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1.  Effect of transarterial chemoembolization with miriplatin plus epirubicin on local control of hepatocellular carcinoma: a retrospective comparison with miriplatin monotherapy 
OncoTargets and therapy  2013;6:1025-1030.
Objective
We aimed to evaluate local tumor control after transarterial chemoembolization (TACE) for hepatocellular carcinoma using miriplatin and low-dose epirubicin combination therapy.
Methods
We retrospectively analyzed the records of patients who underwent TACE using miriplatin plus low-dose epirubicin (30 patients, 61 nodules, August 2011–March 2012) and control patients who underwent TACE using miriplatin alone (36 patients, 70 nodules, June 2010–July 2011). The local control rate was compared between the two groups using the Kaplan–Meier estimator and the log-rank test. Factors affecting local tumor recurrence were analyzed using multivariate logistic regression analysis. Treatment-related toxicity was evaluated using the Common Terminology Criteria for Adverse Events.
Results
The local control rates at 6 months and 1 year were 87% and 65% for the miriplatin plus low-dose epirubicin group, and 61% and 43% for the miriplatin group, respectively. Local tumor control rates were significantly better in the miriplatin plus low-dose epirubicin group than in the miriplatin group (P = 0.038). Multivariate analysis showed that the addition of epirubicin was an independent factor associated with better local tumor control (hazard ratio 0.2, P = 0.001). Overall incidence rates for adverse events were not significantly different between the two groups.
Conclusion
Additional usage of low-dose epirubicin for TACE using miriplatin improved local tumor control of hepatocellular carcinoma with adverse effects comparable to those observed with TACE using miriplatin alone.
doi:10.2147/OTT.S49443
PMCID: PMC3753878  PMID: 23986641
combination therapy; local recurrence; liver; embolization; comparative study
2.  Intra-hepatic arterial administration with miriplatin suspended in an oily lymphographic agent inhibits the growth of tumors implanted in rat livers by inducing platinum-DNA adducts to form and massive apoptosis 
Background
Miriplatin (formerly SM-11355), a novel lipophilic platinum complex developed to treat hepatocellular carcinoma, is administered into the hepatic artery using an oily lymphographic agent (Lipiodol Ultra-Fluide®) as a carrier. We clarified the usefulness of miriplatin as an agent for transarterial chemoembolization.
Methods
Platinum compounds released from miriplatin into serum, medium and Earle’s balanced salt solution were examined. Then, miriplatin and cisplatin were administered to rats bearing hepatoma AH109A tumors in livers. Platinum concentrations in tissues and DNA were assessed.
Results
Miriplatin showed a more sustained release than cisplatin. Dichloro[(1R, 2R)-1, 2-cyclohexane diamine-N, N′]platinum, the most abundant platinum compound released from miriplatin, was as effective as cisplatin in inhibiting the growth of cells. Miriplatin was selectively disposed of in tumors, maintained in tumors longer than cisplatin and caused apparent tumor regression inducing platinum-DNA adducts to form and massive apoptosis.
Conclusion
Miriplatin appears to be a suitable chemotherapeutic agent for transarterial chemoembolization.
doi:10.1007/s00280-008-0895-3
PMCID: PMC2691803  PMID: 19104812
Miriplatin; Lipiodol; Platinum-DNA adducts; Apoptosis; Hepatocellular carcinoma
3.  A randomized phase II trial of intra-arterial chemotherapy using SM-11355 (Miriplatin) for hepatocellular carcinoma 
Investigational New Drugs  2011;30(5):2015-2025.
Background SM-11355 is a platinum complex developed to treat hepatocellular carcinoma (HCC) via administration into the hepatic artery as a sustained-release suspension in iodized oil. We conducted a multicenter phase II trial in patients with HCC to evaluate the efficacy and safety of SM-11355, using a Zinostatin stimalamer suspension in iodized oil as a reference. Methods Patients with unresectable HCC were randomized 2:1 to receive administration of the SM-11355 or Zinostatin stimalamer suspension into the hepatic artery. A second injection was given 4–12 weeks later. Efficacy was evaluated by CT 3 months after treatment and categorized as therapeutic effect (TE) V to I, where TE V was defined as disappearance or 100% necrosis of all treated tumors. Results A total of 122 patients were evaluated for efficacy and toxicity (SM-11355, n = 83; Zinostatin stimalamer, n = 39). Baseline characteristics were similar in the two groups. The TE V rates were 26.5% (22/83) and 17.9% (7/39) in the SM-11355 and Zinostatin stimalamer groups, respectively. In the SM-11355 group,the most frequent drug-related adverse events (AEs) of ≥ grade 3 were elevated AST, elevated ALT, thrombocytopenia, and hyperbilirubinemia. The AEs with the largest difference between the two groups (SM-11355 vs. Zinostatin stimalamer) were hepatic vascular injury (0 vs. 48.4%) and eosinophilia (84.3 vs. 41.0%). The 2-year and 3-year survival rates were 75.9% vs. 70.3% and 58.4% vs. 48.7%, respectively. Conclusions The results suggest that SM-11355 in iodized oil has similar efficacy to Zinostatin stimalamer and that repeated dosing of SM-11355 is possible without hepatic vascular injury in cases of relapse.
doi:10.1007/s10637-011-9776-4
PMCID: PMC3432786  PMID: 22187203
Iodized oil; MIRIPLA; Liver cancer; Suspension; Parallel study
4.  Transarterial chemoembolization with miriplatin-lipiodol emulsion for neuroendocrine metastases of the liver 
World Journal of Radiology  2010;2(12):468-471.
Miriplatin, a cisplatin derivative with a high affinity for iodized oil, is a novel chemotherapeutic agent designed for use in the transarterial treatment of hepatocellular carcinoma. This case report describes our experience with transarterial chemoembolization (TACE) using miriplatin in 2 patients with neuroendocrine liver metastases. A 38-year-old man with multiple neuroendocrine liver metastases was treated by whole liver chemoembolization, and a 35-year-old woman with a single hepatic lesion was treated by superselective chemoembolization. No serious adverse events were noted during the interventional procedures, or during the observation period of 3 mo in either patient. Sufficient iodized oil uptake was observed in the hypervascular lesions on the unenhanced computed tomography (CT) at 7 d after the procedure. Contrast-enhanced CT obtained at 3 mo after chemoembolization revealed that all hepatic lesions were substantially reduced in size irrespective of tumor vascularity or degree of cystic degeneration, although iodized oil accumulation was only marginal for lesions with cystic degeneration. Thus, TACE with miriplatin can be a safe and effective therapeutic option for the treatment of neuroendocrine metastases of the liver.
doi:10.4329/wjr.v2.i12.468
PMCID: PMC3018555  PMID: 21225002
Chemoembolization; Liver; Metastatic tumor; Miriplatin; Neuroendocrine tumor
5.  A Case of Advanced Hepatocellular Carcinoma with Portal Vein Tumor Thrombus Refractory to Epirubicin That Showed Marked Decrease in Tumor Markers after Transcatheter Arterial Infusion with Miriplatin 
Case Reports in Oncology  2010;4(2):327-335.
Miriplatin, a cisplatin derivative with a high affinity for iodized ethyl esters of fatty acids from poppy seed oil, is a novel chemotherapeutic agent designed for use in the transarterial treatment of hepatocellular carcinoma (HCC). Here, we describe transcatheter arterial infusion (TAI) using miriplatin to treat a case of advanced HCC with portal vein tumor thrombus (PVTT) refractory to TAI with epirubicin. A 66-year-old man with advanced hepatitis C virus-related HCC with PVTT in the right lobe of the liver was treated with TAI with epirubicin suspended in iodized oil; however, tumor marker levels (alpha-fetoprotein and des-gamma-carboxy protein) did not decrease. Next, he was treated twice with TAI with miriplatin suspended in iodized oil. The tumor marker levels markedly decreased to a nearly normal range and the size of the main tumor was markedly reduced according to dynamic computed tomography. No serious adverse events occurred during the course of treatment with TAI and miriplatin. Therefore, we suggest that TAI with miriplatin is a safe and effective treatment option for advanced HCCs refractory to TAI with epirubicin.
doi:10.1159/000330106
PMCID: PMC3130984  PMID: 21738504
Miriplatin; Tumor marker; Hepatocellular carcinoma; Epirubicin
6.  Local tumor progression following lipiodol-based targeted chemoembolization of hepatocellular carcinoma: a retrospective comparison of miriplatin and epirubicin 
Purpose
We aimed to compare the local control rates between miriplatin and epirubicin in lipiodol-based transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC).
Patients and methods
Patients who underwent targeted TACE using miriplatin (47 patients, 66 lesions) or epirubicin (64 patients, 79 lesions) as the sole therapy were enrolled. The local control rates were compared using the Kaplan–Meier estimator with the log-rank test. The patient and tumor parameters were subjected to univariate and multivariate analyses using the Cox proportional hazards model.
Results
The overall local recurrence rates were 39.3% and 31.6% for the miriplatin and epirubicin groups, respectively. The local control rate was significantly higher in the epirubicin group than in the miriplatin group (P < 0.001). The local control rates at 6 months and 1 year were 70.7% and 44.8% for the miriplatin group and 83.4% and 69.2% for the epirubicin group, respectively. Multivariate analysis showed that the serum α-fetoprotein level ≥ 20 ng/mL (hazard ratio 2.96; P < 0.001), miriplatin usage (hazard ratio 2.53; P = 0.002), and Child-Pugh class B (hazard ratio 1.89; P = 0.042) affected local progression.
Conclusion
Lipiodol-based targeted TACE using miriplatin had inferior local control rates as compared to epirubicin in patients with HCC.
doi:10.2147/CMAR.S30431
PMCID: PMC3346199  PMID: 22570565
chemoembolization; miriplatin; epirubicin; liver; neoplasms
7.  Transcatheter Arterial Chemotherapy with Miriplatin for Hepatocellular Carcinoma Patients with Chronic Renal Failure: Report of Three Cases 
Gut and Liver  2013;7(2):246-251.
Miriplatin is a novel lipophilic platinum complex that was developed to treat hepatocellular carcinoma (HCC). Although HCC patients frequently have coexisting chronic renal failure, little prospective data are available regarding the clinical toxicity of chemotherapeutic agents used to treat HCC patients with chronic renal failure. In a phase II study, the plasma concentration of total platinum in patients who received miriplatin was very low, and no severe renal toxicity caused by miriplatin injection was reported. Here, we present three cases of HCC with stage 4 chronic renal failure who received transcatheter arterial chemotherapy with miriplatin. All cases were male, ages 72, 84, and 83 years, and had serum creatinine levels of 2.3, 1.6, and 1.9 mg/dL, respectively. Their estimated glomerular filtration rates were 21.9, 20.3, and 22.2 mL/min, respectively. All cases were treated for unresectable HCC with transcatheter arterial chemotherapy with miriplatin. No serious adverse events were observed, and serum creatinine levels did not elevate, even in the patient who experienced renal failure caused by cisplatin administration. These results might suggest that transcatheter arterial chemotherapy with miriplatin can be safely used in HCC patients with chronic renal failure.
doi:10.5009/gnl.2013.7.2.246
PMCID: PMC3607781  PMID: 23560163
Miriplatin; Chronic renal failure; Hepatocellular carcinoma
8.  Active treatments are a rational approach for hepatocellular carcinoma in elderly patients 
AIM: To determine whether an active intervention is beneficial for the survival of elderly patients with hepatocellular carcinoma (HCC).
METHODS: The survival of 740 patients who received various treatments for HCC between 1983 and 2011 was compared among different age groups using Cox regression analysis. Therapeutic options were principally selected according to the clinical practice guidelines for HCC from the Japanese Society of Hepatology. The treatment most likely to achieve regional control capability was chosen, as far as possible, in the following order: resection, radiofrequency ablation, percutaneous ethanol injection, transcatheter arterial chemoembolization, transarterial oily chemoembolization, hepatic arterial infusion chemotherapy, systemic chemotherapy including molecular targeting, or best supportive care. Each treatment was used alone, or in combination, with a clinical goal of striking the best balance between functional hepatic reserve and the volume of the targeted area, irrespective of their age. The percent survival to life expectancy was calculated based on a Japanese national population survey.
RESULTS: The median ages of the subjects during each 5-year period from 1986 were 61, 64, 67, 68 and 71 years and increased significantly with time (P < 0.0001). The Child-Pugh score was comparable among younger (59 years of age or younger), middle-aged (60-79 years of age), and older (80 years of age or older) groups (P = 0.34), whereas the tumor-node-metastasis stage tended to be more advanced in the younger group (P = 0.060). Advanced disease was significantly more frequent in the younger group compared with the middle-aged group (P = 0.010), whereas there was no difference between the middle-aged and elderly groups (P = 0.75). The median survival times were 2593, 2011, 1643, 1278 and 1195 d for 49 years of age or younger, 50-59 years of age, 60-69 years of age, 70-79 years of age, or 80 years of age or older age groups, respectively, whereas the median percent survival to life expectancy were 13.9%, 21.9%, 24.7%, 25.7% and 37.6% for each group, respectively. The impact of age on actual survival time was significant (P = 0.020) with a hazard ratio of 1.021, suggesting that a 10-year-older patient has a 1.23-fold higher risk for death, and the overall survival was the worst in the oldest group. On the other hand, when the survival benefit was evaluated on the basis of percent survival to life expectancy, age was again found to be a significant explanatory factor (P = 0.022); however, the oldest group showed the best survival among the five different age groups. The youngest group revealed the worst outcomes in this analysis, and the hazard ratio of the oldest against the youngest was 0.35 for death. The survival trends did not differ substantially between the survival time and percent survival to life expectancy, when survival was compared overall or among various therapeutic interventions.
CONCLUSION: These results suggest that a therapeutic approach for HCC should not be restricted due to patient age.
doi:10.3748/wjg.v19.i24.3831
PMCID: PMC3699049  PMID: 23840122
Hepatocellular carcinoma; Population aging; Survival; Life expectancy; Active intervention
9.  Transarterial injection of H101 in combination with chemoembolization overcomes recurrent hepatocellular carcinoma 
Transcatheter arterial chemoembolization (TACE) has become the standard treatment modality for unresectable hepatocellular carcinoma (HCC). Nonetheless, the clinical outcomes in patients with unresectable HCC are often unsatisfactory, especially in those with recurrent HCC. H101, an E1B gene deleted adenovirus, is known to have a significant antitumor activity. In addition, local injection of H101 can enhance the effect of antitumor therapies (chemotherapy and radiotherapy). Transarterial H101 gene injection in combination with TACE may help to control refractory and recurrent HCC. In this study, we report a 55-year-old patient with recurrent HCC which was treated with transarterial injection of H101 in combination with TACE, leading to a good clinical prognosis of the patient.
doi:10.3748/wjg.v17.i18.2353
PMCID: PMC3098405  PMID: 21633603
Hepatocellular carcinoma; H101; Transcatheter arterial chemoembolization; Therapy
10.  Unresectable hepatocellular carcinoma treated with transarterial chemoembolization: clinical data from a single teaching hospital 
The aim of this study is to evaluate the survival rates of patients with unresectable hepatocellular carcinoma (HCC) following transarterial chemoembolization (TACE) performed in a single teaching hospital. This study retrospectively assessed the electronic medical records of 217 patients in whom HCC was newly diagnosed from January 2009 to February 2013 at a single medical center. Hepatic artery infusion chemotherapy was performed using one drug or combinations of oxaliplatin, fluorouracil and doxorubicin. The primary endpoint of the study was overall survival (OS). Survival rates were calculated using Kaplan-Meier method. A total of 217 HCC patients (173 men and 44 women; mean age, 56.3 years; age range, 36.1-84.3 years) were treated with TACE in a single center. The overall survival rates at 1 and 2 years were 64% and 40%, respectively. The overall median survival time from the start of TACE treatment was 13 months. Our results indicated that TACE is an effective minimally invasive therapy option for palliative treatment of HCC patients.
PMCID: PMC3664004  PMID: 23724156
Chemoembolization; embolization; hepatocellular carcinoma; transarterial chemoembolization
11.  The combination of sorafenib with transarterial chemoembolisation for hepatocellular carcinoma 
Alimentary pharmacology & therapeutics  2011;34(2):10.1111/j.1365-2036.2011.04697.x.
SUMMARY
Background
Standard of practice involves using transarterial therapy for multifocal hepatocellular carcinoma (HCC) alone and sorafenib only for more advanced HCC, but the sorafenib and transarterial therapy combination may provide greater efficacy.
Aim
To evaluate the safety and efficacy of concurrent sorafenib and transarterial therapy in HCC.
Methods
Consecutive cases of HCC were treated with sorafenib and transarterial therapy, receiving sorafenib 2 to 4 weeks before transarterial therapy. Baseline clinical parameters, adverse events (AEs) and survival were collected.
Results
A total of 47 patients received sorafenib and transarterial therapy. The majority of the patients were male (70%) with HCV (60%), median age of 60 years, good performance status (0–1), stable cirrhosis (Child: A 72%; B 28%), unresectable turnour (stage: B 81%; C 19%) and median AFP of 24 ng/mL. Median follow-up was 12 months and median time on sorafenib was 6 months. LC Bead TACE was used with a median frequency of 3. The majority of the patients (89%) experienced AEs. The most common AEs were fatigue (51%), hand-foot skin reaction (51%) and diarrhoea (43%). Grade 3 and 4 AEs included fatigue (13%) and hand-foot skin reaction (26%). Most patients required a dose reduction (66%). The main AE related to transarterial therapy was post-TACE syndrome (23%). The disease control rate was 68% at 6 months. Overall median survival rate was 18.5 months (95% CI 16.1–20.9 months).
Conclusion
Concurrent sorafenib and transarterial therapy is overall safe with no unexpected side effects and encouraging efficacy that warrants further study.
doi:10.1111/j.1365-2036.2011.04697.x
PMCID: PMC3807574  PMID: 21605146
12.  A comparative study of high-dose hepatic arterial infusion chemotherapy and transarterial chemoembolization using doxorubicin for intractable, advanced hepatocellular carcinoma 
The Korean Journal of Hepatology  2010;16(4):355-361.
Background/Aims
Transarterial chemoembolization (TACE) has long been used as a palliative therapy for unresectable hepatocellular carcinoma (HCC). High-dose hepatic arterial infusion chemotherapy (HAIC) has showed favorable outcomes in patients with intractable, advanced HCC. The aim of this study was to compare the effectiveness and safety of high-dose HAIC and conventional TACE using doxorubicin for advanced HCC.
Methods
The high-dose HAIC group comprised 36 patients who were enrolled prospectively from six institutions. The enrollment criteria were good liver function, main portal vein invasion (including vascular shunt), infiltrative type, bilobar involvement, and/or refractory to prior conventional treatment (TACE, radiofrequency ablation, or percutaneous ethanol injection), and documented progressive disease. Patients received 5-fluorouracil (500 mg/m2 on days 1~3) and cisplatin (60 mg/m2 on day 2 every 4 weeks) via an implantable port system. In the TACE group, 31 patients with characteristics similar to those in the high-dose HAIC group were recruited retrospectively from a single center. Patients underwent a transarterial infusion of doxorubicin every 4~8 weeks.
Results
Overall, 6 patients (8.9%) achieved a partial response and 20 patients (29.8%) had stable disease. The objective response rate (complete response+partial response) was significantly better in the high-dose HAIC group than in the TACE group (16.7% vs. 0%, P=0.030). Overall survival was longer in the high-dose HAIC group than in the TACE group (median survival, 193 vs. 119 days; P=0.026). There were no serious adverse effects in the high-dose HAIC group, while hepatic complications occurred more often in the TACE group.
Conclusions
High-dose HAIC appears to improve the tumor response and survival outcome compared to conventional TACE using doxorubicin in patients with intractable, advanced HCC.
doi:10.3350/kjhep.2010.16.4.355
PMCID: PMC3304604  PMID: 21415578
Carcinoma; Hepatocellular; Hepatic arterial infusion chemotherapy; Transarterial chemoembolization; Doxorubicin
13.  The Current Practice of Transarterial Chemoembolization for the Treatment of Hepatocellular Carcinoma 
Korean Journal of Radiology  2009;10(5):425-434.
Despite remarkable advancement in the surveillance and treatment of hepatocellular carcinoma (HCC) and the availability of novel curative options, a great proportion of HCC patients are still not eligible for curative treatment due to an advanced tumor stage or poor hepatic functional reserve. Therefore, there is a continuing need for effective palliative treatments. Although practiced widely, it has only recently been demonstrated that the use of transarterial chemoembolization (TACE) provides a survival benefit based on randomized controlled studies. Hence, TACE has become standard treatment in selected patients. TACE combines the effect of targeted chemotherapy with the effect of ischemic necrosis induced by arterial embolization. Most of the TACE procedures have been based on iodized oil utilizing the microembolic and drug-carrying characteristic of iodized oil. Recently, there have been efforts to improve the delivery of chemotherapeutic agents to a tumor. In this review, the basic principles, technical issues and complications of TACE are reviewed and recent advancement in TACE technique and clinical applicability are briefed.
doi:10.3348/kjr.2009.10.5.425
PMCID: PMC2731859  PMID: 19721826
Carcinoma, hepatocellular; Chemoembolization, therapeutic; Iodized oil; Doxorubicin; Gelatin sponge, absorbable
14.  Stereotactic body radiation therapy with or without transarterial chemoembolization for patients with primary hepatocellular carcinoma: preliminary analysis 
BMC Cancer  2008;8:351.
Background
The objectives of this retrospective study was to evaluate the efficacy of stereotactic body radiation therapy (SBRT) for small non-resectable hepatocellular carcinoma (HCC) and SBRT combined with transarterial chemoembolization (TACE) for advanced HCC with portal vein tumor thrombosis (PVTT).
Methods
Thirty one patients with HCC who were treated with SBRT were used for the study. We studied 32 HCC lesions, where 23 lesions (22 patients) were treated targeting small non-resectable primary HCC, and 9 lesions (9 patients) targeting PVTT using the Cyberknife. All the 9 patients targeting PVTT received TACE for the advanced HCC. Tumor volume was 3.6–57.3 cc (median, 25.2 cc) and SBRT dose was 30–39 Gy (median, 36 Gy) in 3 fractions for consecutive days for 70–85% of the planned target volume.
Results
The median follow up was 10.5 months. The overall response rate was 71.9% [small HCC: 82.6% (19/23), advanced HCC with PVTT: 44.4% (4/9)], with the complete and partial response rates of 31.3% [small HCC: 26.1% (6/23), advanced HCC with PVTT: 11.1% (1/9)], and 50.0% [small HCC: 56.5% (13/23), advanced HCC with PVTT: 33.3% (3/9)], respectively. The median survival period of small HCC and advanced HCC with PVTT patients was 12 months and 8 months, respectively. No patient experienced Grade 4 toxicity.
Conclusion
SBRT for small HCC and SBRT combined with TACE for advanced HCC with PVTT showed feasible treatment modalities with minimal side effects in selected patients with primary HCC.
doi:10.1186/1471-2407-8-351
PMCID: PMC2615783  PMID: 19038025
15.  A safe and effective dose of cisplatin in hepatic arterial infusion chemotherapy for hepatocellular carcinoma 
Cancer Medicine  2013;2(1):86-98.
Cisplatin (CDDP) is an anticancer agent that is commonly used in hepatic arterial infusion (HAI) chemotherapy for hepatocellular carcinoma (HCC). This study aimed to clarify the safe and effective dose of CDDP in HAI for HCC. The hypervascular area was measured in 42 HCCs before and after HAI with CDDP. Serum platinum concentration was quantified in the peripheral and/or middle hepatic veins by atomic absorption spectrometry. The relation between the HCC response and CDDP dose was statistically analyzed. The multiple HCC nodules in an individual case generally demonstrated the same response to CDDP. The free-platinum concentration stayed relatively constant in the hepatic vein during HAI followed by a rapid decline, while total-platinum gradually increased then slowly disappeared over several days. After CDDP-HAI, 15 HCCs shrunk and 27 HCCs grew. The reduction rate in the shrunken nodules was tended to be correlated with CDDP dose after standardization with the target liver volume. On the other hand, the growth rate of the enlarged HCCs was significantly correlated with CDDP dose after normalization with creatinine clearance. These data support a recommendation of CDDP-HAI infusion where the amount of CDDP (mg) administered is less than patient creatinine clearance (mL/min/1.73 m2) upon an assumption of HCC doubling time of 90 days, and the targeted liver is smaller than 200 times the CDDP dose (mg). A further analysis is required to define appropriate injection speeds.
doi:10.1002/cam4.55
PMCID: PMC3797567  PMID: 24133631
Cisplatin; dose recommendation; hepatic arterial infusion chemotherapy; hepatocellular carcinoma
16.  Prospective, randomized, double-blind, multi-center, Phase III clinical study on transarterial chemoembolization (TACE) combined with Sorafenib® versus TACE plus placebo in patients with hepatocellular cancer before liver transplantation – HeiLivCa [ISRCTN24081794] 
BMC Cancer  2008;8:349.
Background
Disease progression of hepatocellular cancer (HCC) in patients eligible for liver transplantation (LTx) occurs in up to 50% of patients, resulting in withdrawal from the LTx waiting list. Transarterial chemoembolization (TACE) is used as bridging therapy with highly variable response rates. The oral multikinase inhibitor sorafenib significantly increases overall survival and time-to-progression in patients with advanced hepatocellular cancer.
Design
The HeiLivCa study is a double-blinded, controlled, prospective, randomized multi-centre phase III trial. Patients in study arm A will be treated with transarterial chemoembolization plus sorafenib 400 mg bid. Patients in study arm B will be treated with transarterial chemoembolization plus placebo. A total of 208 patients with histologically confirmed hepatocellular carcinoma or HCC diagnosed according to EASL criteria will be enrolled. An interim patients' analysis will be performed after 60 events. Evaluation of time-to-progression as primary endpoint (TTP) will be performed at 120 events. Secondary endpoints are number of patients reaching LTx, disease control rates, OS, progression free survival, quality of live, toxicity and safety.
Discussion
As TACE is the most widely used primary treatment of HCC before LTx and sorafenib is the only proven effective systemic treatment for advanced HCC there is a strong rational to combine both treatment modalities. This study is designed to reveal potential superiority of the combined TACE plus sorafenib treatment over TACE alone and explore a new neo-adjuvant treatment concept in HCC before LTx.
doi:10.1186/1471-2407-8-349
PMCID: PMC2630329  PMID: 19036146
17.  Metastasis of Hepatocellular Carcinoma to the Ovary: A Case Report and Review of the Literature 
Gut and Liver  2011;5(4):543-547.
Metastasis of hepatocellular carcinoma (HCC) to the ovary is notably rare. We present a case of HCC metastasis to the ovary with a review of the literature, which includes only 7 reported cases. A 43-year-old hepatitis B virus carrier was admitted with a right ovarian cystic mass. She had been diagnosed with HCC 2 years prior, for which she underwent transarterial chemoembolization followed by right posterior sectionectomy. Eight months after the hepatectomy, the first intrahepatic recurrence was detected and treated with transarterial chemoembolization. An additional intrahepatic recurrence occurred 12 months after transarterial chemoembolization and was managed with left medial sectionectomy and intra-operative radiofrequency ablation. Over the following 3 months, the patient developed elevated alpha-fetoprotein, and positron emission tomography showed a cystic mass in the right side of the pelvic cavity with focal hypermetabolic activity, which suggested a site of recurrent HCC. An exploratory laparotomy was performed, and a soft, ovoid cystic mass was identified in the right ovary. There was no evidence of metastases in the liver, left ovary, or peritoneum. Because of the absence of tumor on the surface of the ovary and the lack of peritoneal seeding, the mode of metastasis was thought to be hematogenous. Therefore, a right salphingo-oophorectomy was performed. The pathological features showed metastatic HCC with clear resection margins. Although metastasis of HCC to the ovary is very rare, it should be suspected in a female patient with a lower abdominal mass and an elevated serum AFP level in the absence of other demonstrable metastases.
doi:10.5009/gnl.2011.5.4.543
PMCID: PMC3240803  PMID: 22195258
Hepatocellular carcinoma; Metastasis; Ovary
18.  Comparative effectiveness of traditional chemoembolization with or without sorafenib for hepatocellular carcinoma 
World Journal of Hepatology  2013;5(7):364-371.
AIM: To compare the overall survival (OS) and progression-free survival (PFS) with associated adverse events (AE) in patients with unresectable hepatocellular carcinoma (HCC) treated with transarterial chemoembolization (TACE) + sorafenib vs TACE alone.
METHODS: In this retrospective cohort study we collected data on all consecutive patients with a diagnosis of unresectable HCC between 2007 and 2011 who had been treated with TACE + sorafenib or TACE alone. We hypothesized that the combination therapy is superior to TACE alone in improving the survival in these patients. Data extracted included patient’s demographics, etiology of liver disease, histology of HCC, stage of liver disease with respect to model of end stage liver disease score and Child-Turcotte-Pugh (CTP) classification and Barcelona Clinic Liver Cancer (BCLC) staging for HCC. Computed tomography scan findings, alpha fetoprotein levels, number of treatments and related AE were also recorded and analyzed.
RESULTS: Of the 43 patients who met inclusion criteria, 13 were treated with TACE + sorafenib and 30 with TACE alone. There was no significant difference in median survival: 20.6 mo (95%CI: 13.4-38.4) for the TACE + sorafenib and 18.3 mo (95%CI: 11.8-32.9) for the TACE alone (P = 0.72). There were also no statistically significant differences between groups in OS (HR = 0.82, 95%CI: 0.38-1.77; P = 0.61), PFS (HR = 0.93, 95%CI: 0.45-1.89; P = 0.83), and treatment-related toxicities (P = 0.554). CTP classification and BCLC staging for HCC were statistically significant (P = 0.001, P = 0.04 respectively) in predicting the survival in patients with HCC. The common AE observed were abdominal pain, nausea, vomiting and mild elevation of liver enzymes.
CONCLUSION: Combination therapy with TACE + sorafenib is safe and equally effective as TACE alone in patients with unresectable HCC. CTP classification and BCLC staging were the significant predictors of survival. Future trials with large number of patients are needed to further validate this observation.
doi:10.4254/wjh.v5.i7.364
PMCID: PMC3724964  PMID: 23898369
Hepatocellular carcinoma; Transarterial chemoembolization; Sorafenib; Survival; Adverse events
19.  Selective doxorubicin drug eluting beads chemoembolization of hypovascular hepatocellular carcinoma using cone beam computed tomography 
Hepatocellular carcinoma (HCC) of the liver is the third most common cause of cancer-related deaths in the world. Only one-third of patients with HCC are suitable candidates for hepatic resection. Transarterial chemoembolization (TACE) is performed in unresectable HCC. Drug-eluting beads (DEB) TACE is a modification of TACE, in which doxorubicin beads are used as embolizing material. These beads deliver the drug and embolize the vessels; however, it carries the risk of non-target embolization and it is difficult in cases with absent arterial blush on digital subtraction angiography (DSA). This is resolved using C-arm cone-beam computed tomography in the DSA suite. It identifies the tumor-feeding vessels, their area of supply, and differentiates between tumor and normal liver parenchyma. In addition, it is very useful in the embolization of hypovascular HCC. It helps and guides the radiologist in performing TACE effectively and also prevents non-target embolization of normal liver parenchyma.
doi:10.4103/0971-3026.111472
PMCID: PMC3698885  PMID: 23833414
Cone-beam computed tomography; hepatocellular carcinoma; transarterial chemoembolization
20.  Transarterial Chemoembolization Plus Sorafenib: A Sequential Therapeutic Scheme for HCV-Related Intermediate-Stage Hepatocellular Carcinoma: A Randomized Clinical Trial 
The Oncologist  2012;17(3):359-366.
The effectiveness of transarterial chemoembolization combined with sorafenib as a sequential treatment regimen in delaying time to progression of intermediate-stage hepatocellular carcinoma in patients with chronic hepatitis C virus infection was evaluated in a prospective, single-center, placebo-controlled, randomized, double-blind clinical study.
Background.
Recurrence of hepatocellular carcinoma (HCC) is a major problem after surgical or ablative treatments. The aim of this prospective, single-center, placebo-controlled, randomized, double-blind clinical study was to evaluate the effectiveness of transarterial chemoembolization (TACE) combined with sorafenib as a sequential treatment regimen in delaying time to progression (TTP) of intermediate-stage HCC in patients with chronic hepatitis C virus (HCV) infection.
Material and Methods.
Between October, 2007 and January, 2011, 80 HCV-infected patients with Barcelona Clinic Liver Cancer stage B HCC underwent the TACE procedure. All had Child-Pugh class A disease. They were randomized 1:1 to receive sorafenib at a dose of 400 mg twice daily or placebo. Endpoints were the TTP and the rates of adverse events and toxicity.
Results.
Sixty-two of 80 patients (77%), 31 in the sorafenib group and 31 in the control group, completed the study. The median TTP was 9.2 months in the sorafenib group and 4.9 months in the placebo group (hazard ratio, 2.5; 95% confidence interval, 1.66–7.56; p < .001). Metachronous, multicentric HCC progression occurred less frequently in sorafenib-treated patients (p < .05). Adverse reactions to sorafenib caused withdrawal from the study of 9 (22%) patients.
Conclusion.
A conventional TACE procedure followed by sorafenib treatment resulted in a significantly longer TTP in patients with intermediate-stage HCV-related HCC, with no unexpected side effects.
doi:10.1634/theoncologist.2011-0313
PMCID: PMC3316921  PMID: 22334456
Hepatitis C virus; Hepatocellular carcinoma; Liver cirrhosis; Sorafenib; Time to progression
21.  Portal vein thrombosis and arterioportal shunts: Effects on tumor response after chemoembolization of hepatocellular carcinoma 
AIM: To evaluate the effect of portal vein thrombosis and arterioportal shunts on local tumor response in advanced cases of unresectable hepatocellular carcinoma treated by transarterial chemoembolization.
METHODS: A retrospective study included 39 patients (mean age: 66.4 years, range: 45-79 years, SD: 7) with unresectable hepatocellular carcinoma (HCC) who were treated with repetitive transarterial chemoembolization (TACE) in the period between March 2006 and October 2009. The effect of portal vein thrombosis (PVT) (in 19 out of 39 patients), the presence of arterioportal shunt (APS) (in 7 out of 39), the underlying liver pathology, Child-Pugh score, initial tumor volume, number of tumors and tumor margin definition on imaging were correlated with the local tumor response after TACE. The initial and end therapy local tumor responses were evaluated according to the response evaluation criteria in solid tumors (RECIST) and magnetic resonance imaging volumetric measurements.
RESULTS: The treatment protocols were well tolerated by all patients with no major complications. Local tumor response for all patients according to RECIST criteria were partial response in one patient (2.6%), stable disease in 34 patients (87.1%), and progressive disease in 4 patients (10.2%). The MR volumetric measurements showed that the PVT, APS, underlying liver pathology and tumor margin definition were statistically significant prognostic factors for the local tumor response (P = 0.018, P = 0.008, P = 0.034 and P = 0.001, respectively). The overall 6-, 12- and 18-mo survival rates from the initial TACE were 79.5%, 37.5% and 21%, respectively.
CONCLUSION: TACE may be exploited safely for palliative tumor control in patients with advanced unresectable HCC; however, tumor response is significantly affected by the presence or absence of PVT and APS.
doi:10.3748/wjg.v17.i10.1267
PMCID: PMC3068261  PMID: 21455325
Hepatocellular carcinoma; Transarterial chemoembolization; Portal; Shunt; Thrombosis
22.  Endovascular treatment of hepatocellular carcinoma with drug eluting microparticles (DC-Beads): CT evaluation of response to the treatment 
Background and Study Aims:
Our aim was to assess the efficacy and tolerability of drug-eluting beads-transarterial chemoembolization (DEB-TACE) in the treatment of hepatocellular carcinoma (HCC), evaluating the response to the treatment after 1, 6, 12, and 24 months with multidetector computed tomography (MDCT) comparing European Association for the study of the Liver (EASL) and modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria.
Materials and Methods:
We enrolled 154 patients with uni- or multifocal HCC who underwent a DEB-TACE. A total of 278 HCC nodules were treated. CT follow-up was performed at 1, 6, 12, and 24 months after the procedure according to the EASL and RECIST criteria evaluating overall target and target nodule response. We also analyzed the shrinking of nodules in relation to response to treatment.
Results:
A total of 278 nodules of HCC underwent TACE by using DC-Beads: At 24, months complete response was similar for EASL and RECIST criteria (112 vs. 121 nodules) with optimal accordance between methods and readers with k = 0.9. Partial Response resulted significantly different among the two methods within the first month, otherwise was similar after 24-month follow-up. Similar results in both methods were found for nodules classified as Stable Disease (P > 0.05). Progressive Disease results were similar in both the groups according to both the classification criteria without any significant difference (P > 0.05).
Conclusion:
Our study confirmed that EASL and mRECIST criteria are both effective methods for patient follow-up, however with some technical differences.
doi:10.4103/0971-3026.116564
PMCID: PMC3777321  PMID: 24082476
Chemoembolization; computed tomography; hepatocellular carcinoma
23.  Chemoembolization of Hepatocellular Carcinoma with Drug-Eluting Beads Complicated by Interstitial Pneumonitis 
Transarterial chemoembolization has proven benefit in the treatment of unresectable hepatocellular carcinoma (HCC). Commonly reported symptoms following chemoembolization with or without drug-eluting beads include abdominal pain, nausea, and low-grade fever, which typically limited resolve within a few days. A recent study comparing traditional chemoembolization versus chemoembolization with drug-eluting beads demonstrated similar survival between the two techniques, but improved tolerability when the drug-eluting beads were used. This case report describes a patient with unresectable HCC undergoing chemoembolization with drug-eluting beads. The postprocedure course was complicated by interstitial pneumonitis secondary to shunting of the drug-eluting beads containing doxorubicin to both lungs via tumor vasculature. This case highlights the relationship between the number and size of the tumors to be treated, arteriovenous shunting within the liver/tumors, and the size of the embolization particles.
doi:10.1055/s-0031-1280668
PMCID: PMC3193323  PMID: 22654266
Hepatocellular cancer; transarterial chemoembolization
24.  Response of peritoneal solid tumours after intraperitoneal chemohyperthermia treatment with cisplatin or carboplatin. 
British Journal of Cancer  1994;69(2):235-241.
The combination of heat and chemotherapy was studied in an intraperitoneal tumour model. Rats bearing peritoneal CC531 tumours (2-6 mm) were treated i.p. with cDDP or CBDCA [maximal tolerated dose (MTD)] in combination with regional hyperthermia (41.5 degrees C, 1 h) of the peritoneal cavity. The addition of hyperthermia to the i.p. treatment led to a decrease in the MTD of cDDP by 33.3% at 41.5 degrees C. This was due to increased nephrotoxicity. The MTD of CBDCA did not change as a result of hyperthermia treatment. The chemo-hyperthermia treatment resulted in more cDDP or CBDCA DNA adducts in peritoneal tumours after the combined treatment than after chemotherapy alone. The increased tumour platinum concentrations, rising from 1.3 micrograms Pt g-1 tumour at 37 degrees C to 5.4 micrograms Pt g-1 tumour at 41.5 degrees C for cDDP and from 0.2 microgram Pt g-1 tumor to 0.7 microgram Pt g-1 tumour at 41.5 degrees C for CBDCA, contributed considerably to the enhanced numbers of cDDP or CBDCA DNA adducts. As a result of the latter, i.p. chemotherapy combined with regional hyperthermia led to an increase in tumour growth delay (TGD) after increasing the temperature to 41.5 degrees C for cDDP and CBDCA (by 40 days for cDDP, 22 days for CBDCA). These data were in agreement with the in vitro findings, i.e. that higher temperatures led to increased cytotoxicity.
PMCID: PMC1968708  PMID: 8297720
25.  Polyvinyl Alcohol Embolization Adjuvant to Oily Chemoembolization in Advanced Hepatocellular Carcinoma with Arterioportal Shunts 
Korean Journal of Radiology  2007;8(4):311-319.
Objective
To assess the feasibility and safety of polyvinyl alcohol (PVA) embolization adjuvant to transarterial oily chemoembolization (P-TACE) in advanced hepatocellular carcinoma (HCC) with arterioportal shunts (APS).
Materials and Methods
Nineteen patients who underwent PVA embolization for APS before a routine chemoembolization (TACE) procedure were retrospectively reviewed. 10 of these 19 patients underwent follow-up TACE or P-TACE after P-TACE (Group A), but nine patients underwent only initial P-TACE because of progression of HCC and/or underlying liver cirrhosis (Group B). Hepatic function tests, APS grades, and portal flow directions were evaluated before and after P-TACE sessions. Complications after procedures and survival days were also evaluated.
Results
In group A, APS grade was improved in eight patients and five of six patients with hepatofugal flow showed restored hepatopetal flow postoperatively. No immediate complication was developed in either group. Transient hepatic insufficiency developed in eight (42.1%) of 19 patients after P-TACE, and seven (87.5%) of these eight recovered within two weeks under conservative care. The mean and median survival time all study subjects was 280 days and 162 days.
Conclusion
P-TACE is feasible and safe in advanced HCC patients with APS.
doi:10.3348/kjr.2007.8.4.311
PMCID: PMC2627160  PMID: 17673842
Shunts, arterioportal; Hepatic arteries, chemotherapeutic embolization; Liver neoplasms, chemotherapeutic embolization

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