Treatment Of Inoperable Hepatocellular Carcinoma Research Articles

External Beam Radiation therapy After Transarterial Chemoembolization Versus Transarterial Chemoembolization Alone for Treatment of Inoperable Hepatocellular Carcinoma: A Randomized Phase 3 Trial

PurposeTo compare the outcomes of transarterial chemoembolization (TACE) alone with those of TACE combined with external-beam radiotherapy (EBRT) in patients with hepatocellular carcinoma (HCC) in a multicenter randomized study. Methods and MaterialsFrom 2017 to 2022, 74 HCC patients with tumors confined to the liver without vascular invasion were treated with either TACE only (TACE group, 39 patients) or TACE combined with EBRT (TACE+EBRT group, 35 patients). The primary outcome measured was overall survival (OS). Secondary outcomes included progression-free survival (PFS), local tumor control (LC), and the assessment of treatment-related toxicity. ResultsDue to slow accrual, the trial was closed prematurely after enrolling 74 patients. All patients received two cycles of TACE before randomization. The TACE and TACE+EBRT groups showed comparable patient and tumor characteristics. The TACE group underwent an median of 3 TACE cycles, and the TACE+EBRT group received two cycles of TACE and a median of 5,500 cGy in 15 fractions. For the TACE group, the median LC duration was 13.1 months, while for the TACE+EBRT group, the median LC was not achieved (P<0.001). The PFS was recorded at 11.6 months in the TACE group compared to 15.4 months in the TACE+EBRT group (P=0.072). The median OS reached 36.8 months for the TACE group and extended to 47.1 months for the TACE+EBRT group (P=0.654). The incidence of toxicity was comparable between both groups. ConclusionsAlthough the number of patients enrolled in this clinical trial did not meet expectations. TACE combined with EBRT was shown to be more effective than TACE alone in improving local control (LC) without increasing toxicity, while PFS and OS was slightly improved. TACE+EBRT can be used as a standard treatment option for patients with inoperable but confined intrahepatic HCC.

Radiation dose is associated with improved local control for large, but not small, hepatocellular carcinomas

BackgroundWith advances in understanding liver tolerance, conformal techniques, image guidance, and motion management, dose-escalated radiotherapy has become a potential treatment for inoperable hepatocellular carcinoma (HCC). We aimed to evaluate the possible impact of biologically effective dose (BED) on local control and toxicity among patients with HCC.Methods and materialsPatients treated at our institution from 2009 to 2018 were included in this retrospective analysis if they received definitive-intent radiotherapy with a nominal BED of at least 60 Gy. Patients were stratified into small and large tumors using a cutoff of 5 cm, based on our clinical practice. Toxicity was assessed using ALBI scores and rates of clinical liver function deterioration.ResultsOne hundred and twenty-eight patients were included, with a mean follow-up of 16 months. The majority of patients (90.5%) had a good performance status (ECOG 0–1), with Child-Pugh A (66.4%) and ALBI Grade 2 liver function at baseline (55.4%). Twenty (15.6%) patients had a local recurrence in the irradiated field during the follow-up period. Univariate and multivariate Cox proportional hazard analyses showed that only BED significantly predicted local tumor recurrence. Higher BED was associated with improved local control in tumors with equivalent diameters over 5 cm but not in smaller tumors. There was no difference in liver toxicity between the low and high-dose groups.ConclusionsHigher radiotherapy dose is associated with improved local control in large tumors but not in tumors smaller than 5 cm in diameter. High-dose radiotherapy was not associated with increased liver toxicity.

LncRNA AC026401.3 interacts with OCT1 to intensify sorafenib and lenvatinib resistance by activating E2F2 signaling in hepatocellular carcinoma

Multitargeted kinase inhibitors (MKIs) including sorafenib and lenvatinib, are applied for first-line treatment for inoperable hepatocellular carcinoma (HCC) patients, but the therapeutic effect is limited because of drug resistance. Therefore, we sought potential biomarkers to indicate sorafenib and lenvatinib resistance in HCC. In this article, we report a novel long non-coding RNA (lncRNA), AC026401.3, in promoting sorafenib and lenvatinib resistance of HCC cells. AC026401.3 is upregulated in HCC tissues and is positively relevant to HCC patients with large tumor size, cancer recurrence, advanced TNM stage, and poor prognosis. AC026401.3 knockdown or knockout enhances the sensitivity of HCC cells to sorafenib and lenvatinib, respectively. Moreover, AC026401.3 upregulates the expression of the transcription factor E2F2. Mechanistically, AC026401.3 interacts with OCT1 and promotes the recruitment of OCT1 to the promoter region of E2F2, intensifying sorafenib and lenvatinib resistance in HCC by activating the transcription of E2F2. In conclusion, our results reveal that lncRNA AC026401.3 is a risk factor for HCC patients by enhancing sorafenib and lenvatinib resistance of HCC cells, and targeting the AC026401.3-OCT1-E2F2 signaling axis would be a promising strategy for HCC therapeutics.

Efficacy of the immune checkpoint inhibitor nivolumab in the treatment of advanced hepatocellular carcinoma with the exhausted possibilities of therapy with tyrosine kinase inhibitors

Hepatocellular carcinoma is one of the most formidable and deadly cancers. The limited possibilities of surgical methods of treatment as well as the formation of multiple drug resistance caused by the biological characteristics of both the liver tissue itself and tumor cells with their microenvironment determine the unsatisfactory indicators of relapse free survival and overall survival of patients. In addition, therapy with tyrosine kinase inhibitors, which has become the “gold” standard, has limited possibilities: a large number of side effects significantly reduce the quality of life and adherence to treatment in patients with hepatocellular cancer. The search for molecular biological targets, as well as new therapeutic agents that block these targets, does not always lead to positive results. Immunotherapy in this sense is a priority, having good tolerance, a low number of side effects, no need for additional testing of the patient’s biological material before starting treatment, high efficiency and a long response time. However, there are many unresolved questions about the duration of therapy, predicting its efficacy, the optimal combination of drugs or the use of monotherapy, the formation of priority subgroups of patients. Understanding the mechanisms of immune evasion, an ability that hepatocellular carcinoma possesses, – is the key to successful use of immunotherapeutic agents alone, in combination with tyrosine kinase inhibitors, antiangiogenic drugs or among themselves. This article provides an overview of data from clinical studies of modern drugs for the treatment of hepatocellular carcinoma and describes the mechanism of liver immunological tolerance as a possible predictive marker of sensitivity to immunotherapy. It seems promising to study the role of cells in the microenvironment of hepatocellular carcinoma for predicting the effectiveness of immunotherapy. The clinical example is used to demonstrate the successful experience of using the immunotherapeutic drug nivolumab in the treatment of hepatocellular carcinoma resistance to tyrosine kinase inhibitors. This is a classic example of duration of response to therapy, lack of reactivation of chronic viral hepatitis and controlled toxicity. All these indicators enable the clinician to consider immunotherapy as a priority option for the treatment of inoperable hepatocellular carcinoma.

Transcatheter chemoembolization plus percutaneous radiofrequency ablation versus laparoscopic radiofrequency ablation: improved outcome for inoperable hepatocellular carcinoma

Aims To retrospectively compare the efficacy of transcatheter chemoembolization (TACE) plus percutaneous radiofrequency ablation (PRFA) (hereafter, TACE + PRFA) and laparoscopic radiofrequency ablation (LRFA) in the treatment of inoperable hepatocellular carcinoma (HCC). Methods From July 2014 to December 2017, 132 consecutive patients with inoperable HCC were treated with TACE + PRFA (n = 86) or LRFA (n = 46). Overall survival (OS) and recurrence-free survival (RFS) were analyzed using log-rank test and Cox regression analysis. Propensity score matched (PSM) analyses based on patient and tumor characteristics were also conducted. Additionally, we performed exploratory analyses to determine the effectiveness of TACE + PRFA and LRFA in clinically relevant subsets. Results The baseline characteristics of TACE + PRFA patients displayed relatively inferior liver status and a higher rate of BCLC-B disease. For unmatched patients, median OS (55.0 vs. 42.0 months; p = .019) and RFS (20.0 vs. 11.0 months; p < .001) were significantly longer in TACE + PRFA group than that in the LRFA group. After PSM, 39 matched pairs were identified. The difference in median OS (60.0 vs. 44.0 months; p = .009) and RFS (27.0 vs. 11.0 months; p < .001) between the two groups remained significant. Multivariate analysis in matched patients showed that treatment modality and response to initial treatment were significant predictors of OS and RFS, while recurrence after resection was an independent prognostic factor of OS. The benefits of TACE + PRFA were consistent across all the subgroups examined. The different treatments had shared a similar complication rate. Conclusions Compared to LRFA, TACE + PRFA results in improved OS and RFS in patients not amenable to resection.

Empirical 188Re-HDD/lipiodol intra-arterial therapy based on tumor volume, in patients with solitary inoperable hepatocellular carcinoma.

This study aimed to assess the potential benefits and tolerability of an empirical dose of approximately 0.8-1.2 mCi (29.6-44.4 MBq) of Re-4-hexadecyl-1-2,9,9-tetramethyl-4,7-diaza-1,10-decanethiol/lipiodol (Re-HDD/lipiodol) per milliliter of tumor volume, administered after super-selection of the tumor feeding branches of hepatic artery for treatment of inoperable hepatocellular carcinoma (HCC). Patients with advanced HCC or classified as inoperable, with no demonstrated extrahepatic disease and no significant comorbidities were eligible. The patients selected for this study had a single tumoral lesion, measuring less than 150 cc. The range of total activity administered was between 30 and 100 mCi (1.2-3.7) GBq Re-HDD/lipiodol, administered in the super selected branches of the hepatic artery supplying the tumor in 42 Patients. Whole-body scintigraphies and single-photon emission computed tomography-computed tomography (SPECT-CT) of the liver including tumor were performed at four-time points after injection. Absorbed doses to the various organs were calculated according to the Medical Internal Radiation Dose formalism. Blood and urine samples were collected at multiple time points until 72 h after injection. Hematological, hepatic and pulmonary toxicity was assessed until 12 weeks after administration using the Common Toxicity Criteria for Adverse Events (version 3.0) scale. Responses were evaluated on contrast enhanced computed tomography (CECT) and by alfa-fetoprotein (AFP) level monitoring. About 40.6 ± 4.8% of the injected activity was excreted in the urine by 72 h after injection. The mean absorbed dose to the liver, lungs, stomach, kidney and intestine was 14.4 ± 1.8, 4.8 ± 0.6, 5.5 ± 1.1, 5.1 ± 0.7, and 6.5 ± 1.0 Gy (mean ± SD), respectively. Up to 6 days after administration, 26 of 44 patients had adverse events consisting of aggravations of preexisting laboratory changes (24 patients), fatigue (5 patients), vomiting (6 patients), fever (2 patients), right hypochondrial pain (8 patients), and pain at site of femoral catheter insertion (8 patients). Toxicity assessment at weeks 6 and 12 revealed two cases of mild worsening of liver function tests and no lung or hematological toxicity noted. Two patients were lost to follow-up after the 6-week visit. The response was assessed on CECT in all the remaining patients and the classification of results was more standardized when using European Association for the Study of the Liver (EASL) criteria rather than response evaluation criteria in solid tumors (RECIST) criteria. According to EASL criteria, 8 patients had a partial response, 28 patients had a complete response, 4 patients had progressive disease and 4 patients with stable disease were reported. Thirty-six patients had a baseline elevated AFP and on follow-up at 6 weeks, 6 of these patients showed stable AFP, progression in 4 patients and 26 showed a reduction. After the administration of 1.2-3.7 GBq Re-HDD/lipiodol based on empirical activity calculation of 0.8-1.2 mCi/mL of tumor volume, more than half of the patients in the present study had an objective response on imaging and biochemically. No significant adverse side effects were noted and most of the laboratory markers as well as symptoms returned to normal after 48-72 h post-administration. Selective administration of the radiopharmaceutical into the tumor feeding arteries gives a good anti-tumoral effect with minimal side effects and damage to surrounding normal liver tissue.

Software development for hepatopulmonary shunt estimation by gamma camera method in transarterial radioembolization.

Trans-arterial radioembolization (TARE) is an established treatment for inoperable hepatocellular carcinoma and liver metastases from Carcinoma of gastrointestinal tract. Radiation-induced toxicity to the lung parenchyma is the dose-limiting factor in TARE. Pretreatment hepatopulmonary shunt (HPS) is estimated by gamma camera method by transarterial administration of 370MBq 99mTc macro aggregated albumin. We have developed HPS software on XELERIS-1.123 workstation, GE medical systems, Milwaukee, USA, for accurate calculation of HPS. This software has also been tested on a higher version of XELERIS workstation, and it has been found to work well in all versions.

Afatinib, an EGFR inhibitor, decreases EMT and tumorigenesis of Huh‑7 cells by regulating the ERK‑VEGF/MMP9 signaling pathway

Transcatheter arterial embolization (TAE) therapy has been used in the treatment of inoperable hepatocellular carcinoma (HCC). However, tumor recurrence and metastasis are common in patients after TAE, and these processes may be caused by circulating tumor cells (CTCs). Epithelial-mesenchymal transition (EMT) serves important roles in CTCs, and abnormal expression and activation of epidermal growth factor receptor (EGFR) is common in cancer cells. Afatinib is an EGFR-tyrosine kinase inhibitor (TKI). The present study aimed to investigate the effects of afatinib on EMT and tumorigenesis in HCC cells. Western blot analysis suggested that afatinib was able to effectively suppress overactivation of EGFR. Moreover, the expression levels of EMT- and metastasis-associated genes were found to be modulated by afatinib through EGFR inhibition. In addition, Cell Counting Kit-8 and Transwell assays suggested that the viability, migration and invasion of HCC cells were inhibited by afatinib through EGFR inhibition. Furthermore, the activity of the ERK signaling pathway and the expression levels of vascular endothelial growth factor (VEGF) and matrix metalloproteinase 9 (MMP9) were decreased following treatment with afatinib in vitro. Collectively, the present results suggested that the inhibitory effects of afatinib on EMT and tumorigenesis may be associated with the ERK-VEGF/MMP9 signaling pathway. The present study provides new insights into understanding the mechanism underlying HCC and may facilitate the development of novel therapeutic strategies to treat HCC recurrence.

Synthesis and assessment of drug-eluting microspheres for transcatheter arterial chemoembolization

Transcatheter arterial chemoembolization (TACE) is well known as an effective treatment for inoperable hepatocellular carcinoma (HCC). In this study, a novel embolic agent of ion-exchange poly(hydroxyethyl methacrylate-acrylic acid) microspheres (HAMs) was successfully synthesized by the inverse suspension polymerization method. Then, HAMs were assessed for their activity as an embolic agent by investigating morphology, particle size, water retention capability, elasticity and viscoelasticity, microcatheter/catheter deliverability, cytotoxicity, renal arterial embolization to rabbits and histopathological examinations. The ability of drug loading and drug eluting of HAMs was also investigated by using doxorubicin (Dox) as the model drug. HAMs showed to be feasible and effective for vascular embolization and to be as a drug vehicle for loading positively charged molecules and potential use in the clinical interventional chemoembolization therapy. Statement of significanceA novel embolic agent of ion-exchange poly(hydroxyethyl methacrylate-acrylic acid) microspheres (HAMs) was successfully synthesized by the inverse suspension polymerization method and was used as a drug vehicle to load positively charged molecules by ion absorption. Then, a series of assessments including physicochemical properties, mechanical properties, drug-loading capability, and embolic efficacy were performed. Surface and cross-section morphology and pore size of fully hydrated HAMs were first investigated by Phenom ProX SEM, which intuitively disclosed the “honeycomb” network morphology. HAMs also showed to be feasible and effective for vascular occlusion and have potential use in clinical interventional embolization therapy.

Stereotactic body radiation therapy as an ablative treatment for inoperable hepatocellular carcinoma

PurposeTo describe efficacy and safety of stereotactic body radiation therapy (SBRT) for the treatment of inoperable hepatocellular carcinoma. MethodsThe records of 77 consecutive patients treated with SBRT for 97 liver-confined HCC were reviewed. A total dose of 45Gy in 3 fractions was prescribed to the 80% isodose line. Local control (LC), overall survival (OS), progression-free survival (PFS) and toxicity were studied. ResultsThe median follow-up was 12months. The median tumor diameter was 2.4cm. The LC rate was 99% at 1 and 2years. The 1 and 2-year OS were 81.8% and 56.6% respectively. The median time to progression was 9months (0–38). The rate of hepatic toxicity was 7.7% [1.6–13.7], 14.9% [5.7–23.2] and 23.1% [9.9–34.3] at 6months, 1year and 2years respectively. In multivariate analysis, female gender (HR 7.87 [3.14–19.69]), a BCLC B-C stage (HR 3.71 [1.41–9.76]), a sum of all lesion diameters ⩾2cm (HR 7.48 [2.09–26.83]) and a previous treatment (HR 0.10 [0.01–0.79]) were independent prognostic factors of overall survival. ConclusionSBRT allows high local control for inoperable hepatocellular carcinomas. It should be considered when an ablative treatment is indicated in Child A patients.

The importance of scatter correction for the assessment of lung shunting prior to yttrium-90 radioembolization therapy

Treatment of inoperable hepatocellular carcinoma or secondary metastases by radioembolization using yttrium-90 (90Y) microspheres is a promising method for the treatment of unresectable liver metastases. A pretreatment scintigraphy planar scan using 99mTc-labelled macroaggregated albumin (99mTc-MAA) injected directly into the hepatic artery is carried out to assess the degree of portal shunting of blood between the liver and the lungs. The quantitative results of this scan are used to modulate the activity of therapeutic 90Y microspheres injected into the patient to limit the radiation dose received by the lungs. The presence of scattered events in the MAA lung shunt scan leads to an overestimation of the true shunting ratio, which in turn leads to the administered therapeutic activity being lowered unnecessarily to comply with the protocols of radiation protection. Overall, this may impact the efficacy of treatment. This study analyses the impact of a window-based analytical scatter-correction method on lung shunt analysis using an anthropomorphic torso phantom, and retrospectively analysed three patient case studies. Our results of scatter in the phantom show a marked decrease in the lung shunt percentage. Clinical analysis of patient data shows that the lung shunt percentage can be overestimated by up to 50% in clinical cases, and depending on the lung shunt percentage, the efficacy of treatment by therapeutic dose reduction may be compromised. Our results indicate that scatter correction should be used on 90Y pretreatment 99mTc-MAA scans in order to more accurately assess the lung shunting percentage before therapy.

Preliminary result of stereotactic body radiotherapy as a local salvage treatment for inoperable hepatocellular carcinoma

To evaluate the toxicity and efficacy of stereotactic body radiotherapy (SBRT) for the treatment of localized hepatocellular carcinoma (HCC) in the absence of another standard treatment option. The authors reviewed the details of 38 patients with inoperable HCC (diameter <10 cm) treated by SBRT in a prospectively registered database at their institution. All patients had been treated by transcatheter arterial chemoembolization before SBRT, which had been finally deemed ineffective. SBRT dosages (33-57 Gy in three or four fractions) were administered according to tumor volumes, which ranged from 11 to 464 ml (median, 40.5 ml). Two-year overall survival and local progression-free survival rates were 61.4% and 66.4%, respectively. The local response rate was 63% at 3 months after SBRT. A high radiation dose was found to be independently related to survival. A decline in liver function was observed in six patients (16%) and Grade 3 musculoskeletal toxicity in one patient (2.7%). This study showed that SBRT can be safely administered to select HCC patients, and these results suggest that this technique should be considered a salvage treatment. A further well-controlled large-scale study and longer follow-up are needed to determine optimal dose-fraction schedules and characterize late complications.

Rupture and intra-peritoneal bleeding of a hepatocellular carcinoma after a transarterial chemoembolization procedure: a case report

BackgroundTransarterial chemoembolization (TACE) is a well accepted treatment for inoperable hepatocellular carcinoma (HCC). While minor complications involve 10% of all patients, severe complications are rare.Case PresentationWe describe a case of a 90-year-old male with a large, superficial HCC who underwent TACE. He had a significant intraperitoneal bleed secondary to tumor rupture immediately following the procedure.ConclusionTumor size and superficial location must be considered risk factors for tumor rupture and related complications.

Hepatocellular carcinoma and octreotide: Treatment results in prospectively assigned patients with advanced tumor and cirrhosis stage

Treatment of inoperable hepatocellular carcinoma (HCC) remains a major clinical problem. The only efficient treatment options are percutaneous ethanol injection (PEI), radiofrequency ablation (RF) and transarterial chemoembolization (TACE), but these therapies are only applicable to patients with limited tumor spread and sufficient liver function. For patients with advanced tumor and poor liver function a systemic therapy is required. Octreotide, a somatostatin analog with antimitotic activity, is a controversial treatment option. In the current study we prospectively assigned a group of 41 HCC patients with advanced HCC and cirrhosis stage to treatment with octreotide. The clinical and laboratory parameters were monitored and survival was analyzed using a Cox regression model. The medium survival in the group of all patients was 571 days. Using the Cox regression there was a significant difference in survival for alpha-fetoprotein (P = 0.026) and Quick's test (P = 0.009) in consideration of the tumor dimension compared to the other characteristics. The tumor remained stable in 26 patients over a mean follow-up of 21 months and progressed in 14 patients. One patient showed a partial response. There was no incidence of severe side-effects (WHO grade 3-4). During the follow-up time, 14 patients died because of their underlying disease. Treatment with octreotide appears safe and patients show similar survival compared to a group of patients with advanced HCC treated with TACE. Further studies are necessary to investigate somatostatin receptor subtypes or receptor mutations of patients with advanced HCC in relation to their response.

Quality of life as a predicting factor for survival in 235 patients with inoperable hepatocellar carcinoma (HCC)

4125 Background: Patients with inoperable HCC have a dismal prognosis. The objective of this study is to evaluate whether patient-reported baseline quality of life (QOL) measured by the EORTC QLQ-C30 instrument is predictive of survival for these patients. Methods: Two hundred thirty-five patients with inoperable HCC who were recruited into two separate randomized phase III clinical studies, based on palliative chemotherapy and palliative hormonal therapy respectively, were consented and had pre-treatment QOL assessment. EORTC QLQ-C30 scores and clinical variables at the time of study entry (age, sex, ECOG performance score, AFP, total bilirubin, alanine transaminase and albumin levels, prothrombin time, HBsAg positivity, presence of ascites, Child-Pugh’s grading of cirrhosis, vascular involvement, Okuda staging of HCC and entries into the two respective studies) were analyzed to identify factors that influenced survival by applying multivariate analysis. Independent prognosticators for survival were studied by Cox regression analysis. Results: Median survival of the 235 patient was 5.5 months (95% C.I. 4.2 - 6.5 months). Significant independent predictors of shorter survival were advanced Okuda staging (p= 0.0060; HR= 1.935), high baseline AFP (p= 0.0382; HR= 1.045) and total bilirubin (p= 0.0004; HR= 1.013), and worse QOL score in the appetite domain (p= 0.0136; HR= 1.006). Patients who were entered into the chemotherapy trial (p= 0.0006; HR= 0.544), those who scored better in the physical functioning domain (p= 0.0102; HR= 0.993) and the global QOL domain (p= 0.0171; HR= 0.991), were associated with longer survival. Conclusion: Baseline QOL is a predictor of survival for patients with inoperable HCC. When used along with traditional clinical factors, patient-reported baseline QOL assessment using the EORTC QLQ-C30 provides additional prognostic information. Acknowledgements: We thank Asia Pacific Hepatocellular Carcinoma Trials Group for providing QOL data for 77 patients from our centre who were consented into the Randomized Trial of High Dose Tamoxifen versus Placebo for the Treatment of Inoperable Hepatocellular Carcinoma. No significant financial relationships to disclose.

Treatment of inoperable hepatocellular carcinoma with pegylated liposomal doxorubicin (PLD): results of a phase II study

Monthly intravenous pegylated liposomal doxorubicin (PLD) 50 mg m−2, although well tolerated, showed almost no activity in this phase II study of 16 patients with advanced hepatocellular carcinoma with a response rate of 0%, stable disease 19%, median time to progression of 2.4 months, 1-year survival of 25% and median survival of 6.5 months.

Vascular administration of adenoviral vector soaked in absorbable gelatin sponge particles (GSP) prolongs the transgene expression in hepatocytes

Transcatheter hepatic arterial chemoembolization using emulsions composed of anticancer agents and gelatin sponges (GS) has been an efficient and safe palliative treatment for inoperable hepatocellular carcinoma (HCC). We employed catheter-mediated left hepatic arterial embolization (CHAE) to increase transduction efficiency of adenoviral vector in canine hepatocytes. The emulsion was prepared by mixing pieces of GSP and adenoviral vectors expressing recombinant beta-galactosidase (Ad.LacZ) or human hepatocyte growth factor (Ad.hHGF). After the left hepatic artery was catheterized under angiography, CHAE with Ad.LacZ or Ad.hHGF was performed. Livers were removed and stained for LacZ activity on day 7. The expression pattern of LacZ staining was either scarce or patchy around the central hilum of the hepatic artery, or was homogeneously distributed in whole lobes, depending on whether large or small pieces of GSP were used. Hematological and serum biochemical changes during CHAE exhibited only a few effects. The chronological measurement of serum HGF concentration showed that the duration of transgene expression was greater after CHAE with Ad.hHGF. A similar pattern of transgene expression was observed in a rat model after hepatic arterial embolization with differential doses of Ad.hHGF soaked in GSP. These results suggest that hepatic arterial embolization by transcatheter mediated infusion with a mixture of adenovirus-GSP could be used for human HCC.

HEPATOCELLULAR CARCINOMA AND LIVER TRANSPLANTATION: AN ANALYSIS OF PROGNOSTIC FACTORS

O368 Aims: Orthotopic liver transplantation (OLT) is the only curative treatment of inoperable hepatocellular carcinoma (HCC). The prognosis after OLT depends on the characteristics of the primary tumor such as size, grading and vascular invasion and it is still controversial which patient to transplant. We performed an uni- and multivariate analysis of prognostic factors in 64 HCC patients undergoing OLT. Methods: Between 1998 and 12/2003 64 patients suffering from HCC were transplanted. 34 received a neoadjuvant treatment by transarterial chemoembolisation (TACE) with Mitomycin C and Lipiodol at intervalls of 6 weeks (mean 4.9 sessions) while waiting for OLT (male 27, female 7; age 58,5±7.3 years; liver function Child A 76%, Child B 18%, Child C 6%; Milan Criteria (MC) fulfilled 32%, beyond MC 68%). The control group consisted of 30 patients without (19/30) or other (11/30) pretreatment (male 20, female 10; age 56.1±6.4 years; liver function Child A 33%, Child B 20%, Child C 47%; Milan Criteria (MC) fulfilled 60%, beyond MC 40%). The median follow up was 672 days. Univariate and multivariate analyses of several prognostic factors for recurrence-free survival after OLT were performed using Kaplan Meier method and Cox regression, respectively. Results: Recurrence-free survival (5 years) of all patients was 45%, 84% (TACE group) and 23% (non TACE group), respectively. 16/64 patients died after OLT, 6/16 (37%) due to HCC recurrence, 10/16 (63%) due to HCC unrelated causes. 1/34 (3%) patient with TACE pretreatment, but 9/30 (30%) without TACE died due to HCC unrelated causes. HCC recurrence after OLT occurred in 3/34 (9%) patients in the TACE group (2 patients are still alive), and 5/30 (17%) patients in the non-TACE group. In the TACE group MC were fulfilled in 11/34 patients, 23/34 patients were beyond the MC, survival was comparable: 86% vs. 83%. 25/34 TACE patients had stable disease during pretreatment, all of them are recurrence-free after 3 years. 9/34 had progressive tumor under TACE, only 51% are recurrence-free (p=0.001). In the multivariate analysis only TACE vs. non TACE showed an influence on survival (p=0.008). The influence of tumor stage, MC, grading, solitary vs. multifocal growth or waiting time was not significant. The univariate analysis of prognostic factors proved statistical influence on recurrence-free survival for TACE vs. non-TACE (p=0.004) and waiting time >150 days (p=0.028). Vascular invasion (p=0.093), grading (p=0.138), tumor size (p=0.621), MC (p=0.433), and solitary vs. multifocal growth (p=0.967) had no significant influence on survival. Conclusions: Neoadjuvant treatment of HCC patients awaiting OLT influences recurrence-free survival, whereas tumor characteristics as stage, grading and MC do not. Sequential TACE without tumor progress is a strong predictor for recurrence-free survival. Even in patients with large tumors OLT may be justified if the tumor is stable during TACE pretreatment and if TACE is performed in close intervalls.

High-dose tamoxifen in the treatment of inoperable hepatocellular carcinoma: A multicenter randomized controlled trial

In the Asia-Pacific region and elsewhere, almost 85% of patients with hepatocellular carcinoma (HCC) are inoperable at diagnosis and have a dismal prognosis. Tamoxifen (TMX) is believed to inhibit HCC positive for estrogen receptor (ER), but most HCCs are ER negative. Results of previous phase 3 trials in inoperable HCC have been conflicting and inconclusive. At higher doses, however, TMX inhibits HCC through ER-independent mechanisms. A multicenter randomized controlled trial was performed to assess the role of high-dose TMX versus placebo (P) in the treatment of patients with inoperable HCC with respect to survival and quality of life (QoL). A total of 329 patients from 10 centers in 9 countries in the Asia-Pacific region enrolled in a double-blind randomized controlled trial of TMX 120 mg/d (TMX120) against P as a control arm with an intermediate dosage of TMX 60 mg/d (TMX60) to assess possible dose response. An independent data monitoring committee reviewed all aspects of the trial. QoL was assessed using the European Organization for Research and Treatment of Cancer QLQ-C30 questionnaire. Three-month survival rates for the P, TMX60, and TMX120 groups were 44%, 41%, and 35%, respectively, with a statistically significant trend difference in survival across the 3 treatment regimens ( P = .011). There was a significantly higher risk of death in the TMX120 group compared with the P group (hazard ratio, 1.39; 95% confidence interval, 1.07-1.81). Adverse drug reactions were reported in 3% (9 patients), and 8 patients were lost to follow-up. In conclusion, TMX does not prolong survival in patients with inoperable HCC and has an increasingly negative impact with increasing dose. No appreciable advantage to QoL with TMX was observed. (H EPATOLOGY 2002;36:1221-1226.)

Positive octreotide scan in a case of hepatocellular carcinoma

The prognosis of patients with hepatocellular carcinoma (HCC) is poor. Blocking somatostatin receptors using octreotide may serve as a possible treatment of inoperable HCC. Somatostatin receptors on tumor cells were shown in vitro in about 40% of patients with HCC [1]. The remaining 60% should have no reasonable benefit from an octreotide therapy. In vivo imaging using radiolabelled octreotide might help to differentiate between these groups. However, Raderer et al. did not find any positive scans in 15 untreated patients with advanced HCC using 111In-octreotide [2]. Here, we present a case of HCC exhibiting an extraordinary high 111In-octreotide uptake. For somatostatin receptor scintigraphy, images were acquired 4, 24 and 48h after injection of 200MBq 111In-Octreoscan (Amersham Health, Braunschweig, Germany). Whole body scintigraphy showed pathological uptake of the tracer in the left scapula, in the xiphoid, in the 12th thoracic vertebra and in projection onto the left ileosacral joint (left panels). SPECT images of the liver showed a total of four areas with a localised enhancement of radioactivity uptake (right panel). These findings supported the diagnosis of HCC. They did not only visualise its multilocular character in the liver but, furthermore, revealed several metastases in the bones. During the last 2 years, we examined seven other patients with HCC using 111In-Octreoscan. As the tracer uptake did not exceed the octreotide uptake in the surrounding liver tissue, the majority of cases were not visible or even appeared as ‘cold lesions’, confirming previous results [2]. The case presented here demonstrates that in vivo detection of somatostatin receptors by octreotide scintigraphy is possible in some cases of liver lesions and extrahepatic metastases. It remains to be evaluated, if a positive octreotide scan might be a valuable predictor of response to octreotide treatment.