Alternating electric field therapy

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Alternating electric field therapy
Specialty oncology

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.[1][2][3] 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.[4] Despite earning regulatory approval, the efficacy of this technology remains controversial among medical experts.[1][5]

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.[1] 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.[6] This trial was the primary basis for regulatory approval of NovoTTF-100A / Optune in the United States and Europe.[6] 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.[6][7] 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.[7]

Initial results of a Novocure-sponsored, phase-3, randomized clinical trial of TTF in patients with newly diagnosed glioblastoma were reported in November, 2014,[8] and published in December 2015.[9][10] 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.[10] 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.[11] 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.[10] 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.[10] An expert clinical review called the preliminary results “encouraging”.[12]

The adverse effects of TTF in published trials to date have included topical skin rashes caused by prolonged electrode use

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.[13] In preclinical cancer models, TTF appeared to show selective toxicity to proliferating cells through an antimitotic mechanism.[7][13][14][15][16] Proteins and protein complexes that are critical for mitosis and could be affected by electric fields include α/β-tubulin and the mitotic septin heterotrimer.[16] 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.[7]

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.[6][15]When a TTF device is used, electrodes resembling a kind of “electric hat”[17] are placed onto a patient’s shaved scalp. When not in use, the devices are plugged into a power outlet to be re-charged.[17]

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.[18] 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”.[19]

Optune was approved by the FDA for newly diagnosed glioblastoma on Oct. 5, 2015,[20] 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.[8][9]

As of December 2014, treatment with the Optune device cost $21,000 per month, with many patients receiving treatment indefinitely, or until tumor recurrence.[21]Medicare and many private health insurance companies have declined to cover TTF treatment, on the grounds that it is still investigational.[21][22]

  1. ^ Jump up to: a b c “NCCN Guidelines for CNS cancers” (pdf). Retrieved August 2013. Check date values in: |accessdate= (help)
  2. ^ Kirkpatrick, John (October 2014). “Recurrent Malignant Gliomas”. Seminars in Radiation Oncology. 24 (4): 289–298. doi:10.1016/j.semradonc.2014.06.006. PMC 4522935. PMID 25219814. Retrieved 26 December 2014.
  3. ^ Johnson, Derek (August 2014). “Medical Management of High-Grade Astrocytoma: Current and Emerging Therapies”. Seminars in Oncology. 41 (4): 511–522. doi:10.1053/j.seminoncol.2014.06.010. PMID 25173143. Retrieved 26 December 2014.
  4. ^ “ results-Novocure”. Retrieved 26 December 2014.
  5. ^ Wick, Wolfgang (25 February 2016). “TTFields: where does all the skepticism come from?”. Neuro-Oncology. 18 (3): 303–305. doi:10.1093/neuonc/now012. PMC 4767251.
  6. ^ Jump up to: a b c d Batchelor, Tracy; Shih, Helen; Carter, Bob. “Management of recurrent high-grade gliomas”. UpToDate. Retrieved 26 December 2014.
  7. ^ Jump up to: a b c d Calzón Fernández S, Llanos Méndez A (2013). Tumor treating fields therapy (TTF) for glioblastoma. A systematic review of the literature (PDF)(Systematic review) (in Spanish). Agencia de Evaluación de Tecnologías Sanitarias de Andalucía. ISBN 978-84-15600-12-1.
  8. ^ Jump up to: a b Stupp, Roger; Wong, Eric; Scott, Charles; Taillibert, Sophie; Kanner, Andrew; Kesari, Santosh; Ram, Zvi. “Interim Analysis of the EF-14 Trial: A Prospective, Multi-center Trial of NovoTTF-100A Together With Temozolomide Compared to Temozolomide Alone in Patients with Newly Diagnosed GBM (Abstract)”. Neuro-Oncology. 16 (suppl 5): v167. doi:10.1093/neuonc/nou265.40. Retrieved 26 December 2014.
  9. ^ Jump up to: a b Stupp, R; et al. (15 December 2015). “Maintenance Therapy With Tumor-Treating Fields Plus Temozolomide vs Temozolomide Alone for Glioblastoma”. JAMA. 314 (23): 2535–43. doi:10.1001/jama.2015.16669. PMID 26670971.
  10. ^ Jump up to: a b c d Sampson, John H. (15 December 2015). “Alternating Electric Fields for the Treatment of Glioblastoma”. JAMA. 314 (23): 2511. doi:10.1001/jama.2015.16701.
  11. ^ “Novocure Announces FDA Approval of an IDE Supplement Allowing All Control Patients in its Phase III Trial in Newly Diagnosed GBM to Cross Over to Receive Tumor Treating Fields” (PDF).
  12. ^ Batchelor, Tracy. “Initial postoperative therapy for glioblastoma and anaplastic astrocytoma”. UpToDate. Retrieved 26 December 2014.
  13. ^ Jump up to: a b “Disruption of Cancer Cell Replication by Alternating Electric Fields”. Cancer Research. 1 May 2004.
  14. ^ Kirson ED, Dbalý V, Tovarys F, Vymazal J, Soustiel JF, Itzhaki A, Mordechovich D, Steinberg-Shapira S, Gurvich Z, Schneiderman R, Wasserman Y, Salzberg M, Ryffel B, Goldsher D, Dekel E, Palti Y (12 June 2007). “Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors”. PNAS. 104: 10152–7. doi:10.1073/pnas.0702916104. PMC 1886002. PMID 17551011.
  15. ^ Jump up to: a b
  16. ^ Jump up to: a b Swanson, K; et al. (2016). “An Overview of Alternating Electric Fields Therapy (NovoTTF Therapy) for the Treatment of Malignant Glioma”. Current Neurology and Neuroscience Reports. 16 (1): 8. doi:10.1007/s11910-015-0606-5. PMC 4703612. PMID 26739692.
  17. ^ Jump up to: a b
  18. ^ “FDA approval letter – NovoTTF-100A System” (PDF). Retrieved 26 December 2014.
  19. ^ “NovoCure wins nod from panel despite trial, statistical miscues”. Medical Device Daily. 21 March 2011 – via Highbeam.
  20. ^ FDA approves expanded indication for medical device to treat a form of brain cancer. Oct 2015
  21. ^ Jump up to: a b Kotz, Deborah (December 27, 2014). “Scalp device might help patients with brain tumors”. Boston Globe. Retrieved 27 December 2014.
  22. ^ “Anthem Medical Policy – Electric Tumor Treatment Field”. Anthem. Retrieved 27 December 2014.

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