Electrical Device for Cancer Treatment Polarizes Audiences

Toxicity advantage over chemotherapy

Kate Johnson

December 02, 2010

December 2, 2010 (Montreal, Quebec) — An investigational glioblastoma treatment that delivers alternating electric fields through scalp electrodes might also have application in other cancers, particularly nonsmall-cell lung cancer (NSCLC), according to an Israeli presenter here at the Society for Neuro-Oncology 15th Annual Scientific Meeting.

Clinical trials of the device, known as NovoTTF, in glioblastoma and NSCLC have shown that it is either comparable or superior to chemotherapy in terms of overall survival, but much less toxic.

The device is also notable for the responses it elicits from professionals, according to Zvi Ram, MD, professor and chair of neurosurgery at Tel-Aviv Sourasky Medical Center in Israel.

To date, reports about the electrical device have elicited both antagonistic and enthusiastic reaction from oncologists, with "neither the enthusiasts nor the antagonists having significant bases for either kind of acute reaction," Dr. Ram told Medscape Medical News after his presentation.

Dr. Ram did not dwell on the antagonism. "It's human nature," he said about such audience reactions.

Traditional approaches to glioblastoma have a lot of room for improvement, explained Dr. Ram. "We're used to hurting the brain all the time. I operate on these patients; I take chunks of the brain out. Oncologists give toxins and irradiate the brain. That's what we're used to. Now somebody is thinking far outside the box with a new modality that's noninvasive."

Another neuro-oncology expert confirmed that NovoTTF is effective.

"There is little doubt that this device has an antitumor effect and the toxicity profile is nonexistent. The next few years will tell us where NovoTTF will fit into the treatment of glioblastoma and a variety of other difficult tumors," said Philip H. Gutin, MD, chair of the Department of Neurosurgery and Fred Lebow Chair in Neuro-Oncology at Memorial Sloan-Kettering Cancer Center in New York City.

The NovoTTF device delivers low-amplitude "tumor treatment fields," ranging from 100 to 300 kHz, which have been shown in vitro to slow and reverse tumor cell proliferation by inhibiting mitosis, according to a press release from NovoCure, the manufacturer of the device and sponsor of the trial.

The press release states that "alternating electric fields within the tumor exert physical forces on electrically charged cellular components, preventing the normal mitotic process and causing cell death prior to division."

The portable device weighs about 2.75 kg, is connected to a battery pack, and is designed to be worn almost constantly, with a target of at least 20 hours each day.

Some Glioblastoma Results Not Seen "Anywhere"

In a randomized phase 3 clinical trial presented earlier this year at the American Society of Clinical Oncology annual meeting, an intent-to-treat analysis comparing NovoTTF with the best available chemotherapy found no statistical difference in 1-year overall survival in 237 recurrent glioblastoma patients between treatments.

However, a per protocol analysis (which included only patients who wore the device for 70% of the recommended time during the first month) showed a statistically significant benefit with NovoTTF in 1-year survival, compared with chemotherapy (29.5% vs 19.1%; hazard ratio, 0.64; P = .01).

Now, a post hoc analysis of several subgroups in the study has found some additional advantages, reported Dr. Ram.

One subgroup of 110 "good prognosis" patients (younger than 60 years and with a Karnofsky Performance Scale score of more than 80) showed a "more robust" survival benefit than was seen in the overall intent-to-treat analysis, he said.

In this subgroup, patients treated with NovoTTF had a median survival of 9.2 months, compared with 6.6 months for those treated with chemotherapy (P < .01). This compares to 6.6 months and 6.0 months in the overall intent-to-treat group, he explained.

Moreover, 1-year overall survival in this subgroup was 35.2% with NovoTTF group, compared with 20.8% with chemotherapy (P < .01), which is an improvement over the nonsignificant difference between the 2 groups (23.6% vs 20.7%) in the larger analysis.

Another subgroup analysis looked at patients who had previously failed treatment with bevacizumab (roughly 20% of the entire cohort). Both an intent-to-treat analysis and a per protocol analysis showed significant overall survival advantages for NovoTTF, said Dr. Ram.

Among 44 patients in the intent-to-treat group, median overall survival with NovoTTF was 4 months and with chemotherapy was 3.1 months (hazard ratio, 0.43; P < .02). Among 29 patients in the per protocol analysis, median overall survival was 6.3 months with NovoTTF and 3.3 months with chemotherapy (hazard ratio, 0.21; P = .02).

"You don't see this anywhere," he told Medscape Medical News. "There's no drug in the world that could produce such a response in patients who had already failed [bevacizumab]."

The investigators also analyzed a surgery-naive group. "You know these are going to be poor responders, almost identical to bevacizumab failure," said Dr. Ram.

In this group of 38 patients, an intent-to-treat analysis showed that overall survival was 9.8 months with NovoTTF and 5.5 months with chemotherapy.

Finally, an analysis using the Quality of Life Symptom Scale, measured prospectively during the study, showed significant differences between the 2 groups, with NovoTTF-treated patients having more favorable constipation scores (–34 vs –35) and diarrhea scores (+77 vs +50) than chemotherapy-treated patients.

Nausea and vomiting scores were –15 for the NovoTTF group and –61 for the chemotherapy group, and pain scores were –1 and +63, respectively.

A quality-of-life analysis using the EORTC QLQ-C30 showed scores of in favor of NovoTTF for cognitive functioning (+14 vs –7) and for emotional functioning (+7 vs +1).

"We do this to all our patients; we intoxicate them," said Dr. Ram about the adverse effects of chemotherapy. "Even if NovoTTF did not extend survival, if it was equivalent to chemotherapy [for survival], then it may still improve quality of life."

Dr. Ram did not know the median length of time that the NovoTTF cohort wore the device, but an earlier phase 2 study followed some of them for 59 months. "Seventy percent are still alive — that's unheard of," he remarked.

"There were concerns that patients might have more headaches or seizures, but there were none," he said.

Dr. Ram reported that the rate of adverse events related to the central nervous system (CNS) was similar for NovoTTF and chemotherapy (66% vs 67%), as were serious CNS adverse events (21% vs 22%), seizures (15% vs 12%), and headaches (18% vs 13%).

"There are no real concerns that this does anything hazardous to the brain," he said.

NSCLC Data

Dr. Ram also presented evidence suggesting that NovoTTF therapy has benefits in other forms of cancer.

A study reported by his colleagues earlier this year at the European Society for Medical Oncology Congress showed that NovoTTF therapy combined with chemotherapy resulted in significant prolongation of survival in patients with NSCLC, compared with historic controls, he said.

"If this kind of therapy acts against brain cancer cells, it should act also against other tumor types," he reasoned.

In the study, which looked at 42 NSLC patients, NovoTTF was delivered with newly designed electrodes placed on the chest and neck of patients with locally advanced metastatic stage IIIb and IV disease, he explained.

Overall survival was better with the combination of NovoTTF plus pemetrexed than with pemetrexed alone (13.8 vs 8.3 months), as was the rate of 1-year survival rate (57% vs 30%).

"We're talking about something that appears to be acting against cancer cells, regardless of origin," said Dr. Ram. "Action in the lung seems similar to what has been seen in [glioblastoma multiforme] — a slow resolution of malignant pleural effusion and masses within the chest over time."

"It's very interesting and exciting, even if we do not yet have enough definitive data," said Alba B. Brandes, MD, moderator of the session and chair of medical oncology at Azienda USL, a group of 9 hospitals in and around Bologna, Italy.

The study investigators have been criticized for repackaging their nonsignificant intent-to-treat results into per protocol results that show significance, she said.

"An intention-to-treat population and per protocol population are 2 different things and, from a statistical point of view, it is sometimes difficult for the oncologic community to accept."

However, she said, the per protocol observations should not be dismissed, because when looked at this way, the results become "not a little significant, but highly significant," she said.

"I was really surprised to see what happened in the lung cancer. I am a medical oncologist and I have never seen that complete a response. It's surprising. We have to wonder if all that we know about the treatment of tumors is correct."

Dr. Ram acknowledged that the per protocol analysis of the findings is unconventional, but that "there is no precedent for this kind of therapy. I think we may need to redesign the way we assess results in the future. We cannot use the same guidelines and definitions that we were traditionally using."

Dr. Ram is a consultant for NovoCure, which sponsored the trial and manufactures the device. Dr. Gutin and Dr. Brandes have disclosed no relevant financial relationships.

Society for Neuro-Oncology (SNO) 15th Annual Scientific Meeting: Abstract NO-55. Presented November 19, 2010.

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