Alternating electric field therapy

Alternating electric field therapy, sometimes called tumor treating fields (TTFields), is a type of electromagnetic field therapy using low-intensity, intermediate frequency electrical fields to treat cancer.[1][2][3][4] A TTField-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.[5] Despite earning regulatory approval, the efficacy of this technology remains controversial among medical experts.[2][6]

This article is about a specific type of electric field therapy used for treatment of cancer. For other uses of electromagnetic fields in medicine, see Electromagnetic therapy.
Alternating electric field therapy
Other namesTumor treating fields
Specialtyoncology

Medical uses

Recurrent glioblastoma

The American National Comprehensive Cancer Network's official guidelines list TTFields as an option for the treatment of recurrent glioblastoma, but note substantial disagreement among the members of the expert panel making this recommendation.[2] High-quality evidence for the efficacy of TTFields in oncology is limited. The first randomized clinical trial evaluating TTFields was published in November, 2014, and evaluated efficacy of this approach in patients with recurrent glioblastoma.[7] This trial was the primary basis for regulatory approval of NovoTTF-100A / Optune in the United States and Europe.[7] In this study, patients with glioblastoma that had recurred after initial conventional therapy were randomized to treatment either with a TTFields 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 TTFields group than in the conventional therapy group. The results suggested that TTFields and standard chemotherapy might be equally beneficial to patients in this setting, but with different side-effect profiles.[7][8] Two earlier clinical studies had suggested a benefit of TTFields treatment in recurrent glioblastoma, but definitive conclusions could not be drawn due to their lack of randomized control-groups.[8]

Newly diagnosed glioblastoma

Initial results of a Novocure-sponsored, phase-3, randomized clinical trial of TTFields in patients with newly diagnosed glioblastoma were reported in November, 2014,[9] and published in December 2015.[10][11] Interim analysis showed a statistically significant benefit in median survival for patients treated with TTFields 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.[11] On the basis of these results, the FDA approved a modification of the trial protocol, allowing all patients on the trial to be offered TTFields.[12] 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.[11] This discrepancy might have been a result of improved health and survival in TTFields-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.[11] An expert clinical review called the preliminary results "encouraging".[13]

Side effects

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

Mechanism

Alternating electric field therapy / TTFields 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.[14] In preclinical cancer models, TTFields appeared to show selective toxicity to proliferating cells through an antimitotic mechanism.[8][14][15][16][17] 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.[17] 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.[8]

During cell division, a structure called a spindle self-assembles from proteins. The spindle attaches to the 23 chromosomes and pulls the DNA into two new cells. The proteins in the spindle have a positive charge on one end and negative charge on the other end. This division is uncontrolled in cancer cells. The TTFields electric charge prevents the cancer cell from dividing, thereby preventing the cancer from growing and spreading. TFF prevents division and destroys cancers cells with electric fields while sparing healthy tissue.[18]

Additionally, emerging evidence suggests alternating electric fields therapy may disrupt a multitude of biological processes,[19] including DNA repair,[20][21] cell permeability[22] and immunological responses,[23] to elicit therapeutic effects. Greater mechanistic understanding of TTFields may pave the way for new, more effective TTFields-based therapeutic combinations in the future.[24]

Medical device

A clinical TTFields device is manufactured by Novocure under the trade name Optune (formerly NovoTTF-100A), and is approved in the United States, Japan, Israel and multiple countries in 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.[7][16] When a TTFields device is used, electrodes resembling a kind of "electric hat"[25] are placed onto a patient's shaved scalp. When not in use, the device`s batteries are plugged into a power outlet to be re-charged.[25]

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.[26] 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".[27]

Optune was approved by the FDA for newly diagnosed glioblastoma on Oct. 5, 2015,[28] 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.[9][10]

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.[29] Medicare and many private health insurance companies have declined to cover TTFields treatment, on the grounds that it is still investigational.[29][30] Medicare covers it, as of February 2020.[18]

Company

Novocure Ltd. (Nasdaq: NVCR) was founded in 2000. As of December 2020, Novocure Ltd. has over 1000 employees and makes hundreds of millions of dollars in annual sales. Israeli Professor Yoram Palti, professor of physiology and biophysics at the Israel Institute of Technology, is the company's founder and chief technology officer. Novocure Ltd. owns 145 patents.[18]

See also

References
  1. Rominiyi, Ola; Vanderlinden, Aurelie; Clenton, Susan Jane; Bridgewater, Caroline; Al-Tamimi, Yahia; Collis, Spencer James (2020-11-04). "Tumour treating fields therapy for glioblastoma: current advances and future directions". British Journal of Cancer. doi:10.1038/s41416-020-01136-5. ISSN 1532-1827. PMID 33144698.
  2. "NCCN Guidelines for CNS cancers" (PDF). Retrieved 4 August 2013.
  3. 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.
  4. 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.
  5. "ClinicalTrials.gov results-Novocure". ClinicalTrials.gov. Retrieved 26 December 2014.
  6. 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. PMID 26917587.
  7. Batchelor, Tracy; Shih, Helen; Carter, Bob. "Management of recurrent high-grade gliomas". UpToDate. Retrieved 26 December 2014.
  8. Calzón Fernández S, Llanos Méndez A (2013). Tumor treating fields therapy (TTFields) 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.
  9. Stupp, Roger; Wong, Eric; Scott, Charles; Taillibert, Sophie; Kanner, Andrew; Kesari, Santosh; Ram, Zvi (2014). "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.
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  11. Sampson, John H. (15 December 2015). "Alternating Electric Fields for the Treatment of Glioblastoma". JAMA. 314 (23): 2511–3. doi:10.1001/jama.2015.16701. PMID 26670969.
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  14. "Disruption of Cancer Cell Replication by Alternating Electric Fields". Cancer Research. 1 May 2004.
  15. 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 (24): 10152–7. Bibcode:2007PNAS..10410152K. doi:10.1073/pnas.0702916104. PMC 1886002. PMID 17551011.
  16. http://www.discoverymedicine.com/Maciej-M-Mrugala/2013/04/25/advances-and-challenges-in-the-treatment-of-glioblastoma-a-clinicians-perspective/
  17. 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.
  18. Green, Alexander (February 2020). "This Company Destroys Cancer Cells But With Electricity... Not Drugs Or Radiation". The Oxford Communique.
  19. Rominiyi, Ola; Vanderlinden, Aurelie; Clenton, Susan Jane; Bridgewater, Caroline; Al-Tamimi, Yahia; Collis, Spencer James (2020-11-04). "Tumour treating fields therapy for glioblastoma: current advances and future directions". British Journal of Cancer. doi:10.1038/s41416-020-01136-5. ISSN 1532-1827. PMID 33144698.
  20. Giladi, Moshe; Munster, Mijal; Schneiderman, Rosa S.; Voloshin, Tali; Porat, Yaara; Blat, Roni; Zielinska-Chomej, Katarzyna; Hååg, Petra; Bomzon, Ze'ev; Kirson, Eilon D.; Weinberg, Uri (2017-12-29). "Tumor treating fields (TTFields) delay DNA damage repair following radiation treatment of glioma cells". Radiation Oncology (London, England). 12 (1): 206. doi:10.1186/s13014-017-0941-6. ISSN 1748-717X. PMC 5747183. PMID 29284495.
  21. Karanam, Narasimha Kumar; Ding, Lianghao; Aroumougame, Asaithamby; Story, Michael D. (March 2020). "Tumor treating fields cause replication stress and interfere with DNA replication fork maintenance: Implications for cancer therapy". Translational Research: The Journal of Laboratory and Clinical Medicine. 217: 33–46. doi:10.1016/j.trsl.2019.10.003. ISSN 1878-1810. PMID 31707040.
  22. Chang, Edwin; Patel, Chirag B.; Pohling, Christoph; Young, Caroline; Song, Jonathan; Flores, Thomas Anthony; Zeng, Yitian; Joubert, Lydia-Marie; Arami, Hamed; Natarajan, Arutselvan; Sinclair, Robert (2018). "Tumor treating fields increases membrane permeability in glioblastoma cells". Cell Death Discovery. 4: 113. doi:10.1038/s41420-018-0130-x. ISSN 2058-7716. PMC 6281619. PMID 30534421.
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Further reading
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