Κυριακή, 9 Απριλίου 2017

ELECTRIC FIELDS IMPROVES GLIOBLASTOMA SURVIVAL

A wearable battery-powered device that delivers alternating electric fields via electrodes attached to the scalp extends overall survival of patients with newly diagnosed glioblastoma by nearly 5 months, according to final results of a phase 3 trial.
The new data support earlier, interim data from this same trial that served as the basis for the US approval of the Optunedevice (Novocure) for the first-line treatment of glioblastoma in 2015. The device, which delivers tumor treating fields (TTFs), is also approved for use in recurrent glioblastoma.
The investigators hope the new, final data, which were presented here at the American Association of Cancer Research (AACR) 2017 Annual Meeting, will help to improve the stature of the modality in the eyes of clinicians, who have not fully embraced the new technology.
Lead author Roger Stupp, MD, a neuro-oncologist at Northwestern University in Chicago, Illinois, explained that the survival benefit reported with the device is the first seen in glioblastoma in 12 years — since temozolomide (TMZ) (Temodar, Merck) was approved in 2005.
The magnitude of benefit with the new technology is comparable to that seen with TMZ, he added.
"Glioblastoma is most aggressive and deadly brain tumor we have," Dr Stupp also said.
"We need to further improve,” he commented, but the survival benefit seen with this device is another step for the patients. "TTF should be considered part of the standard of care for patients with newly diagnosed glioblastoma," he asserted.
But Dr Stupp also admitted that US clinicians have been skeptical.
The device consists of a generator and battery pack (2.7 lb, with 3 to 4 hours per charge) that are carried in a shoulder bag with a cord that extends to a cap with electrodes that connect with the skull. The treatment, once begun, is permanent, although some patients disconnect the device during sleep.
TTFs disrupt cell division through physical interactions with key molecules during mitosis in solid tumor cancers, according to the company.
"Patients like it. Doctors have more of a problem. They think it's weird," said Dr Stupp.
George Demetri, MD, a medical oncologist from Dana-Farber Cancer Institute in Boston, Massachusetts, who moderated the AACR press conference, acknowledged that TTF is a new modality for treating cancer and thus is "disruptive" and "not easy."
He also praised Dr Stupp for his involvement. Dr Stupp is a long-time glioblastoma researcher and was the lead author of the landmark trial of TMZ published in 2005.
Glioblastoma was "a place nobody wanted to go" in the field of cancer research, Dr Demetri said, referring to the years of unabated treatment failures since 2005. He said Dr Stupp was "brave" to undertake this research, which was "a real commitment."
Dr Demetri also acknowledged that the approach appears "wacky."
"But it's working in this disease," he added. "Wouldn't you want your brother [with glioblastoma] to have this thing?"
Dr Demetri also emphasized the importance of the new final data.
"I think the real reason that people are probably not using it in the community is it was reported in interim data.... We have been trained to not trust interim data — that's a big reason AACR wanted to highlight this."
Use of TTF is not covered currently by Medicare, which may hurt its uptake. Some private insurers cover TTF, which costs more than $20,000.
However, the new findings on TTF were met with a critical eye by another clinician.
"The major scientific limitation of this study is the lack of a double-blinded control group. That is, both physicians and patients knew who was and was not receiving the experimental tumor treating fields," said Stephanie Weiss, MD, a radiation oncologist at Fox Chase Cancer Center in Philadelphia, Pennsylvania, who was asked for comment.
She referred to the study design, in which 695 patients who had been newly diagnosed with glioblastoma were randomly assigned in a 2:1 ratio to TTF delivered by the Optune medical device (n = 466) plus TMZ or to maintenance TMZ therapy alone (n = 229).
The study's primary outcome was progression-free survival. For the patients receiving TTF/TMZ, median progression-free survival was 6.7 months, vs 4 months for TMZ alone. This translated into a 37% reduced risk of the experimental treatment group's disease advancing (hazard ratio [HR], 0.63; = .00005).
The mean overall survival for the TTF/TMZ group was 20.9 months, vs 16.0 months for TMZ alone (HR, 0.63; = .00006).
At 2 years, 43.1% of the TTF/TMZ group was still alive, vs 37.0% of the TMZ-alone group.
But, as Dr Weiss pointed out, there was no sham medical device in the TMZ-alone arm to mask who was and who was not treated with TTF.
She said that "this knowledge [of who has the experimental treatment] may unconsciously influence the behaviors of doctors and patients in ways that favor a better outcome for the experimental group."
She described ways in which this can play out in a trial, in both patients and their physicians.
Patients receiving TTF may feel more optimistic because they are receiving the study treatment and therefore may be more compliant with their chemotherapy, which is known to have a positive effect on survival, Dr Weiss said.
Similarly, if a patient in the TTF group experiences an increase in symptoms, "doctors may be more inclined to give the patient the benefit of the doubt and attribute them to a temporary treatment-related side effect, thus delaying a diagnosis of progression that would have been made otherwise," she asserted.
Dr Stupp dismissed such concerns, saying that an overall survival benefit of nearly 5 months in glioblastoma is large and, in this context, inconceivable as just a "placebo effect."
Dr Demetri sided with Dr Stupp and said the lack of a placebo or sham is "less of a concern" than another issue in the trial: the fact that patients in the TTF/TMZ experimental group received more chemotherapy than those in the TMZ-alone control group
The median number of TMZ cycles was six for the experimental TTF/TMZ arm and five for the TMZ-alone control arm.
"The control group got a little less chemotherapy: could that have been the reason we saw the benefit?" asked Dr Demetri, without answering.
"That's always going to be a problem that hangs over this trial," he told Medscape Medical News.
Dr Stupp countered that the higher median number of adjuvant TMZ cycles in the TTF/TMZ group was easily explained. "They progressed earlier. You treat until progression," he said.
"Duration of the chemo doesn't matter," he further said, and referenced the RTOG-0525 trial, in which intensified-dose TMZ was no better than standard-dose TMZ in the treatment of glioblastoma. "More temozolomide is not that helpful," he argued.
Mechanism of Action
Dr Stupp said that standard therapy is limited to surgery, radiation therapy, and drug treatment with TMZ. Most systemic therapies cannot penetrate the blood-brain barrier, and so there is a need for less conventional approaches to improve outcomes further, he said.
"Tumor treating fields is a treatment somewhat outside the box," he told reporters at meeting press conference.
How does it work? "By exposing [cancer] cells to an electrical field, you...actually affect cell properties," he said.
Dr Demetri commented that the proposed mechanism of action is "still a little fuzzy in my head.
"Let's be honest, the mechanism of action of some of our chemotherapies [in oncology] – 30 or 40 years later, we still don't fully understand," Dr Stupp countered.
"We have a new modality in hand. Now we have to figure out how this is best used," he said.
At the press conference, Dr Stupp also said that next steps for the device in glioblastoma is to combine it with immunotherapy. The company is also considering the device for use in pancreatic cancer.
This study was funded by NovoCure Ltd. Dr Stupp has received travel support from NovoCure Ltd and but has no other financial interest in the company. Dr Demetri has ties to multiple pharmaceutical companies but none relevant to glioblastoma. Dr Weiss has disclosed no relevant financial relationships. 
American Association of Cancer Research (AACR) 2017 Annual Meeting. Abstract CT007, presented April 2, 2017.

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