New Modality for Glioblastoma May Change Standard of Care

Tumor treating fields (TTFields) significantly and consistently prolonged both progression free survival (PFS) and overall survival (OS) in a randomized, phase III trial of patients with glioblastoma.

Roger Stupp, MD

A novel treatment modality added to standard chemotherapy and radiotherapy shows promising results in patients with newly diagnosed glioblastoma. According to a first report of full data presented at the 2015ASCO Annual Meeting, tumor treating fields (TTFields) significantly and consistently prolonged both progression free survival (PFS) and overall survival (OS) in a randomized, phase III trial.

“We have a new standard of care for patients with glioblastoma,” said Roger Stupp, MD, University of Zurich, Zurich, Switzerland. “But beyond that, we have a new cancer treatment modality—well beyond neuro-oncology—that we must evaluate in the cancer field.”

Disrupting Cell Division

As Stupp explained, TTFields are low-amplitude (1-3 V/cm, 200kHz), alternating electrical fields that generate electromagnetic forces to disrupt cell division and interfere with the assembly of organelles, either directly through the membrane or by interrupting spindle checkpoints.

“The forces exerted on the cell and the cell’s organelle will align during mitosis according to the field forces,” he said. “If you do this 200 times per second, randomly alternating, you will actually perturb the cell to the point that it goes into apoptosis.”

Proof of concept was shown via experiment involving two identical cell cultures of cervical cancer cells. In the control culture, researchers observed cell division after only 2 hours. In the cell culture within electric fields, however, cell division was delayed an additional 10 hours.

“If you look after 2 days, you see an outgrowth of cancer cells in the control, while in the dish exposed to electrical fields, all the dividing tumor cells have died,” said Stupp. “The only surviving cells are nondividing cells.”

From Concept to Clinic

Because glioblastoma is a local-regional disease, which occurs mainly in one organ, it was an ideal target, according to Stupp. TTFields are applied by an array of electrodes that are placed on the patient’s shaved skull and connected to a device that delivers these electrical fields with a battery as an energy source. Acknowledging the moderate inconvenience of the machine, which is carried in a backpack, Stupp stressed that the device would continue to decrease in size over time.

An international endeavor, the EF14 study was a randomized, prospective, phase III trial conducted across 12 countries in 83 different sites. Researchers screened 1019 patients with newly diagnosed glioblastoma who had completed a regimen of chemo/radiation therapy. The remaining 695 patients were divided between two arms in a 1-to-1 randomization.

In one arm, patients were treated with maintenance temozolomide. In the other, patients were treated with maintenance temozolomide plus TTFields, and TTFields were given until second progression.

Patient characteristics were well balanced between the two arms, including age, Karnofsky Performance Status, mini-mental state examination score, steroid use, or extent of resection.

Mild Adverse Events

As Stupp reported, approximately half of all patients experienced some reaction to treatment, but this was usually “very mild” and could be handled by the patients and technicians themselves.

“We don’t see any added toxicity other than toxicity related to the local administration of treatment or the carrying of the device,” he said. “What we see is skin reaction to the electrodes or sometimes reaction to the tape where electrodes are attached to the skull.”

There was no increase in seizures or neurological complications in the TTFields arm. Although most adverse events were classified as grade 2, there were some cases of erosion.

Increases in PFS and OS

Patients treated with TTFields, in addition to temozolomide, experienced a median OS of 19.4 months compared with 16.6 months in the control arm. This translated to a reduction in the risk of death by 25% or an HR of 0.75. Patients treated with TTFields also saw a 14% increase in 2-year survival compared with patients in the control arm (43% vs 29%).

Median PFS was 7.1 months for the TTFields group compared with 4.2 months for those patients treated with temozolomide alone (HR = 0.69). Progression was determined by an independent and blinded central radiology review.

Data were consistent between interim and full data set, as well as results from other glioblastoma trials. Subgroup analysis for PFS and OS also showed consistency.

“What we can see is that the benefit of adding TTFields seems to hold up in all subgroups,” he said. “For a full subgroup analysis, however, we are still looking into more detail.”

What about the possibility of placebo effect? Unlikely, in Stupp’s opinion. TTFields clearly show an OS benefit, he said.

Given their proven feasibility and the fact that they are well tolerated without substantial toxicity, Stupp ultimately hopes to push research into the realm of other cancers. Despite these positive results, however, more work remains.

“We are still waiting for the full data set to mature,” Stupp concluded. “We will have to investigate why patients failed and where they failed. We have tumor tissue in at least 75% of the patients, so we hope to understand the mechanisms of response and failure.”

Stupp R, Taillibert S, Kanner A, et al. Tumor treating fields (TTFields): A novel treatment modality added to standard chemo- and radiotherapy in newly diagnosed glioblastoma—First report of the full dataset of the EF14 randomized phase III trial. J Clin Oncol 33, 2015 (suppl; abstr 2000).