Cost-effectiveness of selective internal radiation therapy with Y-90 resin microspheres for intermediate- and advanced-stage hepatocellular carcinoma in Brazil.

AIMS: Hepatocellular carcinoma (HCC) is a severe condition with poor prognosis that places a significant burden on patients, caregivers, and healthcare systems. Selective internal radiation therapy (SIRT) is a treatment available to patients with HCC which addresses some of the limitations of alternative treatment options. A cost-effectiveness analysis was undertaken into the use of SIRT using Y-90 resin microspheres for the treatment of unresectable intermediate- and late-stage HCC in Brazil. MATERIALS AND METHODS: A partitioned-survival model was developed, including a tunnel state for patients downstaged to receive treatments with curative intent. Sorafenib was the selected comparator, a common systemic treatment in Brazil and for which comparative evidence exists. Clinical data were extracted from published sources of pivotal trials, and effectiveness was measured in quality-adjusted life-years (QALYs) and life-years (LYs). The analysis was conducted from the Brazilian private payer perspective and a lifetime horizon was implemented. Comprehensive sensitivity analyses were conducted. RESULTS: LYs and QALYs were higher for SIRT with Y-90 resin microspheres versus sorafenib (0.27 and 0.20 incremental LYs and QALYs, respectively) and costs were slightly higher for SIRT (R$15,864). The base case incremental cost-effectiveness ratio (ICER) was R$77,602 per QALY. The ICER was mostly influenced by parameters defining the sorafenib overall survival curve and SIRT had a 73% probability of being cost-effective at a willingness-to-pay threshold of R$135,761 per QALY (3-times the per-capita gross domestic product in Brazil). Overall, sensitivity analyses confirmed the robustness of the results indicating that SIRT with Y-90 resin microspheres is cost-effective compared with sorafenib. LIMITATIONS: A rapidly evolving treatment landscape in Brazil and worldwide, and the lack of local data for some variables were the main limitations. CONCLUSIONS: SIRT with Y-90 resin microspheres is a cost-effective option compared with sorafenib in Brazil.

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.

[Chinese expert consensus on selective internal radiation therapy with yttrium-90 for primary and metastatic hepatocellular carcinoma].

Liver malignant tumors are one of the most common causes of cancer-related deaths in China. Selective internal yttrium-90 radioembolization therapy ((90)Y-SIRT) is a kind of promising local minimally invasive method, and its effectiveness and safety has been confirmed in clinical application over the past two decades. Moreover, it has been approved by the U.S. National Comprehensive Cancer Network and other international guidelines for the topical treatment of patients with liver malignancies. Taking into account the complexity of the (90)Y-SIRT and the need for multidisciplinary collaboration to improve the safety and success rate of treatment, the Nuclear Medicine Expert Committee of the Chinese society of Clinical Oncology, along with Beijing Nuclear Medicine Quality Control and Improvement Center invited experts from surgical oncology, interventional medicine, nuclear medicine, and other related fields to discuss and form a consensus on the clinical diagnosis, treatment and management, which mainly included definition, indications and contraindications, treatment procedures, postoperative follow-up, adverse reactions and complications, radiation safety management, etc. Herein, we provide the reference guidance to establish (90)Y-SIRT standardized management and treatment system various units for relevant practitioners.

Chinese expert consensus on selective internal radiation therapy with yttrium-90 for primary and metastatic hepatocellular carcinoma / 中华肝脏病杂志

Liver malignant tumors are one of the most common causes of cancer-related deaths in China. Selective internal yttrium-90 radioembolization therapy ((90)Y-SIRT) is a kind of promising local minimally invasive method, and its effectiveness and safety has been confirmed in clinical application over the past two decades. Moreover, it has been approved by the U.S. National Comprehensive Cancer Network and other international guidelines for the topical treatment of patients with liver malignancies. Taking into account the complexity of the (90)Y-SIRT and the need for multidisciplinary collaboration to improve the safety and success rate of treatment, the Nuclear Medicine Expert Committee of the Chinese society of Clinical Oncology, along with Beijing Nuclear Medicine Quality Control and Improvement Center invited experts from surgical oncology, interventional medicine, nuclear medicine, and other related fields to discuss and form a consensus on the clinical diagnosis, treatment and management, which mainly included definition, indications and contraindications, treatment procedures, postoperative follow-up, adverse reactions and complications, radiation safety management, etc. Herein, we provide the reference guidance to establish (90)Y-SIRT standardized management and treatment system various units for relevant practitioners.

Chemical Characteristics, Motivation and Strategies in choice of Materials used as Liver Phantom: A Literature Review.

Liver phantoms have been developed as an alternative to human tissue and have been used for different purposes. In this article, the items used for liver phantoms fabrication are mentioned same as in the previous literature reviews. Summary and characteristics of these materials are presented. The main factors that need to be available in the materials used for fabrication in computed tomography, ultrasound, magnetic resonance imaging, and nuclear medicine were analyzed. Finally, the discussion focuses on some purposes and aims of the liver phantom fabrication for use in several areas such as training, diagnoses of different diseases, and treatment planning for therapeutic strategies - for example, in selective internal radiation therapy, stereotactic body radiation therapy, laser-induced thermotherapy, radiofrequency ablation, and microwave coagulation therapy. It was found that different liver substitutes can be developed to fulfill the different requirements.

Tumor burden and liver function in HCC patient selection for selective internal radiation therapy: SARAH post-hoc study.

Aim: To determine whether a liver tumor burden ≤25% and well-preserved liver function (albumin-bilirubin grade 1) are appropriate criteria for identifying patients with unresectable hepatocellular carcinoma who may benefit from selective internal radiation therapy (SIRT) using 90yttrium resin microspheres versus sorafenib. Patients & methods: Post-hoc analysis of patients in the intention-to-treat population of the SARAH trial (SIRT vs sorafenib) with ≤25% tumor burden and albumin-bilirubin grade 1. Primary end point: overall survival. Results: Median overall survival was 21.9 months (95% CI: 15.2-32.5, n = 37) with SIRT and 17.0 months (11.6-20.8, n = 48) with sorafenib (hazard ratios: 0.73; 95% CI: 0.44-1.21; p = 0.22). Conclusion: A combination of good liver function and low tumor burden may be relevant for selection of hepatocellular carcinoma patients for SIRT.

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.

Metastatic Adrenocortical Carcinoma: a Single Institutional Experience.

Adrenocortical carcinoma (ACC) is a rare malignancy with limited data to guide the management of metastatic disease. The optimal treatment strategies and outcomes of patients with metastatic ACC remain areas of active interest. We retrospectively reviewed patients with ACC who were treated with systemic therapy between January 1997 and October 2016 at The Ohio State University Comprehensive Cancer Center. Kaplan-Meier and Cox proportional hazards regression models were used for survival analysis. We identified 65 patients diagnosed with ACC during the given time period, and 36 patients received systemic therapy for distant metastatic disease. Median age at diagnosis was 50 (range 28-87). Median overall survival (OS) from time of diagnosis of ACC was 27 months (95% CI 19.6-39.3), and median OS from time of systemic treatment for metastatic disease was 18.7 months (95% CI 9.3-26.0). Clinical characteristics at time of initiation of systemic therapy were assessed, and presence of bone metastases (p = 0.66), ascites (p = 0.19), lung metastases (p = 0.12), liver metastases (p = 0.47), as well as hormonal activity of tumor (p = 0.19), were not prognostic for survival. Six patients with liver metastases treated with systemic therapy who received liver-directed therapy with either transarterial chemoembolization (TACE) or selective internal radiation therapy (SIRT) had longer survival than those who did not (p = 0.011). Our data expands the knowledge of clinical characteristics and outcomes of patients with ACC and suggests a possible role for incorporating liver-directed therapies for patients with hepatic metastases.

Single administration of Selective Internal Radiation Therapy versus continuous treatment with sorafeNIB in locally advanced hepatocellular carcinoma (SIRveNIB): study protocol for a phase iii randomized controlled trial.

BACKGROUND: Approximately 20 % of hepatocellular carcinoma (HCC) patients diagnosed in the early stages may benefit from potentially curative ablative therapies such as surgical resection, transplantation or radiofrequency ablation. For patients not eligible for such options, prognosis is poor. Sorafenib and Selective Internal Radiation Therapy (SIRT) are clinically proven treatment options in patients with unresectable HCC, and this study aims to assess overall survival following either SIRT or Sorafenib therapy for locally advanced HCC patients. METHODS: This investigator-initiated, multi-centre, open-label, randomized, controlled trial will enrol 360 patients with locally advanced HCC, as defined by Barcelona Clinic Liver Cancer stage B or stage C, without distant metastases, and which is not amenable to immediate curative treatment. Exclusion criteria include previous systemic therapy, metastatic disease, complete occlusion of the main portal vein, or a Child-Pugh score of >7. Eligible patients will be randomised 1:1 and stratified by centre and presence or absence of portal vein thrombosis to receive either a single administration of SIRT using yttrium-90 resin microspheres (SIR-Spheres®, Sirtex Medical Limited, Sydney, Australia) targeted at HCC in the liver by the trans-arterial route or continuous oral Sorafenib (Nexavar®, Bayer Pharma AG, Berlin, Germany) at a dose of 400 mg twice daily until disease progression, no further response, complete regression or unacceptable toxicity. Patients for both the Sorafenib and SIRT arms will be followed-up every 4 weeks for the first 3 months and 12 weekly thereafter. Overall survival is the primary endpoint, assessed for the intention-to-treat population. Secondary endpoints are tumour response rate, time-to-tumour progression, progression free survival, quality of life and down-staging to receive potentially curative therapy. DISCUSSION: Definitive data comparing these two therapies will help to determine clinical practice in the large group of patients with locally advanced HCC and improve outcomes for such patients. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01135056 , first received 24, May 2010.

A comparison of survival in patients with hepatocellular carcinoma and portal vein invasion treated by radioembolization or sorafenib.

BACKGROUND & AIMS: Sorafenib (SOR) is the standard of care for patients with hepatocellular carcinoma (HCC) and portal vein invasion (PVI), based on the results of phase 3 trials. However, radioembolization (RE) using yttrium-90 microspheres has been shown to achieve higher response rates and better survival in large cohorts and phase 2 trials. This study aimed to compare survival of HCC patients with PVI treated by RE or SOR. METHODS: Survival among patients with HCC and PVI treated with RE or SOR in four Spanish hospitals between 2005 and 2013 was analysed retrospectively. Kaplan-Meier survival curves were plotted and baseline variables tested for prognostic value using the log-rank test. A multivariate prognostic model including variables identified in the univariate analysis and adjusted by a propensity score based on factors that may determine the probability of exposure to RE was generated using Cox regression analyses. RESULTS: After a median follow-up of 6 months, 60 deaths had occurred: 38 and 22 in SOR and RE groups respectively. Median survival was 6.7 months (95%CI 5.2-8.1 months) for the entire cohort, and 8.8 months (95%CI 1.8-15.8) in the RE group and 5.4 months (95%CI 2.7-8.1) in the SOR group (P = 0.047). The difference in survival was still statistically significant when 13 patients in the RE group who started SOR after a median time of 8 months were censored from the analysis. CONCLUSIONS: In a cohort of patients with HCC and PVI treatment with RE was associated with a more prolonged survival compared with SOR.

Management of hepatocellular carcinoma with portal vein thrombosis.

Management of hepatocellular carcinoma (HCC) with portal vein thrombosis (PVT) is complex and requires an understanding of multiple therapeutic options. PVT is present in 10%-40% of HCC at the time of diagnosis, and is an adverse prognostic factor. Management options are limited, as transplantation is generally contraindicated, and surgical resection is only rarely performed in select centers. Systemic medical therapy with sorafenib has been shown to modestly prolong survival. Transarterial chemoembolization has been performed in select cases but has shown a high incidence of complications. Emerging data on treatment of PVT with Y-90 radioembolization suggest that this modality is well-tolerated and associated with favorable overall survival. Current society guidelines do not yet specifically recommend radioembolization for patients with PVT, but this may change with the development of newer staging systems and treatment algorithms. In this comprehensive literature review, we present current and available management options with the relative advantages, disadvantages and contraindications of these treatment options with summarized data on overall survival.