TACE plus sorafenib instead of sorafenib alone, based on the attending physician’s recommendation and the details of
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sorafenib monotherapy and combined treatment strategy. They understood that the effect of the combined treatment might not be better than sorafenib alone. Informed consent was obtained prior to the treatment. TACE was performed with digital subtraction angiography (Philips, type Allura Xper FD20, Veenpluis, The Netherlands). A 4-F catheter (Radiofocus Guide Wire M, Terumo Corporation, Tokyo, Japan) was inserted into the hepatic artery and superior mesenteric artery using the Seldinger technique through the femoral artery. Arteriography was then performed to assess the arterial blood supply to the liver, portal vein patency, and to identify the accessory arteries. Depending on the size, location, and arterial supply of the tumour, the tip of the catheter was advanced into the right or left hepatic artery, or into the tumour-feeding branches. If a conventional catheter could not enter the targeted branch of the hepatic artery due to technical reasons, a 2.9-F microcatheter (Terumo Corporation) was used. An emulsion of 8e30 ml (16 4.5 ml mean standard deviation) of lipiodol (Laboratorie Guerbet, Aulnay-sous-Bois, France), 40e60 mg (50 6.9 ml) of epirubicin (Farmorubicin; Pharmacia, Tokyo, Japan), and 6e10 mg (8 1.5 ml) of mitomycin C (Kyowa Hakko Kogyo, Tokyo, Japan) was injected, followed by embolization with gelatin sponge particles dissected by an operator into 2e3 mm diameter pieces (Gelfoam; Hanzhou, China). The procedure was performed according to the experience gained from previous work.19 The patients were subsequently admitted for observation of potential postembolization syndrome. Contrast-enhanced CT or MRI was performed 4 weeks after the procedure to assess the treatment efficacy. When the residual viable tumours were confirmed, repeat TACE procedures were performed on patients who conformed to the eligibility criteria. Sorafenib (Nexavar; Bayer, Leverkusen, Germany) was taken 3 days after the first TACE procedure at a dose of 400 mg twice a day. A 3-day interruption in sorafenib was adopted after each subsequent TACE cycle. Drug tolerance evaluation involved documenting the history and physical examinations, laboratory tests, and grading adverse events (AEs), which were assessed based on the National Cancer Institute Common Terminology Criteria version 3.0.20 If a patient suffered grade 3/4 drug-related AEs without effective control, a dose reduction to 400 mg once daily or a temporary drug interruption was utilized.5 The treatment continued until an AE requiring permanent discontinuation, radiological progression, or death was observed. Patients with dose discontinuation caused by AEs were not excluded from the survival analysis in the present study.
Assessment and follow-up The follow-up period was defined as the duration from the date of entry into treatment to death or the last followup date of 30 December, 2012. Follow-up examinations were performed at 1 month and then every 3 months after the first TACE procedure, including physical examinations, laboratory tests, contrast-enhanced three-phase CT or MRI, and PET-CT if multiple organic metastases were suspected.
Please cite this article in press as: Pan T, et al., Safety and efficacy of transarterial chemoembolization plus sorafenib for hepatocellular carcinoma with portal venous tumour thrombus, Clinical Radiology (2014), http://dx.doi.org/10.1016/j.crad.2014.09.007
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The tumour response was assessed at the first, third, and sixth month after first TACE and then every 3 months until the date of disease progression, death, or last follow-up. The patients’ response to treatment was evaluated based on the best overall response according to the RESIST1.0 criterion, as described in previous research.5,21 Patients that exhibited a complete response (CR) were closely followed-up, and patients that exhibited a partial response (PR) and stable disease (SD) received continuous combined therapy. Patients with progressive disease (PD) were recommended for other therapies, such as radiotherapy or traditional Chinese medicine according to the doctors’ advice. Simultaneous to the assessment of intra-hepatic lesions, the response of PVTT was evaluated based on the change in the product of the largest perpendicular diameters of tumour thrombus compared to the initial size.8 CR was defined as the complete disappearance of the PVTT; PR was defined as thrombus diameter decrease exceeding 50%; PD was defined as thrombus diameter increase exceeding 25%, and SD was defined as neither sufficient shrinkage to PR nor sufficient increase to PD.8
Statistical methods The time to progression (TTP) was defined as the interval from the date of entry into the treatment to the date of developing local progression (target lesion), a new lesion elsewhere in liver, or extrahepatic disease. The OS was calculated from the date of entry into the treatment to the day of either death from any cause or last follow-up. The TTP and OS were estimated using the KaplaneMeier method. Univariate analysis (log-rank test) was performed to determine the clinicopathological and procedure-related factors that affected OS. A multivariate analysis was performed on all factors with a p-value of 0.10 using the Cox proportional hazards regression model. All analyses were performed using SPSS software (version 16.0; SPSS, Chicago, IL, USA). A p-value of 0.05 (two-tailed) was considered statistically significant.
Results Baseline characteristics The study population was mostly male (92.7%), with a median age of 52 years (range 29e73 years), hepatitis B virus infection (97.6%), PS 0e1 (PS: 0, 48.8%; 1, 51.2%) and ChildePugh class (A 85.4%; B 14.6%). Fourteen patients (34.1%) had nodular-type HCC, and 27 patients (65.9%) had diffuse-type HCC, which was classified according to criteria of the Liver Cancer Study Group of Japan, as previously described.9,16 The numbers of patients with type Vp2, Vp3, and Vp4 were eight (19.5%), 23 (56%), and 10 (24.4%), respectively. Twenty-four (63.4%) patients had three or more tumour lesions, two (4.9%) had two lesions and 13 (31.7%) had only one lesion. The diameters of the largest tumour in each patient ranged from 50e173 mm, with a mean tumour size of 88.1 mm (Table 1). All patients were treated with a total of 86 TACE procedures (per-patient
mean 2.08, median 2, range 1e4); 13 patients received one procedure, 15 received two procedures and 13 received more than two procedures. The patients received sorafenib with a mean daily dose of 788 mg (range 680e800 mg).
Survival outcomes During the median follow-up period of 13.5 months (range 1.4e45 months), 33 patients died and eight patients survived. A total of 31 patients died due to tumour progression, and the other two died of severe hepatic dysfunction. The median OS was 13 months (95% CI ¼ 10.4e15.6; range 1.4e44.8 months) with 6 month, 1, and 2 year OS rates of 87.7%, 53.6%, and 11.9%, respectively. The median TTP was 7 months (95% CI ¼ 5.7e8.3; range 1e18.6 months) with 6 month and 1 year PFS rates of 78% and 28.5%, respectively (Fig 2). According to the RESIST1.0 criteria, one patient (2.4%) had a CR, seven patients (17.1%) had a PR, 25 patients (60.9%) had SD, and eight patients (19.5%) had PD (Fig 3). The disease control rate (DCR) was 80.5%, and the response rate was 19.5%. The median OS did not significantly differ between responders and nonresponders (13.2 months versus 11.6 months, p ¼ 0.286). The patient with CR was alive for 6 months after the combination treatment at the last follow-up and was censored. The median OS of patients classified as PR and SD were significantly longer than those of patients with PD (11.6 and 14 versus 6.3 months, p < 0.001), and the median OS did not significantly differ between patients evaluated as PR and SD (11.6 versus 14 months, p ¼ 0.501). The responses of PVTT were classified as CR, PR, SD, and PD in one, three, 34 and three patients, respectively. The median OS did not significantly differ between responders and non-responders of PVTT (18.5 versus 13 months, p ¼ 0.268). The median OS of patients classified as PR and SD of PVTT were significantly longer than those of patients with PD of PVTT (18.5 and 14 versus 5 months, p < 0.001). The median OS did not significantly differ between patients classified as PR and those classified as SD of PVTT (18.5 versus 14 months, p ¼ 0.363). All listed baseline factors were analysed using univariate analysis, and the factors associated with OS (p 0.05) were identified as ChildePugh class, extrahepatic metastasis, gross morphological classification, and PVTT type (Vp2e3 versus Vp4; Fig 4). The multivariate analysis indicated that ChildePugh class (A versus B; Hazard Ratio (HR) 0.30, p ¼ 0.022), extrahepatic metastasis (absent versus present; HR 2.93, p ¼ 0.009), and gross morphological classification (nodular type versus diffuse type; HR 2.90, p ¼ 0.008) as significant predictors of OS (Table 2).
Complications The most common toxicities related to sorafenib treatment were handefoot skin reaction (HFSR; 68.3%), diarrhoea (53.7%), and fatigue (22%), most of which were grade 1 or 2 (Table 3). The reported grade 3 drug-related AEs were HFSR in three patients (7.3%) and hypertension in one patient (2.4%). Grade 4 AEs were not observed. Three patients
Please cite this article in press as: Pan T, et al., Safety and efficacy of transarterial chemoembolization plus sorafenib for hepatocellular carcinoma with portal venous tumour thrombus, Clinical Radiology (2014), http://dx.doi.org/10.1016/j.crad.2014.09.007
T. Pan et al. / Clinical Radiology xxx (2014) e1ee9
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Figure 2 A 50-year-old man with HCC and PVTT showed a partial response after TACE and sorafenib treatment. (aeb) Contrast-enhanced CT images at diagnosis, showing a 40 mm diameter HCC nodule (white arrow) and multiple small intrahepatic lesions located in the left lobe, together with PVTT in the left and main portal vein (black arrow). (ced) CT images 2 months after diagnosis, showing no enhancing nodular lesions in the left lobe and near complete absence of PVTT without definite enhancement (white arrow).
were subjected to dose reductions for 2 weeks and then reverted to a regular dose after AEs relief. Two patients were subjected to drug interruption periods of 14 and 24 days due to the AEs and then restored to a regular dose after
relief from AEs. These patients with dose reductions or drug interruption were not excluded from the study. Patients were hospitalized for an average of 3 days (range 1e15 days) to manage potential post-TACE AEs. Procedure-related
Figure 3 KaplaneMeier curves for patients with advanced HCC and PVTT who were treated with combination TACE and sorafenib. (a) Median OS was 13 months, with 6-months and 1- and 2-year survival rates of 87.7%, 53.6%, and 11.9%, respectively. (b) Median TTP was 7 months, with 6-month and 1-year of 78% and 28.5%, respectively. Please cite this article in press as: Pan T, et al., Safety and efficacy of transarterial chemoembolization plus sorafenib for hepatocellular carcinoma with portal venous tumour thrombus, Clinical Radiology (2014), http://dx.doi.org/10.1016/j.crad.2014.09.007
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Figure 4 Univariate analysis (log-rank test) was performed to determine prognostic factors for OS. (a) Log-rank analysis of OS stratified according to gross morphological type (p ¼ 0.019). (b) Log-rank analysis of OS stratified according to extrahepatic metastasis (p ¼ 0.003). (c) Logrank analysis of OS stratified according to ChildePugh class (p ¼ 0.031). (d) Log-rank analysis of OS stratified according to PVTT type (p ¼ 0.045).
death did not occur within 1 month of the TACE procedure. The most common AEs related to TACE were fever (56.1%), mild epigastric pain (31.7%), and nausea (19.5%). These symptoms can be relieved during the first week with appropriate treatment. One patient experienced grade 3 myelosuppression. After 1 week of injection with granulocyte colony-stimulating factor, the patient’s white blood cell and platelet counts recovered to the pretreatment level.
Discussion The current standard first-line therapy for advancedstage HCC with PVTT is sorafenib. Although this treatment shows survival benefits with a median OS of 8.1 and 5.6 months in the macrovascular invasion subgroup of the Sorafenib Health Assessment Randomised Protocol and Sorafenib Asia-Pacific (AP) trials, the OS remains modest.4,6 Further clinical studies are needed to optimize treatment strategies; for instance, sorafenib in combination with local therapeutic approaches could be a promising approach.
Previous theories suggested that the upregulation of VEGF and PDGF levels after TACE might account for tumour recurrence. The use of sorafenib can significantly counteract the tyrosine kinases receptor VEGFR-2/3 and PDGFR-b, which decreases the post-TACE VEGF and PDGF upregulation and further enhances the efficacy of TACE.26 Moreover, TACE can improve the tumour response rate, which does not exceed 4% for sorafenib monotherapy. A series of clinical trials have evaluated the combined use of TACE and sorafenib in intermediate-stage and/or advanced-stage HCC. Pawlik et al.14 assessed the safety and response of sorafenib plus TACE with drug-eluting beads in a phase II study that involved 35 patients with mostly advanced HCC. The results showed a promising disease control rate of 95% according to RESIST criteria with manageable toxicity. Another phase II study of sorafenib plus conventional TACE in the treatment of intermediate and advanced HCC also revealed an overall median TTP of 7.1 months and a manageable safety profile.22 Although the preliminary efficacy data were fairly good, the long-term
Please cite this article in press as: Pan T, et al., Safety and efficacy of transarterial chemoembolization plus sorafenib for hepatocellular carcinoma with portal venous tumour thrombus, Clinical Radiology (2014), http://dx.doi.org/10.1016/j.crad.2014.09.007
T. Pan et al. / Clinical Radiology xxx (2014) e1ee9
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Table 2 The primary overall survival outcome and the univariate and multivariate analysis. Variable
All patients (41) Gross classification Diffuse type Nodular type Extrahepatic metastasis Present Absent ChildePugh class A B PVTT type Vp2e3 Vp4 Level of AFP (ng/ml) 400 >400
Primary outcome
Univariate analysis
Median OS (months)
6 month OS
1 year OS
HR
95% CI
13.0
87.7
53.6
10.5 15.6
76.9 85.4
23.1 61.1
Ref 2.31
Ref 1.12e4.75
8.0 15.6
76.0 91.7
24.6 70.6
Ref 3.00
Ref 1.40e6.33
13.2 5.0
94.2 33.3
56.4 0
Ref 0.39
Ref 0.16e0.95
14.0 7.8
93.2 72.7
64.6 21.8
Ref 0.47
Ref 0.22e1.00
11.6 14.0
86.4 83.9
43.5 53.0
Ref 14.0
Ref 8.5e16.5
Multivariate analysis p-Value
HR
95% CI
Ref 2.90
Ref 1.33e6.33
Ref 2.93
Ref 1.31e6.55
Ref 0.30
Ref 0.11e0.84
Ref 0.83
Ref 0.36e1.93
NA NA
NA NA
0.019
p-Value 0.008
0.003
0.009
0.031
0.022
0.045
0.671
0.650 NA NA
OS, overall survival; HR, hazard ratio; Ref, reference; PVTT, portal venous tumour thrombus; AFP, alpha-foetoprotein. Gross classification and PVTT type were both classified according to criteria of the Liver Cancer Study Group of Japan. NA, not applicable; variables that were not significant in the univariate analysis were not included in the multivariate analysis.
survival data in phase III trials were inconsistent. A welldesigned, placebo-controlled, phase III trial found that sorafenib did not significantly prolong TTP compared to placebo (5.4 versus 3.7 months, p ¼ 0.252) in unresectable HCC patients who responded to TACE.12 On the contrary, a significantly prolonged TTP in TACE plus sorafenib compared to TACE plus placebo (9.2 versus 4.9 months, p < 0.001) was observed in another phase III trial for HCVrelated intermediate-stage HCC.23 More recently, evidence from a subgroup of the START study indicated that the combined therapy group had a promising median TTP and OS with 10.6 and 16.5 months, respectively.24 Thus, the utility of combining the two methods remains controversial, and new clinical data are needed. The present study reported an encouraging efficacy for the combination of TACE and sorafenib in HCC patients with PVTT. The result shows a median TTP and OS of 7 and 13 Table 3 Incidence of treatment-related adverse events after TACE and sorafenib treatment. Adverse event
Any grade n (%) Grade 3 n (%) Grade 4 n (%)
Post-TACE adverse events Fever 23 (56.1) Pain 13 (31.7) Nausea 8 (19.5) Vomiting 4 (9.8) Myelosuppression 1 (2.4) Sorafenib-related adverse events Fatigue 9 (22.0) Handefoot skin reaction 28 (68.3) Rash or desquamation 9 (22.0) Alopecia 8 (19.5) Pruritus 3 (7.3) Anorexia 4 (9.8) Diarrhoea 22 (53.7) Hypertension 4 (9.8) Voice changes 2 (4.9) TACE, transarterial chemoembolization.
0 0 0 0 1 (2.4)
0 0 0 0 0
0 3 (7.3) 0 0 0 0 0 1 (2.4) 0
0 0 0 0 0 0 0 0 0
months, respectively. The OS is longer than those reported for either sorafenib or TACE alone, for which the OS ranged from 5.6e8.1 months and 3.8e9.5 months, respectively.2,4,6 The promising OS may be attributed to the integrated control effect that includes locoregional therapy and systemic therapy. Moreover, as advanced HCC with PVTT features has a high risk of intrahepatic spread and distant metastasis, TACE plus sorafenib may be a more effective method than TACE alone to control all the metastatic lesions. A recent retrospective controlled study compared combined therapy with TACE alone in HCC and PVTT patients. The combined group showed similar OS periods of 13 and 15 months in patients with first-branch PVTT and second- or lower-branch PVTT, which was significant longer than the OS of the TACE-only group.15 Other treatment modalities, such as hepatic arterial infusion, radioembolization with yttrium-90 microspheres, and radiotherapy, have also been investigated for advanced HCC with PVTT patients, yielding acceptable OS values of 4.5e11.8, 4.5e10, and 3.8e10.7 months, respectively.2,7,8,18 The present study showed an OS comparable to or even better than those of these methods. Moreover, nearly half of the cases in the present study were merged with extrahepatic metastasis (48.8%). The extrahepatic tumours were well controlled, and none of them directly caused death. Other modalities, such as local perfusion and radiation therapy, could not easily control the extrahepatic lesions, and this subset of patients might constitute a special indication for the combined therapy. In the multivariate analysis, extrahepatic metastasis, the ChildePugh class, and gross morphological type were found to be significant predictors for OS (Table 2). Extrahepatic metastasis and the ChildePugh class are two common factors that were related to the OS of HCC patients with PVTT in several studies.26,27 Patients with PVTT who have ChildePugh class A cirrhosis and no extrahepatic metastasis would benefit more from combined TACE and sorafenib
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therapy. A recent propensity-score matching study of TACE plus sorafenib of the unresectable HCC patients also confirmed that the ChildePugh class together with the metastasis/vascular invasion, use of sorafenib, and BCLC stage could affect survival.27 In addition, the survival period of patients with nodular-type HCC was demonstrated to be significantly longer than those of patients with diffuse-type HCC, and this finding is similar to that of the present study.9 Diffuse-type HCC was more frequently poorly differentiated, and it was more likely related to rapid growth, intrahepatic spread, and early recurrence. The multivariate analysis in the present study did not show a significant difference in the OS between the different types of PVTT, although the OS and the PVTT types (Vp2e3 versus Vp4) slightly correlated in the univariate analysis (p ¼ 0.045). This finding might suggest that combined therapy was suitable for all types of PVTT. In the present study, the majority (n ¼ 34, 83%) of PVTT patients were stable after combined treatment for the entire followup period, suggesting that combined therapy is highly effective in stabilizing PVTT, which prevents further portal vein obstruction and hepatic function deterioration. Moreover, the Vp1 type of PVTT was not included in practice because of the potential to cure this type by resection. These patients might also benefit from the combination of TACE and sorafenib if they refused or were not suitable for resection. A large group of cases of such patients should be analysed in future studies. The present study also revealed that the AEs were well tolerated and mostly related to sorafenib. Treatmentrelated deaths and grade 4 AEs were not observed. The most common toxicities of sorafenib were HFSR (68.3%), diarrhoea (53.7%), and fatigue (22%), most of which were grade 1 or 2. Their incidents were higher than those observed during the Sorafenib AP trial, for which the HFSR, diarrhoea, and fatigue rates were 45.5%, 20.5%, and 20.1%, respectively.28 The possible reason for this might be the different eligibility criteria between the two studies. Patients in the present study all suffered from advanced HCC with PVTT, whereas patients in the Sorafenib AP trial suffered from advanced HCC with less than a 79.5% incidence of PVTT. Furthermore, the addition of TACE increases the risk of adverse reactions such as diarrhoea and fatigue, and the relatively small numbers of patients in the present study could introduce a bias. Although the total AEs rates in the present study were higher than that those in the Sorafenib AP trial, most of the AEs were tolerable and adequately managed using treatment of symptoms. Moreover, the grade 3/4 HFSR and hypertension rates in the present study (7.3% and 2.4%, respectively) were consistent with those from the Sorafenib AP trial, which were, 10.7% and 2%, respectively. The AEs related to TACE were also well tolerated and easily controlled. Major complications, such as liver function failure, were not observed after the TACE procedure. The most common AEs were postchemoembolization syndrome, which consisted of fever (56.1%), mild epigastric pain (31.7%), and nausea (19.5%). All patients considered themselves free of symptoms
within 1 week. A temporary increase in liver enzymes was more common, but could easily be relieved by treatment. The incident was similar to that in previous reports of patients with PVTT treated with TACE alone.10 In conclusion, combined treatment was safe for selected HCC patients with PVTT in the current study, and the AEs were tolerated and well manageable. Previous studies indicated three different models of combined therapy, including the sequential, interrupted, and continuous schemes.29 The sequential scheme was not recommended in clinical practice after the Japan and South Korea trials were published.12 The last two schemes were both used in some randomized clinical trials, but the preferred choice remains unclear. Previous research demonstrated a post-TACE VEGF level stimulus during the first 3 days and rapid decreases thereafter, and a continuous mode might theoretically be more beneficial than the interrupted mode.26 However, the concern in the present study was safety of treatment, because a European clinical trial evaluating continuous sorafenib plus an intensive, high-dose doxorubicin-based TACE stopped early due to safety concerns.30 Some worldwide randomized controlled trials (RCTs), such as the CONSUT and START trials, utilize a 3-day interruption of sorafenib after TACE and showed acceptable rates of AEs.23,25 Moreover, the high nausea and vomiting rates (19.5% and 9.8%) after TACE in the present study made the 3 day interruption of sorafenib more acceptable for patients. Therefore, a relatively acceptable and safe scheme was adopted for advanced HCC patients with PVTT in the present study. The present study has several potential limitations. Although consecutive patient enrolment and clear eligibility criteria were executed, the present study was subject to selection bias due to the retrospective nature and small sample size. Another limitation is that the study lacks a control group, such as TACE alone or sorafenib alone, and further research is needed. Moreover, the RESIST1.0 criterion was used to evaluate tumour response because of the early start of the study. However, the modified RESIST criterion might have a more significant effect and warrants further investigation. In conclusion, the combination of TACE and sorafenib in an interrupted therapeutic scheme was safe and might improve the OS of HCC patients with PVTT, especially in those with ChildePugh class A, no extrahepatic metastasis, or nodular-type HCC. Further RCTs are necessary.
Acknowledgements This work is supported by a grant from the Clinical Scientific Research Special Funds of Wu Jieping Medical Foundation (320.6750.12176). We would like to thank Dr Zhenfeng Zhang for providing editorial and writing assistance.
References 1. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. CA Cancer J Clin 2008;58:71e96.
Please cite this article in press as: Pan T, et al., Safety and efficacy of transarterial chemoembolization plus sorafenib for hepatocellular carcinoma with portal venous tumour thrombus, Clinical Radiology (2014), http://dx.doi.org/10.1016/j.crad.2014.09.007
T. Pan et al. / Clinical Radiology xxx (2014) e1ee9 2. Minagawa M, Makuuchi M. Treatment of hepatocellular carcinoma accompanied by portal vein tumor thrombus. World J Gastroenterol 2006;12:7561e7. 3. Wilhelm SM, Carter C, Tang L, et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 2004;64:7099e109. 4. Bruix J, Raoul JL, Sherman M, et al. Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma: subanalyses of a phase III trial. J Hepatol 2012;57:821e9. 5. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359:378e90. 6. Cheng AL, Guan Z, Chen Z, et al. Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma according to baseline status: subset analyses of the phase III Sorafenib Asia-Pacific trial. Eur J Cancer 2012;48:1452e65. 7. Kulik LM, Carr BI, Mulcahy MF, et al. Safety and efficacy of 90Y radiotherapy for hepatocellular carcinoma with and without portal vein thrombosis. Hepatology 2008;47:71e81. 8. Yoon SM, Lim YS, Won HJ, et al. Radiotherapy plus transarterial chemoembolization for hepatocellular carcinoma invading the portal vein: long-term patient outcomes. Int J Radiat Oncol Biol Phys 2012;82:2004e11. 9. Lee HS, Kim JS, Choi IJ, et al. The safety and efficacy of transcatheter arterial chemoembolization in the treatment of patients with hepatocellular carcinoma and main portal vein obstruction. A prospective controlled study. Cancer 1997;79:2087e94. 10. Luo J, Guo RP, Lai EC, et al. Transarterial chemoembolization for unresectable hepatocellular carcinoma with portal vein tumor thrombosis: a prospective comparative study. Ann Surg Oncol 2011;18:413e20. 11. Zheng JS, Long J, Sun B, et al. Transcatheter arterial chemoembolization combined with radiofrequency ablation can improve survival of patients with hepatocellular carcinoma with portal vein tumour thrombosis: extending the indication for ablation? Clin Radiol 2014;69:e253e63. 12. Kudo M, Imanaka K, Chida N, et al. Phase III study of sorafenib after transarterial chemoembolisation in Japanese and Korean patients with unresectable hepatocellular carcinoma. Eur J Cancer 2011;47:2117e27. 13. Chung YH, Han G, Yoon JH, et al. Interim analysis of START: study in Asia of the combination of TACE (transcatheter arterial chemoembolization) with sorafenib in patients with hepatocellular carcinoma trial. Int J Cancer 2013;132:2448e58. 14. Pawlik TM, Reyes DK, Cosgrove D, et al. Phase II trial of sorafenib combined with concurrent transarterial chemoembolization with drugeluting beads for hepatocellular carcinoma. J Clin Oncol 2011;29:3960e7. 15. Zhu K, Chen J, Lai L, et al. Hepatocellular carcinoma with portal vein tumor thrombus: treatment with transarterial chemoembolization combined with sorafenibda retrospective controlled study. Radiology 2014;272:284e93. 16. Liver Cancer Study Group of Japan. The general rules for the clinical and pathological study of primary liver cancer. Jpn J Surg 1989;19:98e129.
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17. Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology 2005;42:1208e36. 18. Ando E, Tanaka M, Yamashita F, et al. Hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma with portal vein tumor thrombosis: analysis of 48 cases. Cancer 2002;95:588e95. 19. Zhao M, Wang JP, Pan CC, et al. CT-guided radiofrequency ablation after with transarterial chemoembolization in treating unresectable hepatocellular carcinoma with long overall survival improvement. Eur J Radiol 2012;81:2717e25. 20. Trotti A, Colevas AD, Setser A, et al. CTCAE v3.0: development of a comprehensive grading system for the adverse effects of cancer treatment. Semin Radiat Oncol 2003;13:176e81. 21. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000;92:205e16. 22. Park JW, Koh YH, Kim HB, et al. Phase II study of concurrent transarterial chemoembolization and sorafenib in patients with unresectable hepatocellular carcinoma. J Hepatol 2012;56:1336e42. 23. Sansonno D, Lauletta G, Russi S, et al. Transarterial chemoembolization plus sorafenib: a sequential therapeutic scheme for HCV-related intermediate-stage hepatocellular carcinoma: a randomized clinical trial. Oncologist 2012;17:359e66. 24. Han G, Yang J, Shao G, et al. Sorafenib in combination with transarterial chemoembolization in Chinese patients with hepatocellular carcinoma: a subgroup interim analysis of the START trial. Future Oncol 2013;9:403e10. 25. Li X, Feng GS, Zheng CS, et al. Expression of plasma vascular endothelial growth factor in patients with hepatocellular carcinoma and effect of transcatheter arterial chemoembolization therapy on plasma vascular endothelial growth factor level. World J Gastroenterol 2004;10:2878e82. 26. Jia L, Kiryu S, Watadani T, et al. Prognosis of hepatocellular carcinoma with portal vein tumor thrombus: assessment based on clinical and computer tomography characteristics. Acta Med Okayama 2012;66:131e41. 27. Bai W, Wang YJ, Zhao Y, et al. Sorafenib in combination with transarterial chemoembolization improves the survival of patients with unresectable hepatocellular carcinoma: a propensity score matching study. J Dig Dis 2013;14:181e90. 28. 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;10:25e34. 29. Liapi E, Geschwind JF. Combination of local transcatheter arterial chemoembolization and systemic anti-angiogenic therapy for unresectable hepatocellular carcinoma. Liver Cancer 2012;1:201e15. 30. Sieghart W, Pinter M, Reisegger M, et al. Conventional transarterial chemoembolisation in combination with sorafenib for patients with hepatocellular carcinoma: a pilot study. Eur Radiol 2012;22:1214e23.
Please cite this article in press as: Pan T, et al., Safety and efficacy of transarterial chemoembolization plus sorafenib for hepatocellular carcinoma with portal venous tumour thrombus, Clinical Radiology (2014), http://dx.doi.org/10.1016/j.crad.2014.09.007
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Safety and efficacy of transarterial chemoembolization plus sorafenib for hepatocellular carcinoma with portal venous tumour thrombus T. Pan a, X.-S. Li b, Q.-K. Xie a, J.-P. Wang c, W. Li a, P.-H. Wu a, M. Zhao a, * a
Minimally Invasive Interventional Division, Medical Imaging Center, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, Guangzhou, PR China b Department of Interventional Radiology, Guangzhou First People’s Hospital, Guangzhou Medical University, Guangzhou, PR China c Minimally Invasive Interventional and Target Treatment Division and Cancer Center, The First People’s Hospital of Foshan City, The Affiliated Foshan Hospital of Sun Yat-sen University, Guangzhou, PR China
art icl e i nformat ion Article history: Received 19 May 2014 Received in revised form 15 August 2014 Accepted 9 September 2014
AIM: To evaluate the safety and efficacy of combined therapy with transarterial chemoembolization (TACE) and sorafenib for hepatocellular carcinoma (HCC) with portal venous tumour thrombus (PVTT). MATERIALS AND METHODS: This study was approved by the institutional review board. From May 2009 to May 2012, 170 consecutive patients were newly diagnosed with advancedstage HCC and treated with TACE plus sorafenib. Among them, 41 patients with PVTT were retrospectively enrolled in the study. The adverse events (AEs), overall survival (OS), time to progression (TTP), and prognostic factors were analysed. Statistical analysis was performed with the KaplaneMeier method using the log-rank test and Cox regression models. RESULTS: The most common AEs were handefoot skin reaction related to sorafenib and fever related to TACE. Procedure-related mortality and grade 4 AEs were not observed. Grade 3 AEs were observed in five patients. During the median follow-up period of 13.5 months (range 1.4e45 months), the 6-month and 1-year survival rates were 87.7% and 53.6%, respectively. The median OS was 13 months (range 1.4e44.8 months), and the median TTP was 7 months (range 1e18.6 months). The ChildePugh class (p ¼ 0.022), extrahepatic metastasis (p ¼ 0.009), and gross morphological type (nodular type versus diffuse type; p ¼ 0.008) were prognostic factors related to OS in the multivariate analysis. CONCLUSION: TACE plus sorafenib in an interrupted therapeutic scheme was well tolerated and might improve OS for HCC patients with PVTT, especially in those with ChildePugh class A, no extrahepatic metastasis, or nodular-type HCC. Ó 2014 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
* Guarantor and correspondent: Ming Zhao, Minimally Invasive Interventional Division, Medical Imaging Center, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, 651 Dongfeng Road East, Guangzhou 510060, PR China. Tel./ fax: þ86 020 87343272. E-mail address: [email protected] (M. Zhao). http://dx.doi.org/10.1016/j.crad.2014.09.007 0009-9260/Ó 2014 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
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Introduction Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third leading cause of cancer mortality globally.1 Although the development of imaging techniques has improved early HCC diagnosis, portal venous tumour thrombus (PVTT) is still identified in 12.5e39.7% of HCC patients at their initial visits.2 Patients suffering from extremely aggressive HCC with PVTT have a median survival time of only 2.7e4 months if left untreated.2 The current standard of practice recommends sorafenib, a potent multi-kinase inhibitor with anti-angiogenic and anti-proliferative properties that block the Raf/MEK/ERK pathway and the tyrosine kinase receptors VEGFR-2/3, PDGFR-b, c-KIT, and Flt-3.3 This drug has been shown to prolong overall survival (OS) by nearly 3 months in advanced HCC patients and by 1.5e3.2 months in those with PVTT.4e6 Other available therapies including hepatectomy, hepatic arterial infusion, radioembolization with yttrium-90 microspheres and radiotherapy have also been utilized in selected HCC and PVTT patients, yielding acceptable OS periods of 6e14, 4.5e11.8, 4.5e10 and 3.8e10.7 months, respectively.2,7,8 Although transarterial chemoembolization (TACE) is the main treatment modality for unresectable HCC patients, its use in patients with PVTT is controversial. Previous theories suggested that TACE blocks hepatic arterial blood flow, along with the already existing poor blood supply from the portal vein caused by PVTT, which likely worsens hepatic tissue ischaemia and may even lead to hepatic failure. However, some recent prospective studies have demonstrated that TACE can serve as a safe procedure in selected HCC patients with PVTT and proved that hepatic tissue could obtain blood from the incompletely occluded portal vein and collateral circulation around an occluded portal vein.9,10 Moreover, TACE in combination with other treatment modalities, including radiotherapy, radiofrequency ablation, and resection, has been safely applied in HCC patients with PVTT, and its survival benefits were proven to be better than that of TACE alone.2,8,11 Considering the promising efficacy of sorafenib, several clinical trials have tested TACE in combination with sorafenib and proven its safety and efficacy in the treatment of unresectable HCC. However, these studies mainly focused on patients with intermediate-stage HCC12,13; data on advanced-stage HCC are scarce,14 and only one study reported data on HCC patients with PVTT.15 The present study was designed to assess the safety and survival benefit of TACE combined with sorafenib for HCC patients with PVTT. Moreover, suitable candidates were also investigated for the combined treatment with TACE and sorafenib.
treatment. A retrospective review of the electronic medical database from May 2009 to May 2012 revealed that a total of 170 consecutive HCC patients received TACE in combination with sorafenib and 41 patients who also had PVTT were enrolled in the study. The eligibility criteria included the following: (1) newly diagnosed HCC with Vp2, Vp3, and Vp4 type PVTT according to the criteria of the Liver Cancer Study Group of Japan, where PVTT grade was defined as follows: Vp0, no PVTT; Vp1, tumour thrombus in a third or more of peripheral branches of the portal vein; Vp2, tumour thrombus in a second branch of the portal vein; Vp3, tumour thrombus in the first branch of the portal vein; Vp4, tumour thrombus in the trunk of the portal vein16; (2) single tumour with size 5 cm or multiple nodular tumours of >3 cm; (3) Eastern Cooperative Oncology Group (ECOG) performance status of 0e1; (4) ChildePugh class A or B; (5) no history of encephalopathy; (6) adequate haematological, renal function, as indicated by a platelet count >60 109/l; haemoglobin concentration >85 g/l; serum creatinine concentration of 1.5-times the upper limit of the normal range or less; and prothrombin time 6 s above the control. The exclusion criteria were defined as follows: (1) received palliative operative liver transplantation or radiotherapy during the period of combined treatment; (2) suffered from another type of carcinoma (Fig 1). The baseline characteristics of the patients in this study were collected (Table 1). HCC was diagnosed based on histopathology (n ¼ 16, 39%) or clinical features (n ¼ 25, 61%) according to the guidelines of the American Association for the Study of Liver Disease.17 HCC with PVTT was confirmed based on contrastenhanced CT or MRI with the presence of an intraluminal filling defect with generalized enhancement, intrathrombus neovascularity, accompanying portal venous expansion, or direct invasion of the portal vein, as described in previous studies.8,18
Materials and methods Patients The institutional review board approved the study protocol, and informed consent was obtained before
Figure 1 Flow diagram shows patient selection criteria.
Please cite this article in press as: Pan T, et al., Safety and efficacy of transarterial chemoembolization plus sorafenib for hepatocellular carcinoma with portal venous tumour thrombus, Clinical Radiology (2014), http://dx.doi.org/10.1016/j.crad.2014.09.007
T. Pan et al. / Clinical Radiology xxx (2014) e1ee9 Table 1 Univariate analysis by log-rank test for prognostic clinicopathological and procedure-related factors for overall survival (n ¼ 41). Characteristic Gender Male Female Age (years) >75 55e75 30e54 400 Total bilirubin (mg/dl) 2 >2 Albumin (g/l) 35 >35
n (%)
p-Value 0.390
38 (92.7) 3 (7.3) 0.388 2 15 21 3
(4.9) (36.6) (51.2) (7.3) 0.151
40 (97.6) 1 (2.4) 0.031 35 (85.4) 6 (14.6) 0.900 20 (48.8) 21 (51.2) 0.221 13 (31.7) 2 (4.9) 26 (63.4) 0.389 25 (61.0) 16 (39.0) 0.045 8 (19.5) 23 (56.0) 10 (24.4) 0.019 14 (34.1) 27 (65.9) 0.003 11 5 1 1
(26.8) (12.2) (2.4) (2.4) 0.112
4 (9.8) 37 (90.2) 0.650 22 (53.7) 19 (46.3) 0.310 26 (63.4) 15 (36.6) 0.120 5 (12.2) 36 (87.8)
ECOG, Eastern Cooperative Oncology Group. a Tumour size, the maximum diameter of the largest target index lesion.
Treatment procedure The treatment modality of each patient was decided in consensus during a multidisciplinary HCC conference with hepatobiliary surgeons, medical oncologists, interventional radiologists, and diagnostic radiologists. Detailed information regarding TACE and sorafenib treatment, including the efficacy and potential adverse effects (AEs), was explained to all patients. The patients selected their treatment, TACE plus sorafenib instead of sorafenib alone, based on the attending physician’s recommendation and the details of
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sorafenib monotherapy and combined treatment strategy. They understood that the effect of the combined treatment might not be better than sorafenib alone. Informed consent was obtained prior to the treatment. TACE was performed with digital subtraction angiography (Philips, type Allura Xper FD20, Veenpluis, The Netherlands). A 4-F catheter (Radiofocus Guide Wire M, Terumo Corporation, Tokyo, Japan) was inserted into the hepatic artery and superior mesenteric artery using the Seldinger technique through the femoral artery. Arteriography was then performed to assess the arterial blood supply to the liver, portal vein patency, and to identify the accessory arteries. Depending on the size, location, and arterial supply of the tumour, the tip of the catheter was advanced into the right or left hepatic artery, or into the tumour-feeding branches. If a conventional catheter could not enter the targeted branch of the hepatic artery due to technical reasons, a 2.9-F microcatheter (Terumo Corporation) was used. An emulsion of 8e30 ml (16 4.5 ml mean standard deviation) of lipiodol (Laboratorie Guerbet, Aulnay-sous-Bois, France), 40e60 mg (50 6.9 ml) of epirubicin (Farmorubicin; Pharmacia, Tokyo, Japan), and 6e10 mg (8 1.5 ml) of mitomycin C (Kyowa Hakko Kogyo, Tokyo, Japan) was injected, followed by embolization with gelatin sponge particles dissected by an operator into 2e3 mm diameter pieces (Gelfoam; Hanzhou, China). The procedure was performed according to the experience gained from previous work.19 The patients were subsequently admitted for observation of potential postembolization syndrome. Contrast-enhanced CT or MRI was performed 4 weeks after the procedure to assess the treatment efficacy. When the residual viable tumours were confirmed, repeat TACE procedures were performed on patients who conformed to the eligibility criteria. Sorafenib (Nexavar; Bayer, Leverkusen, Germany) was taken 3 days after the first TACE procedure at a dose of 400 mg twice a day. A 3-day interruption in sorafenib was adopted after each subsequent TACE cycle. Drug tolerance evaluation involved documenting the history and physical examinations, laboratory tests, and grading adverse events (AEs), which were assessed based on the National Cancer Institute Common Terminology Criteria version 3.0.20 If a patient suffered grade 3/4 drug-related AEs without effective control, a dose reduction to 400 mg once daily or a temporary drug interruption was utilized.5 The treatment continued until an AE requiring permanent discontinuation, radiological progression, or death was observed. Patients with dose discontinuation caused by AEs were not excluded from the survival analysis in the present study.
Assessment and follow-up The follow-up period was defined as the duration from the date of entry into treatment to death or the last followup date of 30 December, 2012. Follow-up examinations were performed at 1 month and then every 3 months after the first TACE procedure, including physical examinations, laboratory tests, contrast-enhanced three-phase CT or MRI, and PET-CT if multiple organic metastases were suspected.
Please cite this article in press as: Pan T, et al., Safety and efficacy of transarterial chemoembolization plus sorafenib for hepatocellular carcinoma with portal venous tumour thrombus, Clinical Radiology (2014), http://dx.doi.org/10.1016/j.crad.2014.09.007
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The tumour response was assessed at the first, third, and sixth month after first TACE and then every 3 months until the date of disease progression, death, or last follow-up. The patients’ response to treatment was evaluated based on the best overall response according to the RESIST1.0 criterion, as described in previous research.5,21 Patients that exhibited a complete response (CR) were closely followed-up, and patients that exhibited a partial response (PR) and stable disease (SD) received continuous combined therapy. Patients with progressive disease (PD) were recommended for other therapies, such as radiotherapy or traditional Chinese medicine according to the doctors’ advice. Simultaneous to the assessment of intra-hepatic lesions, the response of PVTT was evaluated based on the change in the product of the largest perpendicular diameters of tumour thrombus compared to the initial size.8 CR was defined as the complete disappearance of the PVTT; PR was defined as thrombus diameter decrease exceeding 50%; PD was defined as thrombus diameter increase exceeding 25%, and SD was defined as neither sufficient shrinkage to PR nor sufficient increase to PD.8
Statistical methods The time to progression (TTP) was defined as the interval from the date of entry into the treatment to the date of developing local progression (target lesion), a new lesion elsewhere in liver, or extrahepatic disease. The OS was calculated from the date of entry into the treatment to the day of either death from any cause or last follow-up. The TTP and OS were estimated using the KaplaneMeier method. Univariate analysis (log-rank test) was performed to determine the clinicopathological and procedure-related factors that affected OS. A multivariate analysis was performed on all factors with a p-value of 0.10 using the Cox proportional hazards regression model. All analyses were performed using SPSS software (version 16.0; SPSS, Chicago, IL, USA). A p-value of 0.05 (two-tailed) was considered statistically significant.
Results Baseline characteristics The study population was mostly male (92.7%), with a median age of 52 years (range 29e73 years), hepatitis B virus infection (97.6%), PS 0e1 (PS: 0, 48.8%; 1, 51.2%) and ChildePugh class (A 85.4%; B 14.6%). Fourteen patients (34.1%) had nodular-type HCC, and 27 patients (65.9%) had diffuse-type HCC, which was classified according to criteria of the Liver Cancer Study Group of Japan, as previously described.9,16 The numbers of patients with type Vp2, Vp3, and Vp4 were eight (19.5%), 23 (56%), and 10 (24.4%), respectively. Twenty-four (63.4%) patients had three or more tumour lesions, two (4.9%) had two lesions and 13 (31.7%) had only one lesion. The diameters of the largest tumour in each patient ranged from 50e173 mm, with a mean tumour size of 88.1 mm (Table 1). All patients were treated with a total of 86 TACE procedures (per-patient
mean 2.08, median 2, range 1e4); 13 patients received one procedure, 15 received two procedures and 13 received more than two procedures. The patients received sorafenib with a mean daily dose of 788 mg (range 680e800 mg).
Survival outcomes During the median follow-up period of 13.5 months (range 1.4e45 months), 33 patients died and eight patients survived. A total of 31 patients died due to tumour progression, and the other two died of severe hepatic dysfunction. The median OS was 13 months (95% CI ¼ 10.4e15.6; range 1.4e44.8 months) with 6 month, 1, and 2 year OS rates of 87.7%, 53.6%, and 11.9%, respectively. The median TTP was 7 months (95% CI ¼ 5.7e8.3; range 1e18.6 months) with 6 month and 1 year PFS rates of 78% and 28.5%, respectively (Fig 2). According to the RESIST1.0 criteria, one patient (2.4%) had a CR, seven patients (17.1%) had a PR, 25 patients (60.9%) had SD, and eight patients (19.5%) had PD (Fig 3). The disease control rate (DCR) was 80.5%, and the response rate was 19.5%. The median OS did not significantly differ between responders and nonresponders (13.2 months versus 11.6 months, p ¼ 0.286). The patient with CR was alive for 6 months after the combination treatment at the last follow-up and was censored. The median OS of patients classified as PR and SD were significantly longer than those of patients with PD (11.6 and 14 versus 6.3 months, p < 0.001), and the median OS did not significantly differ between patients evaluated as PR and SD (11.6 versus 14 months, p ¼ 0.501). The responses of PVTT were classified as CR, PR, SD, and PD in one, three, 34 and three patients, respectively. The median OS did not significantly differ between responders and non-responders of PVTT (18.5 versus 13 months, p ¼ 0.268). The median OS of patients classified as PR and SD of PVTT were significantly longer than those of patients with PD of PVTT (18.5 and 14 versus 5 months, p < 0.001). The median OS did not significantly differ between patients classified as PR and those classified as SD of PVTT (18.5 versus 14 months, p ¼ 0.363). All listed baseline factors were analysed using univariate analysis, and the factors associated with OS (p 0.05) were identified as ChildePugh class, extrahepatic metastasis, gross morphological classification, and PVTT type (Vp2e3 versus Vp4; Fig 4). The multivariate analysis indicated that ChildePugh class (A versus B; Hazard Ratio (HR) 0.30, p ¼ 0.022), extrahepatic metastasis (absent versus present; HR 2.93, p ¼ 0.009), and gross morphological classification (nodular type versus diffuse type; HR 2.90, p ¼ 0.008) as significant predictors of OS (Table 2).
Complications The most common toxicities related to sorafenib treatment were handefoot skin reaction (HFSR; 68.3%), diarrhoea (53.7%), and fatigue (22%), most of which were grade 1 or 2 (Table 3). The reported grade 3 drug-related AEs were HFSR in three patients (7.3%) and hypertension in one patient (2.4%). Grade 4 AEs were not observed. Three patients
Please cite this article in press as: Pan T, et al., Safety and efficacy of transarterial chemoembolization plus sorafenib for hepatocellular carcinoma with portal venous tumour thrombus, Clinical Radiology (2014), http://dx.doi.org/10.1016/j.crad.2014.09.007
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Figure 2 A 50-year-old man with HCC and PVTT showed a partial response after TACE and sorafenib treatment. (aeb) Contrast-enhanced CT images at diagnosis, showing a 40 mm diameter HCC nodule (white arrow) and multiple small intrahepatic lesions located in the left lobe, together with PVTT in the left and main portal vein (black arrow). (ced) CT images 2 months after diagnosis, showing no enhancing nodular lesions in the left lobe and near complete absence of PVTT without definite enhancement (white arrow).
were subjected to dose reductions for 2 weeks and then reverted to a regular dose after AEs relief. Two patients were subjected to drug interruption periods of 14 and 24 days due to the AEs and then restored to a regular dose after
relief from AEs. These patients with dose reductions or drug interruption were not excluded from the study. Patients were hospitalized for an average of 3 days (range 1e15 days) to manage potential post-TACE AEs. Procedure-related
Figure 3 KaplaneMeier curves for patients with advanced HCC and PVTT who were treated with combination TACE and sorafenib. (a) Median OS was 13 months, with 6-months and 1- and 2-year survival rates of 87.7%, 53.6%, and 11.9%, respectively. (b) Median TTP was 7 months, with 6-month and 1-year of 78% and 28.5%, respectively. Please cite this article in press as: Pan T, et al., Safety and efficacy of transarterial chemoembolization plus sorafenib for hepatocellular carcinoma with portal venous tumour thrombus, Clinical Radiology (2014), http://dx.doi.org/10.1016/j.crad.2014.09.007
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Figure 4 Univariate analysis (log-rank test) was performed to determine prognostic factors for OS. (a) Log-rank analysis of OS stratified according to gross morphological type (p ¼ 0.019). (b) Log-rank analysis of OS stratified according to extrahepatic metastasis (p ¼ 0.003). (c) Logrank analysis of OS stratified according to ChildePugh class (p ¼ 0.031). (d) Log-rank analysis of OS stratified according to PVTT type (p ¼ 0.045).
death did not occur within 1 month of the TACE procedure. The most common AEs related to TACE were fever (56.1%), mild epigastric pain (31.7%), and nausea (19.5%). These symptoms can be relieved during the first week with appropriate treatment. One patient experienced grade 3 myelosuppression. After 1 week of injection with granulocyte colony-stimulating factor, the patient’s white blood cell and platelet counts recovered to the pretreatment level.
Discussion The current standard first-line therapy for advancedstage HCC with PVTT is sorafenib. Although this treatment shows survival benefits with a median OS of 8.1 and 5.6 months in the macrovascular invasion subgroup of the Sorafenib Health Assessment Randomised Protocol and Sorafenib Asia-Pacific (AP) trials, the OS remains modest.4,6 Further clinical studies are needed to optimize treatment strategies; for instance, sorafenib in combination with local therapeutic approaches could be a promising approach.
Previous theories suggested that the upregulation of VEGF and PDGF levels after TACE might account for tumour recurrence. The use of sorafenib can significantly counteract the tyrosine kinases receptor VEGFR-2/3 and PDGFR-b, which decreases the post-TACE VEGF and PDGF upregulation and further enhances the efficacy of TACE.26 Moreover, TACE can improve the tumour response rate, which does not exceed 4% for sorafenib monotherapy. A series of clinical trials have evaluated the combined use of TACE and sorafenib in intermediate-stage and/or advanced-stage HCC. Pawlik et al.14 assessed the safety and response of sorafenib plus TACE with drug-eluting beads in a phase II study that involved 35 patients with mostly advanced HCC. The results showed a promising disease control rate of 95% according to RESIST criteria with manageable toxicity. Another phase II study of sorafenib plus conventional TACE in the treatment of intermediate and advanced HCC also revealed an overall median TTP of 7.1 months and a manageable safety profile.22 Although the preliminary efficacy data were fairly good, the long-term
Please cite this article in press as: Pan T, et al., Safety and efficacy of transarterial chemoembolization plus sorafenib for hepatocellular carcinoma with portal venous tumour thrombus, Clinical Radiology (2014), http://dx.doi.org/10.1016/j.crad.2014.09.007
T. Pan et al. / Clinical Radiology xxx (2014) e1ee9
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Table 2 The primary overall survival outcome and the univariate and multivariate analysis. Variable
All patients (41) Gross classification Diffuse type Nodular type Extrahepatic metastasis Present Absent ChildePugh class A B PVTT type Vp2e3 Vp4 Level of AFP (ng/ml) 400 >400
Primary outcome
Univariate analysis
Median OS (months)
6 month OS
1 year OS
HR
95% CI
13.0
87.7
53.6
10.5 15.6
76.9 85.4
23.1 61.1
Ref 2.31
Ref 1.12e4.75
8.0 15.6
76.0 91.7
24.6 70.6
Ref 3.00
Ref 1.40e6.33
13.2 5.0
94.2 33.3
56.4 0
Ref 0.39
Ref 0.16e0.95
14.0 7.8
93.2 72.7
64.6 21.8
Ref 0.47
Ref 0.22e1.00
11.6 14.0
86.4 83.9
43.5 53.0
Ref 14.0
Ref 8.5e16.5
Multivariate analysis p-Value
HR
95% CI
Ref 2.90
Ref 1.33e6.33
Ref 2.93
Ref 1.31e6.55
Ref 0.30
Ref 0.11e0.84
Ref 0.83
Ref 0.36e1.93
NA NA
NA NA
0.019
p-Value 0.008
0.003
0.009
0.031
0.022
0.045
0.671
0.650 NA NA
OS, overall survival; HR, hazard ratio; Ref, reference; PVTT, portal venous tumour thrombus; AFP, alpha-foetoprotein. Gross classification and PVTT type were both classified according to criteria of the Liver Cancer Study Group of Japan. NA, not applicable; variables that were not significant in the univariate analysis were not included in the multivariate analysis.
survival data in phase III trials were inconsistent. A welldesigned, placebo-controlled, phase III trial found that sorafenib did not significantly prolong TTP compared to placebo (5.4 versus 3.7 months, p ¼ 0.252) in unresectable HCC patients who responded to TACE.12 On the contrary, a significantly prolonged TTP in TACE plus sorafenib compared to TACE plus placebo (9.2 versus 4.9 months, p < 0.001) was observed in another phase III trial for HCVrelated intermediate-stage HCC.23 More recently, evidence from a subgroup of the START study indicated that the combined therapy group had a promising median TTP and OS with 10.6 and 16.5 months, respectively.24 Thus, the utility of combining the two methods remains controversial, and new clinical data are needed. The present study reported an encouraging efficacy for the combination of TACE and sorafenib in HCC patients with PVTT. The result shows a median TTP and OS of 7 and 13 Table 3 Incidence of treatment-related adverse events after TACE and sorafenib treatment. Adverse event
Any grade n (%) Grade 3 n (%) Grade 4 n (%)
Post-TACE adverse events Fever 23 (56.1) Pain 13 (31.7) Nausea 8 (19.5) Vomiting 4 (9.8) Myelosuppression 1 (2.4) Sorafenib-related adverse events Fatigue 9 (22.0) Handefoot skin reaction 28 (68.3) Rash or desquamation 9 (22.0) Alopecia 8 (19.5) Pruritus 3 (7.3) Anorexia 4 (9.8) Diarrhoea 22 (53.7) Hypertension 4 (9.8) Voice changes 2 (4.9) TACE, transarterial chemoembolization.
0 0 0 0 1 (2.4)
0 0 0 0 0
0 3 (7.3) 0 0 0 0 0 1 (2.4) 0
0 0 0 0 0 0 0 0 0
months, respectively. The OS is longer than those reported for either sorafenib or TACE alone, for which the OS ranged from 5.6e8.1 months and 3.8e9.5 months, respectively.2,4,6 The promising OS may be attributed to the integrated control effect that includes locoregional therapy and systemic therapy. Moreover, as advanced HCC with PVTT features has a high risk of intrahepatic spread and distant metastasis, TACE plus sorafenib may be a more effective method than TACE alone to control all the metastatic lesions. A recent retrospective controlled study compared combined therapy with TACE alone in HCC and PVTT patients. The combined group showed similar OS periods of 13 and 15 months in patients with first-branch PVTT and second- or lower-branch PVTT, which was significant longer than the OS of the TACE-only group.15 Other treatment modalities, such as hepatic arterial infusion, radioembolization with yttrium-90 microspheres, and radiotherapy, have also been investigated for advanced HCC with PVTT patients, yielding acceptable OS values of 4.5e11.8, 4.5e10, and 3.8e10.7 months, respectively.2,7,8,18 The present study showed an OS comparable to or even better than those of these methods. Moreover, nearly half of the cases in the present study were merged with extrahepatic metastasis (48.8%). The extrahepatic tumours were well controlled, and none of them directly caused death. Other modalities, such as local perfusion and radiation therapy, could not easily control the extrahepatic lesions, and this subset of patients might constitute a special indication for the combined therapy. In the multivariate analysis, extrahepatic metastasis, the ChildePugh class, and gross morphological type were found to be significant predictors for OS (Table 2). Extrahepatic metastasis and the ChildePugh class are two common factors that were related to the OS of HCC patients with PVTT in several studies.26,27 Patients with PVTT who have ChildePugh class A cirrhosis and no extrahepatic metastasis would benefit more from combined TACE and sorafenib
Please cite this article in press as: Pan T, et al., Safety and efficacy of transarterial chemoembolization plus sorafenib for hepatocellular carcinoma with portal venous tumour thrombus, Clinical Radiology (2014), http://dx.doi.org/10.1016/j.crad.2014.09.007
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therapy. A recent propensity-score matching study of TACE plus sorafenib of the unresectable HCC patients also confirmed that the ChildePugh class together with the metastasis/vascular invasion, use of sorafenib, and BCLC stage could affect survival.27 In addition, the survival period of patients with nodular-type HCC was demonstrated to be significantly longer than those of patients with diffuse-type HCC, and this finding is similar to that of the present study.9 Diffuse-type HCC was more frequently poorly differentiated, and it was more likely related to rapid growth, intrahepatic spread, and early recurrence. The multivariate analysis in the present study did not show a significant difference in the OS between the different types of PVTT, although the OS and the PVTT types (Vp2e3 versus Vp4) slightly correlated in the univariate analysis (p ¼ 0.045). This finding might suggest that combined therapy was suitable for all types of PVTT. In the present study, the majority (n ¼ 34, 83%) of PVTT patients were stable after combined treatment for the entire followup period, suggesting that combined therapy is highly effective in stabilizing PVTT, which prevents further portal vein obstruction and hepatic function deterioration. Moreover, the Vp1 type of PVTT was not included in practice because of the potential to cure this type by resection. These patients might also benefit from the combination of TACE and sorafenib if they refused or were not suitable for resection. A large group of cases of such patients should be analysed in future studies. The present study also revealed that the AEs were well tolerated and mostly related to sorafenib. Treatmentrelated deaths and grade 4 AEs were not observed. The most common toxicities of sorafenib were HFSR (68.3%), diarrhoea (53.7%), and fatigue (22%), most of which were grade 1 or 2. Their incidents were higher than those observed during the Sorafenib AP trial, for which the HFSR, diarrhoea, and fatigue rates were 45.5%, 20.5%, and 20.1%, respectively.28 The possible reason for this might be the different eligibility criteria between the two studies. Patients in the present study all suffered from advanced HCC with PVTT, whereas patients in the Sorafenib AP trial suffered from advanced HCC with less than a 79.5% incidence of PVTT. Furthermore, the addition of TACE increases the risk of adverse reactions such as diarrhoea and fatigue, and the relatively small numbers of patients in the present study could introduce a bias. Although the total AEs rates in the present study were higher than that those in the Sorafenib AP trial, most of the AEs were tolerable and adequately managed using treatment of symptoms. Moreover, the grade 3/4 HFSR and hypertension rates in the present study (7.3% and 2.4%, respectively) were consistent with those from the Sorafenib AP trial, which were, 10.7% and 2%, respectively. The AEs related to TACE were also well tolerated and easily controlled. Major complications, such as liver function failure, were not observed after the TACE procedure. The most common AEs were postchemoembolization syndrome, which consisted of fever (56.1%), mild epigastric pain (31.7%), and nausea (19.5%). All patients considered themselves free of symptoms
within 1 week. A temporary increase in liver enzymes was more common, but could easily be relieved by treatment. The incident was similar to that in previous reports of patients with PVTT treated with TACE alone.10 In conclusion, combined treatment was safe for selected HCC patients with PVTT in the current study, and the AEs were tolerated and well manageable. Previous studies indicated three different models of combined therapy, including the sequential, interrupted, and continuous schemes.29 The sequential scheme was not recommended in clinical practice after the Japan and South Korea trials were published.12 The last two schemes were both used in some randomized clinical trials, but the preferred choice remains unclear. Previous research demonstrated a post-TACE VEGF level stimulus during the first 3 days and rapid decreases thereafter, and a continuous mode might theoretically be more beneficial than the interrupted mode.26 However, the concern in the present study was safety of treatment, because a European clinical trial evaluating continuous sorafenib plus an intensive, high-dose doxorubicin-based TACE stopped early due to safety concerns.30 Some worldwide randomized controlled trials (RCTs), such as the CONSUT and START trials, utilize a 3-day interruption of sorafenib after TACE and showed acceptable rates of AEs.23,25 Moreover, the high nausea and vomiting rates (19.5% and 9.8%) after TACE in the present study made the 3 day interruption of sorafenib more acceptable for patients. Therefore, a relatively acceptable and safe scheme was adopted for advanced HCC patients with PVTT in the present study. The present study has several potential limitations. Although consecutive patient enrolment and clear eligibility criteria were executed, the present study was subject to selection bias due to the retrospective nature and small sample size. Another limitation is that the study lacks a control group, such as TACE alone or sorafenib alone, and further research is needed. Moreover, the RESIST1.0 criterion was used to evaluate tumour response because of the early start of the study. However, the modified RESIST criterion might have a more significant effect and warrants further investigation. In conclusion, the combination of TACE and sorafenib in an interrupted therapeutic scheme was safe and might improve the OS of HCC patients with PVTT, especially in those with ChildePugh class A, no extrahepatic metastasis, or nodular-type HCC. Further RCTs are necessary.
Acknowledgements This work is supported by a grant from the Clinical Scientific Research Special Funds of Wu Jieping Medical Foundation (320.6750.12176). We would like to thank Dr Zhenfeng Zhang for providing editorial and writing assistance.
References 1. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. CA Cancer J Clin 2008;58:71e96.
Please cite this article in press as: Pan T, et al., Safety and efficacy of transarterial chemoembolization plus sorafenib for hepatocellular carcinoma with portal venous tumour thrombus, Clinical Radiology (2014), http://dx.doi.org/10.1016/j.crad.2014.09.007
T. Pan et al. / Clinical Radiology xxx (2014) e1ee9 2. Minagawa M, Makuuchi M. Treatment of hepatocellular carcinoma accompanied by portal vein tumor thrombus. World J Gastroenterol 2006;12:7561e7. 3. Wilhelm SM, Carter C, Tang L, et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 2004;64:7099e109. 4. Bruix J, Raoul JL, Sherman M, et al. Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma: subanalyses of a phase III trial. J Hepatol 2012;57:821e9. 5. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359:378e90. 6. Cheng AL, Guan Z, Chen Z, et al. Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma according to baseline status: subset analyses of the phase III Sorafenib Asia-Pacific trial. Eur J Cancer 2012;48:1452e65. 7. Kulik LM, Carr BI, Mulcahy MF, et al. Safety and efficacy of 90Y radiotherapy for hepatocellular carcinoma with and without portal vein thrombosis. Hepatology 2008;47:71e81. 8. Yoon SM, Lim YS, Won HJ, et al. Radiotherapy plus transarterial chemoembolization for hepatocellular carcinoma invading the portal vein: long-term patient outcomes. Int J Radiat Oncol Biol Phys 2012;82:2004e11. 9. Lee HS, Kim JS, Choi IJ, et al. The safety and efficacy of transcatheter arterial chemoembolization in the treatment of patients with hepatocellular carcinoma and main portal vein obstruction. A prospective controlled study. Cancer 1997;79:2087e94. 10. Luo J, Guo RP, Lai EC, et al. Transarterial chemoembolization for unresectable hepatocellular carcinoma with portal vein tumor thrombosis: a prospective comparative study. Ann Surg Oncol 2011;18:413e20. 11. Zheng JS, Long J, Sun B, et al. Transcatheter arterial chemoembolization combined with radiofrequency ablation can improve survival of patients with hepatocellular carcinoma with portal vein tumour thrombosis: extending the indication for ablation? Clin Radiol 2014;69:e253e63. 12. Kudo M, Imanaka K, Chida N, et al. Phase III study of sorafenib after transarterial chemoembolisation in Japanese and Korean patients with unresectable hepatocellular carcinoma. Eur J Cancer 2011;47:2117e27. 13. Chung YH, Han G, Yoon JH, et al. Interim analysis of START: study in Asia of the combination of TACE (transcatheter arterial chemoembolization) with sorafenib in patients with hepatocellular carcinoma trial. Int J Cancer 2013;132:2448e58. 14. Pawlik TM, Reyes DK, Cosgrove D, et al. Phase II trial of sorafenib combined with concurrent transarterial chemoembolization with drugeluting beads for hepatocellular carcinoma. J Clin Oncol 2011;29:3960e7. 15. Zhu K, Chen J, Lai L, et al. Hepatocellular carcinoma with portal vein tumor thrombus: treatment with transarterial chemoembolization combined with sorafenibda retrospective controlled study. Radiology 2014;272:284e93. 16. Liver Cancer Study Group of Japan. The general rules for the clinical and pathological study of primary liver cancer. Jpn J Surg 1989;19:98e129.
e9
17. Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology 2005;42:1208e36. 18. Ando E, Tanaka M, Yamashita F, et al. Hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma with portal vein tumor thrombosis: analysis of 48 cases. Cancer 2002;95:588e95. 19. Zhao M, Wang JP, Pan CC, et al. CT-guided radiofrequency ablation after with transarterial chemoembolization in treating unresectable hepatocellular carcinoma with long overall survival improvement. Eur J Radiol 2012;81:2717e25. 20. Trotti A, Colevas AD, Setser A, et al. CTCAE v3.0: development of a comprehensive grading system for the adverse effects of cancer treatment. Semin Radiat Oncol 2003;13:176e81. 21. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000;92:205e16. 22. Park JW, Koh YH, Kim HB, et al. Phase II study of concurrent transarterial chemoembolization and sorafenib in patients with unresectable hepatocellular carcinoma. J Hepatol 2012;56:1336e42. 23. Sansonno D, Lauletta G, Russi S, et al. Transarterial chemoembolization plus sorafenib: a sequential therapeutic scheme for HCV-related intermediate-stage hepatocellular carcinoma: a randomized clinical trial. Oncologist 2012;17:359e66. 24. Han G, Yang J, Shao G, et al. Sorafenib in combination with transarterial chemoembolization in Chinese patients with hepatocellular carcinoma: a subgroup interim analysis of the START trial. Future Oncol 2013;9:403e10. 25. Li X, Feng GS, Zheng CS, et al. Expression of plasma vascular endothelial growth factor in patients with hepatocellular carcinoma and effect of transcatheter arterial chemoembolization therapy on plasma vascular endothelial growth factor level. World J Gastroenterol 2004;10:2878e82. 26. Jia L, Kiryu S, Watadani T, et al. Prognosis of hepatocellular carcinoma with portal vein tumor thrombus: assessment based on clinical and computer tomography characteristics. Acta Med Okayama 2012;66:131e41. 27. Bai W, Wang YJ, Zhao Y, et al. Sorafenib in combination with transarterial chemoembolization improves the survival of patients with unresectable hepatocellular carcinoma: a propensity score matching study. J Dig Dis 2013;14:181e90. 28. 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;10:25e34. 29. Liapi E, Geschwind JF. Combination of local transcatheter arterial chemoembolization and systemic anti-angiogenic therapy for unresectable hepatocellular carcinoma. Liver Cancer 2012;1:201e15. 30. Sieghart W, Pinter M, Reisegger M, et al. Conventional transarterial chemoembolisation in combination with sorafenib for patients with hepatocellular carcinoma: a pilot study. Eur Radiol 2012;22:1214e23.
Please cite this article in press as: Pan T, et al., Safety and efficacy of transarterial chemoembolization plus sorafenib for hepatocellular carcinoma with portal venous tumour thrombus, Clinical Radiology (2014), http://dx.doi.org/10.1016/j.crad.2014.09.007
