ARTICLE IN BRIEF
A therapeutic device that delivers low-intensity alternating electrical fields to the brains of patients with glioblastoma along with temozolomide (TMZ) chemotherapy increased survival and progression-free status in glioblastoma patients, a new analysis found. At two years follow-up, 43 percent of patients in the group that received both maintenance therapies were still alive, compared with 29 percent in those who were only on TMZ.
The addition of a therapeutic device that delivers low-intensity alternating electrical fields to the brains of patients with glioblastoma (GBM) along with chemotherapy increased survival by an average of three months, according to a study published in the December 15, 2015, issue of the Journal of the American Medical Association.
In order to receive the tumor-treating fields (TTFields), people have their skulls shaved and wear four sets of electrode arrays (a total of 36 electrodes) that cover the whole brain. The arrays are attached to a battery-operated device that delivers the electrical fields; it must be worn 18-hours a day and charged continuously.
A planned interim analysis found a significant difference in patients randomized to receive maintenance temozolomide (TMZ) alone and those who were administered the same chemotherapy plus TTFields, marketed as Optune. The analysis is based on the first 315 patients who have been followed for at least 18 months since randomization; commonly, by that time, the majority of patients will have progressed or died of the disease.
The analysis showed a 26 percent reduced risk of death (HR 0.74, 95% CI 0.56-0.98), which translated to a two-year survival rate of 43 percent in patients on TMZ and TTFields, compared with 29 percent in patients on TMZ alone. Based on these results, the independent data monitoring committee recommended that the trial be closed and results made publicly available.
In preclinical studies, TTFields interfered with tumor growth by interrupting or blocking cell division and organelle assembly, ultimately leading to apoptosis.
In October 2015, the US Food and Drug Association (FDA) used these data to approve the use of TTFields as an adjunct therapy for patients newly diagnosed with GBM. The device was initially tested in a clinical trial of 237 patients with recurrent GBM who eceived either TTFields therapy or the best standard of care alone, but not both combined. The overall survival was the same in both groups and the side effects were minimal. With few treatment options for patients, the FDA approved it for recurrent GBM in 2011.
Still, neuro-oncologists have been slow to embrace the novel device. Roger Stupp, MD, a professor and chairman of the department of oncology and the Cancer Center at the University of Zurich and University Hospital Zurich, and the lead investigator of both studies, is hoping that the new findings reported in JAMA will put an end to the skepticism. “I think this is the new standard of care,” he said. “We just need to figure out how best to implement it and find the right patients who would get value from using it.”
Novocure, a company in Portsmouth, NH, developed and sells the device.
STUDY METHODOLOGY AND RESULTS
More than 80 clinical centers signed on to enroll newly-diagnosed GBM patients into the study. The clinicians enrolled 695 patients; and patients were randomized to receive maintenance treatment with TMZ and TTFields combined (n=466) or TMZ alone (n=229). Prior to inclusion in the study, all patients had undergone tumor resection and standard chemoradiation. The patients were enrolled an average of 3.8 months after diagnosis.
Midway through the study, with the first 315 patients enrolled and followed up for at least 18 months, the data safety monitoring committee analyzed the progression-free survival rates in the intent-to-treat population (all those enrolled into the treatment arms whether they had treatment or not), as well as the per-protocol population of those who actually completed the protocol.
Both ways of analyzing the data proved significant for increasing progression-free survival and overall survival. The results were so striking that the FDA agreed that the study should be halted and patients offered the TTFields. Median progression-free survival in the intent-to-treat population was 7.1 months in those receiving both maintenance therapies, compared with four months in those who were receiving TMZ alone (p=.001). The median overall survival in the intent-to-treat group was 19.6 months in the TTFields plus TMZ group, compared with 16.6 months in the TMZ alone group (p=.03).
The median overall survival in the per-protocol population was 20.5 months in the group receiving both TTFields and TMZ and 15.6 months in the group receiving just chemotherapy (P=.004).
At two years follow-up, 43 percent of patients in the group that received both maintenance therapies were still alive, compared with 29 percent in those who were only on TMZ.
Dr. Stupp said that he was surprised by the results of the interim analysis. “Usually, at that point in a study, an analysis tells you that the device is safe or it isn't. But this gave us a clear statistical answer. At two years there were 14 percent more patients alive if they had received the combined treatments. I think this is meaningful.”
Neurology Today asked Dr. Stupp to respond to concerns that the study lacked a control group or a sham treatment as a comparison. He responded that a control arm using a sham device would not have been feasible due to the heat associated with electricity.
“Patients and doctors would rapidly know which treatment they are receiving,” he said. “Furthermore, a blinded control arm serves in particular for treatments with low toxicity and little therapeutic burden. In our trial both progression-free and overall survival are both significantly prolonged if patients were treated with adjuvant TMZ and tumor-treating fields. This cannot be due to a placebo effect.”
He said that there are no plans to conduct a blinded, explaining that it would be too much to expect healthy controls to shave their heads and carry around the device.
Several neuro-oncologists who were not involved with the JAMA analysis agreed that the device was a positive addition to the therapeutic regimen for GBM, though they said it had some drawbacks and was not necessarily right for everyone. Patients may not be comfortable with having their heads shaved and carrying around a five-pound battery pack, for example, they said.
Lynne P. Taylor, MD, FAAN, director of neuro-oncology at Virginia Mason Medical Center in Seattle, originally declined to join the multicenter clinical trial “because I thought it was a crazy idea.” Then, in 2011 she said she accepted a job at Tufts University School of Medicine, where oncologists were recruiting for the study. They enrolled 19 patients. “We started to notice that the patients were functioning incredibly well. Their MRIs looked better than expected and they were reporting a better quality of life.”
She said that she was not surprised when she actually saw the interim data. “It has changed my practice,” she said. “We are finding that it puts the control in the hands of the patient. That sense of control is important.”
She discusses the therapy option with all of her patients, but said she knows it is not for everyone. It would be challenging for elderly patients living alone to use the device, for example.
“It was hard to imagine that this type of treatment would be useful,” said Patrick Y. Wen, MD, FAAN, director for the Center of Neuro-Oncology at the Dana Farber/Brigham and Women's Cancer Center and a professor of neurology at Harvard Medical School. “The phase 3 study for recurrent glioblastoma found it no better and no worse than standard therapy, which has a low efficacy,” Dr. Wen said. “This latest finding was a surprise to many people in the field. It was clearly a positive result.”
Dr. Wen said he has discussed the study findings with his patients. So far, only a handful of patients have opted to use the device. He noted that the device is expensive ($21,000 per month) and insurance coverage to date has been variable, although this may improve, he added.
Nimish A. Mohile, MD, an associate professor of neurology at the University of Rochester, called the results “a big step forward. The nice thing about this device is that it doesn't have overlapping side effects. It is safe and adds a completely different way of targeting tumors.
“It is so different for us and for our patients,” he added. “It is harder to explain and harder for them to use? to understand?. Some patients have said ‘no’ after hearing what it entails. They are willing to go through surgery, radiation and chemotherapy, but for some, using the device seems too difficult.”
Still, Dr. Mohlie said he has been using it since the results were first presented at the Society for Neuro-Oncology meeting in 2014. “It think it's a pretty significant advance.”
Asked if a placebo effect influenced the outcome, he said he doubted that that was so. “The endpoint, overall survival, is objective,” he said, “and there has not been a significant placebo effect seen in other studies in glioblastoma.”
Dr. Wen agreed, adding: “Some people have expressed concerns that there were no sham electrodes in the control group and that there may be a placebo effect. The authors argue that the lack of placebo in radiotherapy trials did not result in a survival benefit such as the one seen in this study. However, there are some trials of palliative care in lung cancer that show improved survival, suggesting the possibility that the TTF group, who probably had more attention and care compared to the control group, may have benefited from a similar effect. It's hard to know if this is the case.”
David Schiff, MD, FAAN, a professor of neurology at University of Virginia, signed on to the first clinical trial on recurrent GBM. “The device has no side effects except for contact dermatitis,” he said.
He added that once patients overcame the hurdles of the device — shaving their heads and carrying around the battery pack — they reported that they felt better.
His team did not initially get involved with the trial for newly-diagnosed patients as they felt “we were not sure how many patients would be attracted to enrolling. It is easier to interest people in a study when the tumor doesn't respond to chemotherapy.” They did, however, end up recruiting a few patients into the trial.
Now, with the new results, he's been talking to newly diagnosed patients about the device. “Temozolomide offered a 2.5-month survival benefit, and this is the same amount of improvement,” he said. “This is certainly not a home run, but it is definitely a base hit.”