Alternating electric field therapy
Other namesTumor treating fields
Specialtyoncology

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] TTFields disrupt cell division by disrupting dipole alignment and inducing dielectrophoresis of critical molecules and organelles during mitosis.[5][6][7] These anti-mitotic effects lead to cell death, slowing cancer growth.[5][6][7] A TTField-treatment 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), malignant pleural mesothelioma (MPM), and is undergoing clinical trials for several other tumor types.[8][9] Despite earning regulatory approval, the efficacy of this technology remains controversial among medical experts.[2][10]

Mechanism

All living cells contain polar molecules and will respond to changes in electric fields.[7] Alternating electric field therapy, or Tumor Treating Fields (TTFields) use insulated electrodes to apply very-low-intensity, intermediate-frequency alternating electrical fields to a target area containing cancerous cells.[7] Polar molecules play a key role in cell division, making mitosis particularly susceptible to interference from outside electric fields. TTFields disrupt dipole alignment and induce dielectrophoresis during mitosis, killing proliferating cells.[6][11][12][13][14][15]

Dipole molecules, such as Septins, become unable to move as needed during mitosis when exposed to TTFields, resulting in cell death.[16]

Dipole Alignment

Polar molecules critical to mitosis include α/β-tubulin and the mitotic septin heterotrimer.[15] Tubulin is necessary for mitotic spindle formation during metaphase, while septins stabilize the cell during cytokinesis. When exposed to TTFields, these molecules align their dipole with the electric field, freezing them in one orientation. This prevents tubulin and septin molecules from moving to and binding where they are needed for successful cell division.[16] This results in mitotic catastrophe, initiating cell death through apoptosis.[16] Uneven chromosome splitting can also be a result of TTFields' affect on dipole alignment, resulting in daughter cells with abnormal chromosome numbers.[7][17]

TTFields induce dielectrophoresis in mitotic cells[7]

Dielectrophoresis

Cells that successfully complete metaphase are later susceptible to TTFields during telophase.[7] At this stage in cell division, the cell takes on an hourglass shape as it prepares to divide in two. This results in a non-uniform electric field within the cell, with high field density at the cell's furrow. This causes polar molecules and organelles to migrate with the electric field toward the furrow.[6][7] This disrupts the cell's division and leads to cell death.

Optimization

In principle, this approach could be selective for cancer cells in regions of the body, such as the brain, where the majority of normal cells are non-proliferating.[11] The frequency of the TTField can be adjusted between 100 and 300kHz to target cancer cells and avoid harming healthy cells.[13][17] Current research supports that cell size is inversely proportional to optimal TTField frequency.[6][7] TTFields can also be optimized by orienting two transducer arrays perpendicular to each other to maximize the amount of cells that will be affected. Cells divide in different orientations and are most affected by an electric field that is parallel to their direction of division (perpendicular to the mitotic plate).[6][7][17] Clinicians determine where to place the transducer arrays to optimize treatment using software that analyzes tumor location and the patient's morphometry.[6]

Other Biological Effects

Emerging evidence suggests that alternating electric field therapy disrupts various biological processes,[1] including DNA repair,[18][19] cell permeability[20] and immunological responses,[21] to elicit therapeutic effects. Greater mechanistic understanding of TTFields may pave the way for new, more effective TTFields-based therapeutic combinations in the future.[1]

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.[22] This trial was the primary basis for regulatory approval of NovoTTF-100A / Optune in the United States and Europe.[22] 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.[11][22] 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.[11]

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,[23] and published in December 2015.[24][25] 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.[25] 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.[26] 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.[25] 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.[25] An expert clinical review called the preliminary results "encouraging".[27]

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.[14][22] When a TTFields device is used, electrodes resembling a kind of "electric hat"[28] 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.[28]

Side effects

The adverse effects of TTFields include local skin rashes and irritation caused by prolonged electrode use.[13][7][6]Compared with other cancer treatment methods, this effect is very minimal and tolerable for the patient.[13] This irritation can be controlled with steroid creams and periodic breaks from treatment.[7]

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 glioblastoma, 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.[29] 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".[30]

Optune was approved by the FDA for newly diagnosed glioblastoma on Oct. 5, 2015,[31] 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.[23][24] In the US, Medicare covers treatment, as of February 2020.[32]

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.[32]

See also

References

  1. 1 2 3 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. 124 (4): 697–709. doi:10.1038/s41416-020-01136-5. ISSN 1532-1827. PMC 7884384. PMID 33144698.
  2. 1 2 3 "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. 1 2 Tuszynski, Jack A.; Wenger, Cornelia; Friesen, Douglas E.; Preto, Jordane (2016-11-12). "An Overview of Sub-Cellular Mechanisms Involved in the Action of TTFields". International Journal of Environmental Research and Public Health. 13 (11): 1128. doi:10.3390/ijerph13111128. ISSN 1660-4601. PMC 5129338. PMID 27845746.
  6. 1 2 3 4 5 6 7 8 Mun EJ, Babiker HM, Weinberg U, Kirson ED, Von Hoff DD (2018-01-15). "Tumor-Treating Fields: A Fourth Modality in Cancer Treatment". Clinical Cancer Research. 24 (2): 266–275. doi:10.1158/1078-0432.CCR-17-1117. ISSN 1078-0432. PMID 28765323. S2CID 36674866.
  7. 1 2 3 4 5 6 7 8 9 10 11 12 Hottinger, Andreas F.; Pacheco, Patricia; Stupp, Roger (October 2016). "Tumor treating fields: a novel treatment modality and its use in brain tumors". Neuro-Oncology. 18 (10): 1338–1349. doi:10.1093/neuonc/now182. ISSN 1523-5866. PMC 5035531. PMID 27664860.
  8. ↑ "ClinicalTrials.gov results-Novocure". ClinicalTrials.gov. Retrieved 26 December 2014.
  9. ↑ "Using Tumor Treating Fields to Combat Mesothelioma". Mesothelioma Center - Vital Services for Cancer Patients & Families. Retrieved 2023-12-04.
  10. ↑ 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.
  11. 1 2 3 4 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.
  12. ↑ Kirson ED, Gurvich Z, Schneiderman R, Dekel E, Itzhaki A, Wasserman Y, Schatzberger R, Palti Y (1 May 2004). "Disruption of Cancer Cell Replication by Alternating Electric Fields" (PDF). Cancer Research. 64 (9): 3288–3295. doi:10.1158/0008-5472.CAN-04-0083. PMID 15126372. Archived from the original (PDF) on 2014-08-02.
  13. 1 2 3 4 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.
  14. 1 2 Mrugala, Maciej M. (25 April 2013). "Advances and Challenges in the Treatment of Glioblastoma: A Clinician's Perspective". Discovery Medicine. 15 (83): 221–230. PMID 23636139.
  15. 1 2 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.
  16. 1 2 3 Gera, Nidhi; Yang, Aaron; Holtzman, Talia S.; Lee, Sze Xian; Wong, Eric T.; Swanson, Kenneth D. (2015). "Tumor treating fields perturb the localization of septins and cause aberrant mitotic exit". PLOS ONE. 10 (5): e0125269. Bibcode:2015PLoSO..1025269G. doi:10.1371/journal.pone.0125269. ISSN 1932-6203. PMC 4444126. PMID 26010837.
  17. 1 2 3 "Tumor Treating Fields". XVIVO Scientific Animation. Retrieved 2023-11-21.
  18. ↑ 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. 12 (1): 206. doi:10.1186/s13014-017-0941-6. ISSN 1748-717X. PMC 5747183. PMID 29284495.
  19. ↑ 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.
  20. ↑ 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.
  21. ↑ Kirson, Eilon D.; Giladi, Moshe; Gurvich, Zoya; Itzhaki, Aviran; Mordechovich, Daniel; Schneiderman, Rosa S.; Wasserman, Yoram; Ryffel, Bernhard; Goldsher, Dorit; Palti, Yoram (2009). "Alternating electric fields (TTFields) inhibit metastatic spread of solid tumors to the lungs". Clinical & Experimental Metastasis. 26 (7): 633–640. doi:10.1007/s10585-009-9262-y. ISSN 1573-7276. PMC 2776150. PMID 19387848.
  22. 1 2 3 4 Batchelor, Tracy; Shih, Helen; Carter, Bob. "Management of recurrent high-grade gliomas". UpToDate. Retrieved 26 December 2014.
  23. 1 2 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.
  24. 1 2 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.
  25. 1 2 3 4 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.
  26. ↑ "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). Archived from the original (PDF) on 2014-12-27. Retrieved 2014-12-26.
  27. ↑ Batchelor, Tracy. "Initial postoperative therapy for glioblastoma and anaplastic astrocytoma". UpToDate. Retrieved 26 December 2014.
  28. 1 2 Herper, Matthew (Apr 15, 2011). "Cancer-Fighting Electric Hat Proves We Live in the Future". Forbes.
  29. ↑ "FDA approval letter - NovoTTF-100A System" (PDF). www.fda.gov. Retrieved 26 December 2014.
  30. ↑ "NovoCure Wins Nod from Panel despite Trial, Statistical Miscues". Medical Device Daily. 21 March 2011. Archived from the original on 10 June 2014 – via Highbeam.
  31. ↑ "FDA approves expanded indication for medical device to treat a form of brain cancer" (Press release). U.S. Food and Drug Administration. October 5, 2015. Archived from the original on 2015-10-08.
  32. 1 2 Green, Alexander (February 2020). "This Company Destroys Cancer Cells But With Electricity... Not Drugs Or Radiation". The Oxford Communique.

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