Patients with newly-diagnosed glioblastoma who received treatment with tumor- treating electrical fields in addition to temozolomide had nearly double the two-year survival of those who received temozolomide alone, according to an article published in the Journal of the American Medical Association.
Santosh Kesari, MD, PhD
Patients with newly-diagnosed glioblastoma who received treatment with tumor- treating electrical fields in addition to temozolomide had nearly double the two-year survival of those who received temozolomide alone, according to an article published in theJournal of the American Medical Association.
According to an article published in theJournal of the American Medical Association1, overall survival (OS) at two years was 43% in the group that received treatment with both drug and device, compared with 29% in those who received temozolomide alone.
The randomized phase III trial, dubbed EF-14, was designed to study results in 700 patients. The trial was halted early in November 2014, after the aforementioned advantage was demonstrated in the first 350 patients after 18 months follow-up. The device received FDA approval October 5, 2015, of this year for combination treatment of newly-diagnosed patients.
“The study would have lasted another year or two longer, but the data was so good at that point that it was halted,” said Santosh Kesari, MD, PhD, professor of neurosciences, John Wayne Cancer Institute in Santa Monica California, and lead U.S. investigator in the trial. All patients in the control group with ongoing maintenance therapy were offered to receive combination treatment with the device, according to the JAMA article.
Tumor-treating fields are administered by Optune, which is a portable, non-invasive device that delivers alternating electric fields, according to Novocure2, who makes the device. Patients are trained to administer the treatment themselves, according to theJAMAarticle1.
In the trial, patients were randomized 2:1 between July 2009 and November 2014. There were  466 patients in the device arm, and 229 patients in the control arm. Treatment was administered using a mapping software system to optimize field intensity.
The median time from diagnosis to randomization was 3.8 months in both groups, and participants were enrolled at 83 centers in the United States, Canada, Europe, Israel, and South Korea; however, 95% of participants were white, and 61% were treated in the United States, the article said. The median age was 57, and 66% of participants were male.
The study included some patients with five-year follow-up data, although 5 year survival as reported in the literature is only 10%, according to the article. Median follow-up was 38 months, according to the article.
The study found a two-year survival advantage for those who received treatment with tumor-treating fields as well as chemotherapy (P= 0.006). The survival advantage was new; when Optune was first approved by the FDA for treatment of those with recurrent disease, it was found to be equivalent to temozolomide standard treatment, with no increase in survival, but with improved quality of life, according to the article.
“Five year survival is like zero for patients with recurrent disease. Before, with temozolomide and radiation, 5 year survival was 10% in newly-diagnosed patients,” said Kesari. “Now we’re just waiting for cure data.”
“We all have long term survivors with glioblastoma, but they are few and far between. Everyone continues in monitoring, because the glioblastomas recur even nine years later; we don’t even use the word ‘remission,’” said Karen L. Fink, MD, PhD, a neuro-oncologist and researcher at Baylor Charles A. Sammons Cancer Center in Dallas, Texas, and author on the study.
Median progression-free survival was 7.1 months in those on combination therapy, compared with four months for those who received chemotherapy alone (P= 0.0013), according to the article.
The result differed slightly depending on whether the measure was of the intent-to-treat population, or only those who continued with the trial. In the intent-to treat group, the median overall survival was 19.6 months in the combination therapy group, versus 16.6 months in those who received chemotherapy alone (P= 0.0329). Results were better in the per protocol group (those who actually received treatment in the trial): median overall survival was 20.5 months in the combination therapy group, versus versus 15.6 months for those who received chemotherapy alone (P= 0.0042), according to the article.
“So many different things could cause a patient not to make it into the per protocol analysis. Most people would want to get the device, because that’s why they signed up, and sometimes a patient who didn’t get device may drop out and do some other trial,” said Kesari.
Of the participants in the device arm, 14 were excluded, while another 21 were excluded from the control arm, he noted.
"A whopping 31.7% of participants who had an initial diagnosis of glioblastoma never got to use the device or participate in the trial,” explained Fink. “They had to sign up 1,019 patients to get 695 who agreed to randomization, made it through radiation and daily temozolomide, and did not have progression at the time of their first post-radiation MRI (which was usually done four or five weeks after radiation treatment was completed),” she added.
Patients in the group which received combination treatment including the device also received greater secondary chemotherapy than patients who received temozolomide alone.
If a patient experienced tumor progression, second-line chemotherapy was offered, but in the device group, treatment with tumor treating fields could also be continued until the second radiological progression or clinical deterioration, for a maximum of 24 months, according to the JAMA article.
Of those in the device group, 67% received second-line treatments, compared with 57% of those who received temozolomide alone. About 40% of second-line therapies included bevacizumab and about 40% included nitrosoureas. Some patients also received temozolomide re-challenge as secondary chemotherapy.
While the most common short term side effects in the tumor-treating fields group was skin irritation at the administration site (mild to moderate skin irritation in 43% of those in the device arm, but experienced as severe in 2% of patients), effects such as mild anxiety, confusion, insomnia, and headaches were reported more frequently in the patients in the device arm, the article said. Classified as psychiatric disorders, these conditions (including two cases of anxiety, and two cases of psychotic disorder, both in the device arm) usually occurred at the onset of tumor treating fields. However, neurological conditions such as seizure and headache were almost identical between the two groups, the article said.
Researchers are also waiting to conduct analysis of data from sub-groups, such as participants when stratified by type of surgical resection (biopsy, partial resection, gross total resection), and by methylation status of tumor, but the data are not expected before the end of next year, the article said.
Clinical trials are also investigating the possible use of the device in patients with secondary brain tumors and metastases.
“They usually do worse, because they don’t respond very well to radiation and chemo,” noted Kesari, who said that while fewer than 100 patients with secondary brain cancer are currently in trials, researchers are already setting up bigger studies.
Researchers are also studying the device in other forms of cancer, such ovarian and pancreatic tumors, low grade gliomas, and meningiomas,” Kesari added.