TTFields with Temozolomide Recommended by NCCN for Newly Diagnosed GBM

The combination of TTFields and temozolomide has been added by the NCCN to its guidelines for Category 1 treatment for patients with newly diagnosed glioblastoma, following maximal safe resection and completion of radiation therapy.

Asaf Danziger

The combination of TTFields (Optune) and temozolomide (Temodar) has been added by the NCCN to its guidelines for Category 1 treatment for patients with newly diagnosed glioblastoma, following maximal safe resection and completion of radiation therapy.

This antimitotic treatment modality, TTFields, interferes with glioblastoma cell division and organelle assembly by delivering low-intensity alternating electric fields to the tumor. Patients recieve the treatment through 4 transducer arrays with 9 insulated electrodes each placed on the shaved scalp, connected to a portable device set to generate low-intensity, 200-kHz electric fields within the brain.

The update was announced in a press release from Novocure, the developer of the device.

“Many physicians look to the NCCN Guidelines as the standard resource when determining the best course of treatment for patients. The introduction of Optune with temozolomide gives newly diagnosed GBM patients the potential for long-term survival," Asaf Danziger, Novocure’s CEO, said in a statement. "We believe the updated NCCN guidelines will increase physician awareness, particularly in the radiation oncology and medical oncology communities, helping us to reach patients earlier in the course of this aggressive disease.”

Based on the 5-year survival results from the phase III EF-14 trial, NCCN added TTFields and temozolomide to the Clinical Practice Guidelines in Oncology for Central Nervous System Cancers. Those data demonstrated that the combination extended overall survival (OS) and progression-free survival (PFS) by 37% compared with temozolomide alone, according to results published in the Journal of the American Medical Associationin December 2017.

A total of 695 patients were enrolled at 83 medical centers worldwide from July 2009 to December 2014 for EF-14. The eligible patients had undergone tumor resection or biopsy, and completed concomitant radiochemotherapy.

Investigators randomly assigned patients to TTFields plus maintenance temozolomide (n = 466) or temozolomide alone (n = 229). The patients in the TTFields arm received low-intensity alternating electric fields treatment was for ≥18 hours per day. All patients in the trial were given 6 to 12 cycles of 150 mg/m2to 200 mg/m2of temozolomide for 5 days in 28-day cycles.

The median PFS was 6.7 months with the combination compared with 4.0 months for the monotherapy (HR, 0.63; 95% CI, 0.52-0.76;P&thinsp;<.001). Median OS was 20.9 months in the TTFields/temozolomide group versus 16.0 months in the temozolomide-alone group (HR, 0.63; 95% CI, 0.53-0.76;P&thinsp;<.001).

Posthoc analyses found that TTFields plus temozolomide was associated with an increase in PFS and OS in all subgroups regardless of age, sex, Karnofsky performance score, MGMT promoter methylation status, geographic region, or extent of resection. Investigators found that the OS benefit associated with the combination was consistent across all patient subgroups including subgroups with the worst prognosis who had less benefit from previous therapies such as patients aged ≥65 years (HR, 0.51; 95% CI, 0.33-0.77) and those with methylated and unmethylated MGMT tumors (HR, 0.66; 95% CI, 0.49-0.85).

In exploratory analyses, 43% (95% CI, 39-48) of the patients were alive at 2 years from randomization, 26% (95% CI, 22-31) at 3 years, and 26% and 13% (95% CI, 9-18) at 5 years in the combination arm in comparison to the temozolomide-only group, with 31% (95% CI, 25- 38;P<.001), 16% (95% CI, 12-23;P= .009), and 5% (95% CI, 2-11;P= .004), respectively.

6-month PFS was 56% (95% CI, 51- 61) in the combination arm compared to 37% (95% CI, 30-44) with temozolomide monotherapy (P<.001).

Investigators did not discover an increase in systemic adverse events (AEs) with the combination (48% vs 44%;P= .58). In the combination arm, patients had a higher number of grade 3/4 AEs. However, investigators attributed the difference to the longer duration of temozolomide treatment in this group due to delayed occurrence of progression. The differences disappeared when investigators controlled for duration of treatment except in the case of e higher incidence of localized skin toxic effects beneath the transducer arrays in patients treated with TTFields plus temozolomide. 52% of patients experienced mild to moderate skin irritation and 2% experienced grade 3 skin involvement.

At interim analysis, patients reported anxiety, confusion, insomnia, and headaches more frequently. The difference was statistically nonsignificant in patients treated with TTFields. Investigators did not find those AEs in the final analysis.

Incidence of seizures was identical in both groups.

The FDA approved a second-generation, lighter version of the device in July 2016, based on earlier results from the EF-14 trial. The new version weighs 2.7 lbs which is about half the size and weight of the original.

The first-generation of Optune was most recently approved in 2015 for use in combination with adjuvant temozolomide as a treatment for patients with newly diagnosed GBM following surgery, chemotherapy, and radiation therapy. Optune was initially approved in 2011 after other surgical and radiation options were exhausted for the treatment of recurrent GBM.


Stupp R, Taillibert S, Kanner A, et al. Survival in patients with glioblastoma: a randomized clinical trial.JAMA.2017;318(23):2306-2316. doi:10.1001/jama.2017.18718.

Over 90% of patients completed the trial before the December 25, 2016 data cutoff.