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Alessandro Granito,1,2 Sara Marinelli,1 Antonella Forgione,1,2 Matteo Renzulli,3 Francesca Benevento,2 Fabio Piscaglia,1,2 Francesco Tovoli1,2 1Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy; 2Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy; 3Radiology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, ItalyCorrespondence: Alessandro GranitoIRCCS Azienda Ospedaliero-Universitaria di Bologna, via Albertoni 15, Bologna, ItalyEmail alessandro.granito@unibo.itAbstract: Regorafenib was the first drug to demonstrate a survival benefit as a second-line agent after sorafenib failure in patients with unresectable hepatocellular carcinoma (HCC). Recent studies have shown that its mechanism of action is not only limited to its very broad spectrum of inhibition of angiogenesis, tumor proliferation, spread, and metastasis, but also to its immunomodulatory properties that have favorable effects on the very intricate role that the tumor microenvironment plays in carcinogenesis and tumor growth. In this review, we discuss rationale and evidence supporting regorafenib efficacy in HCC and that led to its approval as a second-line treatment, after sorafenib failure. We also discuss the evidence from clinical practice studies that confirm the results previously achieved in clinical trials. Finally, we analyze the potential role of regorafenib in emerging combined treatment approach with immunotherapy strategies using immune checkpoint blockade and its potential extension to patient categories not included in the registrative study.Keywords: hepatocellular carcinoma, HCC, regorafenib, tyrosine kinase inhibitor, TKI, systemic treatment, combination treatment

In Italia, la maggior parte dei casi di epatocarcinoma (HCC) insorge in pazienti affetti da cirrosi epatica, che presentano un grado variabile di insufficienza epatica. Pertanto, la prognosi dei pazienti con HCC è condizionata non solo dalla estensione della neoplasia, ma anche dalla residua funzione epatica. Scopo della Tesi Analizzare i principali aspetti della terapia farmacologica del paziente affetto da HCC attraverso: 1. Ricerca di predittori clinico-laboratoristici di risposta al Sorafenib in pazienti ambulatoriali con HCC; 2. Indagare se il decorso naturale e la risposta al trattamento anticoagulante della Trombosi non neoplastica del sistema venoso portale (PVT) nei pazienti con cirrosi complicata da HCC differisca da quelli senza HCC; 3. Fornire nuovi aggiornamenti sull’immunoterapia antineoplastica che promette di plasmare il futuro scenario terapeutico dell'HCC mediante una revisione della letteratura. Studio 1: Ha confermato l'efficacia e il profilo di sicurezza di Sorafenib nel trattamento a lungo termine dei pazienti con HCC, evidenziando come il trattamento con Sorafenib può dare un significativo aumento della sopravvivenza, in presenza anche di un soddisfacente profilo di sicurezza, in una rilevante quota di pazienti (22%). Lo studio 2 ha dimostrato che la presenza di HCC attivo non influisce negativamente sul decorso della Trombosi non neoplastica del sistema venoso portale (PVT) e sull'efficacia del trattamento anticoagulante. Pertanto, il paziente con HCC con Trombosi non neoplastica del sistema venoso portale, non presenta condizioni sfavorevoli al trattamento con anticoagulanti, eventualmente permettendo, in caso di risoluzione della trombosi, terapie altrimenti controindicate (TACE) Lo studio 3 conferma come l'immunoterapia per l'HCC sembra essere un campo di indagine molto intenso, suscitando la speranza che nuove opportunità terapeutiche molto efficaci diventino presto disponibili e portino a nuove e più vantaggiose strategie nella gestione dei pazienti con HCC., In Italy, most cases of Hepatocellular carcinoma (HCC) occur in patients with Liver Cirrhosis, who have a variable degree of liver failure. Therefore, the prognosis of patients with HCC is conditioned not only by the extension of tumour, but also by the residual liver function. Purpose of the thesis: Analyze the main features of pharmacological therapy in patient with Hepatocellular carcinoma through: 1. Research of clinical-laboratory predictors of response to Sorafenib treatment in outpatients with HCC; 2. To investigate whether the natural course and response to anticoagulant treatment of non-neoplastic portal vein thrombosis (PVT) in patients with cirrhosis complicated by HCC differs from those without HCC; 3. Provide new updates on antineoplastic immunotherapy that promises to shape the future therapeutic scenario of HCC through a literature review. Study 1: Confirms the efficacy and safety profile of Sorafenib in the long-term treatment of patients with HCC, highlighting how treatment with Sorafenib can give a significant increase in survival, even in the presence of a satisfactory safety profile, in a significant group of patients (22%) Study 2 : Shows that the presence of active HCC does not negatively influence the course of non-neoplastic portal vein thrombosis (PVT) and the efficacy of anticoagulant treatment. Therefore, patient with HCC with non-neoplastic portal vein thrombosis, does not present unfavorable conditions for treatment with anticoagulants, possibly enabling, in case of resolution of thrombosis, contraindicated alternative therapies (TACE) Study 3 Confirms that immunotherapy for HCC appears to be a very intense field of investigation with the hope that new highly effective therapeutic opportunities will soon become available and lead to new and more advantageous strategies in management of patients with HCC.

Background & Aims: Determining risk for recurrence or survival after curative resection or ablation in patients with hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) is important for stratifying patients according to expected outcomes in future studies of adjuvant therapy in the era of direct-acting antivirals (DAAs). The aims of this meta-analysis were to estimate the recurrence and survival probabilities of HCV-related early HCC following complete response after potentially curative treatment and to identify predictors of recurrence and survival. Methods: Studies reporting time-dependent outcomes (HCC recurrence or death) after potentially curative treatment of HCV-related early HCC were identified in MEDLINE through May 2016. Data on patient populations and outcomes were extracted from each study by three independent observers and combined using a distribution-free summary survival curve. Primary outcomes were actuarial probabilities of recurrence and survival. Results: Eleven studies met the inclusion criteria. Pooled estimates of actuarial recurrence rates were 7.4% at 6months and 47.0% at 2years. Pooled estimates of actuarial survival rates were 79.8% at 3years and 58.6% at 5years. Heterogeneity among studies was highly significant for all outcomes. By univariate meta-regression analyses, lower serum albumin, randomized controlled trial study design and follow-up were independently associated with higher recurrence risk, whereas tumour size and alpha-foetoprotein levels were associated with higher mortality. Conclusions: This meta-analysis showed that recurrence risk and survival are extremely variable in patients with successfully treated HCV-related HCC, providing a useful benchmark for indirect comparisons of the benefits of DAAs and for a correct design of randomized controlled trials in the adjuvant setting.

Background An enhanced surveillance schedule has been proposed for cirrhotics with viral etiology, who are considered at extremely high-risk of hepatocellular carcinoma (HCC). Aims We compared the 3- and 6-months surveillance interval, evaluating cancer stage at diagnosis and patient survival. Methods Data of 777 HBV and HCV cirrhotic patients with HCC diagnosed under a 3-months (n = 109, 3MS group) or a 6-months (n = 668, 6MS group) surveillance were retrieved from the Italian Liver Cancer database. Survival in the 3MS group was considered as observed and adjusted for lead-time bias, and survival analysis was repeated after a propensity score matching. Results The 3-months surveillance interval neither reduced the share of patients diagnosed outside the Milano criteria, nor increased their probability to receive curative treatments. The median survival of 6MS patients (55.0 months [45.9–64.0]) was not significantly different from the observed (47.0 months [35.0–58.9]; p = 0.43) and adjusted (44.9 months [33.4–56.4]; p = 0.30) survival of 3MS patients. A propensity score analysis confirmed the absence of a survival advantage for 3MS patients. Conclusions A tightening of surveillance schedule does not increase the diagnosis of early-stage tumors, the feasibility of curative treatments and the survival. Therefore, we should maintain the 6-months interval in the surveillance of viral cirrhotics.

Background: Inflammation is a long-established hallmark of liver fibrosis and carcinogenesis. Eosinophils are emerging as crucial components of the inflammatory process influencing cancer development. The role of blood eosinophils in patients with hepatocellular carcinoma receiving systemic treatment is an unexplored field. Objective: The objective of this study was to analyse the prognostic role of the baseline eosinophil count in patients with sorafenib-treated hepatocellular carcinoma. Patients and Methods: A training cohort of 92 patients with advanced- or intermediate-stage sorafenib-treated hepatocellular carcinoma and two validation cohorts of 65 and 180 patients were analysed. Overall survival and progression-free survival in relation to baseline eosinophil counts were estimated by the Kaplan–Meier method. Univariate and multivariate analyses were performed. Results: A negative prognostic impact of low baseline eosinophil counts (< 50*109/L) was demonstrated in all cohorts (training cohort: hazard ratio = 50.1, 95% confidence interval 11.6–216.5, p < 0.0001 for low vs high eosinophil counts; first validation cohort: hazard ratio = 4.55, 95% confidence interval 1.24–16.65, p = 0.022; second validation cohort: hazard ratio = 3.21, 95% confidence interval 1.83–5.64, p < 0.0001). Moreover, low eosinophil counts had a negative prognostic role in patients progressing on or intolerant to sorafenib who received second-line regorafenib, but not capecitabine or best supportive care. Conclusions: Our analysis identified baseline blood eosinophil counts as a new prognostic factor in patients with sorafenib-treated hepatocellular carcinoma. Concerning second-line therapies, eosinophil counts were associated with survival outcomes only in regorafenib-treated patients, suggesting a possible predictive role in this setting.

none 7 no Background & Aims: Pain management in cirrhosis is a clinical challenge. Most analgesics are metabolized in the liver and cirrhosis may deeply alter their concentration, favouring the appearance of side effects. We aimed to assess the efficacy and safety of oral prolonged-release association of oxycodone/naloxone tablets (OXN) in the treatment of moderate/severe cancer pain in cirrhotic patients with metastatic hepatocellular carcinoma (HCC). Methods: We enrolled n = 32 HCC patients with moderate/severe cancer pain unresponsive to paracetamol alone or associated with codeine or tramadol. All patients received an initial OXN dose of 5 mg bid to be gradually increased in case of insufficient analgesia. At baseline and follow-up visits, we evaluated: pain intensity (using the Numerical Rating Scale, NRS), patients' autonomy in daily activities (Barthel Functioning Index); bowel dysfunction (Bowel Function Index, BFI), signs of hepatic encephalopathy (HE) and other opioid-induced side effects. Results: No clinically significant adverse effects were reported (median follow-up 122 days). No significant worsening of the BFI score was noted and no cases of HE were detected. Two patients (6.3%) discontinued treatment before T14 because of mild nausea and dizziness. The remaining n = 30 patients were assessed for efficacy. Treatment led to a significant reduction in the mean of pain scores both at T14 (-37.1 ± 16.3%, P < .001) and at T28 (-55.6 ± 21.5%, P < .001); Barthel scores showed gradual and significant increase from T0 (81.6 ± 13.0) to T14 (86.5 ± 11.4, P = .001) and to T28 (88.3 ± 13.6, P = .009). Conclusions: OXN may be considered a safe and effective option in the fragile population of cirrhotic patients. Tovoli, Francesco; De Lorenzo, Stefania; Samolsky Dekel, Boaz G.; Piscaglia, Fabio; Benevento, Francesca; Brandi, Giovanni; Bolondi, Luigi Tovoli, Francesco; De Lorenzo, Stefania; Samolsky Dekel, Boaz G.; Piscaglia, Fabio; Benevento, Francesca; Brandi, Giovanni; Bolondi, Luigi

Sorafenib has been the only approved systemic treatment of hepatocellular carcinoma (HCC) for almost a decade. Recently, two new drugs showed positive results in two Phase III studies. The RESORCE trial identified regorafenib as a valid second-line treatment for patients progressing to sorafenib, the REFLECT trial showed that lenvatinib is noninferior to sorafenib as front-line treatment. Following these trials, the therapeutic scenario will be dominated by anti-VEGFR drugs, with three different molecules showing a proven anticancer activity. Some open problems still remain and different immunotherapy trials are underway, following promising preliminary results. In this review we analyze: the most recent advancements about patients treated with sorafenib; the results of RESORCE and REFLECT trials; and the ongoing Phase III clinical trials. Finally, we discuss how they could address the current problems and possibly reshape the future of the systemic treatments for HCC.

Background No standard second-line treatments are available for hepatocellular carcinoma patients who fail sorafenib therapy. We assessed the safety and efficacy of metronomic capecitabine after first-line sorafenib failure. Methods Retrospective analysis of consecutive hepatocellular carcinoma patients receiving metronomic capecitabine between January 2012 and November 2014. The primary end-point was safety, secondary end-point was efficacy, including time-to-progression and overall survival. Results Twenty-six patients (80% Child–Pugh A, 80% Barcelona Clinic Liver Cancer stage C) received metronomic capecitabine (500 mg/bid). Median treatment duration was 3.2 months (range 0.6–31). Fourteen (53%) patients experienced at least one adverse event. The most frequent drug-related adverse events were bilirubin elevation (23%), fatigue (15%), anaemia (11%), lymphoedema (11%), and hand–foot syndrome (7.6%). Treatment was interrupted in 19 (73%) for disease progression, in 4 (15%) for liver deterioration, and in 1 (3.8%) for adverse event. Disease control was achieved in 6 (23%) patients. Median time-to-progression was 4 months (95% confidence interval 3.2–4.7). Median overall survival was 8 months (95% confidence interval 3.7–12.3). Conclusions Metronomic capecitabine was well tolerated in hepatocellular carcinoma patients who had been treated with sorafenib. Preliminary data show potential anti-tumour activity with long-lasting disease control in a subgroup of patients that warrants further evaluation in a phase III study.