Trend of improving prognosis of hepatocellular carcinoma in clinical practice: an Italian in-field experience.

BACKGROUND: Recent data suggest that outcome of hepatocarcinoma is improving. AIMS: In order to explore whether survival is also increasing in clinical practice, we compared two multicenter independent in-field cohorts of cirrhotics with newly diagnosed HCCs. METHODS: Cohort 1 (C1) consisted of 327 patients enrolled between January and December 1998, and cohort 2 (C2) included 826 patients enrolled between September 2008 and November 2012. Patients were stratified according to Child-Pugh score, MELD score, and HCC staged according to TNM, BCLC systems. RESULTS: At baseline, C2 patients were significantly older, with more frequent comorbidities and better liver function. In C2, HCC was more frequently detected under regular ultrasound surveillance (P < 0.001), BCLC early stages were more frequent, and rates of smaller and uni/paucinodular tumors were significantly higher. Treatment of any type was more frequently offered to C2 patients (P < 0.001). Proportion of patients treated by TACE increased, and radiofrequency ablation was the most used ablative treatment. Survival rate was significantly higher in C2 being C1 and C2 survival at 1-3 years 72-25 and 75-44 %, respectively. Child-Pugh score A, BCLC stage A, single nodule, size ≤ 3 cm, belonging to cohort C2 and treatment per se independently predicted survival. CONCLUSIONS: This in-field study showed a trend on improved HCC outcomes over time, which seems to be mainly due to a better presentation thanks to the wider application of surveillance and increased propensity to treat patients. These encouraging data should support further efforts to implement such approach to HCC in everyday clinical practice.

Adherence to American Association for the Study of Liver Diseases guidelines for the management of hepatocellular carcinoma: results of an Italian field practice multicenter study.

AIM: Adherence to and the applicability of practice guidelines for the management of hepatocellular carcinoma (HCC) in field practice have not been fully addressed. We designed a multicenter field practice prospective study to evaluate the adherence to the 2005 American Association for the Study of Liver Diseases guidelines in Italy. MATERIALS & METHODS: The study began in September 2008 and consecutively enrolled cirrhotic patients with newly diagnosed HCC from 30 local, nonreference centers in Italy. Patients were stratified according to Child-Pugh, the model for end-stage liver disease, tumor-node metastasis, performance status and the Barcelona Clinic Liver Cancer (BCLC) classifications. The diagnostic and therapeutic strategies adopted in each individual patient were recorded. Statistical analysis was carried out on 536 patients using all of the valuable data. RESULTS: A total of 286 (54.5%) patients were ≥70 years old. Comorbidities, recorded in 397 (74%) patients, were classified as moderate to severe in 170 patients (43%). Overall, 174 (59%) patients with early-stage BCLC were ≥70 years; 104 (35%) of these had moderate-to-severe comorbidities and 54% were under a regular US surveillance program. Diagnosis was performed by computed tomography in 93% of patients, contrast-enhanced ultrasound in 62% and MRI in 17%. In patients with nodules of ≤2 cm, adherence to noninvasive diagnostic criteria was 56%. Adherence to the BCLC classification was shown to be suboptimal overall, particularly regarding allocation to surgical procedures, and a total of 119 patients (40%) with BCLC stage A did not receive curative therapies. CONCLUSIONS: This multicenter survey showed that, in the 'real world', adherence to the both the diagnostic and therapeutic American Association for the Study of Liver Diseases 2005 algorithms was low, particularly in patients with early-stage HCC. Difficulties in applying the algorithms in routine clinical practice and the high prevalence of older patients with relevant comorbidities may account for our findings. Strategies to help improve adherence to international guidelines for HCC in field practice are required.

Conventional versus doxorubicin-eluting bead transarterial chemoembolization for hepatocellular carcinoma.

PURPOSE: To compare short- and long-term clinical outcomes after conventional transarterial chemoembolization and drug-eluting bead (DEB) transarterial chemoembolization in hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Patients with unresectable HCC unsuitable for ablative therapies were randomly assigned to undergo conventional or DEB chemoembolization. The primary endpoints of the study were safety, toxicity, and tumor response at 1 month. Secondary endpoints were number of repeated chemoembolization cycles, time to recurrence and local recurrence, time to radiologic progression, and survival. RESULTS: In total, 67 patients (mean age, 70 y ± 7.7) were evaluated. Mean follow-up was 816 days ± 361. Two periprocedural major complications occurred (2.9%) that were treated by medical therapy without the need for other interventions. A significant increase in alanine aminotransferase levels 24 hours after treatment was reported, which was significantly greater after conventional chemoembolization (n = 34) than after DEB chemoembolization (n = 33; preprocedure, 60 IU ± 44 vs 74 IU ± 62, respectively; at 24 h, 216 IU ± 201 vs 101 IU ± 89, respectively; P = 0.007). No other differences were observed in liver toxicity between groups. At 1 month, complete and partial tumor response rates were 70.6% and 29.4%, respectively, in the conventional chemoembolization group and 51.5% and 48.5%, respectively, in the DEB chemoembolization group. No differences were observed between groups in time to recurrence and local recurrence, radiologic progression, and survival. CONCLUSIONS: Conventional chemoembolization and DEB chemoembolization have a limited impact on liver function on short- and long-term follow-up and are associated with favorable clinical outcomes.

Assessment of response to sorafenib in advanced hepatocellular carcinoma using perfusion computed tomography: results of a pilot study.

AIMS: This prospective pilot study investigated the feasibility of perfusion computed tomography parameters as surrogate markers of angiogenesis and early response following sorafenib administration in patients with advanced hepatocellular carcinoma. METHODS: Ten patients were evaluated with perfusion computed tomography before starting sorafenib and after 3 months. Blood flow, blood volume, mean transit time, hepatic arterial fraction, and permeability surface-product were compared in tumour lesions and in hepatic parenchyma at baseline and at follow-up. Correlation between these parameters and changes in alpha-fetoprotein levels was calculated. RESULTS: At baseline, blood volume, blood flow, hepatic arterial fraction and permeability surface values were higher in lesions compared to those in hepatic parenchyma, while mean transit time was lower (p<0.05). After sorafenib treatment, only mean transit time was significantly increased versus baseline (p<0.05). At follow-up, plasma alpha-fetoprotein levels decreased in all patients. At follow-up, an inverse correlation was observed between baseline mean transit time and changes in alpha-fetoprotein (r=-0.6685, p=0.0125), as well as a correlation between baseline blood flow and alpha-fetoprotein (r=0.6476, p=0.0167). CONCLUSION: This pilot study suggests that after sorafenib treatment an increase in mean transit time observed in tumour lesions is inversely correlated with alpha-fetoprotein reductions after therapy. Mean transit time may represent a possible marker of response irrespectively of alpha-fetoprotein values.

Transarterial chemoembolization in very early and early-stage hepatocellular carcinoma patients excluded from curative treatment: a prospective cohort study.

AIM: To assess clinical outcome of transarterial chemoembolization (TACE) in a series of patients with early-stage hepatocellular carcinoma (HCC), within Milan criteria, but clinically unfit for liver transplantation (OLT). METHODS: From January 2006 to May 2009, 67 patients (43 males, mean age 70 ± 7.6 years) with very early or early-stage unresectable HCC, within Milan selection criteria but clinically unfit for OLT, underwent TACE. The primary endpoint of the study was overall survival. Secondary endpoints were: safety, liver toxicity, 1-month tumour response according to the amended RECIST criteria, time to local and distant intrahepatic tumour recurrence and time to radiological progression. RESULTS: Two major periprocedural complications occurred (3%), consisting of liver failure. Periprocedural mortality rate was 1.5% (1 patient). A significant increase in ALT and bilirubin levels 24h after treatment was reported, with progressive decrease at discharge. At 1-month follow-up, complete and partial tumour response rates were 67.2% and 29.8%, respectively, with two cases of progressive disease. Mean follow-up was 37.3 ± 15 months. The 1-, 2-, and 3-year overall survival rates were 90.9%, 86.1%, and 80.5%, respectively. Median expected time to local tumour recurrence and intrahepatic tumour recurrence were 7.9 and 13.8 months, respectively. Radiological disease progression was observed in 12 patients (17.9%) with a mean expected time of 26.5 months. CONCLUSION: In patients with early-stage HCC, clinically excluded from OLT and unfit for surgery or percutaneous ablation, TACE is a safe and effective option, with favourable long-term survival.

Long-term results of sorafenib in advanced-stage hepatocellular carcinoma: what can we learn from routine clinical practice?

BACKGROUND AND AIMS: Prospective randomized trials have proven that sorafenib is a valid treatment option for patients with advanced-stage hepatocellular carcinoma (HCC). The aim of the present study is to evaluate the effectiveness and safety of sorafenib in patients encountered in routine clinical practice. METHODS: From September 2008 to March 2011, 42 cirrhotic patients (30 male; 12 female; mean age: 70.2 ± 7.6 years; range: 56-85 years) with HCC of Barcelona Clinic Liver Cancer stage B (n = 5) or C (n = 37; mean size: 66.6 ± 42.3 mm; mean number per patient: 3.3 ± 2.8) were treated with sorafenib at either a standard dose of 800 mg/day (n = 29; 69.1%) or at 400 mg/day with subsequent dose escalation (ramp-up strategy; n = 13, 30.9%). Baseline clinical parameters were comparable. Clinical data and side effects, laboratory analyses (in particular, serum α-fetoprotein) and radiological data (tumor response according to amended RECIST criteria) were assessed every 3 months. Survival was calculated by Kaplan-Meier analysis. RESULTS: Mean follow-up was 12.2 ± 9 months (range: 1-32 months). Median overall survival was 26.1 months with overall 6- and 12-month survival rates of 92.1 and 85%, respectively. Median time to radiological progression was 8 months. The progression-free rate was 64.3%. Fatigue, skin disorders and diarrhea were the most frequent grade 3-4 side effects. Treatment discontinuation occurred in 25 patients. The starting dose for the last 13 enrolled patients was 400 mg/day; in the absence of toxicity this dosage was gradually increased to 800 mg/day after 3 weeks ('ramp-up strategy'). No grade 3/4 adverse events were observed in the ramp-up group. CONCLUSION: Sorafenib is a valid treatment option for advanced-stage HCC. Starting at a lower dosage may allow prolonged compliance to treatment and might be considered according to patient tolerance.