Tumor-Treating Fields Up Survival in Glioblastoma

Alexander M. Castellino, PhD

December 15, 2015

Preliminary data from a phase 3 study that showed a survival benefit from adding treatment with tumor-treating fields (TTFs) delivered by the Optune device (Novocure) on top of temozolomide (Temodar, Merck Sharp & Dohme Corp) (TMZ) in the first-line treatment of patients with glioblastoma was published online December 15 in JAMA.

"Based on the results of this planned interim analysis, the trial's independent data and safety monitoring committee recommended the termination of the trial," the study authors write in their discussion. This study, sponsored by the manufacturer of the device, was used as the basis of approval of first-line use in glioblastoma last year. The device had already been approved for use in recurrent glioblastoma.

"Given the survival benefit reported in the study, it should now be a priority to understand the scientific basis for the efficacy of TTFields," comments John H. Sampson, MD, PhD, MHSc, from the Department of Neurosurgery at Duke University, Durham, North Caroline, in an accompanying editorial.

"Achieving this may require the development of robust and widely available large animal models for glioblastoma, which do not currently exist," he added.

 
The survival benefit seen is significant, and the data are compelling for a devastating and difficult-to-treat disease. Dr John Sampson
 

"The survival benefit seen is significant, and the data are compelling for a devastating and difficult-to-treat disease," Dr Sampson told Medscape Medical News. "However, there are caveats that may limit its acceptance," he added.

Results in Newly Diagnosed Glioblastoma

The multicenter, open-label, phase 3 study included 700 patients with newly diagnosed glioblastoma. Before randomization, all patients were initially treated with chemoradiation with TMZ added to radiotherapy.

The NovoTTF-100A system. (Courtesy of Novocure.)

Patients whose disease did not progress were randomly assigned to receive either TMZ alone (n = 229) or the combination of TMZ plus TTF therapy using the NovoTTF-100A system (n = 466). TMZ was administered at the dose of 150-200 mg/m2 per day for 5 days every 28 days for 6 to 12 cycles

Treatment with TTF involves wearing four electrically insulated electrodes on the shaved scalp; the electrodes are connected to a portable, battery-operated device, which provides continuous TTFs or alternating electric fields to the region of the tumor.

The transducer array optimized field intensity within the tumor using a mapping software system. Patients were trained to operate the device, and after which they could operate the device on their own.

Treatment with the TTFs was to be started within 4 to 7 weeks after patients had received the last dose of TMZ and radiotherapy.

For the interim analysis, 210 patients had completed the combination treatment, and 105 had completed treatment with TMZ alone.

In October 2014, the trial was terminated prematurely, owing to the trial's meeting its predefined boundaries of success. In the interim analysis, patients were similar with respect to demographics. Median age was 57 years; 66% of the patients were male. Median Karnofsky performance score was 90%, and 64% of patients underwent gross total resection.

Following evidence of progression, patients in the combination arm had received six cycles of TMZ; patients in the TMZ-only arm received four cycles of TMZ. Median duration of the TTF treatment was 9 months, with two thirds of the patients continuing to receive TTF therapy after the first tumor progression. Approximately 75% of the patients who used the device were adherent to treatment; they wore the device for more than 18 hours per day.

The primary endpoint of progression-free survival (PFS). After a median follow-up of 38 months, median PFS was 7.1 months for patients on the device plus TMZ vs 4.0 months (hazard ratio [HR], 62; 98.7% confidence interval [CI], 0.43 - 0.89; P = 0.001).

Overall survival (OS) in the per-protocol population — all patients who had adhered to the protocol — also showed significant OS in favor of patients who were treated with the device and TMZ: 19.6 months vs 16.6 months for the TMZ-alone group (HR. 0.74; 95% CI, 0.56 - 0.98; P = 0.03).

Adding TTF therapy to TMZ was not associated with any additional toxicity except for a higher incidence rate of localized skin toxicity in patients in the combination group — mild to moderate skin reaction, seen in 43% of patients, and severe skin reaction, seen in 2% of patients. Some of the adverse events that occurred more frequently in patients treated with the combination of device and TMZ were mild anxiety, confusion, insomnia, and headaches.

Some Caveats of the Study

This was not a placebo-controlled study, and therefore the potential power of a placebo cannot be assessed, Dr Sampson explains in his editorial.

"A sham or placebo treatment for the control group was considered neither practical (patients would be able to sense heat when they were receiving TTFields) nor appropriate (due to the burden for patients and caregivers and the need to shave the scalp and have the transducer arrays placed)," the study investigators argue.

The fact that the study was not blinded may introduce adherence bias, Dr Sampson told Medscape Medical News. Adherence to therapy was high in the device plus TMZ arm, and patients who adhere to therapy more often exhibit beneficial interactions that produce significant survival advantages, he commented.

A second caveat was that patients in the group that was treated with TMZ alone received less adjuvant chemotherapy before tumor progression (four cycles, vs six cycles for patients in the device plus TMZ group). Why? One explanation could be that patients in the combination arm received more TMZ because they were benefitting from the device. Because this was an open-label study, there is the equal likelihood that patients and physicians could have minimized the signs and symptoms of a recurrent tumor on the assumption that the device was doing its job, he explains in his editorial.

"These are preliminary data," Dr Sampson told Medscape Medical News. "Analysis of the full dataset is awaited to determine if it supports and sustains the data reported in this interim analysis," he said.

The study design also casts doubts on the efficacy of the device. "Perhaps most concerning, because of the study design chosen, doubts remain as to the true efficacy of the study. So, if TTFields therapy fails to be adopted, will this decision be attributed to professional parochialism or to data that are not trusted?” Dr Sampson asks in his editorial.

"The current study provides additional important data on a novel device for the treatment of glioblastoma, but it will not completely resolve that debate," he concludes.

The study was sponsored by Novocure, manufacturer of the TTF device. Several authors received financial support from Novocure, as well as from other pharmaceutical companies. Dr Sampson receives personal fees from several companies and holds patents with Celldex and Annias Therapeutics that are not directly relevant to the study.

JAMA. Published online December 15, 2015. Full text, Editorial

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