Tumor-Treating Fields: Significant Survival in Glioblastoma

Alexander M. Castellino, PhD

December 19, 2017

When glioblastoma makes headlines, the grim prognosis associated with its survival is front and center, as happened recently when Senator John McCain was diagnosed with the disease. Of many approaches tested in clinical trials, very few have improved overall survival (OS) for patients with this cancer.

But one rather different approach has. It involves using a device (Optune, Novocure Ltd) that transmits tumor-treating fields (TTFs).

In new results from a final analysis of a pivotal trial in which all patients received standard chemotherapy, patients who used this device lived longer than those who did not ― a statistically significant 5 months longer.

The patients, all newly diagnosed with glioblastoma, underwent standard-of-care chemoradiation followed by maintenance treatment with temozolomide (Temodar, Merck & Co). Patients were randomly assigned to wear the device or not.

After a median follow-up of 40 months and a minimum follow-up of 24 months, median overall survival was 20.9 months for patients who used the TTF device vs 16.0 months for those who did not (hazard ratio [HR], 0.63; P < .001).

"A significantly higher percentage of patients are alive at 2, 3, and more years after diagnosis," the study's lead author, Roger Stupp, MD, professor of neurologic surgery, neurology and medicine and associate director for strategic initiatives at Northwestern University's Robert H. Lurie Comprehensive Cancer Center, Chicago, Illinois, told Medscape Medical News.

Preliminary results from this trial's final analysis were presented earlier this year at the annual meeting of the American Association of Cancer Research (AACR) and were reported by Medscape Medical News at the time.

The final analysis from the EF-14 study, which includes mature results from all 695 patients who were included in that study, were published online December 19 in JAMA.

"These findings are in contrast to the more than 23 randomized trials conducted over the last decade that have evaluated novel agents or intensified treatment strategies (eg, dose-dense temozolomide, cilengitide, nimotuzumab, bevacizumab, and rindopepimut) for treatment of patients with newly diagnosed glioblastoma and have failed to demonstrate improved survival," the EF-14 study authors point out.

"Innovative treatments for glioblastoma are needed, and we have a treatment that improves survival," Dr Stupp told Medscape Medical News.

Exploratory studies are now underway to determine whether this new modality will prove effective in other cancers, including as cancer of the pancreas and lung, as well as malignant ascites, Dr Stupp added.

How Does the Treatment Work?

That TTFs increase survival in patients with glioblastoma mystifies nonbelievers and agnostics alike. Many experts that Medscape Medical News has talked with in the past say they do not understand how the treatment works.

TTFs are electromagnetic waves that are delivered via an electric field generator through four transducer arrays (similar to electrodes) that are placed on a shaved scalp. Proper placement is guided by MRI. The device is noninvasive and portable and includes a charger, power supply, and batteries should an electrical outlet not be available.

The makers of the device say the second-generation system is smaller and lighter ― it weighs only 2.7 lb. 

What some find mystifying is how electromagnetic fields deliver the clinical benefits reported. Preclinical studies have indicated that the TTFs disrupt cell division by disrupting several steps in the mitotic process that are crucial for cell division. In this way, TTFs kill only glioblastoma cells in the brain and spare the nondividing cells, it has been suggested.

TTFs: Reality vs Perception

Rohan Ramakrishna, MD, Alvina and Willis Murphy Assistant Professor of Neurological Surgery at Weill Cornell Medicine and New York-Presbyterian Hospital, New York City, told Medscape Medical News that although the technology relies on mitotic disruption, no one knows whether it works in patients the same way that it has been shown to work in vitro.

"Clinicians are still trying to figure out how this works," he said. He pointed out that patients still experience disease progression while using this device, and "we do not know the mechanism of action for this progression.... With other therapies, progression is explained based on biochemical evolution/resistance."

Nonetheless, he noted that the EF-14 trial was well designed. TTFs are "exciting because there are very few therapies in the last 50 years in glioblastoma that have provided this level of statistical benefit," he said. "However, at the end of the day, the benefit, while statistically valid, is still just a few months. We need to do better," he said.

In the trial, treatment with TTFs was conducted for 2 years or until disease progression. According to the makers of the device, during the treatment period, patients need to have their heads shaved twice a week, and the microarrays are changed each time. Patients have an option to have periods in which they are off treatment ― for example, when they are going to bed. But for maximum benefit, the device needs to be used continuously for at least 18 hours daily ― the longer, the better, according to the manufacturer.

Dr Stupp has a patient for whom treatment with TTFs began in 2007 and ended in 2010. "He is still doing fine without any further therapy ever," Dr Stupp said.

How is this treatment incorporated into routine clinical practice? Outside of clinical studies, Dr Stupp and his colleagues offer this treatment modality to every patient who are newly diagnosed with glioblastoma. "It is part of the discussion," he said. "One or two out of 10 will say they do not want it, but the majority are grateful that there is another treatment other than chemotherapy" he added.

"It takes getting used to, but the ones who are on it are addicted to it and love it, and it is hard to get them off therapy," Dr Stupp told Medscape Medical News.

Dr Ramakrishna indicated that the neuro-oncology practice at his institution, Weill Cornell Medicine, treatment with TTFs is discussed with newly diagnosed patients, and the therapy is provided to patients who opt to use it. "Tumor-treating fields is an added tool in the tool kit; it is not a game changer, though, in that it does not fundamentally change the prognosis for glioblastoma," he said.

But then neither is surgery or radiotherapy a game changer, and TTFs offer improved survival when compared with current options, Dr Stupp remarked.

Dr Ramakrishna also provided a patient perspective on the device. "Some patients do not want to shave their head twice a week and wear the device for 18 hours a day," he said. The perception is that doing so would make them appear ill, and they would rather avoid looking that way, he noted.

"There remains skepticism in the neuro-oncology community about the device," he said. The perception is that it cannot really work as advertised, but the EF-14 trial was a fairly good study, he added. "Bottom line: tumor-treating fields provide meaningful benefits," he said, "but not as much as we want.

"Generally, this device is not as assimilated in the routine management of patients as perhaps it should be, based on the available evidence," Dr Ramakrishna remarked. "Yet carmustine wafers were widely deployed in clinical practice when the benefit the therapy provided was only marginal," he added.

The EF-14 Study

The EF-14 study enrolled patients with newly diagnosed glioblastoma to receive TTFs and temozolomide (n = 466) or temozolomide alone (n = 229). On the basis of the interim results from this study, reported 2 years ago by Medscape Medical News, the US Food and Drug Administration approved the treatment for first-line use.

The final analysis of the results now confirms the findings from that interim analysis.

In that final analysis, the median progression-free survival (PFS) was 6.7 months for patients who received TTFs and temozolomide, compared with 4.0 months for patients in the standard therapy arm (HR, 0.63; P < .001).

Two-year OS was 43% for patients in the treatment arm and 31% for patients in the standard-therapy arm; the difference in 3-year OS was also significant ― 13% vs 5% (P < .001).

"The majority of patients do not survive, and this underscores the need for other treatments," Dr Ramakrishna said. "Going forward, it will be significant if we can identify a group of patients who benefit more than others with tumor-treating fields," he added.

The EF-14 investigators report that treatment with TTFs, female sex, methylated MGMT promoter, younger age, and higher Karnofsky's performance status were predictors of longer survival. In this global study, country of treatment and extent of resection were not associated with significant survival differences.

Although the study investigators had planned for TTFs to be used until disease progression, in the EF-14 study, half of the patients (51%) continued treatment beyond the first progression. These treatment continuations were based on clinician and patient decisions, Dr Stupp explained. "The reason for this is because the treatment effect is often seen late; it is often impossible to distinguish true progression from pseudoprogression, and there may be synergy with chemotherapy, which may help," he said.

There was a higher incidence of localized toxic effects on the skin that were considered to be skin reactions to the medical device beneath the transducer arrays; 52% of patients experienced such effects using the device. Grade 3 reactions occurred in 2% of patients.

The EF-14 investigators acknowledge that the method of delivering TTFs places a burden on patients."[Yet], 75% of patients achieved a treatment adherence of 75% or more [using the device for at least 18 hours daily], indicating good tolerability," the study authors contend.

The authors note that patients' activities of daily life and cognition, as measured using the Karnofsky performance score and the Mini-Mental State Examination, favored patients treated with TTFs and temozolomide. Detail quality-of-life data are currently in press, Dr Stupp told Medscape Medical News.

Study Limitations

When Medscape Medical News previously reported the interim analysis and the survival data, two main criticisms were leveled against the study. First, the study was an open-label study, and the patients in the standard therapy arm did not have to have their scalps shaven to wear sham arrays.

Dr Ramakrishna voiced a similar concern. "There is no question the study would be a lot stronger if there was a sham control," he said. "Furthermore, the fact that the study was not blinded may have created unconscious biases among treating physicians. And among patients on treatment, they may be more compliant to therapy and make changes in their daily routine that may impact survival," Dr Ramakrishna told Medscape Medical News.

"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 [tumor-treating fields]) 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 argued when the interim data were published.

According to Dr Stupp, this is an unfair criticism. Neither prior or current radiotherapy trials nor trials of temozolomide and many other chemotherapy drugs were placebo controlled, he explained. "Some of my own colleagues are conducting new trials without a placebo control, as they consider it too burdensome and unethical for the patients," he added.

"A lot of patients agreed to take part in the study to prove or disprove whether the treatment works," Dr Stupp said. "We should not abuse the patients' goodwill with the burden of a sham therapy," he added.

In their discussion, the EF-14 investigators concede that a placebo effect may affect subjective measures, such as those of quality of life or even PFS, by influencing the frequency of imaging and its interpretation. However, they also point out that "in the current trial a consistent benefit was observed in PFS, as assessed by blinded central radiology review, as well as in the gold standard of objective outcome, overall survival."

"Survival is a hard endpoint," Dr Stupp told Medscape Medical News.

Another limitation of the study was that patients in the control arm received five cycles of temozolomide, whereas those in the treatment group received six. Moderating the press conference at the AACR's 2017 annual meeting, George Demetri, MD, a medical oncologist from Dana-Farber Cancer Institute in Boston, Massachusetts, pointed this out. "The control group got a little less chemotherapy: could that have been the reason we saw the benefit?" Dr Demetri asked.

Not so, according to Dr Stupp. Patients either received chemotherapy or discontinued chemotherapy on the basis of disease progression, he said. Additionally, he pointed out that trials have shown that there is no difference in outcomes between 12 cycles and 6 cycles of temozolomide, as well as between dose-dense and standard temozolomide regimens.

Another Expert Comments

Also approached for comment, Scott Shepard, MD, associate professor of clinical neurosurgery at the Lewis Katz School of Medicine, Temple University, and the Fox Chase Cancer Center in Philadelphia, Pennsylvania, said TTF therapy is an "intriguing technology," and he emphasized the positive findings from the trial.

This study demonstrated a statistically significant increase in both PFS (6.7 months vs 4.0 months) and OS (20.9 months vs 16.0 months) in the patients who received TTFs and maintenance temozolomide compared with the patients treated with maintenance temozolomide alone. Furthermore, for the patients who wore the device, the 2-year survival rate was 43%, compared with 31% for those who did not.

"This represents a 31% increase in overall survival and a 67% increase in progression-free survival," Dr Shepard pointed out.

"While these gains in overall and progression-free survival appear modest, in glioblastoma patients, an additional survival of 5 months is very significant for both patients and their families," he told Medscape Medical News.

"These survival gains must be interpreted in the context that, since temozolomide became the standard postradiation treatment for glioblastoma over 10 years ago, more than 20 different clinical trials of various systemic treatments have failed to show any meaningful increase in overall survival in this disease," he pointed out.

Dr Shepard acknowledged that the primary limitation of this study is its open- label design. Because of technical and ethical considerations, a sham treatment arm could not be included, and treating physicians and patients were not blinded. Limitations of the TTF approach include its cost, as well as the commitment on the part of patients ― the device should be worn for at least 18 hours per day and requires that patients shave their head.

"Despite these limitations, TTF represents a significant survival benefit for glioblastoma patients who are able to comply with the rigorous treatment requirements," he added.

The study was funded by Novocure Ltd. Dr Stupp's institution is paid fees for his serving on advisory boards of Celgene, Novartis, AbbVie, and Merck KGaA (Darmstadt). He also receives travel support from Novocure, the makers of the device, and his wife works fulltime for Celgene. Conflicts of interest for other authors are included in the article.

JAMA. Published online December 19, 2017.



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