Abstract
Aim: We aimed to retrospectively examine the tolerability and efficacy of transarterial chemoembolization (TACE) in patients with advanced hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT). Patients and Methods: Adverse events were assessed using the Common Terminology Criteria for Adverse Events, version 4.0. The efficacy of TACE in parenchymal tumors (parenchymal response) and PVTT (PVTT response) was separately evaluated by dynamic computed tomography 1 to 2 months after TACE according to the Response Evaluation Criteria in Cancer of the Liver (RECICL). Patients with complete remission plus partial response in parenchymal tumors and PVTT were assessed as parenchymal response-positive and PVTT response-positive, respectively. Results: A total of 33 HCC patients with PVTT were analyzed. Grade 3/4 toxicities included elevated aspartate aminotransferase levels (69.7%), elevated alanine aminotransferase levels (54.5%), hyponatremia (6.1%), thrombocytopenia (6.1%), hyperbilirubinemia (3.0%), leukopenia (3.0%) and anemia (3.0%). All these findings returned to the pre-treatment levels within 1 month after TACE. The number of parenchymal response-positive/negative and PVTT response-positive/negative patients was 20/13 and 13/20, respectively. Kaplan–Meier analyses revealed that the cumulative survival rate was significantly higher in parenchymal response-positive (p=0.04) and PVTT response-positive (p<0.01) patients than in their negative counterparts. PVTT response was a favorable prognostic factor for overall survival in multivariate analysis (p=0.03). Conclusion: TACE was feasible in HCC patients with PVTT and could improve their survival by showing direct therapeutic effect against PVTT.
- Hepatocellular carcinoma
- transcatheter arterial chemoembolization
- portal vein tumor thrombus
- prognosis
- survival
Hepatocellular carcinoma (HCC) is one of the most common malignancies with poor prognosis worldwide (1). Macrovascular invasion such as portal vein tumor thrombus (PVTT) is often observed in patients with advanced HCC (2). The prognosis of HCC patients complicated with PVTT is extremely poor; the median survival time of these patients during the natural course is only 2.7-4.0 months (3, 4).
Transcatheter arterial chemoembolization (TACE) has been widely used to treat patients with unresectable and large/multifocal HCCs (5, 6). TACE enables the administration of highly concentrated anticancer agents mixed with Lipiodol into the tumor-feeding artery as well as the embolization of the tumor-feeding artery by gelatin sponge particles. Because of the potential risk of acute liver failure caused by diminished hepatic artery flow in HCC patients with PVTT, TACE has long been considered to be contraindicated in these patients (7). However, the consensus-based treatment algorithm for HCC, proposed by the Japan Society of Hepatology, shows that TACE is feasible if patients with PVTT in second-order branches show good hepatic function (Child-Pugh A or B) and lack extrahepatic spread (8). Similarly, the Asian Pacific Association for the Study of the Liver guideline suggests that TACE is recommended if patients with PVTT in portal vein branches show good hepatic function (Child-Pugh A or B) (9). In contrast, the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL) guidelines recommend sorafenib administration but not TACE for Child-Pugh A or B patients with PVTT, regardless of the degree of PVTT (10, 11). Taken together, it appears that the safety and therapeutic advantage of TACE against HCC with PVTT is still controversial.
In the present study, we conducted retrospective analyses to examine the tolerability and efficacy of TACE in patients with advanced HCC with PVTT. Of note, we separately evaluated the therapeutic effect of TACE against parenchymal tumors and PVTT and examined whether the therapeutic effect of TACE against PVTT was associated with a favorable prognosis.
Patients and Methods
Patients. Medical records were retrieved for HCC patients with PVTT who were admitted to our hospital (blinded for review) from April 2000 to March 2010. Patients were included if they met the following criteria: (i) presence of PVTT, (ii) no previous treatment after PVTT occurrence, (iii) Child-Pugh A or B, (iv) Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0-2 and (v) follow-up on dynamic computed tomography (CT) 1-2 months after TACE. This study was approved by the Research Ethics Committees of Graduate School of Medicine, Chiba University (approval number 1,594) and Kimitsu Chuo Hospital (approval number 191).
Diagnoses of HCC and PVTT. HCC was identified on the basis of the diagnostic criteria of AASLD (10). PVTT was determined by the detection of an intra-luminal mass extending from parenchymal tumors and expanding in portal vein on ultrasound (US), CT and magnetic resonance imaging. “Thread and streaks” sign in CT with hepatic arteriography (CTHA) and contrast agent filling defect in computed tomography arterial portography (CTAP) were also used to diagnose PVTT. We classified the extent of PVTT into the following 3 types as follows: (i) invasion of the main portal vein, (ii) invasion of a first-order branch of the portal vein and (iii) invasion of a second-order branch of the portal vein. These images were evaluated by 2 experienced hepatologists (Y. O and A. T with 11 and 16 years of experience, respectively).
Data collection. We investigated medical and nursing records, laboratory data, as well as imaging data of HCC patients with PVTT selected, as described above. Data were subjected to linkable anonymization. Adverse events (AEs) observed within 1 month after TACE were collected according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) ver. 4.0 (URL:http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40).
TACE procedure. TACE was performed as described previously (12). In brief, the femoral artery was catheterized under local anesthesia and a 4- or 5-French (Fr) parent Shepherd Hook catheter was inserted. All patients underwent angiography of the celiac artery and superior mesenteric artery to reconfirm the site of HCC. Prior to TACE, CTHA and CTAP were conducted to localize tumors and PVTT. Highly selective catheterization was performed using a 2.0- or 2.5-Fr microcatheter to obtain complete occlusion of the nourishing arteries. A mixture of iodized oil (Lipiodol®, Guerbet Japan, Tokyo, Japan) and anticancer drugs such as cisplatin (Nihon Kayaku, Tokyo, Japan), epirubicin (Nihon Kayaku) and miriplatin (Dainippon Sumitomo Pharma Co., Ltd., Osaka, Japan) were administered into the tumor-feeding artery of HCC with PVTT. After the anticancer drug injection, the tumor-feeding arteries were embolized using 1-mm gelatin cubes (Spongel®, Astellas pharma, Tokyo, Japan or Gelpart®, Nippon Kayaku, Tokyo, Japan).
Taking into consideration the risk of liver failure after TACE (7), patients with HCC invading the main portal vein were treated with TACE only in cases in which sufficient collateral circulation around occluded main portal vein were observed.
Assessment of therapeutic effects against liver parenchymal tumor and PVTT. In this study, the therapeutic responses against parenchymal tumors and PVTT were separately assessed on the basis of the findings of dynamic CT 1–2 months after TACE according to the “Response Evaluation Criteria in Cancer of the Liver” (RECICL) (13). The treatment effect was evaluated as follows: progressive disease (PD), total tumor size enlarged by more than 25%; partial response (PR), overall tumor-necrosis effect or overall tumor size reduction rate of 50-100%; complete remission (CR), complete tumor disappearance or 100% tumor necrosis; stable disease (SD), not classified as PD, PR or CR. Patients with CR or PR in parenchymal tumors and PVTT were assessed as “parenchymal response-positive” and “PVTT response-positive”, respectively. These evaluations were made by 2 experienced hepatologists (Y. O and A. T).
Statistical analysis. The correlation between parenchymal and PVTT response was analyzed by the Fisher's exact test. The prognostic relevance of clinical variables was evaluated by univariate analysis with the log-rank test and by multivariate Cox's regression. Variables in univariate analysis with p<0.10 were included in multivariate analysis. Cumulative survival rates after TACE were calculated using the Kaplan–Meier method and evaluated by log-rank tests. All calculations were performed using JMP software (Version 10; SAS Institute, Cary, NC, USA). Differences were considered statistically significant at p<0.05.
Results
Characteristics of patients and tumors. A total of 81 HCC patients with PVTT were admitted to our hospital (blinded for review) from April 2000 to March 2010. Out of these, 27 patients developed PVTT simultaneously with the first HCC diagnosis and the remaining 54 patients developed PVTT during the follow-up period after HCC treatment. Out of the 81 patients, we excluded 23 patients who were Child-Pugh C, 16 patients who received non-IVR treatments such as hepatic infusion chemotherapy, hepatic resection, radiation therapy, and systematic chemotherapy as the first treatment for HCC with PVTT and 9 patients who did not receive suitable follow-up (Figure 1). The remaining 33 patients received TACE as the first treatment for HCC with PVTT and received suitable follow-up. The characteristics of the 33 patients are summarized in Table I. The 33 patients included 27 males and 6 females having a median age of 68 years (range= 45-88). The numbers of patients with PVTT invading the main portal vein, first-order branches and second-order branches were 4, 12 and 17, respectively. Twenty-nine patients died and 4 were alive at the end of the surveillance period. The median interval between PVTT diagnosis and the TACE procedure was 9 days (range= 0-84 days).
Flow chart showing patients' selection. HCC, Hepatocellular carcinoma; PVTT, portal vein tumor thrombus; IR, interventional radiology.
Characteristics of patients and tumors.
Tolerability of TACE in HCC patients with PVTT. AEs associated with TACE are summarized in Table II. In accordance with a previous report (14), post-embolization syndrome, characterized by nausea, vomiting, abdominal pain and fever was observed frequently. However, the severity of these symptoms was not ≥grade 3 in any patients. In other toxicity data, elevated aspartate aminotransferase (AST) levels, elevated alanine aminotransferase (ALT) level, hyperbilirubinemia, hyponatremia, leukopenia, thrombo-cytopenia and anemia were frequently noted (Table II). Although elevated AST and ALT levels (≥grade 3) were observed in more than 50% patients, other AEs (≥grade 3) were noted only in few patients. All these findings returned to the pre-treatment levels within 1 month after TACE. No patient died within 1 month after TACE. Overall, these toxicities were well-tolerated in HCC patients with PVTT.
Adverse events after TACE.
Therapeutic effect against liver parenchymal tumor and PVTT.
Therapeutic effect of TACE in HCC patients with PVTT. The therapeutic effect of TACE against parenchymal tumors and PVTT was separately evaluated (Figure 2). The number of parenchymal response-positive and -negative patients was 20 and 13, respectively. The number of patients with positive and negative PVTT response was 13 and 20, respectively. There was a significant correlation between parenchymal response and PVTT response (p<0.01) (Table III). Kaplan–Meier analyses demonstrated that parenchymal response-positive patients showed significantly favorable survival compared with parenchymal response-negative patients (p=0.04) (Figure 3A). Mean survival times (MSTs) of parenchymal response-positive and -negative patients were 11.1 and 5.5 months, respectively. Of importance, survival of PVTT response-positive patients was significantly longer than that of PVTT response-negative patients (p<0.01) (Figure 3B). MSTs of PVTT response-positive and -negative patients were 14.0 and 5.8 months, respectively. In the peripheral PVTT (second-order portal branches) subgroup, MSTs of PVTT response-positive and -negative patients were 18.2 and 5.9 months, respectively (p=0.04). In the major PVTT (main portal vein or first-order portal branches) subgroup, MSTs of PVTT response-positive and -negative patients were 11.1 and 5.5 months, respectively (p=0.04).
Representative images from a 53-year-old male with hepatocellular carcinoma (HCC) invading the main portal vein. (A) An axial image of HCC with PVTT before transcatheter arterial chemoembolization (TACE). (B) A coronal image of the portal vein tumor thrombus (PVTT, arrow) accompanied by collateral vessels (arrowhead) before TACE. (C) An axial image taken 2 months after TACE: the parenchymal response was judged as positive. (D) A coronal image taken 2 months after TACE. Arrow indicates the deposition of Lipiodol. The PVTT response was judged as positive. (E) An axial image taken 5 months after TACE showing that the anti-parenchymal tumor effect was sustained. (F) A coronal image at 5 months after TACE showing that the anti-PVTT effect was sustained. Arrow indicates the deposition of Lipiodol.
Univariate and multivariate analyses of the relative risks for overall survival of patients.
Next, we examined the prognostic relevance of clinical variables (Table IV). The variables with p<0.10 on univariate analysis (presence of distant metastasis, PVTT response-positive and parenchymal response-positive) were subjected to multivariate analysis. Multivariate analysis revealed that only PVTT response-positive showed a statistically significant correlation with overall survival (p=0.03).
Discussion
It has been reported that vascular invasion, performance status, constitutional syndrome and distant metastasis are independent predictors for mortality in HCC (3). PVTT, a feature of HCC at the terminal stage, is one of the most typical findings of vascular invasion of HCC (3). PVTT is a definite poor prognostic factor for HCC, because it causes intra-hepatic metastasis, portal hypertension and liver failure. TACE has long been considered as a contraindication for HCC with PVTT because of the potential risk of hepatic insufficiency resulting from ischemia after TACE (15). In fact, the guidelines for HCC proposed by AASLD and EASL show that patients with PVTT have an advanced stage disease, and sorafenib administration or conservative treatment is recommended for these patients (10, 11). However, recent studies have revealed that TACE can be performed in patients with preserved flow of the main portal vein or PVTT invading the main portal vein with sufficient collateral circulation (16, 17). Given that there is scant evidence that sorafenib is effective against HCC with PVTT, TACE still plays an important role in the treatment of unresectable HCC and PVTT.
Prognostic analysis based on the therapeutic effect of transcatheter arterial chemoembolization (TACE). (A) Cumulative survival rate with regard to parenchymal response. (B) Cumulative survival rate with regard to portal vein tumor thrombus (PVTT) response.
In the present study, we first examined the tolerability of TACE in HCC patients with PVTT. Although a transient elevation in AST and ALT levels (≥grade 3) was observed in more than 50% of the patients, these returned to pre-treatment levels within 1 month after TACE. Other AEs such as hyperbilirubinemia, hyponatremia, leukopenia, anemia, and thrombocytopenia were observed only in few patients. Of importance, no patient died within 1 month after TACE. Overall, 4 out of 33 of the patients exhibited tumor thrombus invasion into the main portal vein but they had sufficient collateral circulation. In addition, selective catheterization into the tumor-feeding branch could have contributed to the tolerability of TACE. Taken together, it appears that TACE for HCC patients with PVTT was tolerable even in some patients with PVTT invasion into the main portal vein (18, 19).
We also examined the survival benefit of TACE in view of the parenchymal tumor response and the PVTT response. Kaplan–Meier analyses showed that the cumulative survival rate was significantly higher in parenchymal response-positive (p=0.04) and PVTT response-positive patients (p<0.01). In addition, multivariate analysis revealed that PVTT response was significantly correlated with overall survival (p=0.03). MSTs of all patients, parenchymal response-positive patients and PVTT response-positive patients were 9.1, 11.0 and 14.1 months, respectively. Considering that the MST of untreated HCC patients with PVTT is 2.7-4.0 months (3, 4), TACE targeting PVTT appears to have a survival benefit in these patients. It has been reported that iodized oil deposition in PVTT is associated with a favorable prognosis (20-22). MST of patients analyzed in these studies ranged from 4.0-14.9 months and these results appears to be concordant with our data. Taken together, TACE that targets not only parenchymal tumors but also PVTT may be an important and effective strategy for treatment of HCC patients with PVTT.
This type of analysis, however, has its limitations. First, this study was a retrospective analysis performed in a relatively small number of patients. To validate the efficacy of TACE against PVTT, further prospective analyses in a large number of patients are needed. Second, two-thirds of patients received various treatments before and after TACE, including hepatic arterial infusion chemotherapy and sorafenib administration. Considering that TACE with additional radiation therapy or sorafenib have been shown to exert significant survival benefits (23, 24), these treatments could have influenced the obtained results.
In conclusion, our findings suggested that TACE can be safely performed in HCC patients with PVTT. The cumulative survival rate was significantly higher in parenchymal response-positive and PVTT response-positive patients than in their negative counterparts. In addition, multivariate analysis revealed that PVTT response was a favorable prognostic factor for cumulative survival.
Footnotes
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This article is freely accessible online.
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Conflicts of Interest
Professor Osamu Yokosuka received grant support (scholarship contribution) from Dainippon Sumitomo Pharma Co, Ltd (Osaka, Japan).
- Received April 17, 2014.
- Revision received June 3, 2014.
- Accepted June 4, 2014.
- Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
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