Authors' objectives: BACKGROUND: Zoledronate, ibandronate, and denosumab are licensed bone-targeting agents (BTAs) in Switzerland. Patients with bone metastases are treated monthly with BTAs to reduce fracture risk and hypercalcaemia. Long-term exposure to BTAs is linked to possible severe side effects such as hypocalcaemia, renal failure, or cumulative risk of osteonecrosis of the jaw (ONJ). Recent studies suggest that reduced treatment frequency is as efficacious as the current monthly therapy. Consequently, the question arises as to whether the monthly administration of BTAs in patients with bone metastases should be replaced by a 3-monthly administration. OBJECTIVE: The objective of this health technology assessment (HTA) was to assess the evidence pertaining to 3-monthly versus 1-monthly administration of BTAs in cancer patients with bone metastases in terms of efficacy, effectiveness, and safety, as well as cost, cost-effectiveness, budget impact, legal, social, ethical, and organisational issues.

Authors' results and conclusions: RESULTS: Efficacy, effectiveness, and safety In total, 5,375 records were identified in the literature search. For zoledronate and denosumab, 7 unique randomized controlled trials (RCTs) from 9 publications and 2 retrospective studies were eligible for inclusion. No studies were found for ibandronate. The risk of bias assessment found the studies to be of moderate to low risk of bias. For the meta-analysis, data from 6 RCTs reporting on SREs (4 zoledronate, n=2,668; 2 denosumab, n=160) were included to help answer the research question. The results from the meta-analyses applying the RE model showed no statistically significant effect between both dosing regimens for SREs, AEs, or SAEs. The result for SREs was a risk ratio (RR) of 1.01; 95% confidence interval (CI): 0.82, 1.24 with the RE model. These results indicate SREs may decrease by up to 18% or increase by 24% when 3-monthly dosing is used compared to monthly dosing. Heterogeneity was low (I2=0%). The RR result for AEs with RE model was: RR: 0.97; 95% CI: 0.93, 1.02 in the main analyses. The results suggest that 3-monthly use of BTAs may lead to a reduction in AEs of up to 7% or up to a 2% increase. Heterogeneity between the studies was low (I2=0%). The results indicated no difference in SAEs and AEs of special interest in this indication, like hypocalcaemia, ONJ, or renal AEs. The SAE RE model CIs showed a potential decreased risk of 21% vs a potential increased risk of 9% (RR: 0.93; 95% CI: 0.79, 1.09). Thus, a 3-monthly administration may lead to a benefit in reducing SAEs by up to 21% while increasing SREs by up to 24%. Sensitivity analyses assessing the single BTAs separately and including non-RCTs largely confirmed the results from the main analyses. Cost, cost-effectiveness, and budget impact One cost-effectiveness study retrieved from the literature search was eligible for inclusion. Findings of this United States (US) study could not be transferred to the Swiss context due to the differences in treatment costs. Therefore, a de novo budget impact and cost-comparison model from a payer perspective were developed. The base case budget impact and cost-comparison model accounted for drug costs, administration costs, and treatment discontinuation costs. The cost comparison model is at the single patient level, whereas the budget impact model is at the national level, considering the size of the population eligible for treatment. It is assumed that patients already on treatment will not change their regimen and, as a result, the 3-monthly treatment interval is only relevant for new patients. The incidence of patients with bone metastases and currently on BTA treatment is approximately 2,497 patients, and it was estimated that 15,365 patients would require BTA treatment in year 5. Over this time horizon, the introduction of 3-monthly treatment for patients with bone metastases, instead of the monthly dosing, would result in a reduction in the total budget impact of CHF 53,170,447 (base case). Annually, the reductions in budget impact were CHF 6,747,073 (year 1) up to CHF 12,713,068 (year 5). Univariate sensitivity analyses were conducted to test the sensitivity of the model variations in the model parameters by varying individual parameters over a range between ±10%. Results were most sensitive to the number of eligible incident patients. The cost-comparison model showed an average cost reduction of CHF 2,675 and CHF 988 per patient in the first and fifth year, respectively. In total, a cost reduction of CHF 8,326 per patient was observed over the 5-year time horizon. Legal, social, ethical, and organisational issues No evidence was identified for these HTA domains. CONCLUSION: Whilst evidence to evaluate the use of BTAs with different administration frequencies in cancer patients with bone metastases is limited, meta-analyses of available trial data indicate that the 3-monthly administration of BTAs in cancer patients with bone metastases is associated with a similar risk of SREs, AEs, and SAEs as monthly administration of these BTAs. A longer dosing interval leads to a reduction in treatment cost over a 5-year time horizon. Given the similarity in efficacy/effectiveness and safety, extended-interval dosing of BTAs may lead to a substantial reduction in annual direct costs per patient and, ultimately, in the annual budget impact in Switzerland. Evidence to evaluate the use of BTAs with different administration frequencies in cancer patients with bone metastases remains scarce, limiting the ability to draw definitive conclusions.

Authors' methods: METHODS: A systematic literature search was conducted for all the HTA domains using Medline, Embase, Evidence-Based Medicine Reviews, and Cochrane Central Register of Controlled Trials on January 18, 2021. Outcomes of interest (skeletal-related events [SREs] and adverse events [AEs]) were synthesized in a meta-analysis. A random effects (RE) model was used for the main analysis due to the limited number of included studies. A cost-comparison model and a budget impact model were developed to evaluate economic parameters.

Project Status: Completed

URL for project: https://www.bag.admin.ch/bag/en/home/versicherungen/krankenversicherung/krankenversicherung-leistungen-tarife/hta/hta-projekte/bonetargetingagents.html

Year Published: 2022

URL for published report: https://www.bag.admin.ch/dam/bag/en/dokumente/kuv-leistungen/leistungen-und-tarife/hta/berichte/h0053zole-hta-report.pdf.download.pdf/h0053zole-hta-report.pdf

URL for additional information: https://www.bag.admin.ch/bag/en/home/versicherungen/krankenversicherung/krankenversicherung-leistungen-tarife/hta/hta-programm.html

English language abstract: An English language summary is available

Publication Type: Full HTA

Country: Switzerland

Organisation Name: Swiss Federal Office of Public Health (FOPH)

Contact Address: Federal Office of Public Health, Schwarzenburgstrasse 157, CH-3003 Berne, Switzerland

Contact Name: Stephanie Vollenweider

Contact Email: hta@bag.admin.ch

Copyright: Swiss Federal Office of Public Health