The changing scenario of hepatocellular carcinoma in Italy: an update.

BACKGROUND AND AIMS: Epidemiology of hepatocellular carcinoma (HCC) is changing in most areas of the world. This study aimed at updating the changing scenario of aetiology, clinical presentation, management and prognosis of HCC in Italy during the last 15 years. METHODS: Retrospective analysis of the Italian Liver Cancer (ITA.LI.CA) database included 6034 HCC patients managed in 23 centres from 2004 to 2018. Patients were divided into three groups according to the date of cancer diagnosis (2004-2008, 2009-2013 and 2014-2018). RESULTS: The main results were: (i) a progressive patient ageing; (ii) a progressive increase of non-viral cases and, particularly, of 'metabolic' and 'metabolic + alcohol' HCCs; (iii) a slightly decline of cases diagnosed under surveillance, but with an incremental use of the semiannual schedule; (iv) a favourable cancer stage migration; (v) an increased use of radiofrequency ablation to the detriment of percutaneous ethanol injection; (vi) improved outcomes of ablative and transarterial treatments; (vii) an improved overall survival (adjusted for the lead time in surveyed patients) in the last calendar period, particularly in viral patients; (viii) a large gap between the number of potential candidates (according to oncologic criteria and age) to liver transplant and that of transplanted patients. CONCLUSIONS: During the last 15 years several aspects of HCC scenario have changed, as well as its management. The improvement in patient survival observed in the last period was likely because of a larger use of thermal ablation with respect to the less effective alcohol injection and to an improved management of intermediate stage patients.

Alpha-fetoprotein for Diagnosis, Prognosis, and Transplant Selection.

Reliable biomarkers are of great clinical value in predicting cancer occurrence/recurrence, anticipating its detection at an asymptomatic stage, supporting the radiological diagnosis, stratifying patients for prognosis and proper therapy, and measuring the response to treatment. Despite the plethora of biomarkers proposed for hepatocellular carcinoma (HCC), the first one identified, α-fetoprotein (AFP), remains the most utilized. This article reviews the lights and shadows of AFP as a surveillance test for patients at risk of HCC, and as a diagnostic test for those with chronic liver disease and a suspected hepatic mass. Moreover, the article scrutinizes the large body of evidence supporting the prognostic relevance of AFP in patients undergoing both curative and palliative treatment of HCC and the growing importance attributed to this biomarker (as a static or a dynamic variable) in the selection of potential candidates for liver transplantation. In fact, the inclusion of AFP among transplant criteria would improve the ability of identifying poor candidates due to an unacceptable risk of HCC recurrence regardless of tumor burden, and of adopting flexible morphological selection criteria.

Patients with advanced hepatocellular carcinoma need a personalized management: A lesson from clinical practice.

The Barcelona Clinic Liver Cancer (BCLC) advanced stage (BCLC C) of hepatocellular carcinoma (HCC) includes a heterogeneous population, where sorafenib alone is the recommended treatment. In this study, our aim was to assess treatment and overall survival (OS) of BCLC C patients subclassified according to clinical features (performance status [PS], macrovascular invasion [MVI], extrahepatic spread [EHS] or MVI + EHS) determining their allocation to this stage. From the Italian Liver Cancer database, we analyzed 835 consecutive BCLC C patients diagnosed between 2008 and 2014. Patients were subclassified as: PS1 alone (n = 385; 46.1%), PS2 alone (n = 146; 17.5%), MVI (n = 224; 26.8%), EHS (n = 51; 6.1%), and MVI + EHS (n = 29; 3.5%). MVI, EHS, and MVI + EHS patients had larger and multifocal/massive HCCs and higher alpha-fetoprotein (AFP) levels than PS1 and PS2 patients. Median OS significantly declined from PS1 (38.6 months) to PS2 (22.3 months), EHS (11.2 months), MVI (8.2 months), and MVI + EHS (3.1 months; P < 0.001). Among MVI patients, OS was longer in those with peripheral than with central (portal trunk) MVI (11.2 vs. 7.1 months; P = 0.005). The most frequent treatments were: curative approaches in PS1 (39.7%), supportive therapy in PS2 (41.8%), sorafenib in MVI (39.3%) and EHS (37.3%), and best supportive care in MVI + EHS patients (51.7%). Independent prognostic factors were: Model for End-stage Liver Disease score, Child-Pugh class, ascites, platelet count, albumin, tumor size, MVI, EHS, AFP levels, and treatment type. CONCLUSION: BCLC C stage does not identify patients homogeneous enough to be allocated to a single stage. PS1 alone is not sufficient to include a patient into this stage. The remaining patients should be subclassified according to PS and tumor features, and new patient-tailored therapeutic indications are needed. (Hepatology 2018;67:1784-1796).

Curative therapies are superior to standard of care (transarterial chemoembolization) for intermediate stage hepatocellular carcinoma.

BACKGROUND & AIMS: The Barcelona Clinic Liver Cancer intermediate stage (BCLC-B) of hepatocellular carcinoma (HCC) includes extremely heterogeneous patients in terms of tumour burden and liver function. Transarterial-chemoembolization (TACE) is the first-line treatment for these patients although it may be risky/useless for someone, while others could undergo curative treatments. This study assesses the treatment type performed in a large cohort of BCLC-B patients and its outcome. METHODS: Retrospective analysis of 485 consecutive BCLC-B patients from the ITA.LI.CA database diagnosed with naïve HCC after 1999. Patients were stratified by treatment. RESULTS: 29 patients (6%) were lost to follow-up before receiving treatment. Treatment distribution was: TACE (233, 51.1%), curative treatments (145 patients, 31.8%), sorafenib (18, 3.9%), other (39, 8.5%), best supportive care (BSC) (21, 4.6%). Median survival (95% CI) was 45 months (37.4-52.7) for curative treatments, 30 (24.7-35.3) for TACE, 14 (10.5-17.5) for sorafenib, 14 (5.2-22.7) for other treatments and 10 (6.0-14.2) for BSC (P<.0001). Independent prognosticators were gender and treatment. Curative treatments reduced mortality (HR 0.197, 95%CI: 0.098-0.395) more than TACE (HR 0.408, 95%CI: 0.211-0.789) (P<.0001) as compared with BSC. Propensity score matching confirmed the superiority of curative therapies over TACE. CONCLUSIONS: In everyday practice TACE represents the first-line therapy in an half of patients with naïve BCLC-B HCC since treatment choice is driven not only by liver function and nodule characteristics, but also by contraindications to procedures, comorbidities, age and patient opinion. The treatment type is an independent prognostic factor in BCLC-B patients and curative options offer the best outcome.

The evolutionary scenario of hepatocellular carcinoma in Italy: an update.

BACKGROUND & AIMS: Epidemiology of hepatocellular carcinoma is changing worldwide. This study aimed at evaluating the changing scenario of aetiology, presentation, management and prognosis of hepatocellular carcinoma in Italy during the last 15 years. METHODS: Retrospective analysis of the ITA.LI.CA (Italian Liver Cancer) database including 5192 hepatocellular carcinoma patients managed in 24 centres from 2000 to 2014. Patients were divided into three groups according to the date of cancer diagnosis (2000-2004, 2005-2009 and 2010-2014). RESULTS: The main results were as follows: (i) progressive patient aging; (ii) progressive expansion of non-viral cases and, namely, of "metabolic" hepatocellular carcinomas; (iii) increasing proportion of hepatocellular carcinoma diagnosed during a correct (semi-annual) surveillance programme; (iv) favourable cancer stage migration; (v) increased use of radiofrequency ablation to the detriment of percutaneous ethanol injection; (vi) improved outcomes of ablative and transarterial treatments; (vii) improved overall survival (adjusted for the lead time in surveyed patients), particularly after 2009, of both viral and non-viral patients presenting with an early- or intermediate-stage hepatocellular carcinoma. CONCLUSIONS: During the last 15 years several aetiological and clinical features of hepatocellular carcinoma patients have changed, as their management. The observed improvement of overall survival was owing both to the wider use of semi-annual surveillance, expanding the proportion of tumours that qualified for curative treatments, and to the improved outcome of loco-regional treatments.

Length time bias in surveillance for hepatocellular carcinoma and how to avoid it.

AIM: Length time bias is a selection bias which can lead to an overestimation of survival of screening-detected cases caused by the relative excess of slower-growing tumors detected with respect to symptomatic cases. This leads to the incorrect perception that screening improves outcomes when it only selects tumors with a favorable biology. Data regarding this bias in surveillance for hepatocellular carcinoma (HCC) have never been provided. METHODS: A semi-Markov model was developed to investigate this issue. An exponential tumor growth was applied. During its growth, tumor diagnosis "at surveillance appointments" was made when tumor attained a size equal to or above the size of tumors diagnosed in surveilled patients obtained from pertinent published reports, or "in-between appointments" (due to the development of symptoms) if tumor size attained the size of symptomatic diagnosis, derived from published reports; otherwise the tumor continued to grow until the time horizon had been reached. Tumor doubling time (DT) values were recorded according to the method of diagnosis. RESULTS: In a theoretical cohort of 1000 patients submitted to semiannual surveillance, 72.5% will be diagnosed at a surveillance appointment and 18% because of symptom development, although under surveillance. Patients diagnosed with HCC at a surveillance appointment had a median tumor DT of 100 days (interquartile range, 68-143 days), whereas those diagnosed because of symptoms had a median DT of 42 days (interquartile range, 29-58 days) although under surveillance. CONCLUSION: The surveillance propensity to detect slower-growth tumors is relevant, and practical suggestions to minimize this bias in longitudinal studies are provided.

[Personalized healthcare in hepatocellular carcinoma. Multi-society Italian position paper.] / La personalizzazione delle cure nell'epatocarcinoma. Position paper multisocietario italiano.

Hepatocellular carcinoma (HCC) is a neoplasm characterized by both clinical and biological heterogeneity. Its management requires the expertise of multiple medical specialists and is made complex by the old age of most patients, frequently showing comorbidities. Therefore, HCC management needs a multidisciplinary approach. The aim of this article is to illustrate multi-society recommendations regarding the management of HCC patients, from diagnosis to treatment and follow-up. In particular, in every stage, HCC treatment comprises multiple alternatives and the best option for every patient should be decided by a multidisciplinary team.

Metronomic capecitabine vs. best supportive care in Child-Pugh B hepatocellular carcinoma: a proof of concept.

There is a relative lack of evidence about systemic treatments in patients with hepatocellular carcinoma (HCC) and moderate liver dysfunction (Child-Pugh B). In this multicenter study we retrospectively analyzed data from Child-Pugh B-HCC patients naïve to systemic therapies, treated with MC or best supportive care (BSC). To reduce the risk of selection bias, an inverse probability of treatment weighting approach was adopted. Propensity score was generated including: extrahepatic spread; macrovascular invasion; performance status, alphafetoprotein > 400 ng/ml, Child- Pugh score [B7 vs. B8-9]. We identified 35 MC-treated patients and 70 controls. Median overall survival was 7.5 [95% CI: 3.733-11.267]in MC-patients and 5.1 months [95% CI: 4.098-6.102] in the BSC group (p = 0.013). In patients treated with MC, median progression-free survival was 4.5 months (95% CI: 2.5-6.5). The univariate unweighted Cox regression showed a 42% reduction in death risk for patients on MC (95%CI: 0.370-0.906; p = 0.017). After weighting for potential confounders, death risk remained essentially unaltered. In the MC group, 12 patients (34.3%) experienced at least one adverse event, the most common of which were: fatigue (17.1%), hand-foot syndrome (8.5%), thrombocytopenia (8.5%), and neutropenia (5.7%). MC seems a safe option for Child-Pugh B-HCC patients. Its potential antitumour activity warrants prospective evaluations.

Sustained complete response of advanced hepatocellular carcinoma with metronomic capecitabine: a report of three cases.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most frequent causes of cancer-related death. Sorafenib, a multitarget angiogenesis inhibitor, is an approved frontline treatment for advanced HCC in Western countries, although a complete response (CR) to treatment is infrequently reported. Capecitabine, an oral fluoropyrimidine, has been shown to be effect in both treatment-naïve patients and those previously treated with sorafenib. To date, however, only one case of sustained CR to metronomic capecitabine has been reported. CASE PRESENTATION: We describe three cases of advanced HCC treated with metronomic capecitabine where a CR was obtained. In the first case, capecitabine was administered as first line therapy; in the second case, capecitabine was used after intolerance to sorafenib; while in the third case, capecitabine was administered after sorafenib failure. CONCLUSION: Capecitabine is a potentially important treatment option for patients with advanced HCC and may even represent a cure in certain cases.

Metronomic capecitabine as second-line treatment for hepatocellular carcinoma after sorafenib discontinuation.

PURPOSE: Metronomic capecitabine (MC) is a well-tolerated systemic treatment showing promising results in one retrospective study, as second-line therapy after sorafenib failure, in patients with hepatocellular carcinoma (HCC). METHODS: 117 patients undergoing MC were compared to 112 patients, eligible for this treatment, but undergoing best supportive care (BSC) after sorafenib discontinuation for toxicity or HCC progression. The two groups were compared for demographic and clinical features. A multivariate regression analysis was conducted to detect independent prognostic factors. To balance confounding factors between the two groups, a propensity score model based on independent prognosticators (performance status, neoplastic thrombosis, causes of sorafenib discontinuation and pre-sorafenib treatment) was performed. RESULTS: Patients undergoing MC showed better performance status, lower tumor burden, lower prevalence of portal vein thrombosis, and better cancer stage. Median (95% CI) post-sorafenib survival (PSS) was longer in MC than in BSC patients [9.5 (7.5-11.6) vs 5.0 (4.2-5.7) months (p < 0.001)]. Neoplastic thrombosis, cause of sorafenib discontinuation, pre-sorafenib treatment and MC were independent prognosticators. The benefit of capecitabine was confirmed in patients after matching with propensity score [PSS: 9.9 (6.8-12.9) vs. 5.8 (4.8-6.8) months, (p = 0.001)]. MC lowered the mortality risk by about 40%. MC achieved better results in patients who stopped sorafenib for adverse events than in those who progressed during it [PSS: 17.3 (10.5-24.1) vs. 7.8 (5.2-10.1) months, (p = 0.035)]. Treatment toxicity was low and easily manageable with dose modulation. CONCLUSIONS: MC may be an efficient and safe second-line systemic therapy for HCC patients who discontinued sorafenib for toxicity or tumor progression.

Osteonecrosis of the jaw during sorafenib therapy for hepatocellular carcinoma.

INTRODUCTION: Sorafenib is an oral multiple tyrosine kinase inhibitor and is currently the only evidence-based treatment recommended for advanced hepatocellular carcinoma. We report a case of osteonecrosis of the jaw that occurred during sorafenib therapy in a patient with advanced hepatocellular carcinoma not treated with bisphosphonates or other antiangiogenic drugs. METHODS: A systematic search in PubMed yielded some cases of osteonecrosis of the jaw in patients treated with antiangiogenic agents, alone or in combination with bisphosphonates, for metastatic renal cell carcinoma. The only case of osteonecrosis observed during sorafenib therapy not combined with other predisposing agents was described by Guillet et al. RESULTS: A 74-year-old man diagnosed with hepatocellular carcinoma ensuing in hepatitis C virus infection, who was treated with sorafenib at a daily dose of 400 mg, developed osteonecrosis of the right mandibular body. The lesion was documented by a dental CT scan and surgical evaluation did not lead to an indication for curettage treatment. Sorafenib was discontinued because of the radiological and laboratory features of hepatocellular carcinoma progression and the high risk of jaw fracture. CONCLUSIONS: To our knowledge, this is the first description of osteonecrosis of the jaw detected in a cirrhotic patient on sorafenib therapy not combined with bisphosphonates.

De novo hepatocellular carcinoma of liver allograft: a neglected issue.

De novo hepatocellular carcinoma (HCC) is a rare neoplasm, ensuing after liver transplantation. Its definitive identification requires sophisticated molecular analyses. Hence, some cases, particularly those ensuing in patients who have been transplanted with HCC, are probably misclassified as recurrences of the primary tumor. Nevertheless, a tumor recurrence cannot be excluded in patients transplanted without apparent malignancy, because of an occult HCC. The main risk factor for de novo HCC is the recurrence of hepatitis/cirrhosis in the allograft. All the described de novo HCCs occurred at least 2 years after OLT, whereas most recurrent HCCs develop within 2 years from surgery. The treatment of this tumor can follow the recommendations of guidelines for primary HCC and, unlike recurrent HCC, re-transplant can be considered a therapeutic option for these patients. Prevention of this tumor relies on the prevention/cure of recurrent liver disease in the allograft and on judicious post-transplant immunosuppression. The present review analyzes this topic by addressing seven key questions. An algorithm based on clinical factors - regarding primary and secondary tumors - to trigger the suspicion of de novo origin of a post-transplant HCC is proposed.

Surveillance for early diagnosis of hepatocellular carcinoma: how best to do it?

Surveillance for hepatocellular carcinoma (HCC) is considered a standard of care for patients with chronic liver disease who are at risk of developing this malignancy. Several studies have shown that surveillance can improve the prognosis of patients diagnosed with HCC through an increased likelihood of application of curative or effective treatments. Repetition of liver ultrasonography (US) every 6 mo is the recommended surveillance program to detect early HCCs, and a positive US has to entrain a well-defined recall policy based on contrast-enhanced, dynamic radiological imaging or biopsy for the diagnosis of HCC. Although HCC fulfills the accepted criteria regarding cost-effective cancer screening and surveillance, the implementation of surveillance in clinical practice is defective and this has a negative impact on the cost-effectiveness of the procedure. Education of both physicians and patients is of paramount importance in order to improve the surveillance application and its benefits in patients at risk of HCC. The promotion of specific educational programs for practitioners, clinicians and patients is instrumental in order to expand the correct use of surveillance in clinical practice and eventually improve HCC prognosis.