Original Title: Radioterapia intraoperatoria en tumores y metástasis cerebrales resecables

Authors' objectives: This Health Technology Assessment aims to evaluate the effectiveness, safety, and cost-effectiveness of IORT for resectable malignant primary or metastatic brain tumors.

Authors' results and conclusions: RESULTS: EFFECTIVENESS AND SAFETY: The assessment of effectiveness and safety is based on the results from 2 RCTs and 13 observational studies with a control group. Most studies included mixed samples (glioblastomas, anaplastic astrocytomas, oligodendrogliomas, ependymomas, and/or brain metastases), while seven exclusively involved glioblastoma patients, two focused on low-grade astrocytomas, and one specifically included patients with brain metastases. The majority compared the addition of IORT to treatment as usual (TAU) (i.e., resection surgery and external beam radiotherapy with or without chemotherapy). Most studies showed a high risk of bias. The quality of evidence for outcomes deemed critical and important for decision-making has been classified as very low (⨁◯◯◯), primarily due to the design and risk of bias in individual studies, small sample sizes, and heterogeneity in the evaluated populations. Overall, meta-analyses assessing the addition of IORT to TAU demonstrated favorable outcomes for IORT in terms of one- and two-year survival, with relative increases of 40% (RR = 1.40; 95% CI: 1.08, 1.81; I² = 64%; p = 0.01) and 63% (RR = 1.63; 95% CI: 1.05, 2.56; I² = 45%; p = 0.03), respectively, particularly for tumor types other than glioblastomas. Although differences were not significant at 3 and 5 years, IORT consistently exhibited superiority in median survival, with differences ranging from 3 to 7 months. Disease-free survival also favored IORT in three studies. Regarding recurrence rates, no significant differences were found, except for distal recurrence, where a meta-analysis indicated a higher risk with IORT (RR = 2.95; 95% CI: 1.14, 7.65; I² = 0%; p = 0.01). In terms of safety, one of the included RCTs reported a death due to cerebral edema, but no other severe events were documented. Older studies (pre-2001) revealed two cases of radionecrosis in the IORT group versus four in the control. No studies on quality of life were identified. In summary, although the available results suggest a positive risk/benefit balance for the addition of IORT to standard practice, the low quality of the evidence does not allow for solid conclusions regarding its effectiveness and safety. Additionally, there is limited insight into its differential efficacy based on the type of tumor and the type of IORT. Further high-quality randomized studies are needed. COST-EFFECTIVENESS AND ECONOMIC ANALYSIS: The SR did not identify any economic evaluation meeting the specified criteria. The cost analysis revealed that incorporating IORT into standard treatment would incur an incremental cost of €6353.5 per patient for the population with primary tumors, and savings of €1760.13 for the population with resectable secondary tumors. If equipment acquisition for IORT administration were necessary, an additional cost of between €487.61 and €5688.83 per patient would need to be considered (depending on the number of users of the equipment per year). Moreover, the widespread use of this technology across the target population in Spain would result in an additional €35.2 million (primary tumors) or a saving of €9.7 million (resectable secondary tumors) over 5 years, compared to the current scenario without IORT. ETHICAL, LEGAL, ORGANIZATIONAL, SOCIAL, AND ENVIRONMENTAL ASPECTS: The SR did not identify any study addressing ethical, legal, organizational, social, and environmental aspects related to the evaluated technology. Therefore, a consultation was conducted with two experts in neurosurgery with experience in IORT to assess the feasibility and possible barriers and facilitators of its implementation, professionals' attitudes towards adoption, as well as other contextual and organizational aspects and its potential impact on equity. Regarding the environmental aspect, the manual scope search did not identify any potentially relevant articles for detailed full-text analysis, and the industry responded that it does not have information related to the environmental declaration of IORT. CONCLUSIONS: • The available evidence on the effectiveness and safety of IORT assessed in this report, in terms of survival and tumor recurrence rates in brain cancer, is of very low quality and does not allow for solid conclusions to be drawn. Published studies are scarce, mainly observational, with small sample sizes, and mostly dated. It is not possible to determine differential efficacy based on the type of tumor (only one study exclusively included patients with brain metastases) or the type of IORT. • Considering all types of brain tumors together, the addition of IORT to standard treatment could improve one- and two-year survival rates, as well as the average survival time. In the case of glioblastoma, results were not significant in meta-analyses regarding survival rates, but they were significant in terms of survival time (effect between 3-7 months). • No differences were observed in the local recurrence rate, and there was a discrepancy in the distant recurrence rate between a randomized controlled trial (no differences) and the meta-analysis of 2 observational studies (higher rate with IORT). • Regarding safety, no significant differences in perioperative complication rates were observed when adding IORT to standard treatment. • No published economic evaluations meeting the inclusion criteria of the SR were identified for assessing IORT. • The inclusion of IORT in routine clinical practice would result in an incremental cost of €6353.5 per patient with primary brain tumor, and savings of €1760.13 per patient with resectable secondary brain tumor, from the perspective of the NHS. • The inclusion of IORT in routine clinical practice for the treatment of primary or resectable secondary brain tumors would mean a net budgetary impact of €35.2 million or €-9.7 million, respectively, for the NHS over 5 years. • The expert consultation concludes that the use of IORT can offer a set of significant advantages, from its ability to provide immediate and precise doses to the potential reduction of toxicity and hospital visits. Nevertheless, the implementation faces considerable challenges, such as the need for interdisciplinary coordination with the entire medical team and the requirement for surgical adaptations, as well as the necessity of acquiring specific equipment. To ensure equitable and ethical access to this technology, defined clinical protocols and careful planning and coordination with the entire medical team would be necessary.

Authors' recommendations: Due to the low quality of the currently available evidence, it is not possible to establish a recommendation either in favour or against IORT in the treatment of resectable brain tumors and metastases. Given the uncertainty regarding the risk/benefit balance (i.e., uncertain benefits in critical variables) along with several ongoing studies whose results will be available in the coming years, it would be advisable to postpone the decision on its inclusion in the common services portfolio of the National Health System until higher-quality scientific evidence is available.

Authors' methods: EFFECTIVENESS AND SAFETY: A systematic review (SR) of the literature by independent peers was conducted, consulting databases until March 2023: MEDLINE, Embase, CINAHL, CDSR/CENTRAL, and WOS. Selected studies included SRs with or without meta-analyses (MAs), randomized controlled trials (RCTs), non-randomized controlled trials (NRCTs), and prospective/retrospective observational studies assessing intraoperative radiation therapy (IORT) effectiveness and safety in resectable malignant brain tumors. Outcomes considered were disease-specific mortality, survival, progression-free survival, local tumor/brain metastasis control, health-related quality of life, mental health, and IORT-related complications. Risk of bias was assessed using RoB-2 (RCTs), ROBINS-I (observational studies), and AMSTAR-2 (SRs). Quantitative synthesis was performed when feasible using Review Manager 5.4. The evaluation of evidence quality and recommendation strength followed the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. COST-EFFECTIVENESS AND ECONOMIC ANALYSIS: The SR conducted to assess the previously described effectiveness and safety also incorporated a search for economic evaluations, conducted in parallel to primary studies or models, reporting any of the following outcomes: incremental cost-effectiveness ratio (ICER), costs expressed in monetary units, and benefits expressed in quality-adjusted life years (QALYs), life years gained (LYG), monetary units, or any of the effectiveness outcome measures included in the effectiveness section. Methodological quality assessment was planned using Drummond et al.'s criteria and/or the Critical Reading Sheet (FLC 3.0) from OSTEBA. Data extraction and a narrative synthesis of the results were also envisaged. Additionally, a partial economic evaluation was conducted, comparing the costs of two interventions aimed at treating adult patients with brain tumors (primary or resectable secondary brain tumors): the standard clinical practice in Spain, involving tumor resection surgery followed by external beam radiotherapy, with the optional administration of chemotherapy, versus the addition of IORT to this standard treatment. The treatment with external beam radiotherapy was not included in the evaluated alternative for resectable secondary brain tumors. The analysis was performed from the perspective of the National Health System (NHS) over a one-year time horizon. Regarding costs, expressed in 2023 euros, only costs not common to both strategies were considered. A deterministic sensitivity analysis of a pathway was conducted to assess uncertainty around parameters, including a scenario involving the acquisition of IORT equipment. Finally, the net budgetary impact of incorporating this technology into the NHS was estimated over a 5-year timeframe. ETHICAL, LEGAL, ORGANIZATIONAL, SOCIAL, AND ENVIRONMENTAL ASPECTS: An adaptation of the evaluative framework from the Core Model 3.0 of EUnetHTA, along with the criteria established by the Spanish Network of Health Technology Assessment Agencies (RedETS) of the NHS, was employed. Combining the analysis criteria from these models, a systematic review was developed, building upon the scope of the effectiveness and safety SR described earlier. Qualitative studies, observational studies, SRs (with or without meta-analysis), scoping reviews, realistic reviews, integrative reviews, and narrative reviews with empirical bases were included. A manual search was conducted for the environmental section.

Project Status: Completed

Year Published: 2023

URL for published report: https://sescs.es/informe-rio/

English language abstract: An English language summary is available

Publication Type: Full HTA

Country: Spain

Organisation Name: Canary Health Service

Contact Address: Dirección del Servicio. Servicio Canario de la Salud, Camino Candelaria 44, 1ª planta, 38109 El Rosario, Santa Cruz de Tenerife

Contact Name: sescs@sescs.es

Contact Email: sescs@sescs.es