Cost-effectiveness analysis of transcatheter arterial chemoembolization with or without sorafenib for the treatment of unresectable hepatocellular carcinoma

BACKGROUND: Transcatheter arterial chemoembolization (TACE) and TACE in combination with sorafenib (TACE-sorafenib) have shown a significant survival benefit for the treatment of unresectable hepatocellular carcinoma (HCC). Adopting either as a first-line therapy carries major cost and resource implications. The objective of this study was to estimate the relative cost-effectiveness of TACE against TACE-sorafenib for unresectable HCC using a decision analytic model. METHODS: A Markov cohort model was developed to com-pare TACE and TACE-sorafenib. Transition probabilities and utilities were obtained from systematic literature reviews, and costs were obtained from West China Hospital, Sichuan Uni-versity, China. Survival benefits were reported in quality-ad-justed life-years (QALYs). The incremental cost-effectiveness ratio (ICER) was calculated. Sensitive analysis was performed by varying potentially modifiable parameters of the model. RESULTS: The base-case analysis showed that TACE cost $26951 and yielded survival of 0.71 QALYs, and TACE-sorafenib cost$44542 and yielded survival of 1.02 QALYs in the entire treat-ment. The ICER of TACE-sorafenib versus TACE was $56745 per QALY gained, which was above threshold for cost-effectiveness in China. Sensitivity analysis revealed that the major driver of ICER was the cost post TACE-sorafenib therapy with stable state. CONCLUSION: TACE is a more cost-effective strategy than TACE-sorafenib for the treatment of unresectable HCC.     

Prospective,randomized, controlled study of the efficacy of transcatheter arterial chemoembolization with miriplatin for hepatocellular carcinoma

Aim

Transcatheter arterial chemoembolization (TACE) has been recognized as a treatment option for patients with intermediate hepatocellular carcinoma (HCC). This randomized, controlled study compared the local control efficacy of TACE with miriplatin (platinum monohydrate) or with epirubicin.

Methods

The study group consisted of 200 Japanese patients with unresectable HCC treated at the Kitasato University East Hospital (Sagamihara, Japan) between July 2010 and June 2013. The primary end‐point of the study was time to tumor progression (TTP).

Results

We analyzed 198 patients (99 in the miriplatin group and 99 in the epirubicin group) treated with TACE. The median TTP in the epirubicin group was 5.9 months (95% confidence interval [CI], 4.8–7.0) and 7.6 months (95% CI, 5.8–9.4) in the miriplatin group. There was a significant difference between the two groups (P = 0.021; risk ratio, 1.488; 95% CI: 1.061–2.086). In the epirubicin group, 53 patients (53%) had complete response, 24 patients (24%) had partial response, 12 patients (12%) had stable disease, and 10 patients (10%) had progressive disease. In the miriplatin group, 38 patients (38%) had complete response, 41 patients (41%) had partial response, 2 patients (2%) had stable disease, and 18 patients (18%) had progressive disease. There was no significant difference in the response rate (P = 0.862). Overall incidences of adverse events and adverse drug reactions did not differ significantly between the two groups.

Conclusion

Miriplatin proved more effective than epirubicin in TACE for unresectable HCC. The trial described in this work has been registered under the trial number: UMIN000004790.     

Evaluation of transcatheter arterial embolization prior to percutaneous tumor ablation in patients with hepatocellular carcinoma: a randomized controlled trial.

BACKGROUND: Transcatheter arterial embolization (TAE) may reduce the risk of hepatocellular carcinoma (HCC) recurrence when performed before percutaneous tumor ablation (PTA), either percutaneous ethanol injection therapy (PEIT) or radiofrequency ablation (RFA). We conducted a randomized, controlled trial comparing the use of TAE combined with percutaneous ethanol injection therapy (TAE/PEIT) to the use of PEIT only to assess the effects on HCC recurrence and survival. We continued the study after the introduction of RFA and compared TAE combined with RFA (TAE/RFA) with RFA only. METHODS: Between March 1997 and April 2001, 42 HCC patients were enrolled who satisfied the following inclusion criteria: (1) uninodular HCC as determined by angiography under computed tomography, (2) arterial hypervascularity, and (3) no prior history of HCC treatment. Twenty-two patients were treated with TAE/PTA (PEIT, 12; RFA, 10) and 20 patients with PTA only (PEIT, 14; RFA, 6). RESULTS: There were four cases of local recurrence in the PTA-only group and none in the TAE/PTA group (P=0.043). The four patients with local recurrence were treated with PEIT. None of the patients treated with RFA showed local recurrence. The effect of TAE on overall recurrence was not significant (P=0.4179). In the multivariate analysis, prior TAE was not significant for survival (P=0.514). CONCLUSIONS: TAE has a limited use in suppressing local recurrence when performed before PEIT but not before RFA.     

Transarterial chemoembolization in combination with percutaneous ablation therapy in unresectable hepatocellular carcinoma: a meta‐analysis

Background: Recent evidence suggests that transcatheter arterial chemoembolization (TACE) combined with radiofrequency ablation (RFA) or a percutaneous ethanol injection (PEI) may have a synergistic effect in treating hepatocellular carcinoma (HCC). The aim of the current meta‐analysis was to identify the survival benefits of TACE combined with percutaneous ablation (PA) therapy (RFA or PEI) for unresectable HCC compared with those of TACE or PA alone. Methods: Randomized‐controlled trials (RCTs) published as full papers or abstracts were searched to assess the survival benefit or tumour recurrence for patients with unresectable HCC on electronic databases. The primary outcome was survival. The secondary outcomes were response to therapy and tumour recurrence. Results: Ten RCTs met the criteria to perform a meta‐analysis including 595 participants. TACE combined with PA therapy, respectively improved, 1‐, 2‐, and 3‐year overall survival compared with that of monotherapy [odds ratio (OR) 2.28, 95% confidence interval (CI) 1.14–4.57; P=0.020], (OR=4.53, 95% CI 2.62–7.82, P<0.00001) and (OR=3.50, 95% CI 1.75–7.02, P=0.0004). Sensitivity analysis demonstrated a significant benefit in 1‐, 2‐ and 3‐year overall survival of TACE plus PEI compared with that of TACE alone for patients with large HCC lesions, but not in TACE plus RFA vs RFA for patients with small HCCs. The pooled result of five RCTs showed that combination therapy decreased tumour recurrence compared with that of monotherapy (OR=0.45, 95% CI 0.26–0.78, P=0.004). Conclusion: TACE combined with PA therapy especially PEI improved the overall survival status for large HCCs.     

A pilot study of three-dimensional conformal radiotherapy in unresectable hepatocellular carcinoma

BACKGROUND: The purpose of this study was to determine the potential role of three-dimensional (3-D) conformal radiotherapy (RT) in treatment of unresectable hepatocellular carcinoma (HCC). METHODS: Thirteen patients were included in this study, which was conducted between 1993 and 1996. Nine patients (group A) were treated with 3-D conformal RT alone because of main portal vein thrombosis, inferior vena cava thrombosis, obstructive jaundice and failure of previous transcatheter arterial chemoembolization (TACE) to control the disease. The remaining four patients (group B) were treated with a combination of TACE and 3-D conformal RT. RESULTS: The greatest dimension of the main tumour in the whole group of patients ranged from 6 to 25 cm (median 15 cm). The radiation dose ranged from 40 to 60 Gy. The tumour response was evaluated by computed tomography scans of the liver 6-8 weeks after completion of radiotherapy. Partial response was observed in 58% of the patients (seven of 12) and minimal response in another 25% of patients (three of 12). One patient could not be evaluated because of the development of hepatic failure 1 month after completion of RT. All patients in group B lived for more than 1 year (range 16-40 months). In group A, one patient who had a large tumour (11 x 10 x 21 cm) with portal vein thrombosis was converted to become resectable after 45 Gy of radiation. The resection specimen revealed no residual cancer cells. This patient is alive longer than 15 months after treatment without the evidence of disease. CONCLUSIONS: Our experience indicates that HCC is more radiosensitive than it was traditionally expected. Three-dimensional reconstruction of tumour and surrounding organs helps to avoid excessive exposure of the liver and adjacent organs to RT and makes it a safer treatment modality for unresectable HCC. Our preliminary data show promise and are worthy of further study to explore the potential role of radiotherapy in the treatment strategy for HCC at various stages of involvement.     

Outcome of transarterial chemoembolization monotherapy, and in combination with percutaneous ethanol injection, or radiofrequency ablation therapy for hepatocellular carcinoma

Aim:  Hepatocellular carcinoma (HCC) is one of the most commonly occurring malignances worldwide. Curative therapies such as resection, percutaneous ethanol injection (PEI) and radiofrequency ablation (RFA) have been applied to patients with early-stage HCC. Patients with more advanced cancers require local or systemic therapies. We present the results of our retrospective review conducted to evaluate whether transarterial chemoembolization (TACE) alone and combined TACE with percutaneous ablation for HCC exhibited superior efficacy to palliative treatment.
Methods:  The effects of TACE and of the combined therapies (TACE + PEI or TACE + RFA) on the long-term survival rates were evaluated in 268 untreated HCC patients by various statistical analyses.
Results:  The cumulative survival rates in the TACE alone group were significantly superior to those in the palliative treatment group. Further, the cumulative survival rates in the combined TACE + PEI/RFA group were significantly superior to those in the TACE alone group. When the comparison among the groups was restricted to patients with two or three tumors fulfilling the Milan criteria, significantly greater prolongation of survival was observed in the combined TACE + PEI/RFA group than in the PEI/RFA alone group.
Conclusions:  The aforementioned treatment modalities yielded greater improvements of the survival rate and survival duration as compared to palliative treatment in HCC patients. Furthermore, in terms of the effect on the survival period, combined TACE + PEI/RFA therapy was more effective than TACE monotherapy, and also more effective than PEI or RFA monotherapy in cases with multiple tumors fulfilling the Milan criteria.     

CT引导经导管动脉化疗栓塞治疗肝细胞癌

目的探讨CT引导经导管动脉化疗栓塞（transcatheter arerial chemoembolization,TACE）治疗肝细胞癌（hepatocellular carcinoma,HCC）的初步疗效,分析局部复发的危险因素。方法对32例患者的34个HCC病灶进行了CT引导TACE治疗。结果32例中26例实现局部控制,6例出现局部复发。采用Logistic回归分析发现,TACE治疗后中央型HCC病灶是局部复发的危险因素（P=0．0408）。结论CT引导TACE是治疗小HCC的好方法,其局部控制率高、复发率低。中央型HCC是TACE术后局部复发的危险因素。     

Management of inoperable hepatocellular carcinoma

Abstract   Hepatocellular carcinoma (HCC) is a common and difficult-to-treat malignant tumor. Surgical interventions are feasible in only a small proportion of patients, and non-surgical therapy has been frequently administered to patients with inoperable HCC. Various modalities of loco-regional therapy have gained much interest during the past decade. Among them, transarterial chemoembolization (TACE), percutaneous injection of ethanol (PEI) or acetic acid (PAI), radiofrequency ablation (RFA) and microwave coagulation therapy (MCT) are effective treatment options. TACE can target multiple hypervascular tumors but has the potential risk of inducing hepatic or renal failure. PEI is a well-established method for small (< 3 cm) HCC, and PAI has the advantage over PEI as being more effective with fewer treatment sessions. RFA has excellent tumor ablation ability, and has been extended to treat medium- or large-sized HCC. However, the overall complication rate may be higher than previously assumed. MCT is similar to RFA in its clinical application and adverse effects. Although combination therapy often achieves a higher response rate, the side-effects may also be additive. Other therapies, such as injection of hot saline or yttrium-90 microspheres, interstitial laser photocoagulation and cryoablation are seldom used nowadays. Thalidomide may be useful in a minority of HCC patients, whereas radiotherapy, chemotherapy and tamoxifen are generally ineffective. In conclusion, although long-term survival in patients with inoperable HCC is possible in selected patients, the overall prognosis remains unsatisfactory, especially in those with aggressive tumor behavior. Newer antitumor therapy with better treatment efficacy is urgently needed. Information of the design for a more comprehensive approach using the existing therapeutic options may help refine the treatment strategy.     

Efficacy of combination therapy with transcatheter arterial chemoembolization and radiofrequency ablation for intermediate-stage hepatocellular carcinoma

Abstract

Objectives: Transcatheter arterial chemoembolization (TACE) is the standard therapy for patients with intermediate-stage hepatocellular carcinoma (HCC). This study aimed to determine whether combination therapy with radiofrequency ablation (RFA) and TACE was superior to TACE monotherapy for intermediate-stage HCC and identify cases in which this technique was the most effective.

Materials and methods: We selected patients with intermediate HCC who met the following eligibility criteria: (1) ≥ 20 years of age, (2) receiving initial therapy, (3) ≤7 tumors, and (4) maximum tumor diameter <5?cm. We performed propensity score matching (PSM) using potential confounding factors. We retrospectively compared the cumulative overall survival rate and recurrence-free survival rate between the TACE?+?RFA and TACE groups. Additionally, a sub-group analysis was performed for preoperative factors.

Results: Among the 103 patients, 92 were selected using PSM. The cumulative overall survival rates at 1, 3, and 5 years for the TACE?+?RFA group were 97.4%, 70.4%, and 60.4%, respectively, which were significantly higher than those for the TACE group (92.7%, 55.7%, and 22.8%, respectively, p?=?.045). The recurrence-free survival rates at 0.5, 1, and 2 years for the TACE?+?RFA group were 80.0%, 58.6%, and 33.3%, respectively, which were significantly higher than those for the TACE group (34.5%, 8.8%, and 2.9%, respectively, p?p?=?.036).

Conclusions: The addition of RFA to TACE improved cumulative overall and recurrence-free survival in patients with intermediate-stage HCC, especially in patients with AFP <100.     

Chemotherapy for transarterial chemoembolization in patients with unresectable hepatocellular carcinoma

AIM: To compare the efficacy of different chemotherapeutic agents during conventional transarterial chemoembolization (cTACE) in the treatment of unresectable hepatocellular carcinoma (HCC).METHODS: A retrospective review was undertaken of patients with unresectable HCC undergoing cTACE from May 2003 to November 2011. A total of 107 patients were treated with at least one cTACE session. Irinotecan (CPT-11) was used as a chemotherapeutic agent in 24 patients, gemcitabine (GEM) in 24 and doxorubicin in 59.RESULTS: The time to progression and overall survival rates were significantly superior in patients treated with CPT-11 compared with the GEM or doxorubicin treated groups (11.4, 8.2, 9.5 mo, P = 0.02 and 21.7, 12.7, 14.5 mo, P = 0.004, respectively). Subgroup analysis showed that for intermediate-stage HCC, CPT-11 resulted in a significantly longer time to progression and overall survival compared with the GEM or doxorubicin treated groups (P = 0.022; P = 0.003, respectively). There were no significant differences in adverse events among the three groups (P > 0.05).CONCLUSION: For patients treated with cTACE, the chemotherapeutic agent CPT-11 was significantly associated with improved overall survival and delayed tumor progression compared with GEM or doxorubicin. There were no significant differences in clinical adverse events between the three agents. CPT-11 thus appears to be a promising agent when combined with cTACE for the treatment of HCC.     

肝动脉化疗栓塞术治疗中晚期原发性肝癌的疗效观察

[目的]研究经导管肝动脉化疗栓塞术(TACE)治疗中晚期原发性肝癌的疗效并预测影响患者生存率的相关因素。[方法]80例中晚期原发性肝癌患者经1次或多次TACE治疗后,分别于治疗后第1、3、6、12个月对患者进行CT扫描评估肿瘤对治疗的反应并计算生存率。[结果]对所有患者随访观察3年(或者观察至死亡),80例患者共进行了163次TACE,按Child-pugh分级A级48例(60.0%),B级32例(40.0%);肿瘤大小5cm 18例(22.5%),5~10cm 42例(52.5%),10cm 20例(25.0%);行1、2、3、4次TACE的患者分别为12、56、9、3例;1、2、3年的总生存率分别为71.3%、43.8%和17.5%,肿瘤直径5cm患者TACE后3年生存率显著高于肿瘤直径为5~≥10cm患者。[结论]TACE是治疗中晚期肝癌的一种有效的方法,能有效缓解患者的临床症状并延长生存期,初始肿瘤的大小是决定患者生存率的独立影响因素。     

Phase I/II study of a fine‐powder formulation of cisplatin for transcatheter arterial chemoembolization in hepatocellular carcinoma

Aim: The clinical feasibility of transcatheter arterial chemoembolization (TACE) with fine‐powder cisplatin (CDDP) in patients with hepatocellular carcinoma (HCC) has not been investigated. A phase I/II study was conducted to investigate the safety and tolerability of fine‐powder CDDP when it was used with lipiodol and gelatin sponge particles for TACE. Methods: Fine‐powder CDDP emulsified in lipiodol was injected into tumor arteries. Embolization was subsequently performed with gelatin sponge particles. The CDDP dose was started at 45 mg/m² (level 1) and increased to 65 mg/m² in 10 mg/m² increments. Results: Thirteen patients were enrolled in phase I study since no dose limiting toxicity was observed in any patients, even in seven patients at level 3 (65 mg/m²), the recommended dose was 65 mg/m². The major adverse event was grade 3 thrombocytopenia, which occurred in 8% of patients. The incidence of hematological toxicities was 15% for leukocytopenia, 84% for thrombocytopenia, and 84% for anemia. Increased serum total bilirubin was observed in 54% and increased aspartate aminotransferase or alanine aminotransferase in all patients. All digestive tract symptoms (nausea 77%, anorexia 84%, vomiting 31%) were grade 2 or lower. Total adverse events were grade 3 or higher in 44%. The response rate in 19 patients who received the recommended dose was 21%. Conclusions: TACE with a fine‐powder formulation of CDDP at a dose of 65 mg/m² is well tolerated in patients with unresectable HCC.     

Comparative study of cisplatin and epirubicin in transcatheter arterial chemoembolization for hepatocellular carcinoma

Aim: Transcatheter arterial chemoembolization (TACE) is an established treatment for unresectable hepatocellular carcinoma (HCC). However, it is unclear which chemotherapeutic agent should be selected for TACE. The aim of this study was to compare the efficacy of cisplatin (CDDP) with that of epirubicin (EPI) in TACE for patients with unresectable or relapsed HCC. Methods: We performed a historical cohort study involving 131 patients treated with a first TACE, defined as either an initial treatment for previously untreated HCC or a first treatment for relapsed HCC after curative resections or ablations. Efficacy was estimated as the response rate (RR) and it was adjusted for the confounding factors that were defined in this study. Results: The RR were 62.5% (20/32) for the first TACE with CDDP and 51.5% (51/99) for that with EPI. In the adjusted analysis for a history of hepatectomy, percutaneous treatment combined with TACE and tumor factors, the odds ratio was 1.72 (95% confidence interval [CI] = 0.70–4.48). However, a test for interaction between the number of tumors and the chemotherapeutic agent was statistically significant (P = 0.016). In multiple HCC, the RR were 66.7% (10/17) for CDDP and 39.6% (30/46) for EPI. The odds ratio was 4.11 (95% CI = 1.14–17.2). Conclusion: CDDP may be more effective than EPI in TACE for multiple HCC. A randomized controlled study is needed to clarify the efficacy of CDDP in TACE in patients with multiple HCC.     

Biliary phenotype of hepatocellular carcinoma after preoperative transcatheter arterial chemoembolization

Background and Aim: Transcatheter arterial chemoembolization (TACE) is now the mainstay of treatment for non‐curative hepatocellular carcinoma (HCC), and hoped to have chemotherapeutic and ischemic effects; however, the histopathological changes of HCC caused by TACE have not been sufficiently discussed so far. We aimed to assess the morphological and immunohistochemical features of HCC treated with TACE by immunostaining cytokeratin (CK) 7, CK14, CK19 and vimentin, and to correlate these data with observed clinicopathological characteristics. Methods: Eighty cases of surgically resected HCC with preoperative TACE and 146 cases of HCC resected without TACE as a control were analyzed. Results: The incidences of intrahepatic metastasis, poorly differentiated histology, multinucleated giant cells, mitotic figures and cytoplasmic inclusion bodies in the TACE group were significantly higher than those in the non‐TACE group. The TACE group showed reactivity for CK7 in 56.3% (45/80) of patients, CK14 in 12.5% (10/80), CK19 in 23.8% (19/80) and vimentin in 6.3% (5/80) of patients. CK19 expression in the TACE group was significantly higher than in the non‐TACE group (P = 0.0423). There was no correlation between immunoreactivity and the number of times TACE was carried out, but the expression of CK19 and vimentin in the massive necrotic group was higher than that in the mild necrotic group (P = 0.0197, P = 0.0229, respectively). Only TACE was an independent determinant of CK19 expression in all cases by multivariate analysis. Conclusions: These results suggest that preoperative TACE may have an impact on the biliary phenotype of HCC. Some post‐therapeutic HCC patients might develop HCC with a biliary phenotype indicating more aggressive malignancies.