Clinical trialPhase 3Brain tumours

Effect of Tumor-Treating Fields Plus Maintenance Temozolomide vs Maintenance Temozolomide Alone on Survival in Patients With Glioblastoma: A Randomized Clinical Trial

JAMA · 2017695 patients (466 TTFields + temozolomide, 229 temozolomide alone)

Stupp R, Taillibert S, Kanner A, et al. JAMA. 2017. 318:2306-2316

Study type: Clinical trial
Study name: EF-14
Phase: Phase 3
Design: Randomised, open-label (no sham device), multicentre (83 centres) trial, 2:1 randomisation; report of the final analysis
Sample size: 695 patients (466 TTFields + temozolomide, 229 temozolomide alone)
Source: JAMA · 2017
Trial registration: NCT00916409

In plain words

TTFields is a portable device that sends weak electric fields into the brain through several pads (arrays) stuck onto the shaved scalp; these fields disrupt the division of tumour cells. The device is painless but has to be worn for most of the day and night (at least 18 hours). In this study, patients who used the device together with temozolomide tablets after finishing radiotherapy lived on average about 5 months longer. The most common side effect was mild irritation of the scalp under the pads. Cost and access to this device are limited in many countries.

Key results

20.9 vs 16.0 months

Median overall survival

HR 0.63 (95% CI 0.53 to 0.76); P<0.001; from randomisation

6.7 vs 4.0 months

Median progression-free survival

HR 0.63 (95% CI 0.52 to 0.76); P<0.001

48% vs 44%

Systemic adverse events

Mild to moderate skin irritation under the arrays: 52% in the TTFields group

Drugs in this study:Temozolomide (Temodal)

Dose and schedule cards

TTFields + maintenance temozolomide (EF-14)

Newly diagnosed glioblastoma after completion of chemoradiotherapy with temozolomide, without disease progressionEach drug’s schedule in the tableOn the page “Brain tumours” · Newly diagnosed glioblastoma: after surgery

Newly diagnosed glioblastoma after completion of chemoradiotherapy with temozolomide, without disease progression

Drug	Dose	Route	Schedule
TTFields (200 kHz alternating electric field)	Via 4 transducer arrays on the shaved scalp, connected to a portable device	On the scalp	At least 18 hours a day, continuously
Temozolomide	150 to 200 mg/m² once daily	Oral	Days 1 to 5, every 28 days

Cycle schedule: Temozolomide every 28 days; TTFields continuously, at least 18 hours a day
Duration: Temozolomide 6 to 12 cycles

Mild to moderate skin irritation under the arrays occurred in 52% of patients; systemic adverse events occurred in 48% vs 44%. Temozolomide monitoring as in the “Common safety considerations”.

On the page “Brain tumours” · Newly diagnosed glioblastoma: after surgery

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1TTFields + maintenance temozolomide

Tumour-treating fields (TTFields): low-intensity alternating electric fields at a frequency of 200 kHz, at least 18 hours per day, delivered through 4 transducer arrays on the shaved scalp connected to a portable device (NovoTTF-100A / Optune).

Temozolomide 150 to 200 mg/m², 5 days of each 28-day cycle (6 to 12 cycles). Per ClinicalTrials.gov: cycle 1 at 150 mg/m², escalated to 200 mg/m² from cycle 2 if tolerated.

2Maintenance temozolomide alone

Temozolomide 150 to 200 mg/m², 5 days of each 28-day cycle (6 to 12 cycles).

Source of the regimen details: TTFields specifications (200 kHz, ≥18 hours per day, 4 arrays) and temozolomide dose (150 to 200 mg/m², 5 days out of 28, 6 to 12 cycles) from the published abstract of the JAMA 2017 paper; the dose escalation schedule from 150 to 200 and the eligibility criteria from ClinicalTrials.gov NCT00916409.

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Adults with newly diagnosed glioblastoma who had completed concurrent chemoradiotherapy with temozolomide after surgery (resection or biopsy) and had no progressive disease; KPS ≥70. Randomisation 4 to 7 weeks after the end of chemoradiotherapy (ClinicalTrials.gov). Median time from diagnosis to randomisation 3.8 months, median age 56 years.

Endpoints

Primary endpoint: progression-free survival (PFS).

Secondary endpoint (hierarchical testing): overall survival (OS); also comparison of adverse events.

Safety and side effects

Systemic adverse events occurred in 48% of the TTFields + temozolomide group and 44% of the temozolomide-alone group. Mild to moderate skin toxicity under the transducer arrays occurred in 52% of patients in the TTFields group (none in the control group). No significant increase in systemic adverse events was reported.

Clinical significance and place in guidelines

The Optune device (TTFields) is approved in the United States, on the basis of this trial, for newly diagnosed glioblastoma together with temozolomide. However, the EANO 2021 guideline notes that TTFields during temozolomide maintenance "remains controversial" despite the positive results of this phase 3 trial (because of the lack of a sham group and questions about the mechanism and the interpretation of the data) and is not widely available in Europe; it is therefore an option to discuss with the patient.

Limitations

Open-label design without a sham device; possible placebo effect or differences in care. Patients were enrolled after completing chemoradiotherapy and without progression (selection of patients with a better prognosis). Adherence to prolonged daily use, the practical burden and high cost, and the effect on quality of life are debated.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.