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Immunotherapy has revolutionised the treatment of advanced hepatocellular carcinoma (HCC). In addition, several phase III trials of immunotherapy in combination with surgical or locoregional therapies for early-to intermediate-stage HCC have recently reported positive results, and other phase III trials in the same patient population are currently in progress. As the application of immunotherapy is shifting to include patients with earlier stages of HCC, one looming question now emerges: What is the role of immunotherapy in the pre-liver transplant population? Liver transplantation is a potentially curative therapy for HCC and confers the additional advantage of restoring a normal, healthy liver. In pre-transplant patients, immunotherapy may improve downstaging success and tumour control at the cost of some immunologic risks. These include immune-related toxicities, which are particularly relevant in a uniquely vulnerable population with chronic liver disease, and the possibility of acute rejection after transplantation. Ultimately, the goal of immunotherapy in this population will be to effectively expand access to liver transplantation while preserving pre- and post-transplant outcomes. In this review, we discuss the mechanisms supporting combination immunotherapy, summarise key recent clinical data from major immunotherapy trials, and explore how immunotherapy can be applied in the neoadjuvant setting prior to liver transplantation in selected high-risk patients.
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BACKGROUND AND AIM: Treatment with immune checkpoint inhibitors (ICIs) for hepatocellular carcinoma (HCC) prior to liver transplantation (LT) has been reported; however, ICIs may elevate the risk of allograft rejection and impact other clinical outcomes. This study aims to summarize the impact of ICI use on post-LT outcomes. MATERIALS AND METHODS: In this individual patient data meta-analysis, we searched databases to identify HCC cases treated with ICIs before LT, detailing allograft rejection, HCC recurrence, and overall survival. We performed Cox regression analysis to identify risk factors for allograft rejection. RESULTS: Among 91 eligible patients, with a median (interquartile range [IQR]) follow-up of 690.0 (654.5) days, there were 24 (26.4%) allograft rejections, 9 (9.9%) HCC recurrences, and 9 (9.9%) deaths. Age (adjusted hazard ratio [aHR] per 10 years=0.72, 95% confidence interval [CI]=0.53, 0.99, P=0.044) and ICI washout time (aHR per 1 week=0.92, 95% CI=0.86, 0.99, P=0.022) were associated with allograft rejection. The median (IQR) washout period for patients with ≤20% probability of allograft rejection was 94 (196) days. Overall survival did not differ between cases with and without allograft rejection (log-rank test, p=0.2). Individuals with HCC recurrence had fewer median (IQR) ICI cycles than those without recurrence (4.0 [1.8]) vs. 8.0 [9.0]); p=0.025). The proportion of patients within Milan post-ICI was lower for those with recurrence vs. without (16.7% vs. 65.3%, p=0.032) CONCLUSION: Patients have acceptable post-LT outcomes after ICI therapy. Age and ICI washout length relate to the allograft rejection risk, and a 3-month washout may reduce it to that of patients without ICI exposure. Number of ICI cycles and tumor burden may affect recurrence risk. Large prospective studies are necessary to confirm these associations. IMPACT AND IMPLICATIONS: This systematic review and individual patient data meta-analysis of 91 patients with hepatocellular carcinoma and immune checkpoint inhibitors use prior to liver transplantation suggests acceptable overall post-transplant outcomes. Older age and longer immune checkpoint inhibitor washout period have a significant inverse association with the risk of allograft rejection. A 3-month washout may reduce it to that of patients without ICI exposure. Additionally, a higher number of immune checkpoint inhibitor cycles and tumor burden within Milan criteria at the completion of immunotherapy may predict a decreased risk of hepatocellular carcinoma recurrence, but this observation requires further validation in larger prospective studies. CODE FOR INTERNATIONAL PROSPECTIVE REGISTER OF SYSTEMATIC REVIEWS (PROSPERO): CRD42023494951.
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Liver transplantation offers the best chance of cure for most patients with non-metastatic hepatocellular carcinoma (HCC). Although not all patients with HCC are eligible for liver transplantation at diagnosis, some can be downstaged using locoregional treatments such as ablation and transarterial chemoembolization. These aforementioned treatments are being applied as bridging therapies to keep patients within transplant criteria and to avoid them from dropping out of the waiting list while awaiting a liver transplant. Moreover, immunotherapy might have great potential to support downstaging and bridging therapies. To address the contemporary status of downstaging, bridging, and immunotherapy in liver transplantation for HCC, European Society of Organ Transplantation (ESOT) convened a dedicated working group comprised of experts in the treatment of HCC to review literature and to develop guidelines pertaining to this cause that were subsequently discussed and voted during the Transplant Learning Journey (TLJ) 3.0 Consensus Conference that took place in person in Prague. The findings and recommendations of the working group on Downstaging, Bridging and Immunotherapy in Liver Transplantation for Hepatocellular Carcinoma are presented in this article.
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Carcinoma Hepatocelular , Quimioembolización Terapéutica , Neoplasias Hepáticas , Trasplante de Hígado , Humanos , Carcinoma Hepatocelular/cirugía , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/cirugía , Neoplasias Hepáticas/patología , Trasplante de Hígado/efectos adversos , Resultado del Tratamiento , Quimioembolización Terapéutica/efectos adversos , Terapia Neoadyuvante/efectos adversos , Estadificación de Neoplasias , InmunoterapiaRESUMEN
Safety of regorafenib in hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT) has been recently demonstrated. We aimed to assess the survival benefit of regorafenib compared with best supportive care (BSC) in LT patients after sorafenib discontinuation. This observational multicenter retrospective study included LT patients with HCC recurrence who discontinued first-line sorafenib. Group 1 comprised regorafenib-treated patients, whereas the control group was selected among patients treated with BSC due to unavailability of second-line options at the time of sorafenib discontinuation and who were sorafenib-tolerant progressors (group 2). Primary endpoint was overall survival (OS) of group 1 compared with group 2. Secondary endpoints were safety and OS of sequential treatment with sorafenib + regorafenib/BSC. Among 132 LT patients who discontinued sorafenib included in the study, 81 were sorafenib tolerant: 36 received regorafenib (group 1) and 45 (group 2) received BSC. Overall, 24 (67%) patients died in group 1 and 40 (89%) in group 2: the median OS was significantly longer in group 1 than in group 2 (13.1 versus 5.5 months; P < 0.01). Regorafenib treatment was an independent predictor of reduced mortality (hazard ratio, 0.37; 95% confidence interval [CI], 0.16-0.89; P = 0.02). Median treatment duration with regorafenib was 7.0 (95% CI, 5.5-8.5) months; regorafenib dose was reduced in 22 (61%) patients for adverse events and discontinued for tumor progression in 93% (n = 28). The median OS calculated from sorafenib start was 28.8 months (95% CI, 17.6-40.1) in group 1 versus 15.3 months (95% CI, 8.8-21.7) in group 2 (P < 0.01). Regorafenib is an effective second-line treatment after sorafenib in patients with HCC recurrence after LT.
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Antineoplásicos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Trasplante de Hígado , Antineoplásicos/efectos adversos , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/cirugía , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/cirugía , Trasplante de Hígado/efectos adversos , Compuestos de Fenilurea/efectos adversos , Piridinas , Estudios Retrospectivos , Sorafenib/uso terapéuticoRESUMEN
BACKGROUND: Indications for liver transplantation for hepatocellular carcinoma are evolving and so-called expanded criteria remain debated. Locoregional therapies are able to downstage hepatocellular carcinoma from beyond to within the Milan criteria. We aimed to investigate the efficacy of liver transplantation after successful hepatocellular carcinoma downstaging. METHODS: We did an open-label, multicentre, randomised, controlled trial designed in two phases, 2b and 3, at nine Italian tertiary care and transplantation centres. Patients aged 18-65 years with hepatocellular carcinoma beyond the Milan criteria, absence of macrovascular invasion or extrahepatic spread, 5-year estimated post-transplantation survival of at least 50%, and good liver function (Child-Pugh A-B7) were recruited and underwent tumour downstaging with locoregional, surgical, or systemic therapies according to multidisciplinary decision. After an observation period of 3 months, during which sorafenib was allowed, patients with partial or complete responses according to modified Response Evaluation Criteria in Solid Tumors were randomly assigned (1:1) by an interactive web-response system to liver transplantation or non-transplantation therapies (control group). A block randomisation (block size of 2), stratified by centre and compliance to sorafenib treatment, was applied. Liver transplantation was done with whole or split organs procured from brain-dead donors. The control group received sequences of locoregional and systemic treatment at the time of demonstrated tumour progression. The primary outcomes were 5-year tumour event-free survival for phase 2b and overall survival for phase 3. Analyses were by intention to treat. Organ allocation policy changed during the course of the study and restricted patient accrual to 4 years. This trial is registered with ClinicalTrials.gov, NCT01387503. FINDINGS: Between March 1, 2011, and March 31, 2015, 74 patients were enrolled. Median duration of downstaging was 6 months (IQR 4-11). 29 patients dropped out before randomisation and 45 were randomly assigned: 23 to the transplantation group versus 22 to the control group. At data cutoff on July 31, 2019, median follow-up was 71 months (IQR 60-85). 5-year tumour event-free survival was 76·8% (95% CI 60·8-96·9) in the transplantation group versus 18·3% (7·1-47·0) in the control group (hazard ratio [HR] 0·20, 95% CI 0·07-0·57; p=0·003). 5-year overall survival was 77·5% (95% CI 61·9-97·1) in the transplantation group versus 31·2% (16·6-58·5) in the control group (HR 0·32, 95% CI 0·11-0·92; p=0·035). The most common registered grade 3-4 serious adverse events were hepatitis C virus recurrence (three [13%] of 23 patients) and acute transplant rejection (two [9%]) in the transplantation group, and post-embolisation syndrome (two [9%] of 22 patients) in the control group. Treatment-related deaths occurred in four patients: two (8%) of 23 patients in the transplantation group (myocardial infarction and multi-organ failure) versus two (9%) of 22 patients in the control group (liver decompensation). INTERPRETATION: Although results must be interpreted with caution owing to the early closing of the trial, after effective and sustained downstaging of eligible hepatocellular carcinomas beyond the Milan criteria, liver transplantation improved tumour event-free survival and overall survival compared with non-transplantation therapies Post-downstaging tumour response could contribute to the expansion of hepatocellular carcinoma transplantation criteria. FUNDING: Italian Ministry of Health.
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Carcinoma Hepatocelular/cirugía , Neoplasias Hepáticas/cirugía , Trasplante de Hígado/mortalidad , Recurrencia Local de Neoplasia/cirugía , Adolescente , Adulto , Anciano , Carcinoma Hepatocelular/patología , Estudios de Casos y Controles , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Tasa de Supervivencia , Adulto JovenRESUMEN
OBJECTIVE: The aim of this study was to evaluate the survival benefit of sirolimus in patients undergoing liver transplantation (LT) for hepatocellular carcinoma (HCC) (exploratory analysis of the SiLVER-trial). SUMMARY AND BACKGROUND DATA: Patients receiving LT) for HCC are at a high risk for tumor recurrence. Calcineurin inhibitors have shown evidence to promote cancer growth, whereas mammalian target of rapamycin (mTOR) inhibitors like sirolimus have anticancer effects. In the SiLVER-trial (Clinicaltrials.gov: NCT00355862), the effect of sirolimus on the recurrence of HCC after LT was investigated in a prospective randomized trial. Although the primary endpoint of improved disease-free survival (DFS) with sirolimus was not met, outcomes were improved for patients in the sirolimus-treatment arm in the first 3 to 5 years. To learn more about the key variables, a multivariate analysis was performed on the SiLVER-trial data. PATIENTS AND METHODS: Data from 508 patients of the intention-to-treat analysis were included in exploratory univariate and multivariate models for overall survival (OS), DFS and a competing risk analysis for HCC recurrence. RESULTS: Sirolimus use for ≥3 months after LT for HCC independently reduced the hazard for death in the multivariate analysis [hazard ratio (HR): 0.7 (95% confidence interval, CI: 0.52-0.96, P = 0.02). Most strikingly, patients with an alpha-fetoprotein (AFP) ≥10 ng/mL and having used sirolimus for ≥3 months, benefited most with regard to OS, DFS, and HCC-recurrence (HR: 0.49-0.59, P = 0.0079-0.0245). CONCLUSIONS: mTOR-inhibitor treatment with sirolimus for ≥3 months improves outcomes in LT for HCC, especially in patients with AFP-evidence of higher tumor activity, advocating particularly for mTOR inhibitor use in this subgroup of patients. CLINICAL TRIAL REGISTRATION: EudraCT: 2005-005362-36 CLINICALTRIALS.GOV:: NCT00355862.
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Carcinoma Hepatocelular/cirugía , Inmunosupresores/uso terapéutico , Neoplasias Hepáticas/cirugía , Trasplante de Hígado , Recurrencia Local de Neoplasia/prevención & control , Sirolimus/uso terapéutico , Anciano , Carcinoma Hepatocelular/mortalidad , Femenino , Humanos , Análisis de Intención de Tratar , Neoplasias Hepáticas/mortalidad , Trasplante de Hígado/mortalidad , Masculino , Persona de Mediana Edad , Tasa de SupervivenciaRESUMEN
Wilson's disease (WD) is a rare genetic disorder with protean manifestations. Even if liver transplantation (LT) could represent an effective therapeutic option for patients with end-stage liver disease, it has remained controversial in the presence of neuropsychiatric involvement. This study aimed to examine the frequency of adult LT for WD in Italy, focusing on the disease phenotype at the time of LT. A retrospective, observational, multicenter study was conducted across Italy exploring the frequency and characteristics of adults transplanted for WD between 2006 and 2016. A total of 29 adult WD patients underwent LT during the study period at 11 Italian LT centers (accounting for 0.4% of all LTs performed), and 27 of them were considered in this analysis (male/female, n = 9/18; age at LT, 29 years [19-60 years]; median Model for End-Stage Liver Disease score at LT, 27 [6-49]). Isolated hepatic phenotype was the indication for LT in 17 (63%) patients, whereas 2 (7%) patients underwent LT for neurological impairment on compensated liver disease. Overall 1- and 5-year patient survival was excellent (88% and 83%, respectively). Neuropsychiatric symptoms early after LT completely recovered in only a few patients. In conclusion, WD remains an uncommon, unusual indication for LT in Italy, displaying good post-LT graft and patient survival. Because isolated neuropsychiatric involvement represents a rare indication to LT, more data are needed to properly assess the value of LT for WD in this subset of patients.
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Enfermedad Hepática en Estado Terminal , Degeneración Hepatolenticular , Trasplante de Hígado , Adulto , Enfermedad Hepática en Estado Terminal/cirugía , Femenino , Degeneración Hepatolenticular/cirugía , Humanos , Italia/epidemiología , Trasplante de Hígado/efectos adversos , Masculino , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
Fibroblast growth factor receptor 2 (FGFR2) might have an important role in the pathogenesis and biology of cholangiocarcinoma (CCA). We examined FGFR expression in CCA tumor specimens obtained from patients and CCA cell lines, and then determined the effects of the novel FGFR inhibitor, derazantinib (DZB; formally, ARQ 087), which is currently in clinical phase 2 trials for intrahepatic CCA. DZB inhibited the growth of CCA cell lines in a dose-dependent manner, and extracellular signal-regulated kinase 1/2 and AKT. It also activated apoptotic and cell growth arrest signaling. DZB reduced the in vitro invasiveness and the expression of key epithelial-mesenchymal transition genes. The in vitro data correlated with the expression of FGFRs in human CCA specimens by immunohistochemistry (FGFR1, 30% positive; and FGFR2, 65% positive) and the CCA cell lines assayed by Western blot analysis. These correlated in vitro studies suggest that FGFR may play an important role in the pathogenesis and biology of CCA. Our findings support the notion that FGFR inhibitors, like DZB, should be further evaluated at the clinical stage as targeted therapy for CCA treatment.
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Compuestos de Anilina/farmacología , Neoplasias de los Conductos Biliares/patología , Colangiocarcinoma/patología , Transición Epitelial-Mesenquimal/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Quinazolinas/farmacología , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/antagonistas & inhibidores , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Neoplasias de los Conductos Biliares/metabolismo , Proliferación Celular , Colangiocarcinoma/tratamiento farmacológico , Colangiocarcinoma/metabolismo , Humanos , Fosforilación , Transducción de Señal , Células Tumorales CultivadasRESUMEN
The gut-liver axis plays a pivotal role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD), which is the third leading cause of hepatocellular carcinoma (HCC) worldwide. However, the link between gut microbiota and hepatocarcinogenesis remains to be clarified. The aim of this study was to explore what features of the gut microbiota are associated with HCC in patients with cirrhosis and NAFLD. A consecutive series of patients with NAFLD-related cirrhosis and HCC (group 1, 21 patients), NAFLD-related cirrhosis without HCC (group 2, 20 patients), and healthy controls (group 3, 20 patients) was studied for gut microbiota profile, intestinal permeability, inflammatory status, and circulating mononuclear cells. We finally constructed a model depicting the most relevant correlations among these features, possibly involved in hepatocarcinogenesis. Patients with HCC showed increased levels of fecal calprotectin, while intestinal permeability was similar to patients with cirrhosis but without HCC. Plasma levels of interleukin 8 (IL8), IL13, chemokine (C-C motif) ligand (CCL) 3, CCL4, and CCL5 were higher in the HCC group and associated with an activated status of circulating monocytes. The fecal microbiota of the whole group of patients with cirrhosis showed higher abundance of Enterobacteriaceae and Streptococcus and a reduction in Akkermansia. Bacteroides and Ruminococcaceae were increased in the HCC group, while Bifidobacterium was reduced. Akkermansia and Bifidobacterium were inversely correlated with calprotectin concentration, which in turn was associated with humoral and cellular inflammatory markers. A similar behavior was also observed for Bacteroides. Conclusion: Our results suggest that in patients with cirrhosis and NAFLD the gut microbiota profile and systemic inflammation are significantly correlated and can concur in the process of hepatocarcinogenesis.
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Carcinoma Hepatocelular/congénito , Carcinoma Hepatocelular/microbiología , Microbioma Gastrointestinal , Inflamación/complicaciones , Cirrosis Hepática/complicaciones , Neoplasias Hepáticas/complicaciones , Neoplasias Hepáticas/microbiología , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Anciano , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Key Points ⢠Recurrent HCC after OLT management is challenging and notoriously difficult. ⢠High oncologic-risk patient identification and close follow-up are essential. ⢠Recurrences diagnosed within the first 2 years after OLT can be classified as early-onset and are associated with poor prognosis. ⢠Surgical resection should be the first curative attempt when it is technically feasible. ⢠TACE in patients who have undergone OLT appears to be effective and safe. ⢠Sorafenib can be used as systemic therapy in cases with multi-organ recurrence; newer therapies are emerging. ⢠The benefit of immunosuppression with an mTOR inhibitor has not been established. ⢠In the posttransplant setting, a combination treatment approach is warranted.
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Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , Trasplante de Hígado , Recurrencia Local de Neoplasia/patología , Carcinoma Hepatocelular/etiología , Carcinoma Hepatocelular/cirugía , Terapia Combinada , Femenino , Hepatitis C/patología , Humanos , Neoplasias Hepáticas/etiología , Neoplasias Hepáticas/cirugía , Persona de Mediana Edad , Recurrencia Local de Neoplasia/etiología , Recurrencia Local de Neoplasia/terapia , Factores de Riesgo , Resultado del TratamientoRESUMEN
BACKGROUND: Next-generation sequencing has identified actionable genetic aberrations in intrahepatic cholangiocarcinomas (iCCA), including the fibroblast growth factor receptor 2 (FGFR2) fusions. Derazantinib (ARQ 087), an orally bioavailable, multi-kinase inhibitor with potent pan-FGFR activity, has shown preliminary therapeutic activity against FGFR2 fusion-positive iCCA. METHODS: This multicentre, phase 1/2, open-label study enrolled adult patients with unresectable iCCA with FGFR2 fusion, who progressed, were intolerant or not eligible to first-line chemotherapy (NCT01752920). Subjects received derazantinib in continuous daily doses. Tumour response was assessed according to RECIST 1.1 every 8 weeks. RESULTS: Twenty-nine patients (18 women/11 men; median age, 58.7 years), 2 treatment-naive and 27 who progressed after at least one prior systemic therapy, were enrolled. Overall response rate was 20.7%, disease control rate was 82.8%. Estimated median progression-free survival was 5.7 months (95% CI: 4.04-9.2 months). Treatment-related adverse events (AE) were observed in 27 patients (93.1%, all grades), including asthenia/fatigue (69.0%), eye toxicity (41.4%), and hyperphosphatemia (75.9%). Grade ≥ 3 AEs occurred in 8 patients (27.6%). CONCLUSION: Derazantinib demonstrated encouraging anti-tumour activity and a manageable safety profile in patients with advanced, unresectable iCCA with FGFR2 fusion who progressed after chemotherapy. A pivotal trial of derazantinib in iCCA is ongoing (NCT03230318).
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Alcaloides/administración & dosificación , Colangiocarcinoma/tratamiento farmacológico , Proteínas de Fusión Oncogénica/genética , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/genética , Adulto , Anciano , Anciano de 80 o más Años , Alcaloides/efectos adversos , Colangiocarcinoma/genética , Colangiocarcinoma/patología , Ensayos Clínicos como Asunto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mutación , Proteínas de Fusión Oncogénica/efectos de los fármacos , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversosRESUMEN
Regorafenib is one option for second-line treatment of hepatocellular carcinoma (HCC), improving overall survival (OS) of sorafenib-tolerant patients who develop progression. We aim to evaluate the safety and outcomes of regorafenib as second-line treatment for HCC recurrence after liver transplantation (LT). This is a retrospective, multicenter, international study including regorafenib-treated LT patients (2015-2018), with analysis of baseline characteristics and evolutionary events during sorafenib/regorafenib treatment. Twenty-eight LT patients (57 years, 7% cirrhotics, 54% performance status 1) were included. Median time from LT to regorafenib initiation was 3.9 (1.1-18.5) years; median time on sorafenib was 11.3 (0.7-76.4) months and 14 (1-591) days from sorafenib discontinuation to regorafenib. During regorafenib (6.3 months), all patients had at least one adverse event (AE), the most common grade 3/4 AEs were fatigue (n = 7) and dermatological reaction (n = 5). While no liver rejection was observed, plasma levels of immunosuppressive drugs increased in five. Twenty-four patients developed progression (38% extrahepatic growth, 33% new extrahepatic lesions/vascular invasion). Median OS from regorafenib initiation was 12.9 (95% CI, 6.7-19.1) and 38.4 months (95% CI, 18.5-58.4) for the sorafenib initiation. This is the first study showing safety of regorafenib after LT, thus providing the rational of considering regorafenib in the clinical decision-making in sorafenib-tolerant patients with HCC recurrence after LT.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma Hepatocelular/cirugía , Resistencia a Antineoplásicos/efectos de los fármacos , Neoplasias Hepáticas/cirugía , Trasplante de Hígado/efectos adversos , Recurrencia Local de Neoplasia/tratamiento farmacológico , Adulto , Anciano , Carcinoma Hepatocelular/patología , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/etiología , Recurrencia Local de Neoplasia/patología , Compuestos de Fenilurea/administración & dosificación , Pronóstico , Piridinas/administración & dosificación , Estudios Retrospectivos , Sorafenib/administración & dosificación , Adulto JovenRESUMEN
BACKGROUND & AIMS: Yttrium-90 transarterial radioembolization (TARE) has shown promising efficacy in the treatment of patients with hepatocellular carcinoma (HCC), associated with portal vein tumor thrombus (PVTT). The aim of this study is to identify prognostic factors for survival in patients with HCC and PVTT undergoing TARE, and build a prognostic classification for these patients. METHODS: This is a single center retrospective study conducted over six years (2010-2015), on consecutive patients undergoing TARE. Patients were included if they met the following criteria: presence of at least one measurable HCC, presence of PVTT not occluding the main portal trunk, absence of extrahepatic metastases, Child-Pugh score within B7, Eastern Cooperative Oncology Group performance status 0-1. Uni- and multivariable analysis was used to explore the variables that showed an independent relationship with survival. A prognostic score was then derived, and three prognostic categories were identified. RESULTS: A total of 120 patients were included in the study. Median overall survival (OS) was 14.1â¯months (95% CI 10.7-17.5) and median progression-free survival (PFS) was 6.5â¯months (95% CI 3.8-9.2). The only variables independently correlated with OS were bilirubin, extension of PVTT and tumor burden. Three prognostic categories were identified: favourable prognosis (0 points), intermediate prognosis (2-3 points) and dismal prognosis (>3 points). Median OS in the three categories was 32.2â¯months, 14.9â¯months and 7.8â¯months respectively (pâ¯<0.0001). PFS (pâ¯=â¯0.045) and the risk of liver decompensation (pâ¯<0.0001) also significantly differed along the same prognostic categories. CONCLUSIONS: Radioembolization with Yttrium-90 is an effective therapy for patients with HCC and PVTT. The proposed prognostic stratification may help to better identify good candidates for the treatment, and those for whom TARE may be futile. LAY SUMMARY: Yttrium-90 transarterial radioembolization (TARE) is a microembolic procedure that minimizes alterations to hepatic arterial flow, and thus can be safely performed in patients with hepatocellular carcinoma (HCC) and portal vein tumor thrombus (PVTT). In this study, we retrospectively evaluated the independent predictors of long-term outcomes in patients with HCC and PVTT treated with TARE. Bilirubin level, extension of PVTT and tumor burden were independently related to post-treatment survival: the combination of these factors allowed us to build a prognostic stratification that may help to better identify good candidates for the treatment, and those for whom TARE may be futile.
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Carcinoma Hepatocelular/terapia , Embolización Terapéutica/métodos , Neoplasias Hepáticas/terapia , Vena Porta/patología , Radioisótopos de Itrio/uso terapéutico , Anciano , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/patología , Femenino , Humanos , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Pronóstico , Estudios RetrospectivosRESUMEN
BACKGROUND: Trans-arterial radio-embolization (TARE) is an emerging treatment for the management of hepatocellular carcinoma (HCC). TARE may compete with systemic chemotherapy, sorafenib, in intermediate stage patients with prior chemoembolization failure or advanced patients with tumoral macrovascular invasion with no extra-hepatic spread and good liver function. We performed a budget impact analysis (BIA) evaluating the expected changes in the expenditure for the Italian Healthcare Service within scenarios of increased utilization of TARE in place of sorafenib over the next five years. METHODS: Starting from patient level data from three oncology centres in Italy, a Markov model was developed to project on a lifetime horizon survivals and costs associated to matched cohorts of intermediate-advanced HCC patients treated with TARE or sorafenib. The initial model has been integrated with epidemiological data to perform a BIA comparing the current scenario with 20 and 80% utilization rates for TARE and sorafenib, respectively, with increasing utilization rates of TARE of 30, 40 and 50% over the next 1, 3 and 5 years. RESULTS: Compared to the current scenario, progressively increasing utilization rates of TARE over sorafenib in the next 5 years is expected to save globally about 7 million Euros. CONCLUSIONS: Radioembolization can be considered a valuable treatment option for patients with intermediate-advanced HCC. These findings enrich the evidence about the economic sustainability of TARE in comparison to standard systemic chemotherapy within the context of a national healthcare service.
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Carcinoma Hepatocelular/terapia , Embolización Terapéutica/métodos , Neoplasias Hepáticas/terapia , Embolización Terapéutica/economía , Costos de la Atención en Salud , Recursos en Salud , Humanos , Cadenas de MarkovRESUMEN
BACKGROUND & AIMS: Hepatitis C virus (HCV) re-infection following liver transplant (LT) is associated with reduced graft and patient survival. Before transplant, Sofosbuvir/Ribavirin (SOF/R) treatment prevents recurrent HCV in 96% of those patients achieving viral suppression for at least 4 weeks before transplant. We evaluated whether a bridging SOF-regimen from pre- to post-transplant is safe and effective to prevent HCV recurrence in those patients with less than 4 weeks of HCV-RNA undetectability at the time of transplant. METHODS: From July 2014 SOF/R was given in 233 waitlisted HCV cirrhotics with/without hepatocellular carcinoma (HCC) within an Italian Compassionate Program. One hundred patients were transplanted and 31 patients (31%) treated with SOF/R bridging therapy were studied. RESULTS: Liver transplant indication in bridge subgroup was HCC in 22 and decompensated cirrhosis in 9. HCV-genotype was 1/4 in 18 patients. SOF 400 mg/day and R (median dosage 800 mg/day) were given for a median of 35 days before LT. At transplant time, 19 patients were still HCV-RNA positive (median HCV-RNA 58 IU/mL). One recipient had a virological breakthrough at week 4 post-transplant; one died, on treatment, 1-month post-transplant for sepsis and 29/31 achieved a 12-week sustained virological response (94%). Acute cellular rejection occurred in three recipients. On September 2016, 30 recipients (97%) were alive with a median follow-up of 18 months (range 13-25). CONCLUSIONS: In patients with suboptimal virological response at LT, a bridging SOF/R regimen helps avoiding post-transplant graft reinfection.
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Antivirales/uso terapéutico , Hepatitis C/tratamiento farmacológico , Trasplante de Hígado , Ribavirina/uso terapéutico , Sofosbuvir/uso terapéutico , Adulto , Anciano , Antivirales/efectos adversos , Carcinoma Hepatocelular/terapia , Quimioterapia Combinada , Femenino , Hepacivirus/genética , Hepatitis C/prevención & control , Humanos , Italia , Cirrosis Hepática/terapia , Neoplasias Hepáticas/terapia , Masculino , Persona de Mediana Edad , Periodo Posoperatorio , Periodo Preoperatorio , Recurrencia , Estudios Retrospectivos , Ribavirina/efectos adversos , Sofosbuvir/efectos adversos , Respuesta Virológica SostenidaRESUMEN
BACKGROUND & AIMS: Various grades of adverse events are associated with sorafenib and have recently been considered as a surrogate of response in patients with advanced hepatocellular carcinoma. The aim of this prospective study was to measure the efficacy of a sorafenib dose reduction regimen, adjusted on patient's tolerability, and aimed at increasing the exposure to the drug. METHODS: A total of 73/140 patients with advanced hepatocellular carcinoma receiving sorafenib developed relevant adverse events (grade ≥2) and were managed with a tolerable-adverse-event-protocol consisting of a drug stepwise dose reduction adjusted on patient's tolerability. The remaining 67 patients with toxicity grade 0-1 (minor adverse event group) were managed conventionally with just symptomatic treatment. RESULTS: Median follow-up was 7 months. By adopting the tolerable-adverse-event-protocol, 48% of patients meant to transiently or definitively interrupt the drug were kept on treatment. Macrovascular invasion with/out extra-hepatic spread (HR = 1.9, 95% CI: 1.3-2.8; P = 0.001) and sorafenib exposure <2 months (HR = 4, 95% CI: 2.5-6.4; P < 0.0001) were independently related to a worse survival. Overall disease control rate, time to progression and survival were: 63.5%, 6 and 9.1 months respectively. The tolerable-adverse-event-protocol group experienced a more favourable outcome with respect to the minor adverse event group as for disease control rate (78% vs. 48%: P < 0.0001), time to progression (9.5 vs. 3 months; HR = 0.3, 95% CI: 0.2-0.5, P < 0.0001) and survival (12.5 vs. 5.7 months; HR = 0.4, 95% CI: 0.3-0.6; P < 0.0001). CONCLUSIONS: In patients with advanced hepatocellular carcinoma, sorafenib dose adjustments based on inducing tolerability of relevant adverse events prolong drug exposure and maximize survival.
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Antineoplásicos/efectos adversos , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Niacinamida/análogos & derivados , Compuestos de Fenilurea/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/administración & dosificación , Progresión de la Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Italia , Masculino , Persona de Mediana Edad , Análisis Multivariante , Estadificación de Neoplasias , Niacinamida/administración & dosificación , Niacinamida/efectos adversos , Compuestos de Fenilurea/administración & dosificación , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Sorafenib , Factores de Tiempo , Privación de Tratamiento , Adulto JovenRESUMEN
BACKGROUND AND AIM: Solid demonstrations of superior efficacy of drug-eluting beads transarterial chemoembolization with respect to conventional chemoembolization in hepatocellular carcinoma patients are lacking. The aim of the study was to compare these two techniques in two large cohorts of unresectable hepatocellular carcinoma patients. METHODS: A single center series of 249 early/intermediate hepatocellular carcinoma patients who underwent "on demand" chemoembolization in the period 2007-2011 was analyzed. Overall survival, time to progression, tumor response rate, and safety were compared between 104 patients who underwent conventional chemoembolization and 145 who underwent drug-eluting beads chemoembolization. Time-to-event data were analyzed using the Cox univariate and multivariate regression. RESULTS: The two cohorts resulted balanced for liver function and tumor stages. Objective response rate was 85.3% after conventional and 74.8% after drug-eluting beads chemoembolization (P = 0.039), and median time to progression was 17 (95% confidence interval: 14-21) versus 11 months (9-12), respectively (P < 0.001). Treatment regimen was the sole independent predictor of progression at multivariate analysis (hazard ratio = 2.01; 1.45-2.80; P < 0.001). Median survival was 39 (32-47) and 32 (24-39) months in the two groups, respectively (hazard ratio = 1.33; 0.94-1.87; P = 0.10), but conventional chemoembolization was significantly associated with a survival advantage in patients with bilobar neoplasia, portal hypertension and alpha fetoprotein above normal limits. No significant differences in severe adverse events were found. CONCLUSION: In a large series of Western hepatocellular carcinoma patients, drug-eluting beads chemoembolization with 100-300 µm particles did not seem to improve survival in comparison with conventional chemoembolization, which in turn provided better tumor responses and time to progression.
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Carcinoma Hepatocelular/terapia , Quimioembolización Terapéutica/métodos , Neoplasias Hepáticas/terapia , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antibióticos Antineoplásicos/administración & dosificación , Quimioembolización Terapéutica/mortalidad , Estudios de Cohortes , Progresión de la Enfermedad , Doxorrubicina/administración & dosificación , Femenino , Humanos , Infusiones Intraarteriales , Neoplasias Hepáticas/mortalidad , Masculino , Persona de Mediana Edad , Tamaño de la Partícula , Modelos de Riesgos Proporcionales , Análisis de Regresión , Tasa de Supervivencia , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) has become a major cause of liver-related death and indication to liver transplantation (LT) in patients with chronic hepatitis B virus (HBV) infection following the widespread adoption of antiviral therapy with nucleos(t)ide analogs (NUCs). Yet, the long-term outcome of patients undergoing liver transplantation for an HCC developed during effective NUC treatment is unknown. METHODS: We evaluated 101 patients with persistently compensated cirrhosis who were consecutively transplanted for HCC in two centers in Milan. At LT, 91 (90%) patients had undetectable serum HBV DNA (<12 IU/ml) and 90 (89%) were within Milan criteria (MC). All patients received post-transplant HBV prophylaxis with specific immunoglobulins (HBIgs) and NUCs. End-points were long-term patient survival and recurrence of HCC and HBV. RESULTS: During 106 (range 3-165) months following LT, HCC recurred in 11 (11%) patients (nine beyond MC at explant, two with HBV recurrence). Age (HR 1.1, 95%CI 1.0-1.2, P = 0.04) and exceeding MC (HR 9.6, 95%CI 2.9-32, P < 0.0001) were the only independent pretransplant predictors of tumour recurrence. The 10-year cumulative rate of HCC recurrence was 7% among patients transplanted within MC compared with 45% among those beyond MC at LT (P = 0.004). Overall, 18 patients (18%, nine HCC, nine non liver-related events) died with a 10-year cumulative probability of overall and liver-related survival of 79% and 89% respectively. CONCLUSIONS: Extended survival of HBV cirrhotics transplanted for HCC can be achieved by coupling MC at listing with persistent pharmacological suppression of HBV.