Impact of remnant vital tissue after locoregional treatment and liver transplant in hepatocellular cancer patients. A multicentre cohort study

The role of pathological findings after locoregional treatments as predictors of hepatocellular cancer recurrence after liver transplantation has been poorly addressed. The aim of the study was to identify the role of remnant vital tissue (RVT) of the target lesion in predicting hepatocellular cancer recurrence. Two hundred and seventy-six patients firstly undergoing locoregional treatment and then transplanted between January 2010 and December 2015 in four European Transplant Centres (i.e. Rome Tor Vergata, Birmingham, Brussels and Ancona) were enrolled in the study to investigate the role of pathological response at upfront locoregional treatment. At multivariable Cox regression analysis, RVT ≥2 cm was a strong independent risk factor for post-LT recurrence (HR = 5.6; P < 0.0001). Five-year disease-free survival rates were 60.8%, 80.9% and 95.0% in patients presenting a RVT ≥2 cm vs. 0.1-1.9 vs. no RVT, respectively. When only Milan Criteria-IN patients were analysed, similar results were reported, with 5-year disease-free survival rates of 58.1%, 79.0% and 94.0% in patients presenting a RVT ≥2 cm vs. 0.1-1.9 vs. no RVT, respectively. RVT is an important determinant of tumour recurrence after liver transplantation performed for hepatocellular cancer. Its discriminative power looks to be evident also in a Milan-IN setting, suggesting to more liberally use locoregional treatments also in these patients

Role of transarterial chemoembolization as neoadjuvant treatment in T2 stage patients waiting for liver transplantation

RIASSUNTO Scopo: Valutare retrospettivamente i risultati clinici a lungo termine di pazienti cirrotici con HCC allo stadio T2 sottoposti a trapianto ortotopico di fegato (TOF) dopo chemioembolizzazione intraarteriosa (TACE), rispetto ai risultati ottenuti in un’analoga serie di pazienti non sottoposti ad alcun trattamento loco-regionale pre-TOF. Materiali e Metodi: Lo studio ha incluso 168 pazienti cirrotici (147 maschi, età media 55,8 anni) trapiantati per HCC allo stadio T2 dal 1996 al 2010. In pazienti sottoposti a TACE pre-TOF, lo studio TC eseguito prima del trapianto è stato revisionato per stimare la risposta tumorale al trattamento secondo i criteri RECIST modificati. I pazienti sono stati suddivisi in 3 gruppi: A) nessun trattamento pre-TOF; B) risposta completa (CR) dopo TACE; C) risposta parziale, stabilità o progressione di malattia dopo TACE. Le sopravvivenze cumulativa (OS), libera da recidiva (RFS) e libera da malattia (DFS) sono state calcolate secondo l’analisi di Kaplan-Meyer e comparate mediante test log-rank. Risultati: Il gruppo A era costituito da 56 pazienti, il gruppo B da 60 e il gruppo C da 52; i dati clinici dei tre gruppi erano sovrapponibili. A 5 anni, OS, RFS e DFS sono state 75,2%, 92,7% e 73,2%, rispettivamente. Le sopravvivenze sono state significativamente maggiori nel gruppo B rispetto al gruppo C e sovrapponibili fra gruppo A e B. In pazienti con diametro tumorale totale >3cm, RFS e DFS censurata per morti periprocedurali (n=7) sono state significativamente superiori nel gruppo B rispetto al gruppo A. Conclusioni: In pazienti con HCC allo stadio T2 sottoposti a TOF, la CR dopo TACE pre-operatoria è un fattore prognostico favorevole di sopravvivenza e recidiva tumorale. La TACE pre-TOF può apportare un beneficio clinico in pazienti T2 con HCC >3cm. SUMMARY Aim: To provide a retrospective assessment of long-term results in cirrhotic patients with stage T2 hepatocellular carcinoma (HCC) treated by orthotopic liver transplantation (LT). Materials e Methods: The study included 168 cirrhotic patients (147 males, mean age 55.8 years) transplanted for stage T2 HCC from 1996 to 2010. In patients submitted to pre-LT transarterial chemoembolization (TACE), the CT study carried out prior to LT was reviewed to estimate tumour response to treatment in accordance with the modified RECIST criteria. The patients were subdivided into 3 groups: A) no pre-LT treatment; B) complete response (CR) after TACE; C) partial response, stable or progressive disease after TACE. Overall survival (OS) and recurrence-free (RFS) and disease-free (DFS) survival were calculated according to the Kaplan-Meyer analysis and compared using log-rank tests. Results: Group A was made up of 56 patients, group B of 60 and Group C of 52. The clinical data were comparable for the three groups. At 5 years, OS, RFS and DFS were 75.2%, 92.7% and 73.2%, respectively. Survival rates were significantly higher in Group B than in Group C, and comparable in Groups A and B. In patients with total tumour diameter of >3cm, RFS and DFS censored in peri-procedural deaths (n=7) were significantly higher in Group B than in Group A. Conclusions: In patients with T2-stage HCC submitted to LT, CR after pre-operative TACE is a favourable prognostic factor for survival and absence of tumour recurrence. Pre-OLT TACE may be clinically beneficial for T2-stage HCC patients with tumour size >3cm

Diagnostic imaging for hepatocellular carcinoma

Hepatocellular carcinoma (HCC) occurs mostly in individuals with cirrhosis, which is why the guidelines of the most important scientific societies indicate that these patients are included in surveillance programs through the repetition of an ultrasound examination every 6 months. The aim is to achieve early identification of the neoplasia in order to increase the possibility of curative therapies (liver transplantation, surgery or local ablative therapies) and to increase patient survival. HCC nodules arising in cirrhotic livers show characteristic angiographic behavior that can be evaluated with dynamic multidetector computed tomography and dynamic magnetic resonance imaging (MRI). However, the use of these techniques in real life is often hindered by the lack of uniform terminology in reporting and in the interpretation of the exams reflected in the impossibility of comparing examinations performed in different centers and/or at different times. Liver Imaging Reporting and Data System® was created to standardize reporting and data collection of computed tomography and MRI for HCC. In some cases HCC arises in patients with healthy livers and, although there is evidence that angiographic behavior is not different from cirrhotic patients in this clinical situation, the guidelines still indicate the execution of a biopsy. Frequent use of palliative therapeutic techniques such as transarterial chemoembolization, transarterial radioembolization or administration of antiangiogenic drugs (sorafenib) poses problems of interpretation of the therapeutic response with repercussions on the subsequent choices that have been attempted to resolve with the use of stringent criteria such as Modified Response Evaluation Criteria In Solid Tumors

Transarterial RAdioembolization versus ChemoEmbolization for the treatment of hepatocellular carcinoma (TRACE) : study protocol for a randomized controlled trial

Background: Hepatocellular carcinoma is a primary malignant tumor of the liver that accounts for an important health problem worldwide. Only 10 to 15% of hepatocellular carcinoma patients are suitable candidates for treatment with curative intent, such as hepatic resection and liver transplantation. A majority of patients have locally advanced, liver restricted disease (Barcelona Clinic Liver Cancer (BCLC) staging system intermediate stage). Transarterial loco regional treatment modalities offer palliative treatment options for these patients; transarterial chemoembolization (TACE) is the current standard treatment. During TACE, a catheter is advanced into the branches of the hepatic artery supplying the tumor, and a combination of embolic material and chemotherapeutics is delivered through the catheter directly into the tumor. Yttrium-90 radioembolization (Y-90-RE) involves the transarterial administration of minimally embolic microspheres loaded with Yttrium-90, a beta-emitting isotope, delivering selective internal radiation to the tumor. Y-90-RE is increasingly used in clinical practice for treatment of intermediate stage hepatocellular carcinoma, but its efficacy has never been prospectively compared to that of the standard treatment (TACE). In this study, we describe the protocol of a multicenter randomized controlled trial aimed at comparing the effectiveness of TACE and Y-90-RE for treatment of patients with unresectable (BCLC intermediate stage) hepatocellular carcinoma. Methods/design: In this pragmatic randomized controlled trial, 140 patients with unresectable (BCLC intermediate stage) hepatocellular carcinoma, with Eastern Cooperative Oncology Group performance status 0 to 1 and Child-Pugh A to B will be randomly assigned to either Y-90-RE or TACE with drug eluting beads. Patients assigned to Y-90-RE will first receive a diagnostic angiography, followed by the actual transarterial treatment, which can be divided into two sessions in case of bilobar disease. Patients assigned to TACE will receive a maximum of three consecutive transarterial treatment sessions. Patients will undergo structural follow-up for a timeframe of two years post treatment. Post procedural magnetic resonance imaging (MRI) will be performed at one and three months post trial entry and at three-monthly intervals thereafter for two years to assess tumor response. Primary outcome will be time to progression. Secondary outcomes will be overall survival, tumor response according to the modified RECIST criteria, toxicities/adverse events, treatment related effect on total liver function, quality of life, treatment-related costs and cost-effectiveness

Polyethylene Glycol Epirubicin-Loaded Transcatheter Arterial Chemoembolization Procedures Utilizing a Combined Approach with 100 and 200 μm Microspheres: A Promising Alternative to Current Standards

PURPOSE:To report clinical effectiveness, toxicity profile, and prognostic factors of combined 100 μm ± 25 and 200 μm ± 50 epirubicin-loaded polyethylene glycol (PEG) microsphere drug-eluting embolic transcatheter arterial chemoembolization protocol in patients with hepatocellular carcinoma. MATERIALS AND METHODS: In this prospective, single-center, single-arm study with 18 months of follow-up, 36 consecutive patients (mean age 69.9 y ± 10.8; 26 men, 10 women; 54 naïve lesions) were treated. Embolization was initiated with 100 μm ± 25 microspheres, and if stasis (10 heart beats) was not achieved, 200 μm ± 50 microspheres were administered. Each syringe (2 mL) of PEG microsphere was loaded with 50 mg of epirubicin. Results were evaluated using Modified Response Evaluation Criteria In Solid Tumors with multidetector computed tomography/magnetic resonance imaging at 1, 3-6, 9-12, and 15-18 months. Toxicity profile was assessed by laboratory testing before and after the procedure. Complications were recorded. Postembolization syndrome (PES) was defined as onset of fever/nausea/pain after the procedure. Patient/lesion characteristics and treatment results were correlated with predicted outcome using regression analysis. Child-Pugh score was A in 86.1% of patients (31/36) and B in 13.9% (5/36). RESULTS: In 10 of 21 lesions, &lt; 2 cm in diameter (47.5%) stasis was achieved with 100 μm ± 25 microspheres only, whereas all other lesions required adjunctive treatment with 200 μm ± 50 microspheres. Reported adverse events were grade 1 acute liver bile duct injury (3/39 cases, 7.7%) and PES (grade 2; 3/39 cases, 7.7%). Complete response (CR) at 1, 3-6, 9-12, and 15-18 months was 61.1%, 65.5%, 63.63%, and 62.5%. Objective response (CR + partial response) at 1, 3-6, 9-12, and 15-18 months was 83.3%, 65.85%, 63.63%, and 62.5%. No single factor (laboratory testing, etiology, patient status, hepatic status, tumor characteristics, administration protocol) predicted outcomes except for albumin level at baseline for CR (P &lt; .05, odds ratio = 1.09). CONCLUSIONS: The combined microsphere sizing strategy was technically feasible and yielded promising results in terms of effectiveness and toxicity

Contrast-enhanced ultrasound identifies early extrahepatic collateral contributing to residual hepatocellular tumor viability after transarterial chemoembolization.

The mainstay of treatment for unresectable hepatocellular carcinoma is locoregional therapy including percutaneous ablation and transarterial chemo- and radioembolization. While monitoring for tumor response after transarterial chemoembolization is crucial, current imaging strategies are suboptimal. The standard of care is contrast-enhanced magnetic resonance imaging or computed tomography imaging performed at least 4 to 6 weeks after therapy. We present a case in which contrast-enhanced ultrasound identified a specific extra-hepatic collateral from the gastroduodenal artery supplying residual viable tumor and assisting with directed transarterial management

Prospective Phase II trial of drug-eluting bead chemoembolization for liver transplant candidates with hepatocellular carcinoma and marginal hepatic reserve.

Purpose: To determine whether chemoembolization using drug-eluting beads (DEB-TACE) is safe and effective for liver transplantation candidates with liver-limited hepatocellular carcinoma (HCC) without vascular invasion and baseline hepatic dysfunction. Materials and methods: Seventeen adult liver transplantation candidates (median age 66 years, range 58-73 years; 13 men) with HCC were treated with DEB-TACE as a part of Stage 1 of a prospective single-institution Phase II trial. All patients had marginal hepatic reserve based on at least one of the following criteria: ascites (n=14), bilirubin between 3 and 6 mg/dL (n=5), AST 5-10 times upper normal limit (n=1), INR between 1.6 and 2.5 (n=4), portal vein thrombosis (n=2), and/or portosystemic shunt (n=2). Primary study objectives were safety and best observed radiographic response. Results: Thirty-seven DEB-TACE procedures were performed. Objective response rate and disease control rate were 63% and 88%, respectively. HCC progression was observed in 12 patients. Median time to progression was 5.6 months (range 0.9-13.6 months). Within 1 month following DEB-TACE, 13 patients (76%) developed grade 3 or 4 AE attributable to the procedure. Four patients (all within Milan Criteria) were transplanted (2.7-6.9 months after DEB-TACE), and 12 patients died (1.8-32 months after DEB-TACE). All deaths were due to liver failure that was either unrelated to HCC (n=5), in the setting of metastatic HCC (n=5), or in the setting of locally advanced HCC (n=2). Mortality rate at 1 month was 0%. Conclusions: DEB-TACE achieves tumor responses but carries a high risk of hepatotoxicity for liver transplant candidates with HCC and marginal hepatic reserve

Objective response by mRECIST as a predictor and potential surrogate end point of overall survival in advanced HCC

Background & Aims: The Modified Response Evaluation Criteria in Solid Tumors (mRECIST) was developed to overcome the limitations of standard RECIST criteria in response assessment of hepatocellular carcinoma (HCC). We aimed to investigate whether objective response by mRECIST accurately predicted overall survival (OS) in patients with advanced HCC treated with systemic targeted therapies and also to preliminarily assess this endpoint as a potential surrogate of OS.Methods: Individual patient data from the BRISK-PS randomized phase III trial comparing brivanib vs. placebo (the first to prospectively incorporate mRECIST) were used to analyze objective response as a predictor of OS in a time-dependent covariate analysis. Patients with available imaging scans during follow-up were included (n = 334; 85% of those randomized). Moreover, a correlation of the survival probability in deciles vs. the observed objective response was performed to evaluate its suitability as a surrogate end-point.Results: Objective response was observed in 11.5% and 1.9% of patients treated with brivanib and placebo respectively, and was associated with a better survival (median OS 15.0 vs. 9.4 months, p < 0.001). In addition, objective response had an independent prognostic value (HR = 0.48; 95% confidence interval [CI], 0.26-0.91, p = 0.025) along with known prognostic factors. Finally, objective response showed promising results as a surrogate of OS in this trial (R = -0.92; 95% CI, -1 to -0.73, p < 0.001). It was an early indicator of the treatment effect (median time to objective response was 1.4 months).Conclusions: Objective response by mRECIST in advanced HCC predicts OS and thus can be considered as a candidate surrogate end-point. Further studies are needed to support this finding.Lay summary: There is a need to identify surrogate end-points for overall survival in advanced hepatocellular carcinoma. We studied patients from the phase III BRISK trial, comparing brivanib treatment with placebo after sorafenib progression. We demonstrate that objective response is an independent predictor of survival and qualifies as a potential surrogate end-point for overall survival in this patient population.Clinical trial number: NCT00825955

Sarcopenia Is a Negative Prognostic Factor in Patients Undergoing Transarterial Chemoembolization (TACE) for Hepatic Malignancies

Background and Aims: While transarterial chemoembolization (TACE) represents a standard of therapy for intermediate-stage hepatocellular carcinoma (HCC) and is also routinely performed in patients with liver metastases, it is still debated which patients represent the ideal candidates for TACE therapy in terms of overall survival. Sarcopenia, the degenerative loss of skeletal muscle mass and strength, has been associated with an adverse outcome for various malignancies, but its role in the context of TACE has largely remained unknown. Here, we evaluated the role of sarcopenia on the outcome of patients undergoing TACE for primary and secondary liver cancer. Methods: The patients’ psoas muscle size was measured on axial computed tomography (CT) scans and normalized for the patients’ height squared. This value was referred to as the psoas muscle index (PMI). The PMI was correlated with clinical and laboratory markers. Results: While pre-interventional sarcopenia had no impact on the direct tumor response to TACE, sarcopenic patients with a pre-interventional PMI below our ideal cut-o value of 13.39 mm/m2 had a significantly impaired long-term outcome with a median overall survival of 491 days compared to 1291 days for patients with a high PMI. This finding was confirmed by uni- and multivariate Cox-regression analyses. Moreover, a progressive rapid decline in muscle mass after TACE was a predictor for an unfavorable prognosis. Conclusion: Our data suggest that sarcopenia represents a previously unrecognized prognostic factor for patients undergoing TACE therapy which might yield important information on the patients’ post-interventional outcome and should therefore be implemented into clinical stratification algorithms