Prognostic value of baseline imaging and clinical features in patients with advanced hepatocellular carcinoma.

AIMS: To investigate the prognostic value of baseline imaging features for overall survival (OS) and liver decompensation (LD) in patients with hepatocellular carcinoma (HCC). DESIGN: Patients with advanced HCC from the SORAMIC trial were evaluated in this post hoc analysis. Several radiological imaging features were collected from baseline computed tomography (CT) and magnetic resonance imaging (MRI) imaging, besides clinical values. The prognostic value of these features for OS and LD (grade 2 bilirubin increase) was quantified with univariate Cox proportional hazard models and multivariate Least Absolute Shrinkage and Selection Operator (LASSO) regression. RESULTS: Three hundred and seventy-six patients were included in this study. The treatment arm was not correlated with OS. LASSO showed satellite lesions, atypical HCC, peritumoral arterial enhancement, larger tumour size, higher albumin-bilirubin (ALBI) score, liver-spleen ratio <1.5, ascites, pleural effusion and higher bilirubin values were predictors of worse OS, and higher relative liver enhancement, smooth margin and capsule were associated with better OS. LASSO analysis for LD showed satellite lesions, peritumoral hypointensity in hepatobiliary phase, high ALBI score, higher bilirubin values and ascites were predictors of LD, while randomisation to sorafenib arm was associated with lower LD. CONCLUSIONS: Imaging features showing aggressive tumour biology and poor liver function, in addition to clinical parameters, can serve as imaging biomarkers for OS and LD in patients receiving sorafenib and selective internal radiation therapy for HCC.

Efficacy of combined transarterial radioembolization and sorafenib in the treatment of hepatocarcinoma: A meta-analysis.

BACKGROUND: Adjuvant sorafenib may further enhance the efficacy of transarterial radioembolization for the treatment of hepatocellular carcinoma. AIMS: To evaluate the efficacy and safety of radioembolization plus sorafenib in hepatocellular carcinoma patients. METHODS: With a literature search through October 2020, we identified 9 studies (632 patients). Primary outcome was overall survival. Results were expressed as pooled median, odds ratio, or hazard ratio and 95% confidence intervals. RESULTS: Pooled overall survival after radioembolization plus sorafenib was 10.79 months (95% confidence interval 9.19-12.39) and it was longer in Barcelona Clinic Liver Cancer (BCLC) B (14.47 months, 9.07-19.86) as compared to BCLC C patients (10.22 months, 7.53-12.9). No difference between combined therapy versus radioembolization alone was observed in terms of overall survival (hazard ratio 1.07, 0.89-1.30). Pooled median progression-free survival was 6.32 months (5.68-6.98), with 1-year progression-free survival pooled rate of 38.5% (12.7%-44.2%). No difference in progression-free survival (hazard ratio 0.94, 0.79-1.12) between the two treatments was observed. Pooled rate of severe adverse events was 48.9% (26.7%-71.2%), again with no difference between the two treatment regimens (odds ratio 1.52, 0.15-15.02). CONCLUSIONS: The association of sorafenib does not seem to prolong survival nor delay disease progression in patients treated with radioembolization.

Liver function after combined selective internal radiation therapy or sorafenib monotherapy in advanced hepatocellular carcinoma.

BACKGROUND & AIMS: SORAMIC is a previously published randomised controlled trial assessing survival in patients with advanced hepatocellular carcinoma who received sorafenib with or without selective internal radiation therapy (SIRT). Based on the per-protocol (PP) population, we assessed whether the outcome of patients receiving SIRT+sorafenib vs. sorafenib alone was affected by adverse effects of SIRT on liver function. METHODS: The PP population consisted of 109 (SIRT+sorafenib) vs. 173 patients (sorafenib alone). Comparisons were made between subgroups who achieved a significant survival benefit or trend towards improved survival with SIRT and the inverse group without a survival benefit: <65 years-old vs. ≥65 years-old, Child-Pugh 5 vs. 6, no transarterial chemoembolisation (TACE) vs. prior TACE, no cirrhosis vs. cirrhosis, non-alcohol- vs. alcohol-related aetiology. The albumin-bilirubin (ALBI) score was used to monitor liver function over time during follow-up. RESULTS: ALBI scores increased in all patient groups during follow-up. In the PP population, ALBI score increases were higher in the SIRT+sorafenib than the sorafenib arm (p = 0.0021 month 4, p <0.0001 from month 6). SIRT+sorafenib conferred a survival benefit compared to sorafenib alone in patients aged <65 years-old, those without cirrhosis, those with Child-Pugh 5, and those who had not received TACE. A higher increase in ALBI score was observed in the inverse subgroups in whom survival was not improved by adding SIRT (age ≥65 years-old, p <0.05; cirrhosis, p = 0.07; Child-Pugh 6, p <0.05; prior TACE, p = 0.08). CONCLUSION: SIRT frequently has a negative, often subclinical, effect on liver function in patients with hepatocellular carcinoma, which may impair prognosis after treatment. Careful patient selection for SIRT as well as prevention of clinical and subclinical liver damage by selective treatments, high tumour uptake ratio, and medical prophylaxis could translate into better efficacy. CLINICAL TRIAL NUMBER: EudraCT 2009-012576-27, NCT01126645 LAY SUMMARY: This study of treatments in patients with hepatocellular carcinoma found that selective internal radiation therapy (SIRT) has an adverse effect on liver function that may affect patient outcomes. Patients should be carefully selected before they undergo SIRT and the treatment technique should be optimised for maximum protection of non-target liver parenchyma.

Duration of response after DEB-TACE compared to lipiodol-TACE in HCC-naïve patients: a propensity score matching analysis.

OBJECTIVES: To retrospectively compare long-term outcomes of first-line drug-eluting particle (DEB)- transarterial chemoembolization (TACE) and lipiodol-TACE, in patients with unresectable hepatocellular (HCC). METHODS: We retrospectively reviewed our database to identify adult patients with treatment-naïve unresectable HCC, who underwent TACE from 2006 to 2013. Patients were excluded in the absence of complete medical records relative to first TACE, 1-month follow-up, and/or sufficient follow-up data. Periprocedural complications, duration of hospitalization, 1-month tumor response by mRECIST, time to tumor progression (TTP) and target tumor progression (TTTP), and overall survival (OS) were evaluated. RESULTS: Out of an initial series of 656 patients, 329 patients were excluded for unavailability of sufficient baseline and/or follow-up data. The remaining 327 patients underwent either lipiodol-TACE (n = 160) or DEB-TACE (n = 167). Patients treated with lipiodol-TACE had a significantly higher tumor burden. By propensity score, patients were matched according to baseline differences (BCLC stage, uninodular or multinodular HCC, and unilobar or bilobar HCC), resulting in 101 patients in each treatment group. Lipiodol-TACE was associated with a significantly higher incidence of adverse events (p = 0.03), and longer hospitalization (mean, 2.5 days vs 1.9 days; p = 0.03), while tumor response, TTP, and OS were comparable. In patients achieving 1-month complete response (CR) of target tumor, TTTP was significantly (p = 0.009) longer after DEB-TACE compared to lipiodol-TACE (median, 835 vs 353 days), resulting in a lower number of re-treatments during the entire follow-up (0.75 vs 1.6, p = 0.01). CONCLUSION: Compared to lipiodol-TACE, DEB-TACE offers higher tolerability, reduced hospitalization, and more durable target tumor response after CR. KEY POINTS: • Compared to lipiodol-TACE, DEB-TACE is better tolerated and has reduced side effects, which translates into shorter hospitalization. • When complete radiological response according to the mRECIST is obtained 1 month after the procedure, DEB-TACE offers a more durable local tumor control compared to lipiodol-TACE. • In these patients, the longer duration of response after DEB-TACE translates into a lower number of re-interventions.

Oligometastatic Colorectal Cancer Management: A Survey of the Italian College of Interventional Radiology.

AIM: European Society for Medical Oncology (ESMO) and National Comprehensive Cancer Network guidelines (NCCN) have recently included interventional procedures among the standard treatments for the management of colorectal cancer (CRC) oligometastatic disease (OMD). This study overviews the practice of Interventional Radiology (IR) in Italian centers. METHODS: A practice focused questionnaire on locoregional treatments of CRC-OMD was submitted to all Italian IR centers to assess practice patterns. RESULTS: Thirty-three IR centers completed the questionnaire. The majority reported practice was established within a tumor board (97%), which included input from hepatobiliary surgery (94%). When considering the number of percutaneous ablation and liver-directed trans-arterial therapies performed for all tumor types, 33.5% and 13.4% were performed to specifically treat CRC-OMD. Lung ablations for CRC OMD were performed in 45.5% of centers. Regarding liver ablation, The most common technology was the microwave ablation (68.1%), which was typically performed under US guidance (78%) with conscious sedation used as the most common anaesthesia method (81%). While indication for percutaneous IR treatments was heterogeneous, 51% were performed in combination with chemotherapy in unresectable OMD. Despite new ESMO and NCCN guidelines, 59% of centers did not subjectively appreciate any change in the perception of IR treatments by other specialists; however, 63%of respondents believe that IR will have a more relevant role in the CRC-OMD management in the future. CONCLUSION: CRC-OMD treatment represents a relevant part of the everyday clinical practice of the IR Italian centers with promising future prospects. Heterogeneity persists in clinical indications, requiring more robust evidence to set indications and to diffuse clinical applications.

Impact of combined selective internal radiation therapy and sorafenib on survival in advanced hepatocellular carcinoma.

BACKGROUND & AIMS: Sorafenib is the recommended treatment for patients with advanced hepatocellular carcinoma (HCC). We aimed to compare the efficacy and safety of a combination of sorafenib and selective internal radiation therapy (SIRT) - with yttrium-90 (90Y) resin microspheres - to sorafenib alone in patients with advanced HCC. METHODS: SORAMIC is a randomised controlled trial comprising diagnostic, local ablation and palliative cohorts. Based on diagnostic study results, patients were assigned to local ablation or palliative cohorts. In the palliative cohort, patients not eligible for TACE were randomised 11:10 to SIRT plus sorafenib (SIRT + sorafenib) or sorafenib alone. The primary endpoint was overall survival (OS; Kaplan-Meier analysis) in the intention-to-treat (ITT) population. RESULTS: In the ITT cohort, 216 patients were randomised to SIRT + sorafenib and 208 to sorafenib alone. Median OS was 12.1 months in the SIRT + sorafenib arm, and 11.4 months in the sorafenib arm (hazard ratio [HR] 1.01; 95% CI 0.81-1.25; p = 0.9529). Median OS in the per protocol population was 14.0 months in the SIRT + sorafenib arm (n = 114), and 11.1 months in the sorafenib arm (n = 174; HR 0.86; p = 0.2515). Subgroup analyses of the per protocol population indicated a survival benefit of SIRT + sorafenib for patients without cirrhosis (HR 0.46; 0.25-0.86; p = 0.02); cirrhosis of non-alcoholic aetiology (HR 0.63; p = 0.012); or patients ≤65 years old (HR 0.65; p = 0.05). Adverse events (AEs) of Common Terminology Criteria for AE Grades 3-4 were reported in 103/159 (64.8%) patients who received SIRT + sorafenib, 106/197 (53.8%) patients who received sorafenib alone (p = 0.04), and 8/24 (33.3%) patients who only received SIRT. CONCLUSION: Addition of SIRT to sorafenib did not result in a significant improvement in OS compared with sorafenib alone. Subgroup analyses led to hypothesis-generating results that will support the design of future studies. LAY SUMMARY: Sorafenib given orally is the recommended treatment for patients with advanced hepatocellular carcinoma (HCC). In selective internal radiation therapy (SIRT), also known as radioembolisation, microscopic, radioactive resin or glass spheres are introduced into the blood vessels that feed the tumours in the liver. This study found that the addition of SIRT with 90yttrium-loaded resin microspheres to sorafenib treatment in people with advanced HCC did not significantly improve overall survival compared with sorafenib treatment alone. However, the results give an indication of how future studies using this combination therapy in people with advanced HCC could be designed. STUDY REGISTRATION: EudraCT 2009-012576-27, NCT0112 6645.

Monitoring of Thermal-Induced Changes in Liver Stiffness During Controlled Hyperthermia and Microwave Ablation in an Ex Vivo Bovine Model Using Point Shear Wave Elastography.

PURPOSE: To investigate liver stiffness changes-evaluated by point shear wave elastography (pSWE)-in controlled hyperthermia and microwave ablation (MWA) in an ex vivo animal model. MATERIALS AND METHODS: Five samples of ex vivo bovine liver were uniformly heated to temperatures ranging from 40 to 100 °C. B-mode ultrasound imaging and pSWE were acquired simultaneously, and shear wave velocity (SWV) was measured in a region of interest (ROI). The threshold value of SWV at 60 °C (avg60) was identified. Subsequently, MWA was performed in 11 liver samples at 60 W until avg60 + 0.5 m/s was reached. SWV was measured in ROIs at 10-40 mm from the antenna feed. The correlation of mean values of SWV with location (within, border, or outside necrotic area) at gross pathology was evaluated. RESULTS: In controlled hyperthermia experiments, a steep transition in liver stiffness was observed at 63.0 ± 2.4 °C (SWV 3.54 ± 0.68 m/s). Avg60 was of 2.5 m/s. In 8/9 MWA experiments, interrupted when SWV of 3 m/s was measured, the ROI was at the inner side of the necrotic area border at pathology (accuracy 89%). No correlation between SWV values for outside, border, and within necrosis could be identified. CONCLUSIONS: pSWE can provide a velocity threshold predictive of the presence of coagulation necrosis during MWA in ex vivo liver model. However, pSWE is not able to reliably capture changes in stiffness within, at the border, and outside the necrotic zone in this experimental model.

Clinical outcomes with long-term sorafenib treatment of patients with hepatocellular carcinoma: a multicenter real-life study.

AIM: This multicenter field-practice study evaluates outcomes of long-term sorafenib in hepatocellular carcinoma (HCC) patients. METHODS: Consecutive HCC patients on sorafenib were enrolled. We evaluated those receiving sorafenib for ≥12 months. RESULTS: Out of 800 patients on sorafenib, 81 (10%) received long-term treatment. Median duration of treatment was 22.7 months (range: 12.3-92.6). Only 21 (26%) reported grade 3/4 adverse events. Complete response was reported in 11 patients (14%). Median overall survival was 34.8 months (95% CI: 29.9-44.3). Only baseline Child-Pugh class was associated with survival. CONCLUSION: Sorafenib could result in long-term control of HCC in a relevant proportion of patients. Given the availability of regorafenib in the second-line setting, an earlier introduction of systemic therapy may be considered according to clinical indications.

Identification of responders to sorafenib in hepatocellular carcinoma: is tumor volume measurement the way forward?

OBJECTIVES: Early assessment of hepatocellular carcinoma (HCC) response during sorafenib (SO) treatment is challenging, since tumor necrosis, extension and radiological appearance can be inhomogeneous. We evaluated the predictive value of different imaging criteria - such as Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, European Association for the Study of the Liver (EASL), modified RECIST (mRECIST), tumor density and volume variations - in the early follow-up of SO treatment. METHODS: The study included 22 patients. CT images from baseline and 2 months were reviewed to assess response according to RECIST 1.1, mRECIST, EASL, Choi's criteria (decreased tumor density by ≥15%) and arterial-enhancing tumor volume ratio; α-fetoprotein (AFP) variations were expressed as AFP ratio. RESULTS: The response criteria and volume measurements were reproducible (k > 0.80). The overall disease control rate was 40.9% by EASL and mRECIST, and 27.3% by RECIST 1.1; a ≥15% decrease in tumor density was observed in 9 patients (40.9%). The mean volume ratio was 1.73 ± 2.12, the mean AFP ratio 14 ± 37. The 1-year survival rate was 65.9%. Volume ratio was the only predictive factor for survival, with 1-year cumulative survival rates of 90% for volume ratios ≤1.1 and of 45.4% for volume ratios >1.1 (p = 0.04). CONCLUSIONS: Tumor volume measurements are reproducible and might provide an early predictive marker of response in HCC patients treated with SO.

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.

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.

Complete response for advanced liver cancer during sorafenib therapy: case report.

BACKGROUND: Hepatocellular carcinoma (HCC) is the fifth most common neoplasia in the world. In the past, treatment of advanced HCC with conventional antineoplastic drugs did not result in satisfactory outcomes: recently, in this patient population the oral multikinase inhibitor sorafenib has been able to induce a statistically significant improvement of overall survival. Similarly to other anti-angiogenic drugs employed in other tumour types, also sorafenib seldom induces the dimensional tumour shrinking usually observed with conventional cytotoxic drugs: data gathered from studies carried out with sorafenib and other competitors under development do not report any complete response in HCV-induced HCC. CASE PRESENTATION: An 84-year old man with a long-lasting history of chronic HCV hepatitis was referred to our Institution for an ultrasonography investigation of a focal hepatic lesion. To better characterize the liver disease and clearly define the diagnosis of the focal hepatic lesion, the patient was hospitalized in our department. Laboratory and instrumental investigations confirmed the clinical picture of HCV-related liver cirrhosis and identified a hepatic lesion of about 6 cm featuring infiltrating HCC with thrombosis of the portal trunk. Due to the advanced stage of the disease, therapy with sorafenib 400 mg bid was started. Right from one month after the treatment was started, a reduction of alpha-fetoprotein level was observed which, by the third month, turned down within the normal limits. In addition the CT scan showed 50% reduction of the neoplastic lesion along with canalization of the portal trunk. At the sixth month the normalization of the alpha-fetoprotein level at the lower limit of normality was confirmed and the MRI showed complete disappearance of the neoplasia. In addition a reduction of a metallo-proteinase serum level was observed. At the twelfth month a further MRI confirmed complete response had been maintained. At present the patient is in a follow-up program to evaluate the duration of the complete response. CONCLUSIONS: This case is worth mentioning since, to the best of our knowledge, it represents the first evidence of complete response to sorafenib in an elderly patient with advanced HCV-related HCC.