Original Title: Terapia de campos eléctricos alternos para el tratamiento de tumores (Tumor Treating Fields, TTFields) en personas con glioblastoma de nuevo diagnóstico

Authors' objectives: • To assess the effectiveness and safety of TTFields in the treatment of adults with ndGBM. • To assess the cost-effectiveness of TTFields in the treatment of adults with ndGBM. • To identify ethical, legal, organizational, social and environmental considerations related to the technology. • To identify research needs and standard outcome measures from the perspective of patients, family members/caregivers, healthcare professionals and research staff on the use of TTFields in the treatment of ndGBM.

Authors' results and conclusions: RESULTS EFFECTIVENESS/SAFETY Fifteen studies were included: 1 SR, 1 RCT reported in 3 articles, 6 COS and 6 US. PROGRESSION-FREE SURVIVAL (PFS) The EF-14 RCT obtained median PFS (from randomization) of 6.7 (TTFields) vs. 4.0 months (control), a statistically significant effect (HR = 0.63, 95% CI: 0.52, 0.76). The difference in the rate of progression-free patients of was significantly higher with TTFields at 6 months (56% vs. 37%, RD = 19%, 95% CI: 15, 23). The difference was also significant at 1 year (30% vs. 20%, RD = 10%, 95%CI: 3, 17) but not at 2 years (14% vs. 10%, RD = 4%, 95%CI: -1, 9) (non-prespecified analyses in EF-14 conducted by the report’s authors) (high-quality evidence). The MA with four COS obtained a similar result for PFS throughout the follow-up period (HR = 0.60, 95%CI: 0.47, 0.76; I2 = 35%), and stronger effects in the 6 month (RD = 24%, 95%CI: 9, 38; I2 = 78.4%) and 2 years rates (RD = 16%, 95%CI: 7, 26; I2 = 22.1%). OVERALL SURVIVAL (OS) The EF-14 RCT obtained median survival (from randomization) of 20.9 (TTFields) vs. 16.0 months (control), a statistically significant effect (HR = 0.63, 95%CI: 0.53, 0.76). The difference in the rate of patients alive was significantly higher with TTFields at 2 years (RD = 12%, 95%CI: 4, 18), 3 years (RD = 10%, 95%CI: 3, 17), 4 years (RD = 12%, 95%CI: 5-19) and 5 years (RD = 8%, 95%CI: 2, 14) (high quality). The MA with 6 COS obtained a similar result for OS throughout the follow-up period (HR = 0.67, 95%CI: 0.51, 0.88; I2 = 37.1%), as well as in the 2-year (RD = 12%, 95%CI: 1, 24; I2 = 51.9%) and 4-year rates (4 studies; RD = 10%, 95%CI: 1, 18; I2 = 42.8%). For both PFS and OS, the EF-14 study found a significant effect of the intervention in all subgroups evaluated, based on sex, age (younger than 65 vs. 65 or older), geographic region (USA vs. others), type of resection (biopsy, partial, total), Karnofsky score (90-100 vs. ≤80), and MGMT gene methylation. Longer use time was associated with better OS outcomes in the EF-14 RCT and in the 5 observational studies that performed this analysis. HEALTH-RELATED QUALITY OF LIFE The EF-14 RCT did not observe significant differences in 8 subscales evaluated quarterly for one year: general health, physical health, cognitive, role, social and emotional functioning, pain and weakness in the legs. Significant differences were only observed in itchy skin, with a worse result (higher scores) in the TTFields group (p < 0.001 for the mixed model of repeated measures) at 3 months (10.4 vs. -2.3, p = 0.005), 6 months (8.1 vs. -4.2, p = 0.008) and 9 months (5.3 vs. -5.2, p = 0.04), but not at 12 (4.6 vs. -1.9, p = 0.66) (low quality). SAFETY In the EF-14 RCT, there were no significant differences in the rate of patients with at least one adverse event (AE) (96% vs. 91%), nor in patients with severe AEs (grade 3-4): TTFields: 48% vs. Control: 44% (p = 0.58). The rate of cutaneous AEs was more frequent in the intervention group; 52% were mild/moderate and 2% severe (moderate quality). In an observational registry study (n = 5887 with ndGBM), 51% suffered at least one AE possibly related to the device, the most frequent being local skin reactions (38%), followed by electric sensation (11%) and heat (11%), headache (7%), pain (5%), fatigue (4%) and discomfort (2%). The overall assessment of the quality of the evidence has been moderate. COST-EFFECTIVENESS Six economic evaluations were included, evaluating TTFields + TMZ versus TMZ. The methodological quality was considered moderate. Four studies estimated ICERs well above €100,000/QALY. A fifth study, conducted in China, estimated a ratio equivalent to €35,900/QALY. The only Spanish study, which is unpublished and was provided by the industry, estimated an ICER of €152,273 per QALY from the perspective of the National Health System (SNS). ETHICAL, LEGAL, ORGANIZATIONAL, SOCIAL AND ENVIRONMENTAL CONSIDERATIONS The implementation of Optune® as a complement to conventional treatments for glioblastoma is well accepted by patients who adopt the technology. The review of the literature has limits in terms of the number of studies and the contextual relevance of the results, since there are only studies carried out outside Spain. Aspects such as the impact on the quality of life of patients, logistical and organizational needs, and the necessary intensive involvement of the manufacturing company for installation and technical support are aspects to be taken into account for its adoption. Regarding equity, there is currently differential access in the SNS, since the technology is available only in some regions. CONCLUSIONS • There is high-quality evidence, represented by the EF-14 RCT, that TTFields (Optune®), applied concurrently with TMZ after chemoradiotherapy, statistically significantly increases progression-free survival and overall survival in adults with ndGBM. No evidence was found that this effectiveness differs significantly based on the sociodemographic and clinical characteristics of the individuals, although more research is needed on this. • The average increase in survival is small in absolute terms (2.7 months of progression-free survival and 4.9 months of overall survival in EF-14). However, in relative terms, it represents a clinically significant benefit given the low survival rates achieved with standard treatment. Furthermore, the effect could double with high device usage (≥90%). • Observational evidence shows very similar survival results (although with a greater effect on PFS rates), and a significant and consistent relationship has been observed between the time of daily use of the device and survival increase. • Evidence on the impact of TTFields on health-related quality of life, also from the EF-14 study, has been rated as low quality. A significant deterioration was only observed due to itching at the application site. Regardless of progression, which explains most of the deterioration in quality of life, there may be an increase in deterioration-free survival in some dimensions such as leg pain or weakness, but further research is needed in this regard • The device shows a good safety profile (moderate-quality evidence), and adverse effects are as expected, local skin adverse effects (2% of them severe). In a registry study with more than 5800 participants with ndGBM, other adverse events possibly related to the device were electric sensation, heat, headache, scalp pain, fatigue and discomfort, with rates between 2-11%. It is expected that cutaneous adverse effects will decrease with the latest version of the transducers. • Therefore, it can be stated with high confidence that, on average, TTFields shows a favorable risk-benefit balance in peope with ndGBM. • When comparing TTFields+TMZ versus TMZ from the perspective of the NHS, an EE provided by the industry estimated an ICER around €150,000/QALY. Most of the foreign EEs identified also obtained very high ICERs.

Authors' methods: An SR of the available literature on effectiveness, safety, cost-effectiveness and ethical, legal, organizational, social and environmental (ELOSA) aspects related to the technology was performed. The Medline, Embase, CINAHL, CDRS/CENTRAL and WPRIM - BRISA/ RedETSA - IBECS databases were consulted from January 2011 to June 2024. Randomized controlled trials (RCTs) and non-randomized controlled trials (RCTs), controlled observational studies (COS) and uncontrolled studies (US), economic evaluations (EE), cross-sectional and qualitative studies (ELOSA aspects), and systematic reviews (for all domains) and narrative reviews (ELOSA aspects) were searched. Information was also requested from industry regarding potential EE conducted in Spain, ongoing studies, and the technology’s environmental impact. Methodological quality was assessed using the following tools: AMSTAR-2 scale (SR), RoB-2 tool (RCT), ROBINS-I tool (RCT and COS), Joanna Briggs Institute checklist (US), Drummond et al. criteria (EE), OSTEBA FLC 3.0 Critical Reading Sheet (descriptive studies), CASPe instrument (qualitative studies), SANRA (narrative reviews). The study selection process, risk of bias assessment and data extraction were performed by independent reviewers. For the synthesis of effectiveness and safety data, a meta-analysis (MA) was performed for the variables progression-free survival (PFS) and overall survival (OS). The Hazard ratio (HR) was calculated to compare survival during follow-up, as well as the risk difference (RD) for the contrast between rates at different time points. The accumulated results were estimated using the inverse variance method. Heterogeneity was assessed using Cochran's Q and Higgins' I2 statistics. A random-effects model (Sidik-Jonkman) was used, comparing it with the fixed-effects model when the I2 value was less than 30%. A sensitivity analysis was performed by eliminating one study at a time. The synthesis of the SR of EE and ELOSA aspects was done narratively.

Project Status: Completed

Year Published: 2025

URL for published report: https://sescs.es/en/ttfields-glioblastoma/

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