Extrahepatic Spread Research Articles

FDG PET/CT to Detect Incidental Findings in Patients With Hepatocellular Carcinoma-Additional Benefit for Patients Considered for Liver Transplantation?

FDG PET/CT has been described for noninvasive grading, detection of extrahepatic spread, and recurrence in hepatocellular carcinoma (HCC). As compared with localized imaging approaches (MRI, ultrasonography), FDG PET/CT not only focuses on the liver, but covers a long field of view from the base of the skull to the thighs, visualizing pathologic findings not related to HCC. The aims of this retrospective study were to (1) describe the frequency of relevant incidental findings on FDG PET/CT in HCC patients, (2) evaluate the impact on treatment strategy in HCC patients considered for liver transplantation, and (3) to discuss the role of FDG PET/CT in patients considered for transplantation in general. Four hundred thirty-nine FDG PET/CT examinations of 345 HCC patients were screened for incidental findings. The clinical information system was searched for examinations performed after FDG PET/CT and aimed at verification of incidental findings. Of 345 HCC patients, 81 patients were considered for liver transplantation. The impact of incidental findings was recorded separately for this subgroup. One hundred one patients with incidental findings in 439 FDG PET/CT examinations were identified. The incidental findings comprised 22 neoplasms (9 malignant) and 52 inflammations. Liver transplantation was not performed because of an incidental finding on FDG PET/CT in 9 (11.1%) of 81 patients. FDG PET/CT is capable of identifying relevant incidental findings (ie, secondary malignancy, benign tumors, and inflammation) in HCC patients and HCC patients considered for liver transplantation and thus influencing HCC patient management. FDG PET/CT might also be beneficial in patients considered for transplantation of different organs.

Are radiological endpoints surrogate outcomes of overall survival in hepatocellular carcinoma treated with transarterial chemoembolization?

Time to progression (TTP) and progression-free survival (PFS) are commonly used as surrogate endpoints in oncology trials. We aimed to assess the surrogacy relationship of TTP and PFS with overall survival (OS) in studies of transarterial chemoembolization (TACE) for unresectable hepatocellular carcinoma (u-HCC) by innovative methods. A search of databases for studies of TACE for u-HCC reporting both OS and TTP or PFS was performed. Individual patient data were extracted from TTP/PFS and OS Kaplan-Meier curves of TACE arms. Pooled median TTP and OS were obtained from random-effect model. The surrogate relationships of hazard ratios (HRs) and median TTP for OS were evaluated by the coefficient of determination R2 . We identified 13 studies comparing TACE vs systemic therapy or vs TACE plus systemic therapy and including 1932 TACE-treated patients. Pooled median OS was 11.2months (95% confidence interval [95%CI] 7.9-17.8), and pooled median TTP was 5.4months (95%CI 3.8-8.0). Heterogeneity among studies was highly significant for both outcomes. The correlation between HR TTP and HR OS was moderate (R2 =0.65. 95%CI 0.08-0.81). R2 value was 0.04 (95%CI 0.00-0.35) between median TTP and median OS. In studies of TACE for u-HCC, the surrogate relationship of radiology-based endpoints with OS is moderate. Multiple endpoints including hepatic decompensation, macrovascular invasion and extrahepatic spread are needed for future trials comparing systemic therapies or combination of TACE with systemic therapies vs TACE alone.

Sequential Treatment of Sorafenib-Regorafenib Versus Sorafenib-Physician's Choice: A Propensity Score-Matched Analysis.

Regorafenib has been shown to improve clinical outcomes compared to placebo, becoming a standard second-line therapy for sorafenib-progressed and -tolerated hepatocellular carcinoma (HCC) patients. We performed a multicentre, retrospective study in Italy and Korea to evaluate the effectiveness of the treatment sequence sorafenib-regorafenib compared with sorafenib and physician's choice in a real-life setting. A propensity score model was developed to control the results for baseline variable imbalances between the arm treated with sorafenib and regorafenib (S-R) and the arm treated with sorafenib and physician's choice (S-P). Survival analysis was conducted on the matched population. After the application of propensity score matching, we analysed 99 patients in the arm treated with S-R and 99 patients in the arm treated with S-P. For the S-R group, the median overall survival was 22.2 months (95% CI 17.1-27.4), compared to 17.9 months (95% CI 15.1-50.0) for the S-P group. The results of the univariate analysis showed a 31% reduction of death risk for patients treated with S-R (p = 0.0382) compared to patients treated with S-P. Interaction tests highlighted the predictive role of alpha-fetoprotein (AFP), neutrophil-to-lymphocyte ratio (NLR), and extrahepatic spread. This study provides additional proof of the superiority of the S-R treatment over the S-P treatment approach in advanced HCC patients from a real-life setting.

Machine-learning analysis of contrast-enhanced computed tomography radiomics predicts patients with hepatocellular carcinoma who are unsuitable for initial transarterial chemoembolization monotherapy: A multicenter study

IntroductionDue to the high heterogeneity of hepatocellular carcinoma (HCC), patients with non-advanced disease who are unsuitable for initial transarterial chemoembolization (TACE) monotherapy may have the potential to develop extrahepatic spread or vascular invasion. We aimed to develop and independently validate a radiomics-based model for predicting which patients will develop extrahepatic spread or vascular invasion after initial TACE monotherapy (EVIT). Materials and methodsThis retrospective study included 256 HCC patients (training set: n = 136; testing set: n = 120) who underwent TACE as initial therapy between April 2007 and June 2018. Clinicoradiological predictors were selected using multivariate logistic regression and a clinicoradiological model was constructed. The radiomic features were extracted from contrast-enhanced computed tomography (CT) images and a radiomics signature was constructed based on a machine learning algorithm. A combined model integrated clinicoradiological predictor and radiomics signature was developed. The predictive performance of the two models was evaluated and compared based on its discrimination, calibration, and clinical usefulness. ResultsIn the training set, 34 (25.0%) patients were confirmed to have EVIT, whereas 26 (21.7%) patients in the testing set had EVIT. When the radiomics signature was added, the combined model showed improved discrimination performance compared to the clinicoradiological model (area under the curves [AUCs] 0.911 vs. 0.772 in the training set; AUCs 0.847 vs. 0.746 in the testing set) and could divide HCC patients into three strata of low, intermediate, or high risk in the two sets. Decision curve analysis demonstrated that the two models were clinically useful, and the combined model provided greater benefits for discriminating patients than the clinicoradiological model. ConclusionsThis study presents a model that integrates clinicoradiological predictors and CT-based radiomics signature that could provide a preoperative individualized prediction of EVIT in patients with HCC.

Survival Benefit of Hepatic Arterial Infusion Chemotherapy over Sorafenib in the Treatment of Locally Progressed Hepatocellular Carcinoma.

Simple SummaryNot all patients with hepatocellular carcinoma (HCC) benefit from treatment with systemic treatments such as sorafenib. Hepatic arterial infusion chemotherapy (HAIC) is the treatment using an indwelling catheter port system. The regimen of HAIC used in the study is New FP which is consisted of a fine-powder cisplatin and 5-fluorouracil. In the study, for the patients with locally progressed HCC, such as HCC with vascular invasion, initial administration of local hepatic treatment using HAIC was superior to systemic treatment using sorafenib.BACKROUND: Not all patients with hepatocellular carcinoma (HCC) benefit from treatment with molecular targeted agents such as sorafenib. We investigated whether New-FP (fine-powder cisplatin and 5-fluorouracil), a hepatic arterial infusion chemotherapy regimen, is more favorable than sorafenib as an initial treatment for locally progressed HCC. METHODS: To avoid selection bias, we corrected the data from different facilities that did or did not perform New-FP therapy. In total, 1709 consecutive patients with HCC initially treated with New-FP or sorafenib; 1624 (New-FP, n = 644; sorafenib n = 980) were assessed. After propensity score matching (PSM), overall survival (OS) and prognostic factors were assessed (n = 344 each). Additionally, the patients were categorized into four groups: cohort-1 [(without macrovascular invasion (MVI) and extrahepatic spread (EHS)], cohort-2 (with MVI), cohort-3 (with EHS), and cohort-4 (with MVI and EHS) to clarify the efficacy of each treatment. RESULTS: New-FP prolonged OS than sorafenib after PSM (New-FP, 12 months; sorafenib, 7.9 months; p < 0.001). Sorafenib treatment, and severe MVI and EHS were poor prognostic factors. In the subgroup analyses, the OS was significantly longer the New-FP group in cohort-2. CONCLUSIONS: Local treatment using New-FP is a potentially superior initial treatment compared with sorafenib as a multidisciplinary treatment in locally progressed HCC without EHS.

Trends of clinical outcomes with sorafenib in randomized controlled trials for patients with treatment-naïve advanced hepatocellular carcinoma.

327 Background: Sorafenib was first approved by the US FDA to treat patients with advanced hepatocellular carcinoma (HCC) after two landmark trials (SHARP and Asia-Pacific) showed improved overall survival (OS). Since those two landmark trials, median OS has increased in the sorafenib arms in several recent phase III trials in HCC. We analyzed trends in OS, progression-free survival (PFS), and objective response rates (ORR) in published randomized clinical trials of sorafenib in HCC to better understand factors underlying the improvements. Methods: We searched PubMed for all published trials of sorafenib in advanced HCC. Trials were included if the patients were naïve to systemic therapy and had a comparison arm that was active systemic therapy or placebo. We extracted demographic and trial-level outcome data to correlate outcomes such as OS, PFS, ORR, and duration of therapy. T-tests were used to compare outcomes and linear regression was used to identify temporal trends with significance set at p£0.05. Results: The PubMed search returned 100 studies. A total of 15 studies met inclusion criteria with a total of 3755 patients treated with sorafenib (9 phase III and 6 phase II). Included trials enrolled patients from 2005-2019. The median OS in all trials was 10.0 mos (range: 6.5-14.8 mos). OS has significantly improved since the first trial began accruing (p = 0.04). A total of 12 studies provided data on PFS using RECIST 1.1, with a median PFS of 4.0 months (range: 2.7-6.6 mos). PFS has not changed over time (p = 0.99). However, ORR assessed by RECIST 1.1 have trended toward improvement over time (p = 0.08). Median duration of therapy with sorafenib has decreased by 53% since the enrollment of the first clinical trial in 2005, from 23.1 weeks to 12.2 weeks (p = 0.02). Despite this, no significant correlations were observed with the interaction of duration of therapy and OS (p = 0.92). Further, there was no significant change in the age of patients included, proportion of patients with Childs-Pugh A, Barcelona Clinic Liver Cancer (BCLC) B, BCLC C, ECOG performance status 0, HBV or HCV, proportion of patients with extrahepatic spread or vascular invasion at time of enrollment, or proportion of patients who have undergone prior locoregional therapies to explain the OS findings. Conclusions: The OS of patients with advanced HCC on the sorafenib arm in published trials has been increasing, however the reasons for this increase are not apparent from data available in the published literature. At the same time, the median duration of treatment with sorafenib has been decreasing over time and PFS is unchanged, suggesting improvements in sorafenib delivery may not be the primary factor. It is possible these trends represent heretofore unquantified changes in patient selection for systemic therapy, improvements in supportive care, or post-progression treatment for patients on HCC clinical trials.

A Phase II Trial of Y90-Resin Microspheres Radioembolization Followed by Nivolumab in Advanced Hepatocellular Carcinoma– CA 209-678

Proposed short titleY90-Resin Microspheres Radioembolization Followed by Nivolumab in Advanced Hepatocellular CarcinomaBackground : Nivolumab (N) and Y90-resin microspheres radioembolization (Y90-RE) aretherapeutic options in advanced hepatocellular carcinoma (aHCC). Emerging evidence suggests synergy between radiotherapy and immune checkpoint inhibitors. Methods : Eligible Child-Pugh A aHCC patients were treated with Y90-RE followed by N 240mg, 21 days after Y90-RE and every 2 weeks thereafter. Pre- and on-treatment tumor biopsies were obtained. Primary end-point was overall response rate (ORR) (RECIST v1·1), defined as the composite overall response observed for lesions both within and outside Y90-RE field. Secondary end points included progression free survival (PFS), overall survival (OS), and safety. This study is registered with ClinicalTrials.gov, NCT03033446 .Findings : Forty patients were enrolled, 36 received Y90-RE followed by N. At baseline: 61·1% had hepatitis B; 66·7% BCLC stage C; 50·0% had AFP > 400ng/mL; median number of liver lesions was 5 (range 1- >20); median size of largest liver lesion was 78·5 mm (range 14-177mm); 38·9% had prior TACE/RFA/MWA; and 12·5% had prior systemic therapy. ORR was 30·6% (16·4% to 48·1%). ORR was 43·5% in patients with no extra-hepatic spread (EHS) (n=23). 81% of target lesions within Y90-RE field regressed. Median PFS and OS were 5·6 months (95% CI 2·1 to 8·8 months) and 16.9 months (95% CI 8·1 to 27·6 months). Treatment was well tolerated with only 13·8% experiencing grade (G) 3/4 treatment related adverse events (TRAEs). Immune activation predicted response to Y90-RE followed by N. Interpretation : Y90-RE followed by N resulted in an encouraging ORR of 30·6% in aHCC and of 43·5% in subjects with no EHS. 81% of target lesions within Y90-RE field regressed suggesting synergy. Importantly, this combination is safe and tolerable with low G 3/4 TRAEs of 13·8%. Trial Registration: NCT number: NCT03033446 Funding: Funding for this study was acquired from National Medical Research Council Singapore (NMRC/CIRG/1454/2016), Bristol-Myers Squibb (BMS), and SIRTEX Declaration of Interest: David Tai All support for the present manuscript (e.g., funding, provision of study materials, medical writing, article processing charges, etc.): BMS, SIRTEX, NMRC Singapore (CIRG/1470/2017) Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: IPSEN, Eisai, BMS Consulting fees: Novartis, BMS, MSD Choo Su Pin Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Roche, BMS, Ipsen, Lilly, AZ, Roche. Consulting fees: BMS, Roche, Ipsen, Servier, Eisai, AstraZeneca. Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid: MOH Medishield Life Cancer Drug committee Stock or stock options: BMS David Ng All support for the present manuscript (e.g., funding, provision of study materials, medical writing, article processing charges, etc.): SIRTEX Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: SIRTEX Joycelyn Lee Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: BMS, IPSEN, Bayer Research Funding: Bayer Pierce K.H. Chow Grants or contracts from any entity: Sirtex Medical, Ipsen, IQVIA, New B Innovation, Perspectum, AMiLi, MiRXES, Genentech, Engine Biosciences. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Sirtex Medical, Ipsen, Oncosil, Bayer, Roche, New B Innovation, MSD, BTG PLC, Eisai, Abbott, AZ, IQVIA, Genentech, Worrell Guerbet, LEK Consulting, COR2ED. Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid: AVATAMED Stock or stock options: AVATAMED Too Chow Wei Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: SIRTEX Consulting fees: SIRTEX Ethical Approval: All patients provided written informed consent and the institutional review board committee approved the protocol (Singhealth IRB Ref No. 2016/2613). The study was done in accordance with the Declaration of Helsinki and Good Clinical Practice.

Comparing Liver Resection versus Sorafenib in BCLC-C Patients: A National Weighted Multicentric Study in a Real Scenario

Introduction: The treatment of hepatocellular carcinoma (HCC) in BCLC-C stage is still controversial. The aim of the study was to compare the overall survival (OS) of patients treated with surgery (SURG) vs. Sorafenib (SOR) in a national cohort. Methods: BCLC-C patients without extra-hepatic spread were considered. Surgical patients were enrolled from the Hepatocarcinoma-Recurrence-on-the-Liver-Study (HE.RC.O.LE.S.) Register, while Sorafenib patients from the Italian-Liver-Cancer (ITA.LI.CA.) Register. Inverse Probability Weighting (IPW) was used to weight the confounders. Results: Between 2008 and 2019, 478 patients were eligible, 303 in SURG and 175 in SOR group. ECOG PS, presence of cirrhosis, steatosis, Child-score, HBV, HCV, alcohol intake, collateral veins, bilobar disease, localization of the tumor thrombus, number of nodules, age and Charlson Comorbidity index were weighted by IPW to create two balanced pseudo-populations (SURG=374 and SOR=263). After IPW, 1-3-5 years OS was 83.6%, 68.1% and 55.9% and 42.3%, 17.8% and 12.8% for SURG and SOR, respectively (p<0.001, figure 1). Surgery achieved longer OS also in case of ECOG-PS>0, and in any intra-hepatic localization of the tumor thrombus. After adjustment for confounders, being treated by SOR rather than by SURG was an independent predictor of mortality (HR: 4.436; 95%CI: 3.197-6.156; p<0.001), together with a point-increase of the Charlson Index (HR: 1.162; 95%CI: 1.062-1.271; p: 0.010). Conclusions: In BCLC-C patients surgical resection, when feasible, guarantees an increased survival compared to systemic treatment.

Hepatic Arterial Infusion Chemotherapy Combined with Radiation Therapy for Advanced Hepatocellular Carcinoma with Tumor Thrombosis of the Main Trunk or Bilobar of the Portal Vein

Background: Overall survival of patients with advanced hepatocellular carcinoma (HCC) with Vp4 (tumor thrombosis of the main trunk or bilobar of the portal vein) is extremely poor. Purpose: The purpose of this study is to clarify the prognosis of hepatic arterial infusion chemotherapy (HAIC) combined with radiation therapy (RT) for advanced HCC with Vp4 and to analyze the factors that contribute to the prognosis. Methods: In this retrospective cohort study, 51 HCC patients who were treated with HAIC and RT for portal vein tumor thrombosis and met the following criteria were enrolled: (i) with Vp4; (ii) Child-Pugh score of 5–7; (iii) Eastern Cooperative Oncology Group performance status of 0 or 1; (iv) no history of systemic therapy; and (v) from September 2004 to April 2019. Results: Median overall survival and median progression-free survival were 12.1 and 4.2 months, respectively. Multivariate analysis showed >50% of relative tumor volume in the liver (HR, 3.027; p = 0.008) and extrahepatic spread with (HR, 3.773; p = 0.040) as significant and independent factors of OS. The total overall response rate (ORR) was 19.6%; ORR in main tumor was 13.7%; and ORR in Vp4 was 51.0%. None of the patients who received HAIC combined with RT for advanced HCC with Vp4 developed hepatic failure. This combination therapy of HAIC with RT was safe and well tolerated in all cases. Conclusion: Combination therapies of HAIC and RT might be good therapy for advanced HCC with Vp4.

A Machine-learning Algorithm to Select the Best Potential Treatment Providing the Longer Survival for Recurrent Hepatocellular Carcinoma: An Italian Multicentric Proposal

Purpose: How to select effective treatments for patients with hepatocellular carcinoma recurrence (rHCC) after surgery is still unclear. The aim was to develop a machine-learning predictive model of survival after recurrence(SAR) to allocate patients to curative treatments(CT: redo-surgery or thermoablation), Sorafenib(SOR) or chemoembolization(TACE). Methods: Data were obtained from the Italian register on rHCC (HE.RC.O.LE.S. Group). A LASSO-penalized Cox regression was employed to select predictors of SAR. Those features were tested also with their second-order interactions with the treatments; then the prediction model was developed. Potential SAR was estimated under each treatment in each patient, and the best potential treatment(BPT) was the one achieving the longer SAR. Results: Between 2008 and 2019, 701rHCC were enrolled. CT-patients were 293(41.8%), while 188(26.8%) underwent SOR and 220(31.4%) TACE. Treatment, age, cirrhosis, number, size and lobar localization of the recurrent nodules, extra-hepatic spread and time to recurrence were treatment-effect modifiers and SAR predictors, and were employed in the prediction model. The AUC was 79.4% at 5-years after recurrence. According to our model, 611(87.2%) patients would have benefited from CUR, 37(5.2%) from SOR, and 53(7.6%) from TACE in terms of potential SAR. By the combination of all the 8 features in the model, risk profiles were defined and decision threes were drawn. To extend the impact of the model, a web-app has been released. Conclusions: Curative treatments were the BPT in most of the cases. Our study provides a machine-learning model to allocate to the BPT each patient in a tailored and highly accurate fashion.

Real-Life Clinical Data of Cabozantinib for Unresectable Hepatocellular Carcinoma

Introduction: Cabozantinib has been approved by the European Medicine Agency (EMA) for hepatocellular carcinoma (HCC) previously treated with sorafenib. Cabozantinib is also being tested in combination with immune checkpoint inhibitors in the frontline setting. Real-life clinical data of cabozantinib for HCC are still lacking. Moreover, the prognostic factors for HCC treated with cabozantinib have not been investigated. Methods: We evaluated clinical data and outcome of HCC patients who received cabozantinib in the legal context of named patient use in Italy. Results: Ninety-six patients from 15 centres received cabozantinib. All patients had preserved liver function (Child-Pugh A), mostly with an advanced HCC (77.1%) in a third-line setting (75.0%). The prevalence of performance status (PS) > 0, macrovascular invasion (MVI), extrahepatic spread, and alpha-fetoprotein (AFP) >400 ng/mL was 50.0, 30.2, 67.7, and 44.8%, respectively. Median overall survival (OS) and progression-free survival were 12.1 (95% confidence interval 9.4–14.8) and 5.1 (3.3–6.9) months, respectively. Most common treatment-related adverse events (AEs) were fatigue (67.7%), diarrhoea (54.2%), anorexia (45.8%), HFSR (43.8%), weight loss (24.0%), and hypertension (24.0%). Most common treatment-related Grade 3–4 AEs were fatigue (6.3%), HFSR (6.3%), and increased aminotransferases (6.3%). MVI, ECOG-PS > 0, and AFP >400 ng/mL predicted a worse OS. Discontinuation for intolerance and no new extrahepatic lesions at the progression were associated with better outcomes. Conclusions: In a real-life Western scenario (mostly in a third-line setting), cabozantinib efficacy and safety data were comparable with those reported in its registration trial. Data regarding the prognostic factors might help in patient selection and design of clinical trials.

Toripalimab Combined With Hepatic Arterial Infusion Chemotherapy Versus Lenvatinib for Advanced Hepatocellular Carcinoma

Purpose: Immunotherapy combined with chemotherapy have synergistic effects in multiple malignancies. We aimed to compare the efficacy and safety of toripalimab plus hepatic arterial infusion chemotherapy (HAIC) of oxaliplatin, fluorouracil, and leucovorin versus lenvatinib in advanced hepatocellular carcinoma (HCC). Materials and Methods: We conducted this retrospective study at 3 hospitals in China and eligible patients were 18 years or older and had a primary diagnosis of unresectable HCC with macroscopic vascular invasion and/or extrahepatic spread. These patients were treated with toripalimab plus HAIC or lenvatinib monotherapy. The primary endpoint was progression-free survival (PFS) and the secondary endpoints were overall survival (OS), disease control rate per response evaluation criteria in solid tumors (RECIST) 1.1, and objective response rate (ORR) per RECIST 1.1. The results were compared by Student's test or the chi-square test, and the survival curves were calculated by the Kaplan–Meier method, and propensity-score matching (PSM) was used to reduce bias. Results: A total of 118 patients were recruited for this study: 53 in the TorHAIC group and 65 in the lenvatinib group. We found that the TorHAIC group showed a longer PFS (9.3 [95% CI, 7.81-10.8] vs 4.8 months [95% CI, 3.31−6.29]; hazard ratio [HR] = 0.57, 95% CI, 0.38-0.85; p = .006), a longer OS (17.13 [95% CI, 13.99−20.27] vs 10.1 months [95% CI, 8.14−12.06]; HR = 0.5, 95% CI, 0.31 − 0.81; p = .005), a higher disease control rate (86.8% vs 69.2%, p = .002) and a higher ORR (47.2% vs 9.2%, p < .001) by RECIST criteria than the lenvatinib group. Both toripalimab plus HAIC and lenvatinib had acceptable safety profiles. No treatment-related deaths occurred in this study. In the propensity score-matched cohorts (47 pairs), the outcomes in the TorHAIC group were also better than those in the lenvatinib group (p < .05). Conclusion: Toripalimab plus HAIC was tolerable and effective in advanced HCC and the result needs to be confirmed in the phase III trial.

Intraoperative Use of Indocyanine Green Fluorescence in Hepatobiliary and Pancreatic Cancer Resections: Current State and Considerations

Introduction: Surgery for hepatobiliary and pancreatic malignancies often has unfavourable outcomes due to incomplete resection, with positive histopathological margins and locoregional metastases. Intraoperative use of indocyanine green fluorescence (ICG) with near-red infrared light can improve tumor detectability and achieve R0 status. Methods: Review of current literature. Results: ICG fluorescence and bile excretion allows for real-time visualisation of malignant tissues and assessment of resection margins. In liver surgery it can identify subcapsular lesions, a property especially useful in minimally invasive surgery where there is loss of tactile feedback and direct visual inspection. It can also delineate hepatic segmental anatomy for anatomical resections. Hepatocellular carcinomas tend to uniformly uptake ICG, whereas primary or metastatic adenocarcinomas like cholangiocarcinomas and colorectal liver metastases as well as poorly differentiated hepatocellular carcinomas show rim enhancement. In pancreatic cancer, fluorescence of the resection margin has been shown to correspond to presence of malignancy on histopathological assessement. ICG can also help to detect micrometastases and extrahepatic spread and distinguish between scar tissue and disease following neoadjuvant chemoradiotherapy. However the technique has limitations: wide variability of method and dose of administration, no visualisation of deep seated lesions, high background fluorescence, false positives up to 40% requiring additional verification by other modalities like intraoperative ultrasound or frozen section for newly detected lesions. Conclusion: ICG fluorescence can offer increased detectability of malignancy and improve post-operative outcomes in hepatobiliary and pancreatic resections. However there are limitations such as superficial depth of detection and low specificity which need improvement to achieve maximum benefit.

Complete Remission of Lung Metastases in Hepatocellular Carcinoma Treated with Thalidomide

Introduction: Advanced-stage hepatocellular carcinoma (HCC) has poor prognosis mainly because of the underlying liver disease and lack of effective therapeutic options. Pulmonary metastases is the most common site of extra-hepatic spread. Methods: We report the case of complete response with thalidomide for multiple pulmonary metastases from HCC. Results: A 63-year old female, who was a carrier of hepatitis C virus, was preoperatively diagnosed with double primary malignancies of the liver and ampulla. Pancreaticoduodenectomy with synchronous liver resection was performed. Pathology revealed a 4cm moderately differentiated HCC classified as stage IIIB (pT3bN0) with LHV tumor thrombus and a 1cm moderately differentiated adenocarcinoma at the papilla of vater classified as stage IA (pT1N0). Four months later, AFP levels elevated markedly and chest radiograph demonstrated multiple variable sized nodules in both lungs. She was started on sorafenib. However, a tenfold increase in AFP levels and progressive disease on chest radiograph were found after 6 weeks. We changed the regimen to thalidomide at a daily dose of 100mg. Within a month, AFP levels declined rapidly and the number and size of the metastatic lung nodules decreased. After two months, chest radiograph showed complete response of the lung metastases. The patient has received thalidomide for the past three years, and no signs of recurrence of lung metastases have been observed. Conclusions: The role of systemic chemotherapy for metastatic HCC has not yet been clarified. Our findings suggest that treatment with thalidomide may be a promising method for patients with metastatic lung cancer from HCC.

. Role Of PET/CT in Assessment Of Post Interventional Treatment of Hepatocellular Carcinoma

Purpose: to highlight the role of PET/CT in evaluation of post interventional treatment (radiofrequency ablation & TACE) of hepatocellular carcinoma. Background: Hepatocellular carcinoma (HCC) is one of the major causes of mortality among patients with cirrhosis. It represents about 11.85% of the malignancies of all GIT organs and 1.78% of the total malignancies among Egyptians. Patients and methods: From February 2018 to November 2019, twenty five patients (20 males and 5 females, their age ranged from 44 to 75 years with mean age of 60.60 ± 7.35 years) were referred to the radiology unit with hepatocellular carcinoma and had underwent TACE ( 2 patients had history of combined TACE and RFA procedures ). 18F-FDG PET/CT and triphasic CT examinations were conducted in a private radiology center in Cairo for all patients using combined PET-CT machine (Philips intgenuity TF PET/CT 128 slices). Results:PET/CT showed true positive results in 20 patients, true negative results in 3 patients, false negative results at one patient and false positive results at one patient. In our study, the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy of 18F -FDG PET/CT were 95.24%, 75%, 95.24%, 75% and 92% respectively. Conclusion:PET/CT showed higher accuracy in assessment of the intervention bed without affection by lipiodol artifact as well as detection of extra hepatic spread of HCC in single whole body examination which is crucial for patients preparing for liver transplantation and differentiation between benign and malignant portal vein thrombosis.

Predictive factors for long-term survival in patients with advanced hepatocellular carcinoma treated with sorafenib.

Sorafenib, used for advanced-stage hepatocellular carcinoma (HCC), has an overall survival (OS) of 10 months. However, some patients have better response and long-term survival (LTS). Aims to assess predictive factors for LTS. Retrospectively reviewed 77 advanced HCC patients, starting sorafenib treatment between 2007 and 2016, with LTS (OS ≥24 months) as primary endpoint. Univariate and multivariable analysis of clinical variables were performed in order to identify predictive factors for LTS. Patients: seventy (90.9%) males; median age: 65 years (39-82). All had cirrhosis mostly HCV infection (n = 32, 41.6%). Majority were Child-Pugh class A (n = 50, 64.9%); median MELD-Na: 11 (6-30). Multinodular HCC: 74% (n = 57); portal vein invasion (PVI): 50.6% (n = 39); extrahepatic spread: 18.2% (n = 14). Median time between HCC diagnosis and sorafenib start: 3.3 months (0-37.6). Median OS: 13 months [95% confidence interval (CI) 8.2-17.8]. Twenty-five (32.5%) patients were considered LTS, with amedian OS: 52.3 months (95% CI 17.1-87.4). Multivariable analysis identified Child-Pugh class A [odds ratio (OR) 11.1, 95% CI 1.78-69.54] and absence of PVI (OR 7.88, 95% CI 1.56-39.8) as independent predictors of LTS. Sub-analysis of Child-Pugh class A: absence of PVI (OR 7.13, 95% CI 1.69-30.2) and alpha-fetoprotein <400 ng/ml (OR 5.82, 95% CI 1.18-28.75) independently related to LTS. Despite global short median OS, sorafenib treatment is associated with longer than 2-year survival in a sub-group, more likely in compensated liver disease and absence of PVI.

Personalised versus standard dosimetry approach of selective internal radiation therapy in patients with locally advanced hepatocellular carcinoma (DOSISPHERE-01): a randomised, multicentre, open-label phase 2 trial

All randomised phase 3 studies of selective internal radiation therapy for advanced hepatocellular carcinoma published to date have reported negative results. However, these studies did not use personalised dosimetry. We aimed to compare the efficacy of a personalised versus standard dosimetry approach of selective internal radiation therapy with yttrium-90-loaded glass microspheres in patients with hepatocellular carcinoma. DOSISPHERE-01 was a randomised, multicentre, open-label phase 2 trial done at four health-care centres in France. Patients were eligible if they were aged 18 years or older and had unresectable locally advanced hepatocellular carcinoma, at least one measurable lesion 7 cm or more in size, a hepatic reserve of at least 30% after selective internal radiation therapy, no extrahepatic spread (other than to the lymph nodes of the hilum, with a lesion <2 cm in size), and no contraindications to selective internal radiation therapy, as assessed by use of a technetium-99m macro-aggregated albumin scan. Patients were randomly assigned (1:1) by use of a permutated block method, with block sizes of four and without stratification, to receive either standard dosimetry (120 ± 20 Gy) targeted to the perfused lobe; standard dosimetry group) or personalised dosimetry (≥205 Gy targeted to the index lesion; personalised dosimetry group). Investigators, patients, and study staff were not masked to treatment. The primary endpoint was the investigator-assessed objective response rate in the index lesion, according to European Association for the Study of the Liver criteria, at 3 months after selective internal radiation therapy in the modified intention-to-treat population. Safety was assessed in all patients who received at least one selective internal radiation therapy injection, and analysed on the basis of the treatment actually received (defined by central dosimetry assessment). The trial is registered with ClinicalTrials.gov, NCT02582034, and has been completed. Between Dec 5, 2015, and Jan 4, 2018, 93 patients were assessed for eligibility. Of these patients, 60 were randomly assigned: 31 to the personalised dosimetry group and 29 to the standard dosimetry group (intention-to-treat population). 56 (93%) patients (28 in each group) were treated (modified intention-to-treat population). In the modified intention-to-treat population, 20 (71% [95% CI 51-87]) of 28 patients in the personalised dosimetry group and ten (36% [19-56]) of 28 patients in the standard dosimetry group had an objective response (p=0·0074). In the safety analysis population, a least one serious adverse event was reported in seven (20%) of the 35 patients who received personalised dosimetry, and in seven (33%) of the 21 patients who received standard dosimetry. The most frequent (ie, occurring in >5% of patients) grade 3 or higher adverse events were ascites (one [3%] patient who received personalised dosimetry vs two [10%] patients who received standard dosimetry), hepatic failure (two [6%] vs none), lymphopenia (12 [34%] vs nine [43%]), increased aspartate aminotransferase concentrations (three [9%] vs two [10%]), increased alanine aminotransferase concentrations (three [9%] vs none), anaemia (two [6%] vs one [5%]), gastrointestinal haemorrhage (none vs two [10%]), and icterus (none vs two [10%]). One treatment-related death occurred in each group. Compared with standard dosimetry, personalised dosimetry significantly improved the objective response rate in patients with locally advanced hepatocellular carcinoma. The results of this study suggest that personalised dosimetry is likely to improve outcomes in clinical practice and should be used in future trials of selective internal radiation therapy. Biocompatibles UK, a Boston Scientific Group company.

Current treatment options for hepatocellular carcinoma.

Hepatocellular carcinoma remains a serious global disease. Its incidence is increasing. Standard procedures have been developed for each stage. The complexity of this disease shows that the selection of patients in stage 0/A for different types of surgical treatment is very complicated. Treatment methods of stage B, especially locoregional treatment represented by TACE (transarterial chemoembolization or radioembolization of TARE), radiofrequency ablation and others, move freely to lower and higher stages as adjunctive therapy. Lenvatinib can replace TACE with equal efficacy in cases where locoregional treatment cannot be used. Until 2016, the only systemic treatment option for stage C was sorafenib. Lenvatinib became a second-line drug to show non-inferiority to sorafenib in OS. Retrospective analyzes revealed that patients who responded to the treatment with lenvatinib or sorafenib had a median survival of over 22 months. Sequential treatment with sorafenib and regorafenib in the RESOURCE study with a median survival of more than 24 months was similar. Ramucirumab was effective only in patients with high AFP levels. The study demonstrated the importance of selecting patients according to prognostic factors (extrahepatic spread and vascular invasion). Second-line cabozantinib has shown the same benefit as regorafenib. In the second line, immunotherapy represented by anti PD-1 antibodies nivolumab and pembrolizumab was used. Sequential administration after sorafenib prolonged the median overall survival of about 22 months. We currently have sorafenib and lenvatinib in the first line, regorafenib, cabozantinib, ramucirumab (AFP 400 &#956;g/L), pembrolizumab and nivolumab in the second line. The possibilities of monotherapy have been exhausted. The discovery of a synergistic effect of angiogenesis inhibitors, which convert a cold tumor into a hot one and facilitate the efficacy of anti-PD-1 / anti-PDL-1 antibodies, has led to a highly effective combination therapy. In study IMbrave150, the combination of atezolizumab and bevacizumab was successfully used compared to sorafenib in the first-line treatment. Additional studies are currently underway using other tyrosin kinase inhibitors - regorafenib, lenvatinib and cabozantinib - in combination with nivolumab, ipilimumab and pembrolizumab. This development of treatment at all stages evoked with renewed urgency the need to find a suitable way to search for the early stages of HCC and to create a more effective system for selecting patients for the most appropriate treatment.

Is Transarterial Chemoembolization Only Treatment Option in Patients with Intermediate Stage of Hepatocellular Carcinoma?: in Perspectives of Surgery.

In the Barcelona Clinic Liver Cancer staging system, intermediate stage hepatocellular carcinoma (HCC) is defined as large multinodular tumors without vascular invasion or extrahepatic spread in an asymptomatic patient with good performance status. Intermediate stage HCC includes various subgroups and it is characterized by extensive heterogeneity. Current guidelines recommend transarterial chemoembolization (TACE) as the standard treatment modality for patients with intermediate stage HCC. Although TACE provides improved survival benefits compared with supportive care for patients with intermediate stage HCC, all of them are not good candidates for TACE. TACE refractoriness is another obstacle to effective treatment of patients with intermediate stage HCC. Given that many studies recently reported improved survival in patients treated with hepatic resection over TACE, we reviewed the survival outcomes of TACE and hepatic resection as a treatment strategy of intermediate stage HCC.

Pretreatment Neutrophil-to-Lymphocyte Ratio Predicts Survival and Liver Toxicity in Patients With Hepatocellular Carcinoma Treated With Stereotactic Ablative Radiation Therapy

The objective of this study was to determine whether pretreatment neutrophil-to-lymphocyte ratio (NLR) could predict survival outcomes and liver toxicity in hepatocellular carcinoma (HCC) patients treated with stereotactic ablative radiation therapy (SABR). In this retrospective study we collected pretreatment NLR of HCC patients treated with SABR between December 2007 and August 2018 and determined its association with overall survival (OS), progression-free survival, and radiation-related liver toxicity defined as an increase in the Child-Turcotte-Pugh score by ≥2 within 3 months after SABR in the absence of disease progression. A total of 153 patients with a median follow-up of 13.3 months were included. Receiver operating characteristic curve analysis found that an NLR ≥2.4 was optimum (area under the curve, 0.762; 95% confidence interval [CI], 0.682-0.841, P < .001) for predicting poor 1-year OS (38.2% vs 83.6%, P < .001). Multivariable analysis demonstrated that NLR was significantly associated with OS, both as a continuous (P = .006) and a binary variable (NLR set at 2.4; P = .003). Multiple tumors (P = .003), macrovascular invasion (P = .024), extrahepatic spread (P = .002), and albumin-bilirubin score (P = .020) were also significant predictors of OS. Elevated NLR independently prognosticated poor progression-free survival (P = .016). Liver toxicity was seen in 22 evaluable patients (15.4%). Receiver operating characteristic curve analysis found NLR ≥4.0 was optimum at predicting liver toxicity (31.4% vs 10.2%, P = .005). A higher NLR (P = .049) and albumin-bilirubin score (P = .002) were independent risk factors for liver toxicity. NLR is an objective and ubiquitous inflammatory marker that can predict OS and liver toxicity in HCC patients undergoing SABR. NLR could be a useful biomarker for patient risk stratification and therapeutic decision-making.