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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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Curative therapies for hepatocellular carcinoma (HCC), such as resection and liver transplantation, can only be applied in selected patients with early tumors. More advanced stages require local or systemic therapies. Resection of HCC offers the only hope for cure. Even in patients undergoing resection, recurrences are common. Chemoembolization, a technique combining intra-arterial chemotherapy with selective tumor ischemia, has been shown by randomized controlled trials to be efficacious in the palliative setting. There is now renewed interest in transarterial embolization/transarterial chemoembolization (TACE) with regards to its use as a palliative tool in a combined modality approach, as a neoadjuvant therapy, in bridging therapy before transplantation, for symptomatic indications, and even as an alternative to resection. There have also been rapid advances in the agents being embolized trans-arterially (genes, biological response modifiers, etc.). The current review provides an evidence-based overview of the past, present and future trends of TACE in patients with HCC.

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.

Background/Aims

Transarterial chemoembolization (TACE) improves the survival of patients with unresectable hepatocellular carcinoma (HCC) and has been recommended as a first-line therapy for nonsurgical patients with large or multifocal HCC. The long-term outcome of HCC patients receiving TACE prior to hepatic resection is uncertain.

Methods

Between January 1997 and December 2007, 1,530 patients underwent hepatic resection for HCC at our center. Thirty-two patients received 1~12 sessions of TACE followed by surgical resection (TACE-surgery group). Their overall and recurrence-free survival rates were compared with those of 64 age- and sex-matched controls who underwent surgery only (surgery group). Overall and recurrence-free survival rates were analyzed.

Results

The 1-, 2-, and 5-year overall survival rates did not differ significantly between the TACE-surgery group and the surgery group (78%, 60%, and 26%, respectively, vs. 97%, 83%, and 45%, respectively; P=0.11); however, the 1-, 2-, and 5-year recurrence-free survival rates were significantly lower in the TACE-surgery group than in the surgery group (58%, 36%, and 7%, respectively, vs. 77%, 58%, and 32%, respectively; P=0.01). The distribution of recurrence sites in the TACE-surgery group were intrahepatic in 85.7% and extrahepatic in 14.3%, and did not differ from those in the surgery group (91.4% and 8.6%, respectively; P=0.66).

Conclusions

HCC patients who underwent TACE before resection appear to have overall survival rates that are comparable to those without preoperative therapy, although recurrence rates appear to be higher in patients with TACE.

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.

ABSTRACT

Transarterial therapies play an important role in the treatment of hepatocellular carcinoma, both in a palliative setting and as an adjunct to surgery. These therapies exploit the dual blood supply of the liver to selectively target tumors via the hepatic artery, while sparing nontumorous liver. Currently available therapies include transarterial embolization; chemoembolization, with or without drug-eluting beads; and radioembolization. Transarterial techniques are also being used in the development of novel therapies. This article provides an outline of the technical and clinical applications of intraarterial therapies in the treatment of HCC and highlights pertinent future directions.

Reactivation of hepatitis B virus (HBV) replication is a frequent phenomenon in patients receiving immunosuppressants or chemotherapy. It was recently reported that regional therapy, such as transarterial chemotherapy (TAC) or radiotherapy, can also induce HBV reactivation in patients with hepatocellular carcinoma (HCC), and this can be prevented by preemptive lamivudine treatment. We report an unusual case of fatal hepatitis caused by reactivation of the tyrosine-methionine-aspartate-aspartate (YMDD) lamivudine-resistant strain in a 51-year-old male patient with HCC who was receiving preemptive lamivudine therapy. This patient received combined helical tomotherapy and TAC for the treatment of HCC with pulmonary metastasis. HBV reactivation and hepatitis exacerbation occurred after 2 months of therapy, but preemptive antiviral therapy was continued. Laboratory tests showed that the serum HBV DNA level had increased by more than 10,000-fold and a severe elevation of the aminotransferase level to 1,060 U/L. Although adefovir was added to lamivudine immediately after detecting the YMDD mutants, the patient eventually died of hepatic failure. Our experience suggests that for preemptive therapy, the use of potent antiviral drugs with a low risk of drug resistance as well as close viral monitoring are important for chronic HBV carriers undergoing intensive anticancer therapy.

Most patients with hepatocellular carcinoma (HCC) are not eligible for curative treatment, which is resection or transplantation. Two recent series have emphasized the potential benefits of preoperative arterio-portal embolization prior to surgical resection of such tumours. This preoperative strategy offers a better disease free survival rate and a higher rate of total tumor necrosis. In case of non resectable HCC it is now widely accepted that transarterial chemoembolization (TACE) leads to a better survival when compared to conservative treatment. Thus, the question remains whether combined portal vein embolization (PVE) may enhance the proven efficiency of TACE in patients with unresectable HCC. We herein report the case of a 56-year-old cirrhotic woman with a voluminous HCC unsuitable for surgical resection. Yet, complete tumour necrosis and prolonged survival could be achieved after a combined porto-arterial embolization. This case emphasizes the potential synergistic effect of a combined arterio-portal embolization and the hypothetical survival benefit of such a procedure, in selected patients, with HCC not suitable for surgery or local ablative therapy.

AIM: To evaluate the effectiveness of hepatic arterial infusion chemotherapy (HAIC) for advanced hepatocellular carcinoma (HCC) resistant to transarterial chemoembolization (TACE).

METHODS: This study was conducted on 42 patients who received HAIC for advanced HCC between 2001 and 2010 at our hospital. 5-fluorouracil (5-FU) was administered continuously for 24 h from day 1 to day 5 every 2-4 wk via an injection reservoir. Intra-arterial cisplatin or subcutaneous interferon was administered in combination with the 5-FU. The patients enrolled in this retrospective study were divided into two groups according to whether or not they fulfilled the criteria for resistance to TACE proposed by the Japan Society of Hepatology in 2010 (written in Japanese); one group of patients who did not fulfill the criteria for TACE resistance (group A, n = 23), and another group who fulfilled the criteria for TACE resistance (group B, n = 19). We compared the outcomes in terms of the response and survival rates between the two groups.

RESULTS: Both the response rate and tumor suppression rate following HAIC were significantly superior in group A than in group B (response rate: 48% vs 16%, P = 0.028, tumor suppression rate: 87% vs 53%, P = 0.014). Furthermore, both the progression-free survival rate and survival time were significantly superior in group A than in group B (3-, 6-, 12-, and 24-mo = 83%, 70%, 29% and 20% vs 63%, 42%, 16% and 0%, respectively, P = 0.040, and 9.8 mo vs 6.2 mo, P = 0.040). A multivariate analysis (Cox proportional hazards regression model) showed that resistance to TACE was an independent predictor of poor survival (P = 0.007).

CONCLUSION: HAIC administrating 5-FU was not effective against advanced HCC resistant to TACE. Other tools for treatment, i.e., molecular-targeting agents may be considered for these cases.

Objective

To investigate the expression level of serum vascular endothelial growth factor (VEGF) in patients with unresectable hepatocellular carcinoma (HCC) and its relationship with the clinicopathological characteristics, and to assess the impact of serum VEGF as a predictive factor for HCC prognosis during transarterial chemoembolization (TACE) treatments.

Methods

Serum VEGF levels were measured using enzyme-linked immunosorbent assay (ELISA) in 60 random patients who underwent TACE or transarterial infusion (TAI) for unresectable HCC between May and September 2008 and 12 healthy volunteers were also involved in this study to serve as control. All patients’ clinicopathological features were retrospectively analyzed. Serum VEGF levels were correlated with clinicopathological features of the HCC patients. The patients’ survival rates were analyzed with Kaplan-Meier survival curves and compared by the log-rank test. The prognostic significance of serum VEGF levels and factors related to survival rate were evaluated by univariate and multivariate analysis.

Results

The median serum VEGF level in the HCC patients was 285 pg/ml (range 14-1,207 pg/ml), significantly higher than that of healthy controls (P=0.021). The serum VEGF levels were significantly correlated with platelet counts (r=0.396, P=0.002) but not other clinicopathological features. Patients with serum VEGF level >285 pg/ml had worse overall survival compared with those with serum VEGF level <285 pg/ml (P=0.002). By multivariate analysis, the serum VEGF level was a significant prognostic factor.

Conclusion

High serum VEGF levels may predict poor prognosis of HCC after TACE. This study highlights the importance of tumor biomarker as a prognostic predictor in TACE therapy for HCC, which has an intrinsic problem of unavailability of histopathological prognostic features.

AIM: To identify prognostic factors from pretreatment variables of the initial transarterial chemoembolization (TACE) procedure in unresectable hepatocellular carcinoma (HCC).

METHODS: One thousand and five hundred and sixty-nine patients with unresectable HCC underwent TACE as initial treatment were retrospectively studied. Pretreatment variables of the initial TACE procedure with a P value less than 0.05 by univariate analysis were subjected to Cox proportional hazards model.

RESULTS: The median overall survival time and 1-, 5-, 10-year survival rates were 10.37 mo, 47%, 10%, and 7%, respectively. A Cox proportional hazard model showed that 8 pretreatment factors of regional lymph nodes metastasis, Child-Pugh class, macrovascular invasion, greatest dimension, α-fetoprotein (AFP), Hepatitis virus B, tumor capsule, and nodules were independent prognostic factors. Patients with multimodality therapy have better survival than those with TACE treatment only.

CONCLUSION: Tumor status, hepatic function reserve, AFP, and hepatitis virus B status were independent prognostic factors for unresectable HCC. Distant metastasis might not be a contraindication to TACE. Multimodality therapy might improve survival.

Purpose

Patients with advanced hepatocellular carcinoma (HCC) have few treatment options. Thymalfasin (thymosin α-1) is an immunomodulator that may increase response to ablative therapy through direct anti-tumor action or enhanced protection against infections. We compared transarterial chemoembolization (TACE) plus thymalfasin with TACE alone for unresectable HCC.

Methods

In this phase II, randomized trial, 25 patients received either TACE plus thymalfasin (1.6 mg SC, 5 times weekly; n = 14) or TACE alone (n = 11) for 24 weeks. Response was defined as transition to transplant eligibility or lack of disease progression through week 72. Survival was assessed through 24 months post-treatment.

Results

Eight of fourteen (57.1%) patients in the TACE + thymalfasin group versus 5 of 11 (45.5%) patients in the TACE-only group became responders (P = 1.0). Four of fourteen TACE + thymalfasin patients versus none of 11 TACE-only patients became eligible for transplant. Median overall survival time was 110.3 weeks for the TACE + thymalfasin group versus 57.0 weeks for the TACE-only group (P = 0.45). Seven patients in each group experienced serious adverse events; there were no bacterial infections in the TACE + thymalfasin group versus 4 in the TACE-only group. There were 3 deaths in the TACE + thymalfasin group and 5 in the TACE-only group.

Conclusions

In patients with unresectable HCC, TACE + thymalfasin resulted in numerically higher rates of survival and tumor response, including transplant candidacy, with fewer bacterial infections, than TACE alone. Treatment regimens for HCC including thymalfasin as an immunomodulator should be evaluated in larger trials.