Authors' objectives: Glioblastoma (GBM) is an aggressive type of brain cancer characterised by poor prognosis, with an estimated median survival of 13.1 months on a population level. A surgical resection or biopsy of the tumour followed 3-6 weeks later by radiochemotherapy, and maintenance chemotherapy with temozolomide (TMZ) represents the standard of care for patients with newly diagnosed GBM (ndGBM). Treatment at recurrence is varied; the majority of recurrent GBM (rGBM) patients receive systemic treatment, mostly lomustine or less frequently rechallenge with TMZ, or patients can receive bevacizumab, second surgery is an option for subgroups of patients, and re-irradiation can be administered for patients with small tumours. Tumour treating fields (TTFields) are an additional treatment option in combination with TMZ maintenance chemotherapy starting 4–7 weeks after radiochemotherapy. In Switzerland, TTFields are temporarily covered by the mandatory health insurance and limited to ndGBM up to first progression, and a maximum treatment duration of 2 years. In Switzerland, TTFields are not covered for the treatment of rGBM. Whether the medical technology qualifies for statutory health insurance coverage is reconsidered in 2024 based on re-evaluation of the available and new evidence. This health technology assessment (HTA) report assesses the efficacy, effectiveness, safety, cost-effectiveness and budget impact as well as ethical, legal, social, and organisational benefits and harms of: 1) either TTFields in combination with maintenance chemotherapy or TTFields alone after maintenance chemotherapy has stopped in the treatment of ndGBM adult patients until 1st progression 2) TTFields alone or in combination with second-line systemic therapy (physician’s choice chemotherapy) in the treatment of adult GBM patients at 1st progression.

Authors' results and conclusions: RESULTS In the clinical review, 5 articles reporting data on 2 RCTs (one in patients with ndGBM and one in patients with rGBM) and 2 retrospective cohort studies in patients with ndGBM were included. One multi-country RCT in patients with ndGBM treated with TTFields plus TMZ compared with TMZ alone showed a statistically significant longer median overall survival of 20.9 months versus 16.0 months from randomisation (HR for death 0.63 [95% CI 0.53-0.76], p<0.001; 1 RCT; moderate certainty evidence) and a statistically significant longer median progression-free survival of 6.7 months versus 4.0 months from randomisation (HR for progression 0.63 [95% CI 0.52-0.76], p<0.001; 1 RCT; moderate certainty evidence). Furthermore, health-related quality of life (HRQoL) was comparable, only itchy skin was statistically significant worse compared with TMZ alone (1 RCT; low certainty evidence), and there was no statistically significant difference in grade 3-4 severe adverse events (RR 1.09 [95% CI 0.91-1.30], p=0.58; 1 RCT; low certainty evidence). Effectiveness data of TTFields plus TMZ compared with TMZ alone in patients with ndGBM showed discrepant results in two single-centre retrospective cohort studies: no statistically significant difference in overall survival was found in the USA (HR for death 0.93 [95% CI 0.58-1.47], p=0.741; very low certainty evidence) and a statistically significant longer overall and progression-free survival was found in China (HR for death 0.19 [95% CI 0.09-0.41], p<0.001; HR for progression 0.35 [95% CI 0.14-0.91], p=0.031; low certainty evidence). A post-hoc analysis of the multi-country RCT in patients with GBM at first recurrence treated with TTFields plus chemotherapy compared with chemotherapy alone showed a statistically significant longer overall survival, with a median of 11.8 months versus 9.2 months from progression (HR for death 0.70 [95% CI 0.48-1.00], p=0.049; 1 RCT - post-hoc analysis; low certainty evidence), and there was borderline no statistically significant difference in grade 3-4 severe adverse events (RR 1.48 [95% CI 0.997-2.19], p not reported; 1 RCT - post-hoc analysis; very low certainty evidence). A second multi-country RCT in patients with GBM at all recurrences (i.e. 12% at 1 st recurrence, 47% at 2 nd recurrence, and 41% at ≥3rd recurrence) treated with TTFields compared with chemo-therapy reported no statistically significant difference in overall survival with a median overall survival of 6.6 months versus 6.0 months from randomisation (HR for death 0.86 [95% CI 0.66-1.12], p=0.27; 1 RCT; low certainty evidence), but overall survival became statistically significant longer in a posthoc analysis of this RCT when limiting the study population to patients receiving at least one course of TTFields therapy with a median overall survival of 7.8 versus 6.0 months from randomisation (HR for death 0.69 [95% CI 0.52-0.92], p=0.0093; 1 RCT - post-hoc analysis; low certainty evidence). The RCT also did not show a statistically significant difference in progression-free survival, with a median of 2.2 versus 2.1 months from randomisation (HR for progression 0.81 [95% CI 0.60-1.09], p=0.16; 1 RCT; low certainty evidence); no post-hoc analysis was conducted for the outcome progression-free survival. The HRQoL domains did not seem to differ or seemed in favour of TTFields, except for physical functioning (1 RCT; very low certainty evidence) and statistically significant less grade 3-4 severe adverse events were reported for TTFields compared with chemotherapy (RR 0.37 [95% CI 0.16-0.86], p=0.022; 1 RCT; moderate certainty evidence). In the economic review 3 cost-effectiveness studies on TTFields for patients with ndGBM were included: 2 from a French healthcare payer perspective using different model structures (a partitioned survival model and a Markov model) and one from a US healthcare payer perspective. While the first 2 studies concluded that TTFields were not cost-effective, the latter concluded the opposite, under local cost-effectiveness thresholds. The results of the cost-effectiveness model developed for Switzerland showed that, for the ndGBM population, treatment with TTFields plus TMZ leads to higher costs, but also additional benefit compared with treatment only with TMZ, with an ICER of CHF 555,465 per QALY gained. Scenario analyses and sensitivity analyses showed the robustness of the results. An ICER of CHF 6,552,337 per QALY gained was estimated for the rGBM population as the additional benefit was smaller and the estimated costs higher. Finally, according to the budget impact analysis, reimbursement of TTFields in Switzerland can result in additional expenses of CHF 31 million over the span of 5 years, for the ndGBM population. Expanding reimbursement to the rGBM population is associated to a budget impact of CHF 49 million over the span of 5 years. Sixteen articles on ELSO domains were included. In the ethical domain, physician recommendations and patient perspectives on treatment challenges are discussed. Additionally, patient’s socioeconomic status, conflicts of interest for academic centers, and the high cost of TTFields are identified as potential barriers to patient access to treatment with TTFields. Discrepancies regarding TTFields treatment in international clinical practice guidelines exist. No relevant legal issues were identified. In the social domain, it is discussed that the use of TTFields in GBM patients is heavily reliant on social support, necessitating the involvement of caregivers in both the physician's and patient's decision-making process. Compliance to the treatment of both patients and caregivers is emphasized in order for optimal benefits of the treatment to be achieved. Finally, the expanding role of oncology nurses is highlighted, as they play a pivotal role in guiding patients and caregivers through the initiation and adherence to TTFields therapy. CONCLUSION The clinical evidence is based on 1 RCT and 2 retrospective cohort studies in patients with ndGBM, 1 RCT in patients with GBM at all recurrences (i.e. 88% at ≥2nd recurrence), and 2 unplanned post-hoc analyses of these RCTs. In patients with ndGBM, treatment with TTFields plus TMZ compared with TMZ alone is probably efficacious in terms of survival (1 RCT; moderate certainty evidence), may result in little or no difference in severe adverse events (1 RCT; low certainty evidence), and may have little or no effect on HRQoL except for itchy skin (1 RCT; low certainty evidence). Two single-centre retrospective cohort studies in patients with ndGBM showed inconclusive results for the effectiveness of TTFields plus TMZ compared with TMZ alone. In patients with GBM at first recurrence, treatment with TTFields plus chemotherapy compared with chemotherapy alone may be efficacious in terms of survival (1 RCT – post-hoc analysis; low certainty evidence) and may result in little or no difference in severe adverse events but the evidence is very uncertain (1 RCT – post-hoc analysis; very low certainty evidence). In patients with GBM at all recurrences, TTFields treatment alone compared with chemotherapy may result in little or no difference in efficacy in terms of survival (1 RCT; low certainty evidence), probably shows less severe adverse events than chemotherapy (1 RCT; moderate certainty evidence), and may show little or no difference in HRQoL but the evidence is very uncertain (1 RCT; very low certainty evidence). From a health economic perspective, for both ndGBM and rGBM at first recurrerence, the reimbursement of TTFields is likely to improve survival and QALYs and to increase costs. The budget impact analyses showed that the budgetary impact of TTFields is mainly driven by the costs of TTFields. Finally, the use of TTFields is associated with important ethical, social and organisational issues.

Authors' methods: For the clinical review, a systematic literature search of the PubMed (MEDLINE), Embase.com, and Cochrane Library databases was conducted adhering to international methodological standards. A stepwise approach was implemented to search for studies on TTFields in patients with GBM, first for randomised controlled studies (RCTs) and an additional search for comparative non-randomised studies. Studies were selected by applying pre-specified exclusion criteria during the selection process. The included studies were critically appraised with the revised Cochrane Risk of Bias tool for randomised trials (RoB 2) and the Risk of Bias in Non-randomised Studies - of Interventions (ROBINS-I) tool, and the extracted data were summarised in tables and narrative text. Based on the heterogeneity of the study populations, the results were stratified in 3 populations: patients with ndGBM, patients with GBM at first recurrence, and patients with GBM at all recurrences. The systematic literature search for the economic review followed a procedure similar to the one described above. The searches were conducted in PubMed (MEDLINE), Embase.com, Cochrane Library, as well as the economic databases of Cost Effectiveness Analysis (CEA) Registry, Tufts Medical Centre Cost-Effectiveness Analysis Registry, and National Health Service Economic Evaluation Database (NHS EED). The quality of the studies was assessed using the Consolidated health Economic Evaluation Reporting Standards (CHEERs) and the Consensus Health Economic Criteria (CHEC) checklists. Two partitioned survival models (one for ndGBM and one for rGBM) were built to estimate the cost-effectiveness of TTFields plus TMZ compared with TMZ only. Efficacy inputs, costs and utilities were collected from literature. A Swiss healthcare payer perspective and a lifetime time horizon were used. Starting age in the model was 56 years. Cycle length was one month. Ethical, legal, social, and organisational (ELSO) issues were searched through the systematic literature searches and pragmatic searches, and described narratively.

Project Status: Completed

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

URL for protocol: https://www.bag.admin.ch/dam/bag/en/dokumente/kuv-leistungen/leistungen-und-tarife/hta/berichte/h0076ttfg-hta-protocol.pdf.download.pdf/h0076ttfg-hta-protocol.pdf

Year Published: 2024

URL for published report: https://www.bag.admin.ch/dam/bag/en/dokumente/kuv-leistungen/leistungen-und-tarife/hta/berichte/h0076ttfg-hta-report.pdf.download.pdf/h0076ttfg-hta-report.pdf

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