Alternating electric field therapy
Alternating Electric Field Therapy (sometimes caled Tumor Treating Fields, abbreviated as TTF or TTFields) is a type of electromagnetic field therapy using low-intensity electrical fields to treat cancer. A TTF-generating device manufactured by the Israeli company Novocure is approved in the United States and Europe for the treatment of recurrent glioblastoma multiforme (GBM), and is undergoing clinical trials for several other tumor types. Despite earning regulatory approval, the efficacy of this technology remains controversial among medical experts.
Proposed biological mechanism
Alternating electric field therapy / TTF was initially described in 2004 as the use of insulated electrodes to apply very-low-intensity, intermediate-frequency alternating electrical fields to a target area containing proliferating cells. In preclinical cancer models, TTF appeared to show selective toxicity to proliferating cells through an antimitotic mechanism. In principle, this approach could be selective for cancer cells in regions of the body, such at the brain, where the majority of normal cells are non-proliferating.
A clinical TTF device is manufactured by Novocure under the trade name Optune (formerly NovoTTF-100A), and is approved in the United States and Europe for the treatment of recurrent glioblastoma. These devices generate electromagnetic waves between 100 and 300 kHz. The devices can be used in conjunction with regular patterns of care for patients, but are only available in certain treatment centers, and require specific training and certification on the part of the prescribing physician. When a TTF device is used, electrodes resembling a kind of "electric hat" are placed onto a patient's shaved scalp. When not in use, the devices are plugged into a power outlet to be re-charged.
The American National Comprehensive Cancer Network's official guidelines list TTF as an option for the treatment of recurrent glioblastoma, but note that there was substantial disagreement among the members of the expert panel in making this recommendation. High-quality evidence for the efficacy of TTF in oncology is limited; only one randomized clinical trial evalating TTF has been published in the peer-reviewed literature as of November 2014. This trial was the primary basis for regulatory approval of NovoTTF-100A / Optune in the United States and Europe. In this study, patients with glioblastoma that had recurred after initial conventional therapy were randomized to treatment with either a TTF device (NovoTTF-100A / Optune) or their treating physician's choice of standard chemotherapy. Survival or response rate in this trial was approximately 6 months, and was not significantly better in the TTF group than in the conventional therapy group. The results suggested that TTF and standard chemotherapy might be equally beneficial to patients in this setting, but with different side effect profiles. Two earlier, clinical studies had suggested a benefit of TTF treatment in recurrent glioblastoma, but definitive conclusions could not be drawn due to their lack of randomized control groups.
Preliminary results of a Novocure-sponsored randomized clinical trial of TTF in patients with newly diagnosed glioblastoma were reported at a meeting of the Society for Neuro-Oncology in November, 2014. Interim analysis showed a statistically significant benefit in median survival for patients treated with TTF plus conventional therapy (temozolomide, radiation, and surgery) versus patients treated with conventional therapy alone, a result which led the trial's independent data monitoring committee to recommended early study termination. On the basis of these results, the FDA approved a modification of the trial protocol, allowing all patients on the trial to be offered TTF. These results were noted as "encouraging" in an expert clinical review, although the authors declined to issue recommendations for TTF use in newly diagnosed GBM until the results of this trial have been subject to peer review.
The adverse effects of TTF in published trials to date have included topical skin rashes caused by electrode use, while patients treated instead with standard chemotherapy more frequently experienced severe nausea, weight loss, digestive and blood problems,and hair loss.
The NovoTTF-100A / Optune device was approved by the U.S. Food and Drug Administration (FDA) in April 2011 for the treatment of patients with recurrent gioblastoma, based on clinical trial evidence suggesting a benefit in this population. Because the evidence for therapeutic efficacy was not deemed conclusive, the device manufacturer was required to conduct additional clinical trials as a condition of device approval. Critics suggested that pleas of cancer patients in the room of the FDA hearing swayed the opinions of many during the related FDA panel, and that approval was granted despite "huge misgivings on several points".
As of December 2014, treatment with the Optune device cost $21,000 per month, with many patients receiving treatment indefinitely, or until tumor recurrence. Medicare and many private health insurance companies have declined to cover TTF treatment, on the grounds that it is still investigational.
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