Alternating electric field therapy, sometimes called tumor treating fields (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 newly diagnosed and 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.
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Medical uses
The American National Comprehensive Cancer Network's official guidelines list TTF as an option for the treatment of recurrent glioblastoma, but note substantial disagreement among the members of the expert panel making this recommendation. High-quality evidence for the efficacy of TTF in oncology is limited. The first randomized clinical trial evaluating TTF was published in November, 2014, and evaluated efficacy of this approach in patients with recurrent glioblastoma. 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 either with a TTF device (NovoTTF-100A / Optune) or with 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.
Initial results of a Novocure-sponsored, phase-3, randomized clinical trial of TTF in patients with newly diagnosed glioblastoma were reported in November, 2014, and published in December 2015. 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. This was the first large-scale trial in a decade to show a survival benefit for patients with newly diagnosed glioblastoma. 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. Potential methodological concerns in this trial included the lack of a "sham" control group, raising the possibility of a placebo effect, and the fact that patients receiving TTFields received more cycles of chemotherapy than control patients. This discrepancy might have been a result of improved health and survival in TTF-treated patients, allowing for more cycles of chemotherapy, but also could have been due to conscious or unconscious bias on the part of clinical investigators. An expert clinical review called the preliminary results "encouraging".
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Side effects
The adverse effects of TTF in published trials to date have included topical skin rashes caused by prolonged electrode use, while patients treated instead with standard chemotherapy more frequently experienced severe nausea, weight loss, digestive and blood problems, and hair loss.
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. Proteins and protein complexes that are critical for mitosis and could be affected by electric fields include ?/?-tubulin and the mitotic septin heterotrimer. These molecules possess an uneven distribution of charged amino acid residues (a dipole), that could prevent their normal orientation and function when exposed to alternating electric fields. 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.
Medical device
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.
Society and culture
Regulatory approval
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".
Optune was approved by the FDA for newly diagnosed glioblastoma on Oct. 5, 2015, as a result of randomized phase 3 trial results that reported a 3-month advantage in overall survival and progression-free survival when added to chemotherapy with temozolomide.
Cost
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.
See also
- Angiogenesis inhibitors
- Experimental cancer treatment
- Pulsed electromagnetic field therapy
References
Further reading
- Davies, Angela M.; Weinberg, Uri; Palti, Yoram (2013). "Tumor treating fields: A new frontier in cancer therapy". Annals of the New York Academy of Sciences. 1291 (1): 86-95. doi:10.1111/nyas.12112. PMID 23659608.
- Kirson; Gurvich, Z; Schneiderman, R; Dekel, E; Itzhaki, A; Wasserman, Y; Schatzberger, R; Palti, Y; et al. (2004). "Disruption of Cancer Cell Replication by Alternating Electric Fields" (PDF). Cancer Research. 64 (9): 3288-95. doi:10.1158/0008-5472.CAN-04-0083. PMID 15126372.
- Kirson, Eilon D.; Dbaly, V.; Tovarys, F.; Vymazal, J.; Soustiel, J. F.; Itzhaki, A.; Mordechovich, D.; Steinberg-Shapira, S.; et al. (2007). "Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors". PNAS. 104 (24): 10152-7. doi:10.1073/pnas.0702916104. PMC 1886002 . PMID 17551011.
- Stupp; et al. (2010). "A prospective, randomized, open-label, phase III clinical trial of NovoTTF-100A versus best standard of care chemotherapy in patients with recurrent glioblastoma". Journal of Clinical Oncology. 28.
- Kirson; et al. (2010). "A phase II study of tumor treating fields (TTFields) in combination with pemetrexed for advanced non small cell lung cancer (NSCLC)". Ann Oncol. 64: viii122. doi:10.1093/annonc/mdq518.
External links
- Treating cancer with electric fields Bill Doyle TED talk
- Can an Electric Hat Fight Tumors? comment in Science
- Alternating electric fields disrupt glioblastoma tumor growth in pilot study comment in Nature Clinical Practice Neurology
- Approval acknowledgement from FDA
Source of the article : Wikipedia
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