Background
Phase III, open-label, RCT (EF-14). 695 patients with newly diagnosed GBM who had completed standard RT + concurrent TMZ. Randomized 2:1 to maintenance TMZ + TTFields vs maintenance TMZ alone. Tumor Treating Fields (TTFields) are low-intensity (1–3 V/cm), intermediate-frequency (200 kHz) alternating electric fields delivered via scalp transducer arrays 18+ hours/day. Device: Optune (Novocure). First successful phase III trial demonstrating survival benefit beyond the Stupp backbone.
Interventions and follow up
Arm A: Temozolomide alone — 150–200 mg/m² days 1–5 every 28-day cycle (standard maintenance)
Arm B: TTFields (Optune device, 200 kHz, ≥18 hr/day compliance) + temozolomide (same schedule)
Primary endpoint: Overall survival and progression-free survival
mFollow up: Median 40 month
Arm B: TTFields (Optune device, 200 kHz, ≥18 hr/day compliance) + temozolomide (same schedule)
Primary endpoint: Overall survival and progression-free survival
mFollow up: Median 40 month
Results
OS: 20.9 vs 16.0 months, HR 0.63 (95% CI 0.53–0.76), P<.001
PFS: 6.7 vs 4.0 months, HR 0.63 (95% CI 0.52–0.76), P<.001
2-year OS: 43% vs 31%
5-year OS: 13% vs 5%
PFS: 6.7 vs 4.0 months, HR 0.63 (95% CI 0.52–0.76), P<.001
2-year OS: 43% vs 31%
5-year OS: 13% vs 5%
Adverse events
Main adverse events: Grade 1–2 scalp skin irritation: 52% of TTFields arm (from transducer arrays). No grade ≥3 device-related AEs. Systemic TMZ-related AEs similar between arms. Compliance of ≥18 hr/day associated with better outcomes. QoL maintained similarly (no global QoL deterioration attributable to TTFields).
Conclusions
Adding TTFields to maintenance TMZ improved OS (20.9 vs 16.0mo) and PFS (6.7 vs 4.0mo) in patients with newly diagnosed GBM after chemoRT, with no significant additional systemic toxicity. FDA approved Optune for this indication in 2015 based on this trial.
Key Limitations
Key Limitations: Unblinded design — placebo/sham device not used, creating quality-of-life assessment bias and potential investigator/patient expectation effects. The 2:1 randomization (vs 1:1) reduces statistical efficiency. Compliance with device (≥18 hr/day head shaving required) is burdensome and achievable only in motivated, fit patients. The survival benefit may be partly influenced by the more intensive monitoring of the device arm. Excluded patients unable to comply with device requirements. Cost: Optune is extremely expensive and not widely reimbursed globally. Not applicable to elderly/frail patients.
Clinical Context
FDA approved TTFields (Optune) + TMZ for newly diagnosed GBM in 2015. NCCN and ESMO include it as a category 1 or 2A recommendation. Real-world adoption is limited by cost, device burden, and compliance challenges. In clinical practice, TTFields is most commonly used in young, motivated, high-KPS patients with MGMT-methylated GBM. The lack of blinding is the major methodological criticism.
References
References: Stupp R et al, JAMA 2017 (EF-14)