Transarterial chemoembolization followed by moderately hypofractionated radiotherapy in hepatocellular carcinoma: Long-term results of RTF3 regimen.

PURPOSE: In early-stage hepatocellular carcinoma (HCC) patients merely fit for surgery, transarterial chemoembolization (TACE) achieve low long-term disease control. We evaluated the efficacy and safety of its combination with moderately hypofractionated radiotherapy (hRT) using RTF3 regimen. MATERIAL AND METHODS: Between 2006 and 2016, 61 consecutive patients treated in our single expert center for a Barcelona Clinic Liver Cancer (BCLC) A HCC by TACE followed by hRT 3Gy/fraction were retrospectively included. RESULTS: Sixty of the 61 included presented Child-Pugh A cirrhosis (A5, n=41, 67.2%; A6: n=19, 31.1%). Fourteen patients (22.9%) were already treated for a HCC, mainly by radiofrequency (n=12). All patient received a TACE followed by 3Gy per fraction hRT. Mean radiation dose was 54Gy (range: 48-60). After a median follow-up of 118 months, median time-to-progression, progression-free survival (PFS) and overall survival (OS) was 21.3, 18.1, and 31.5 months, respectively. In univariate analysis, PFS was related to dose > 54Gy (HR: 2, P=0.036), and OS was correlated to Child-Pugh A6 or B7 (HR: 1.93, P=0.03) and overall hRT time (HR: 1.06, P=0.015). At progression, orthotopic liver transplantation was performed in 8 patients (13.1%). Severe symptomatic adverse events occurred in 12 patients (19.7%), mainly ascites (n=7). CONCLUSION: In BCLC-A Child-Pugh A HCC patients ineligible to surgery or thermoablation, TACE-hRT is a safe and effective treatment. Prospective studies are needed to compare this association with radioembolization, TACE-stereotactic radiotherapy, and systemic treatments combinations.

Une lésion labiale inhabituelle.

A 75 years old patient presented with a papular easily bleeding lesion of the lower lip that had been growing for two months. He was known for alcoholic cirrhosis complicated with hepatocellular carcinoma treated since one year. A working diagnostic hypothesis of benign vascular lesion was proposed. Microscopic examination showed a neoplastic dermal proliferation that had been fully excised, made of lobules segregated by thin fibrous septae. The neoplastic architecture was trabecular and delineating spaces forming pseudo-rosettes. Tumour cells were monomorphic, cuboidal or cylindric with abundant eosinophilic and granulous cytoplasm and centered by a lone nucleus that often contained a prominent nucleolus. Some spaces were filled with a brownish-greenish pigmented material. Immunohistochemical study showed that tumour cells were positive with the hepatocyte paraffin 1 antibody as well as cytokeratin 8 antibody. Chromogranin A and synaptophysin stainings were negative. Thus we concluded to a lip metastasis from the previously known hepatocellular carcinoma. Skin metastasis arise in around 3% of cases of hepatocellular carcinoma. They account for less than 1% of all cutaneous metastasis. Overall appearance of cutaneous metastasis of hepatocellular carcinoma is associated with a poor prognosis and an aggravated risk of metastasis to other locations and organs and a median overall survival of less than 5 months. Since incidence of hepatocellular carcinoma is rising pathologists might face more frequently in years to come to cutaneous metastasis whose varied clinical presentations make a diagnostic challenge.

[Differential diagnostic between hepatocellular carcinoma and hepatoid carcinoma with bone metastasis revelation: What tools can be used?] / Diagnostic différentiel entre un carcinome hépatocellulaire et un carcinome hépatoïde à révélation métastatique osseuse : quels outils sont à disposition ?

Bone metastases of hepatocellular carcinoma (HCC) are rare and disease-revealing bone metastasis are exceptional. Here, we report the case of a 69-year-old man with a cervical vertebral metastasis of hepatocellular carcinoma. Morphological aspect of a metastatic tumor with eosinophilic and polygonal cells raises the question of the differential diagnosis between a localization of a hepatocellular carcinoma or an hepatoid carcinoma, notably when the metastasis is the first clinical manifestation. The morphological aspect by itself does not provide strong enough arguments for diagnosis. Well selected immunohistochemical markers can sometimes help to orientate towards one of the two hypotheses, in particular SALL4 and LIN28 which are in favour of hepatoid carcinoma when both are positive. Finally, as these two entities have different molecular profiles, molecular study can also be helpful to distinguish them. Indeed, HCCs often present TERT promoter, CTNNB1 mutations and IL-6/JAK/STAT pathway activation while hepatoid adenocarcinoma frequently presents chromosome 20 long arm gain. TP53 mutations are found in both entities and are therefore not discriminating. Differential diagnosis is important because the treatment will be that of the primary. Prognostic data for HCC revealed by bone metastasis are scarce, although they seem to be associated with a poor prognosis, with a 1 to 2 months overall survival. There is currently no data for hepatoid adenocarcinoma with bone metastasis.

[Stereotactic body radiotherapy of primary liver tumours: Indications and new techniques]. / Radiothérapie stéréotaxique des tumeurs primitives hépatiques : indications et nouvelles techniques.

The incidence of primary hepatic tumours is increasing and the reference treatments by liver transplantation or surgical resection do not allow to compensate for this increase because of the lack of grafts, or the low proportion of initially resectable tumours. The challenges for radiotherapy of primary liver tumors are multiple: physical, biological, medical and technological. Liver stereotactic body radiotherapy is sometimes the only local treatment option and is progressively finding its place for these tumors, even if the recognition of the indications would deserve a better standardization of international recommendations. The heterogeneity of practices and techniques is a major obstacle to the development of randomized studies, despite the excellent oncological results published. The latest ASTRO 2022 guidelines, the recent publication of the guidelines from the French society for radiation oncology on external radiotherapy and brachytherapy procedures ("RecoRad™ 2.0"), and the inclusion in prospective clinical trials will help to homogenize protocols and improve recognition of the technique. The first data from the new techniques of adaptive radiotherapy and MR-guided radiotherapy, whose objectives are to improve targeting and reduce liver or gastrointestinal toxicity, confirm the excellent results of liver SBRT and allow the potential indications to be extended to locations that were previously difficult to treat.

[hPG80 and cancer: A new blood biomarker in development for patient monitoring]. / hPG80 et cancer : un nouveau biomarqueur sanguin en développement pour le suivi des patients.

Recent technological advances coupled with our improved understanding of the molecular and cellular mechanisms associated with cancer development have enabled better overall patient care. Among the newly identified biomarkers such as circulating tumor DNA or circulating tumor cells, hPG80 (circulating progastrin) that is easy to detect and quantify by a simple ELISA assay has the potential to become a new routine clinical tool in oncology if on-going studies validated its utility. Indeed, on the one hand, hPG80 was found in the blood of patients with different tumors (colorectal, pancreatic, liver, lung, stomach, kidney cancers) at a significantly higher concentration than in healthy donors. Moreover, some studies suggested a potential association between hPG80 concentration changes and anti-cancer treatment efficacy in patients with gastro-intestinal and hepatocellular carcinomas. Finally, hPG80 might be a prognostic factor for overall survival in metastatic renal cell carcinoma cancer (mRCC) and in hepatocellular carcinoma (HCC). If these hypotheses were validated, hPG80 might help better stratify patients according to their prognosis, and also become a tool to monitor relapse and predict treatment response. Prospective validation studies are on-going.

Hepatic tumours and radiotherapy.

We present the update of the recommendations of the French society of oncological radiotherapy on hepatic tumours. Recent technological progress led to develop the concept of focused liver radiation therapy. We must distinguish primary and secondary tumours, as the indications are restricted and must be discussed as an alternative to surgical or medical treatments. The tumour volume, its liver location close to the organs at risk determine the irradiation technique (repositioning method, total dose delivered, dose fractionation regimens). Tumour (and liver) breathing related motions should be taken into account. Strict dosimetric criteria must be observed with particular attention to the dose-volume histograms of non-tumoral liver as well as of the hollow organs, particularly in case of hypofractionated high dose radiotherapy "under stereotaxic conditions". Stereotactic body radiotherapy is being evaluated and is often preferred to radiofrequency for primary or secondary tumours (usually less than 5cm). An adaptation can be proposed, with a conformal fractionated irradiation protocol with or without intensity modulation, for hepatocellular carcinomas larger than 5cm.

Delta-tocotrienol enhances the anti-tumor effects of interferon alpha through reactive oxygen species and Erk/MAPK signaling pathways in hepatocellular carcinoma cells.

The complexity of hepatocellular carcinoma (HCC) signaling and the failure of pharmacological therapeutics reveal the significance of establishing new anti-cancer strategies. Interferon alpha (IFN-α) has been used as adjuvant therapy for reducing HCC recurrence and improving survival. Delta-tocotrienol (δ-tocotrienol), a natural unsaturated isoform of vitamin E, is a promising candidate for cancer treatment. In this study, we evaluated whether the combination of δ-tocotrienol with IFN-α displays significant advantages in the treatment of HCC cells. Results showed that the combination significantly decreased cell viability, migration and invasion of HCC cells compared with single therapies. Combining δ-tocotrienol and IFN-α enhanced the decrease in proliferating cell nuclear antigen (PCNA) and matrix metalloproteinase (MMP) 7 and MMP-9. The combination also produced an enhancement of apoptosis together with increased Bax/Bcl-xL ratio and reactive oxygen species (ROS) generation. δ-tocotrienol induced Notch1 activation and changes in Erk and p38 MAPK signaling status. Blocking experiments confirmed that ROS and Erk are involved, at least in part, in the anti-cancer effects of the combined treatment. In conclusion, the combination of δ-tocotrienol with IFN-α therapy showed promising results for HCC cell treatment, which makes the combination of cytokine-based immunotherapy with natural products a potential strategy against liver cancer.

Stereotactic radiotherapy for hepatocellular carcinoma induced by hepatitis C and the relationships of changes in carbohydrate antigen 19-9 with AFP and PIVKA-II.

PURPOSE: Assessing the therapeutic effects of stereotactic body radiotherapy (SBRT) for hepatocellular carcinoma (HCC) takes time. Purpose of our study was to explore the relationships of changes in carbohydrate antigen 19-9 (CA 19-9) with those in the existing markers alpha-fetoprotein (AFP) and protein induced by vitamin K absence or antagonist-II (PIVKA-II). PATIENTS AND METHODS: The subjects were 16 patients who underwent SBRT for solitary HCC ≤3cm induced by hepatitis C between June 2016 and July 2019. Observation periods ranged from 8-43 (median: 28) months, ages from 59-85 (median: 65) years. RESULTS: Changes in CA 19-9 levels after SBRT were categorised into three patterns: 1) a transient elevation followed by a decline (75%); 2) a transient decline followed by an elevation (18.8%); and 3) no change (6.3%). Among patients showing a transient CA 19-9 elevation followed by a decline, which was the most frequent pattern, 75% showed these changes in synchronisation with AFP and preceded the changes in PIVKA-II, while in the other 25%, CA 19-9 changes were in synchronisation with PIVKA-II and preceded those in AFP. At the time of recurrence, 62.5% showed a continuous CA 19-9 elevation, either in synchronisation with other markers or by itself. CONCLUSIONS: This is the first investigation of changes in CA 19-9 levels after SBRT for HCC induced by hepatitis C. Characteristic changes in CA 19-9, AFP, and PIVKA-II levels were observed as responses after treatment. As for its correlations with tumour markers, the acute responses of PIVKA-II tended to be slower than those of CA 19-9 and AFP. Although the sample size was small, our findings raise the possibility that measuring these 3 biomarkers after SBRT may be useful for monitoring patients for HCC recurrence.

I125 irradiation stent for treatment of hepatocellular carcinoma with portal vein thrombosis: A meta-analysis.

PURPOSE: A meta-analysis aimed to systematically evaluate the safety and efficiency of I125 irradiation stent placement for patients with hepatocellular carcinoma (HCC) combined with portal vein tumor thrombosis (PVTT). MATERIALS AND METHODS: The Cochrane library, PubMed/Medline, EMBASE, CNKI, Wanfang Data and CQVIP were systematically screened out from the earliest to December 2019. The qualities of all included studies were assessed. The primary endpoints were the 6-month, 12-month stent cumulative patency rate and 6-month, 12-month, 24-month overall survival rate while the secondary endpoints were the objective response rate of PVTT, main portal venous pressure changes and treatment-related adverse events. Our meta-analysis was conducted using Stata 12.0 software. RESULTS: Totally seven studies with 1018 patients were included in the final analysis, in which 602 patients received TACE and I125 irradiation stent placement, and 416 patients in control group underwent TACE and stent placement without endovascular brachytherapy (EVBT). Meta-analysis showed that the I125 irradiation stent improved the cumulative stent patency rates in 6months [OR=1.65, 95% CI (1.32-2.05), P<0.001] and 12months [OR=2.55, 95% CI (1.90-3.42), P<0.001] and the survival rates in 6months [OR=1.77, 95% CI (1.41-2.22), P<0.001], 12months [OR=3.14, 95% CI (2.24-4.40), P<0.001] and 24months [OR=7.39, 95% CI (3.55-15.41), P<0.001]. However, there was no difference in the objective response rate of PVTT [OR=1.13, 95% CI (0.87-1.48), P=0.365], main portal venous pressure and the occurrence adverse event [OR=0.88, CI=0.72-1.08, P=0.212] between two groups. CONCLUSION: I125 irradiation stent seems to be more effective in treating hepatocellular carcinoma with portal vein tumor thrombosis. The usage of portal vein stent combined endovascular brachytherapy has the potential to act as an alternative therapy for HCC with PVTT. On account of the limitation of studies included, more studies with high-level evidence, such as RCTs, are requisite to support the above promising results.

[Hepatitis B vaccine and liver cancer]. / Vaccination contre le virus de l'hépatite B et prévention du cancer du foie.

Hepatitis B Virus (HBV) chronic infection contributes to a high risk of hepatocellular cancer (HCC) development. HBV is a strong cancer inducer, due to natural history of infection, virological characteristics and viral DNA integrations events in host genome. Prolonged infection and high viral loads, particularly frequent in patients infected in childhood, are risk factors of HCC development for patients with HBV chronic infection. A HBV vaccine, based on immunization against the surface protein HBs, showed a strong efficacy to prevent chronic HBV infection. The development of universal neonatal vaccination programmes contributed to the decrease of HBV chronic infection incidence in children of high endemic areas. Although HBs antibodies levels diminished years after vaccination, HBV neonatal vaccination programmes led to a lower incidence of chronic HBV infection among young adults. The decrease of HBV chronic infection incidence was associated to a reduction of HCC incidence in children and young adults from areas with a high prevalence of HBV infection.

The role of visfatin and resistin in an in vitro model of obesity-induced invasive liver cancer.

Obesity is associated with the development of liver disease and its progression to hepatocellular carcinoma. This link may be attributed to adipocytokines such as visfatin and resistin which have been shown to promote liver cancer incidence and progression. Studies have yet to determine the role of visfatin and resistin in liver cancer, specifically in the context of obesity. The objective of this study was to investigate the effect of neutralizing visfatin and resistin in obese (OB) or normal weight (NW) sera to determine the contribution of these proteins in obesity-induced invasive liver cancer. Sera from OB or NW males was used to determine the efficacy of neutralizing visfatin and resistin to reduce the obesity-induced liver cancer phenotype. HepG2 and SNU-449 cells were exposed to OB and NW sera ± antibodies for visfatin or resistin. The neutralizing antibodies differentially suppressed invasion, reactive oxygen species production, and matrix metalloproteinase-9 secretion. These changes corresponded with a decrease in phosphorylated extracellular signal-regulated kinases and protein kinase B in HepG2 cells, but differences were not observed in CAP1 or ß-catenin. In conclusion, visfatin and resistin have differential roles in obesity-associated liver cancer and may be potential targets to reverse the impact of obesity on liver cancer progression.

Differences between exhausted CD8+ T cells in hepatocellular carcinoma patients with and without uremia.

The purpose of this study was to explore the differences between exhausted CD8+ T cells in hepatocellular carcinoma (HCC) patients with and without uremia. We enrolled 45 uremic patients who were recently diagnosed with HCC into the HCC + uremia cohort and similar patients with HCC but without uremia into the HCC-only cohort. Lymphocytes were obtained from the two cohorts, and exhausted CD8+ T cells, comprising PD-1+CD8+, TIM-3+CD8+, and LAG-3+CD8+ T cells, were sorted and expanded in vitro. After expansion, the proportions of PD-1+CD8+, TIM-3+CD8+, and LAG-3+CD8+ T cells were significantly higher in the HCC-only cohort than in the HCC + uremia cohort. CD8+ T cells expressing PD-1, TIM-3, or LAG-3 showed increased tumor reactivity and release of interferon-γ in vitro; however, these cells demonstrated weaker anti-tumor activity in HCC + uremia patients than in HCC-only patients. Among the expanded lymphocytes, only the decreased proportion of PD-1+CD8+ T cells significantly correlated with the HCC + uremia cohort (odds ratio of 2.731, p = 0.009). We concluded that peripheral CD8+ T cells expressing PD-1, TIM-3, or LAG-3 from the HCC + uremia cohort were dysfunctional in vitro. Among these populations, PD-1+CD8+ T cells were most evident in HCC patients with uremia.

Long noncoding RNA RP11-909N17.2 promotes proliferation, invasion, and migration of hepatocellular carcinoma by regulating microRNA-767-3p.

Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related deaths worldwide, especially in developing countries. Although advances in surgical procedures and targeted medicine have improved the overall survival of patients with HCC, the prognosis is poor. Hence, there is a need to identify novel therapeutic targets for HCC. Here, we report that the expression of RP11-909N17.2, a novel, long, noncoding RNA (lncRNA), is dysregulated in patients with HCC and cell lines. Additionally, this study demonstrated that RP11-909N17.2 facilitates the proliferation and invasion of HCC cells by binding to miRNA-767-3p, a tumor-suppressive microRNA (miRNA). Small integral membrane protein 7 (SMIM7) was identified as the downstream target of miRNA-767-3p. The expression of SMIM7 was upregulated in HCC clinical samples and cell lines. Moreover, SMIM7 was involved in the proliferation and invasion of HCC cells. Furthermore, SMIM7 inhibited the apoptosis of HCC cells, which indicated the oncogenic role of SMIM7 in HCC. The findings of this study suggest that the lncRNA-miRNA-mRNA regulatory axis, which regulates the pathogenesis of HCC, can be a potential novel diagnostic and therapeutic target for HCC.

Chondroitin polymerizing factor (CHPF) contributes to malignant proliferation and migration of hepatocellular carcinoma cells.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the human digestive system, and has been recognized as a serious threat to public health worldwide. This study explored the role of chondroitin polymerizing factor (CHPF) in the development and metastasis of HCC. Immunohistochemistry analysis was performed to detect CHPF expression in HCC tissues and para-carcinoma tissues. qRT-PCR and Western blot analysis were used to determine the mRNA and protein expression of CHPF. MTT assays, colony formation assays, and flow cytometry were used to evaluate the cell proliferation, colony formation, and cell apoptosis, respectively. Wound-healing and Transwell assays were performed to evaluate cell migration. The results show that CHPF was not only up-regulated in HCC tissues compared with para-carcinoma tissues, but was also related with more advanced stages of HCC. Further studies revealed that CHPF knockdown significantly inhibited cell proliferation and colony formation, and induce cell apoptosis of HCC cells. Moreover, suppressing the expression of CHPF reduced the migration and invasiveness of HCC cells. In conclusion, we demonstrated that CHPF plays important roles in the development and progression of HCC, and high expression levels of HCC may be related with poorer prognosis. The results from this study may provide a potential therapeutic target for HCC treatment.

RP5-1120P11.3 promotes hepatocellular carcinoma development via the miR-196b-5p-WIPF2 axis.

Hepatocellular carcinoma (HCC) remains a huge threat to human health even though the diagnosis and treatment strategies have improved rapidly in the past few decades. Increasing evidence has illustrated the critical role noncoding RNA and their regulatory network play in the pathology of HCC. Here, we identified a novel long noncoding RNA, RP5-1120P11.3, that is ectopically expressed in HCC. Further characterization of RP5-1120P11.3 revealed that it promoted proliferation and invasion of HCC cells while inhibiting apoptosis. Importantly, our data revealed that miR-196b-5p interacted with and was regulated by RP5-1120P11.3 via a sponging mechanism. Inhibition of miR-196b-5p attenuated the phenotypes resulting from RP5-1120P11.3 inhibition. Moreover, our data showed that miR-196b-5p inhibited the expression of WIPF2 in HCC, illustrating a regulatory axis of RP5-1120P11.3-miR-196b-5p-WIPF2 that facilitated the progression of HCC. In addition, our data showed that RP5-1120P11.3 contributed to xenograft generation in vivo by regulating miR-196b-5p and WIPF2. These findings suggested that the RP5-1120P11.3-miR-196b-5p-WIPF2 axis is a potential target for treatment of HCC.

[Liver stereotactic body radiotherapy: Clinical features and technical consequences, results. Which treatment machine in which situation?] / Radiothérapie stéréotaxique hépatique : particularités cliniques et implications techniques, résultats. Quelle machine pour quelle situation ?

Liver stereotactic body radiotherapy is a developing technique for the treatment of primary tumours and metastases. Its implementation is complex because of the particularities of the treated organ and the comorbidities of the patients. However, this technique is a treatment opportunity for patients otherwise in therapeutic impasse. The scientific evidence of liver stereotactic body radiotherapy has been considered by the French health authority as insufficient for its widespread use outside specialized and experienced centers, despite a growing and important number of retrospective and prospective studies, but few comparative data. This article focuses on the specific features of stereotactic body radiotherapy for liver treatments and the results of published studies of liver stereotactic body radiotherapy performed with classic linear accelerators and dedicated radiosurgery units.

[Nodulocystic eruption induced by sorafenib]. / Éruption nodulo-kystique induite par le sorafénib.

INTRODUCTION: Sorafenib is a multikinase inhibitor used in the treatment of hepatocellular carcinoma, advanced renal cell carcinoma, and differentiated thyroid carcinoma. Cutaneous adverse events are numerous and occur frequently. PATIENTS AND METHODS: We present two cases of nodulocystic lesions associated with comedones in patients treated with sorafenib for hepatocellular carcinoma. In the first patient, a 64-year-old man, lesions appeared on the trunk one year after beginning sorafenib. Histopathological examination revealed a non-granulomatous, perivascular and perisudoral polymorphic cellular infiltrate associated with comedones and microcysts. These lesions progressed via inflammatory episodes interrupted by long periods of spontaneous remission without any specific treatment. In the second patient, a 53-year-old woman, a rash appeared on the buttocks three months after starting sorafenib and then spread to the lumbar region and thighs. Histopathological examination was consistent with granulomatous acne lesions. The initial treatment (oral tetracycline and zinc) given for 3 months proved ineffective. Patient follow-up over 3 years showed gradual regression without the appearance of any further lesions. DISCUSSION: In the literature, several reports discuss acneiform rashes in patients treated with targeted therapy. In most cases, these lesions were papulopustular without retentional lesions. There are few reports of nodulocystic eruptions associated with comedones following sorafenib therapy. The mechanisms of emergence of these lesions seem to involve inhibition of the RAF pathway, C-KIT, and the PDGF signaling pathway.

[Stereotactic body radiation therapy for hepatocellular carcinoma: Results from a retrospective multicentre study]. / Radiothérapie en conditions stéréotaxiques du carcinome hépatocellulaire : résultats d'une étude rétrospective multicentrique.

PURPOSE: The purpose of this paper was to describe local control, overall survival, progression-free survival and toxicity of CyberKnife®-based stereotactic body radiation therapy of hepatocellular carcinoma. MATERIAL AND METHODS: Records of all the patients treated for hepatocellular carcinoma at the Eugene-Marquis cancer centre, Rennes and the Bretonneau hospital, Tours (France), between November 2010 and December 2016, were reviewed. Radiation therapy was performed as a salvage treatment, while awaiting liver transplantation or if no other treatment was possible. RESULTS: One hundred and thirty-six patients were consecutively included in the study. The median follow-up was 13months. Median total dose prescribed, fractionation and overall treatment time were respectively 45Gy, three fractions and 5 days. Overall survival, progression-free survival and local control rates at 1year and 2years were 79.8 % and 63.5 %, 61.3 % and 39.4 %; 94.5 % and 91 %. Two grade 3 acute toxicity events and two grade 4 late toxicity events corresponding to a duodenal ulcer have been reported. Seven patients underwent classic radiation-induced hepatitis and 13 patients showed non-classical radiation-induced hepatitis. Barcelona Clinic Liver Cancer stage, World Health Organisation grade and planning target volume were correlated with overall survival in univariate Cox analysis. CONCLUSION: Stereotactic body radiation therapy is effective and well-tolerated for inoperable hepatocellular carcinoma or as a bridge to liver transplantation. Toxicity is mainly related to cirrhotic background and requires a selection of patients and strict dose constraints.