Background
EF-14 was a phase III randomized open-label trial evaluating the addition of tumor-treating fields (TTFields, NovoTTF-100A/Optune device, 200 kHz) to adjuvant temozolomide (TMZ) maintenance chemotherapy in patients with newly diagnosed GBM who had completed standard concurrent chemoradiation (Stupp protocol). TTFields is a locoregional therapy delivering alternating electric fields through scalp transducer arrays, disrupting mitotic spindle formation and selectively killing dividing cells. EF-14 was the first positive phase III trial in GBM since Stupp (NEJM 2005) to show an OS benefit.
Interventions and follow up
Arm A: Adjuvant temozolomide 150–200 mg/m² days 1–5 q28d × 6–12 cycles (standard maintenance after Stupp CRT)
Arm B: TTFields (Optune device, 200 kHz, ≥18 hours/day) + adjuvant temozolomide × 6–12 cycles
Primary endpoint: Progression-free survival (PFS)
Key secondary: OS
mFollow-up: 40 months
Arm B: TTFields (Optune device, 200 kHz, ≥18 hours/day) + adjuvant temozolomide × 6–12 cycles
Primary endpoint: Progression-free survival (PFS)
Key secondary: OS
mFollow-up: 40 months
Results
mOS: 20.9 vs 16.0 months (HR 0.63, 95% CI 0.53–0.76, P<.001)
mPFS: 6.7 vs 4.0 months (HR 0.63, 95% CI 0.52–0.76, P<.001)
5-yr OS: 13% vs 5%
By MGMT: methylated mOS 31.6 vs 21.2 months; unmethylated mOS 16.9 vs 14.7 months
mPFS: 6.7 vs 4.0 months (HR 0.63, 95% CI 0.52–0.76, P<.001)
5-yr OS: 13% vs 5%
By MGMT: methylated mOS 31.6 vs 21.2 months; unmethylated mOS 16.9 vs 14.7 months
Adverse events
Systemic: Grade ≥3 AEs similar between arms (TMZ-related hematologic toxicity, fatigue); no systemic adverse effects from TTFields
Device-specific: scalp skin reaction beneath arrays in 52% (Grade ≥3 2%), managed with array rotation and topical agents; no impact on QoL (EQ-5D similar between arms); compliance ≥18h/day achieved in 75% of device arm; no device-attributable cognitive impairment
Device-specific: scalp skin reaction beneath arrays in 52% (Grade ≥3 2%), managed with array rotation and topical agents; no impact on QoL (EQ-5D similar between arms); compliance ≥18h/day achieved in 75% of device arm; no device-attributable cognitive impairment
Conclusions
TTFields plus temozolomide significantly improved OS (20.9 vs 16.0 months, HR 0.63) and PFS compared to temozolomide alone in newly diagnosed GBM following standard chemoradiation, representing the first phase III OS benefit in this disease since the Stupp regimen and establishing a new standard-of-care when combined with adjuvant temozolomide in eligible patients.
Key Limitations
Open-label design — a placebo-controlled device trial is logistically impossible; 2:1 randomization (unequal) leaves the control arm smaller; patient compliance (device wear hours) confounds outcomes; scalp maintenance burden (shaving, array changes) and psychosocial impact of a visible device not fully captured; crossover not permitted; MGMT-unmethylated subgroup showed marginal benefit; enrolled post-CRT patients who remained progression-free (selection bias toward favorable biology); cost and access barriers significant (device ~$21,000/month in the US); long-term cognitive impact not well characterized; conducted at specialized academic centers.
Clinical Context
EF-14 led to FDA approval of TTFields (Optune) + TMZ for newly diagnosed GBM in 2015 (approval preceded full publication, based on interim data). ASCO-SNO and EANO guidance support TTFields for patients with good performance status following concurrent CRT. The survival benefit (mOS 20.9 months) remains the benchmark improvement over Stupp's 14.6 months. Real-world compliance is a major challenge — device wear correlates with outcome (>22h/day: mOS 24.9 months). TTFields is also approved for pleural mesothelioma (STELLAR trial). Ongoing trials explore TTFields combinations with bevacizumab, immunotherapy, and recurrent GBM (EF-11, negative vs bev). Adoption varies internationally due to cost, practical barriers, and reimbursement.