Association of adverse events and quality of life in patients with unresectable hepatocellular carcinoma.

PURPOSE: Hepatocellular carcinoma (HCC) is the third-leading cause of cancer-related deaths globally. Patients are often diagnosed with advanced disease, in which systemic and locoregional therapies are commonly used as first-line treatment. Such treatments can cause adverse events (AEs) that negatively affect quality of life (QoL), which is particularly undesirable where prognosis is poor. The aim of the present study was to evaluate the impact of common AEs on QoL in patients with HCC. METHODS: Data from the SARAH randomized controlled trial (RCT) were analyzed. Given the large number of distinct AEs that occurred in the trial, AEs were grouped as in the SARAH trial and prioritized using principal component analysis (PCA). Linear mixed-effects models were then applied with age, ECOG status, and AEs as predictors of the QoL change as measured with the EORTC Core Quality of Life Questionnaire (QLQ-C30). RESULTS: The PCA resulted in the selection of 28 AEs for inclusion in the linear mixed-effects models. Of the 28 AEs, diarrhea, decreased appetite, abdominal pain, and palmar-plantar erythrodysesthesia syndrome (hand-foot syndrome) were significant drivers of reductions in QoL as measured using the QLQ-C30 global health status scale. Diarrhea, abdominal pain, and hand-foot syndrome were also significant drivers of reduced QoL outcomes. CONCLUSION: The present analysis showed that diarrhea, decreased appetite, abdominal pain, and palmar-plantar erythrodysesthesia were significantly associated with reduced QoL in patients with unresectable HCC. Reducing the incidence and/or severity of these AEs should therefore be a key focus when selecting the optimal treatments for these patients.

Cost-utility analysis of selective internal radiation therapy with Y-90 resin microspheres in hepatocellular carcinoma.

Background: The study assessed the cost-utility of selective internal radiation therapy (SIRT) with Y-90 resin microspheres versus sorafenib in UK patients with unresectable hepatocellular carcinoma ineligible for transarterial chemoembolization. Materials & methods: A lifetime partitioned survival model was developed for patients with low tumor burden (≤25%) and good liver function (albumin-bilirubin grade 1). Efficacy, safety and quality of life data were from a European Phase III randomized controlled trial and published studies. Resource use was from registries and clinical surveys. Results: Discounted quality-adjusted life-years were 1.982 and 1.381, and discounted total costs were £29,143 and 30,927, for SIRT and sorafenib, respectively. Conclusion: SIRT has the potential to be a dominant (more efficacious/less costly) or cost-effective alternative to sorafenib in patients with unresectable hepatocellular carcinoma.

Patient preferences for advanced hepatocellular carcinoma treatment: a multicountry stated preference study.

The present study aimed to explore patient preferences for attributes of advanced hepatocellular carcinoma (HCC) treatments. A stated preference survey was completed by 150 patients with HCC living in Europe. Overall survival (OS) was the most important attribute, closely followed by risk of diarrhea and hypertension, and other adverse event (AE) risks. Patients were willing to trade OS to reduce AE risks. While less important than OS and AEs, patients also preferred shorter waiting times, and one-off administration of selective internal radiation therapy and oral tablets over intravenous infusions. Although patients placed the most value on extending OS, they were willing to forego OS to avoid risk of treatment-related AEs, to maintain their quality of life.

Lay abstract This study aimed to understand patient preferences for characteristics of advanced hepatocellular carcinoma (HCC) treatments. A total of 150 people with HCC in Europe were presented a series of questions asking them to choose between two hypothetical treatments. Overall, length of life was the most important issue for patients, followed by avoiding diarrhea and hypertension, and then other side effects and treatment risks. Patients were willing to forego some months of life to avoid side effects or risks. Patients preferred to be given their treatment via a single minimally invasive hospital procedure or oral daily tablets compared with intravenous drips. In conclusion, although patients placed the most value on overall length of life, side effects and treatment risks were also important.

Efficacy of transarterial radioembolization using Y-90 resin microspheres versus atezolizumab-bevacizumab in unresectable hepatocellular carcinoma: A matching-adjusted indirect comparison.

INTRODUCTION: No head-to-head trials compared the efficacy of transarterial radioembolization (TARE, also known as selective internal radiation therapy) to combination immunotherapy in hepatocellular carcinoma (HCC). The analysis objective was to compare effectiveness outcomes of TARE using Y-90 resin microspheres and atezolizumab-bevacizumab (AB) in advanced unresectable HCC. METHODS: Patient-level data from SARAH randomized controlled trial for TARE and aggregate real-world data from AB-real study were used in an unanchored matching-adjusted indirect comparison. The basecase analysis used per-protocol data from SARAH; intention-to-treat data were used in sensitivity analyses. The following prognostic variables and effect modifiers were identified from literature: cause of disease, macrovascular invasion, Eastern Cooperative Oncology Group Performance Status, alpha-fetoprotein level and albumin-bilirubin score. Weights were assigned to patients from SARAH to balance baseline characteristics across studies and reflect characteristics of AB-real patients. Overall survival (OS), progression-free survival (PFS) and response rates (overall response rates [ORR]) were calculated and compared. RESULTS: The analysis of OS and PFS included 140 patients receiving TARE and 131 for the analysis of response rates, compared to 202 receiving AB. Median OS was 15.0 and 14.9 months for TARE and AB, respectively (HR=0.980; 95% confidence interval [CI]: 0.658-1.461; p-value=0.922). Median PFS was 4.4 and 6.8 months for TARE and AB, respectively (HR=0.745; 95%CI: 0.544-1.022; p-value=0.068). ORR were 19.8% and 25% with TARE and AB, respectively (OR for AB=1.386, 95%CI: 0.746-2.668; p-value=0.306). Sensitivity analyses generated similar results. CONCLUSION: In HCC patients receiving treatment, TARE using Y-90 resin microspheres may achieve comparable effectiveness outcomes compared with AB.

Selective Internal Radiation Therapy Using Y-90 Resin Microspheres for Metastatic Colorectal Cancer: An Updated Systematic Review and Network Meta-Analysis.

INTRODUCTION: This literature review and exploratory network meta-analysis (NMA) aimed to compare the clinical effectiveness and tolerability of selective internal radiation therapy (SIRT) using yttrium-90 (Y-90) resin microspheres, regorafenib (REG), trifluridine-tipiracil (TFD/TPI), and best supportive care (BSC) in adult patients with chemotherapy-refractory or chemotherapy-intolerant metastatic colorectal cancer (mCRC). METHODS: In light of recently published data, the literature was searched to complement and update a review published in 2018. Studies up to December 2022 comparing two or more of the treatments and reporting overall survival (OS), progression-free survival (PFS), or incidence of adverse events (AE) were included. The NMA compared hazard ratios (HRs) for OS and PFS using Markov chain Monte Carlo techniques. RESULTS: Fifteen studies were included, with eight studies added (none addressing SIRT). All active treatments improved OS in relation to BSC. SIRT had the longest OS among all treatments, although without statistically significant differences (HR [95% credible interval] for SIRT, 0.48 [0.27, 0.87]; TFD/TPI, 0.62 [0.46, 0.83]; REG, 0.78 [0.57, 1.05]) in a fixed effects model. Information regarding SIRT was insufficient for PFS analysis, and TFD/TPI was the best intervention (HR 2.26 [1.6, 3.18]). One SIRT study reported radioembolization-induced liver disease in > 10% of the sample; this was symptomatically managed. Non-haematological AEs (hand-foot skin reaction, fatigue, diarrhoea, hypertension, rash or desquamation) were more common with REG, while haematological events (neutropoenia, leukopenia, and anaemia) were more common with TFD/TPI. CONCLUSION: Current evidence supports SIRT treatment in patients with chemotherapy-refractory or chemotherapy-intolerant mCRC compared to newer oral agents, with comparable OS and low incidence of AEs.

Advances in Delivery of Selective Internal Radiation Therapy (SIRT): Economic and Logistical Effects of Same-Stay Work-Up and Procedure in the Treatment of Unresectable Liver Tumors in England.

INTRODUCTION: Selective internal radiation therapy (SIRT) is a targeted method of treatment for unresectable liver tumors in which radiation therapy is directly delivered to the tumor(s) via the hepatic vasculature. Successful outcomes with SIRT are dependent on the specific vasculature of the liver and tumor, and the patient therefore needs to attend a "work-up" to map the hepatic vasculature prior to the SIRT procedure. Recent advances in SIRT delivery have enabled same-day or same-stay work-up and procedure, requiring only one hospital visit rather than two. We aimed to evaluate the economic, travel time, and transport-related environmental impact of a new brachytherapy device delivery program, the order-map-treat (OMT) program, in patients with unresectable hepatocellular carcinoma (HCC) in England. METHODS: A healthcare resource group (HRG)-based analysis of costs from a national payer (Department of Health and Social Care, DHSC) perspective was conducted assuming that, with OMT, patients would have to attend hospital only once for both the SIRT work-up and procedure versus twice without OMT. Patient travel time and CO2 emissions were then estimated by identifying the SIRT center closest to the centroid of each clinical commissioning group (CCG) and calculating straight-line distances with a "detour index" to capture the effect of indirect routes via road or rail. RESULTS: It was estimated that 856 patients per annum would be eligible for SIRT treatment for unresectable HCC in England. OMT would be anticipated to save GBP 2842 per patient versus performing SIRT without OMT. Furthermore, across all patients with HCC eligible for SIRT in England, OMT would avoid 74,500 km of travel, 2299 h of travel time, and 13.9 metric tons of patient transport-related CO2 emissions annually. CONCLUSION: OMT reduces the number of hospital visits required for SIRT by 50%, resulting in financial savings from the DHSC perspective, time savings from the patient perspective, and reduced CO2 emissions arising from patient transport.

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.

Transarterial Radioembolization Versus Atezolizumab-Bevacizumab in Unresectable Hepatocellular Carcinoma: A Matching-Adjusted Indirect Comparison of Time to Deterioration in Quality of Life.

INTRODUCTION: Given the relatively short life expectancy of patients with hepatocellular carcinoma (HCC), quality of life (QOL) plays a significant role in treatment selection. This analysis aimed to compare time to deterioration (TTD) in QOL with transarterial radioembolization (TARE) and atezolizumab-bevacizumab, as well as sorafenib, in advanced and unresectable HCC. METHODS: Patient-level data from SARAH (TARE using SIR-Spheres® Y-90 resin microspheres [SIR-Spheres] versus sorafenib) and aggregate data from IMbrave150 (atezolizumab-bevacizumab versus sorafenib) randomized controlled trials were used to conduct an anchored matching-adjusted indirect comparison (MAIC). Patients with a Child-Pugh score B in SARAH were excluded to align with exclusion criteria in IMbrave150. To identify potential effect modifiers for adjustment, the literature was searched and multivariate Cox proportional hazards models were implemented using SARAH data. Patients from SARAH were then weighted to balance with baseline characteristics from IMbrave150. Median TTD in QOL and hazard ratios (HRs) were calculated. RESULTS: Four potential effect modifiers were identified and used for adjustment: cause of disease (viral/non-viral), macrovascular invasion, Eastern Cooperative Oncology Group performance score, and alpha-fetoprotein level. The MAIC included 217 patients from SARAH (TARE = 94; sorafenib = 123). Median TTD in QOL was 11.23 and 8.64 months for atezolizumab-bevacizumab and TARE, respectively (HR = 1.06; 95% confidence interval [CI] 0.75-1.50; p = 0.725). A sensitivity analysis was conducted adjusting for cause of disease defined as hepatitis B/hepatitis C/non-viral: median TTD in QOL was higher for TARE compared with atezolizumab-bevacizumab (19.88 vs 11.23 months; HR = 0.66; 95% CI 0.36-1.19; p = 0.163). Sorafenib resulted in the shortest TTD in QOL, with statistically significant differences in both base case and sensitivity analyses. CONCLUSION: TARE using SIR-Spheres may achieve similar TTD in QOL compared with atezolizumab-bevacizumab, as the analyses found no statistically significant differences between these two interventions. Both TARE using SIR-Spheres and atezolizumab-bevacizumab seem to be more efficacious than sorafenib in maintaining QOL.

For patients with hepatocellular carcinoma, as well as physicians treating hepatocellular carcinoma, the quality of life that different treatments can offer represents an increasingly important aspect to consider when choosing treatments. Transarterial radioembolization and atezolizumab­bevacizumab are two potential treatments for advanced and unresectable hepatocellular carcinoma, but no clinical trials have directly compared the outcomes of these two therapeutic options. With the data available (patient-level data from a clinical trial of transarterial radioembolization using SIR-Spheres^® Y-90 resin microspheres [SIR-Spheres] versus sorafenib and data from a trial of atezolizumab­bevacizumab versus sorafenib from the literature), this study indirectly compared the time to deterioration of quality of life (i.e., how long quality of life is maintained) after treatment with transarterial radioembolization and atezolizumab­bevacizumab. The study showed that quality of life may be preserved over a similar time period with transarterial radioembolization using SIR-Spheres and atezolizumab­bevacizumab; also, both transarterial radioembolization using SIR-Spheres and atezolizumab­bevacizumab seem to maintain patients' quality of life over a longer period of time compared with sorafenib. These results are expected to enrich the existing evidence on which patients and physicians can base their decisions, allowing them to choose the most appropriate treatment by assessing the treatments' characteristics as a whole.

Changes in treatment pattern and costs in advanced hepatocellular carcinoma (HCC).

INTRODUCTION: While essential for cost-effectiveness analyses, there are no current resource use and cost data available for advanced hepatocellular carcinoma (HCC) and selective internal radiation therapy (SIRT). The study aims to assess current resource use and costs in HCC and for SIRT compared to historical survey data. AREAS COVERED: To address this data gap, resource use was elicited via surveys and interviews with medical professionals experienced with HCC and SIRT in the United Kingdom. Unit costs were from publicly available databases. Resource use and costs were estimated and compared to prior surveys. EXPERT OPINION: From eleven responses, pre-progression costs for SIRT and systemic therapy were £256.77 and £292.27/month, respectively. One-off progression and post-progression costs were £209.98 and £522.84/month. Monthly costs were 54%-79% lower than in previous surveys, due to reduction in hospitalizations and funded social care. Furthermore, substantial differences in resource use associated with SIRT between clinical practice and clinical trials were found. In conclusion, increased availability and familiarity with systemic treatments has led to important changes in HCC care and SIRT administration. The uncertainty from the use of expert opinion and the limited number of hospitals with SIRT experience can be addressed with future research using large databases, registries.

A systematic literature review and network meta-analysis of first-line treatments for unresectable hepatocellular carcinoma based on data from randomized controlled trials.

BACKGROUND: Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer. First-line treatment options for unresectable HCC include sorafenib, lenvatinib, selective internal radiation therapy (SIRT), and transarterial chemoembolization (TACE). The present study reviewed randomized controlled trials (RCTs) of first-line therapies for unresectable HCC in TACE-ineligible patients. RESEARCH DESIGN AND METHODS: A systematic literature review (SLR) was conducted to identify RCTs of first-line treatments for TACE-ineligible patients with unresectable HCC. Data on overall survival (OS) and progression-free survival were extracted and a contrast-based Bayesian network meta-analysis (NMA) was conducted using Markov Chain Monte Carlo techniques. RESULTS: The SLR identified three RCTs: two comparing Y-90 resin microspheres with sorafenib, and one comparing sorafenib with lenvatinib. No RCTs were identified comparing other SIRT technologies with any other approved first-line HCC therapies. The NMA showed no significant OS differences between Y-90 resin microspheres and sorafenib (hazard ratio [HR] 0.92, 95% credible interval [CrI]: 0.79-1.08) or lenvatinib (HR: 0.88, 95% CrI: 0.63-1.22). CONCLUSIONS: An SLR and NMA showed no significant differences between sorafenib, lenvatinib, and Y-90 resin microspheres in treating unresectable HCC. RCT evidence was not available for any other SIRT technologies and an evaluation of their relative efficacy was therefore not possible.

Effects of Trial Population Selection on Quality of Life and Healthcare Decision-Making: A Systematic Review and Example in the Treatment of Hepatocellular Carcinoma with Radioembolization.

BACKGROUND AND AIMS: Quality of life is among the most important considerations in the treatment of hepatocellular carcinoma (HCC), arguably second only to overall survival. Measuring and modeling patient quality of life is also crucial in the evaluation of the cost-effectiveness of health interventions. In the present study, we aimed to identify cost-utility analyses comparing selective internal radiation therapy (SIRT) with systemic therapy in patients with unresectable HCC and to compare the modeled incremental quality of life differences between the two therapies. METHODS: A systematic literature review was conducted. PubMed, EMBASE, the Cochrane Library, and health technology assessment agency websites were searched to identify cost-utility studies of SIRT versus systemic therapies in the treatment of HCC. Key characteristics of the studies, modeled populations and incremental quality of life outcomes were extracted from the included studies. RESULTS: The systematic literature review retrieved 1140 studies, of which four were ultimately included. Hand searches then identified two distinct analyses, and an updated version of one of the four studies identified initially. From these seven studies, 18 analyses were included. Analyses using data from the overall trial populations reported incremental quality-of-life estimates spanning -0.09 to +0.28 quality-adjusted life years (QALYs), with that range expanding to -0.09 to +0.60 QALYs when also considering post hoc sub-group analyses. CONCLUSION: The wide range of incremental QALYs, with substantial differences between overall trial populations and subgroups, illustrates the impact that the choice of target population may have on the relative quality of life outcomes of the compared interventions, which may in turn affect clinical decision-making. The small differences also highlight both the importance of reporting measures of dispersion around the findings, and the limitations of the incremental cost-effectiveness ratio (ICER) for assessing the relative cost-effectiveness of interventions that are predicted to result in similar quality-of-life outcomes.

A cost analysis of SIR-Spheres yttrium-90 resin microspheres versus tyrosine kinase inhibitors in the treatment of unresectable hepatocellular carcinoma in France, Italy, Spain and the UK.

Background and aims: A wide range of treatment options are available for hepatocellular carcinoma (HCC), including systemic treatment with tyrosine kinase inhibitors (TKIs) such as sorafenib and lenvatinib, immunotherapies, locoregional therapies such as selective internal radiation therapy (SIRT) and treatments with curative intent such as resection, radiofrequency ablation and liver transplantation. Given the substantial economic burden associated with HCC treatment, the aim of the present analysis was to establish the cost of using SIRT with SIR-Spheres yttrium-90 (Y-90) resin microspheres versus TKIs from healthcare payer perspectives in France, Italy, Spain and the United Kingdom (UK).Methods: A cost model was developed to capture the costs of initial systemic treatment with sorafenib (95%) or lenvatinib (5%) versus SIRT in patients with HCC in Barcelona Clinic Liver Cancer (BCLC) stages B and C. A nested Markov model was utilized to model transitions between progression-free survival (PFS), progression and death, in addition to transitions between subsequent treatment lines. Cost and resource use data were identified from published sources in each of the four countries.Results: Relative to TKIs, SIRT with SIR-Spheres Y-90 resin microspheres were found to be cost saving in all four country settings, with the additional costs of the microspheres and the SIRT procedure being more than offset by reductions in drug and drug administration costs, and treatment of adverse events. Across the four country settings, total cost savings with SIR-Spheres Y-90 resin microspheres fell within the range 5.4-24.9% and SIRT resulted in more patients ultimately receiving treatments with curative intent (4.6 vs. 1.4% of eligible patients).Conclusion: SIR-Spheres Y-90 resin microspheres resulted in cost savings relative to TKIs in the treatment of unresectable HCC in all four country settings, while increasing the proportion of patients who become eligible for treatments with curative intent.

Systematic review and network meta-analyses of third-line treatments for metastatic colorectal cancer.

BACKGROUND: Limited treatment options are available in chemotherapy-refractory metastatic colorectal cancer (mCRC). The objective was to conduct a systematic literature review (SLR) and exploratory network meta-analysis (NMA) to compare the tolerability and effectiveness of SIRT with Y-90 resin microspheres, regorafenib, TAS-102 (trifluridine/tipiracil), and best supportive care (BSC) as third-line treatment in patients with mCRC. METHODS: An SLR was conducted to identify studies comparing two or more of the treatments and reporting overall survival (OS), progression-free survival, tumor response, or adverse event (AE) incidence. An exploratory NMA was conducted to compare hazard ratios (HRs) for OS using Markov chain Monte Carlo (MCMC) techniques. RESULTS: Seven studies were identified in the SLR: two double-blind randomized-controlled trials (RCT) for each drug, one open-label RCT, and two non-randomized comparative studies for SIRT. Patient selection criteria differed between studies, with SIRT studies including patients with liver-dominant colorectal metastases. Nausea and vomiting were more frequent with TAS-102 than regorafenib or SIRT; diarrhea was more common with TAS-102 and regorafenib than SIRT. The exploratory NMA suggested that all active treatments improved OS, with HRs of 0.48 (95% CrI 0.30-0.78) for SIRT with Y-90 resin microspheres, 0.63 (0.38-1.03) for TAS-102, and 0.67 (0.40-1.08) for regorafenib each compared to BSC. CONCLUSIONS: Regorafenib, TAS-102 and SIRT using Y-90 resin microspheres are more effective than BSC in third-line treatment of mCRC; however, study heterogeneity made comparisons between active treatments challenging. SIRT is a viable treatment for third-line mCRC and its favorable AE profile should be considered in the therapeutic decision-making process.