Skip to main content

Advertisement

SpringerLink
Log in

Tumor treating fields: a new approach to glioblastoma therapy

  • Topic Review
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

Glioblastoma is an aggressive brain malignancy with poor outcomes. Current standard of care involves surgery, radiotherapy and chemotherapy. Even with optimal treatment, 5-year survival rates are low. Many patients are unable to tolerate the considerable side effects that therapy involves and suffer from low quality of life. Anti-mitotic tumor treating fields have shown potential in treating glioblastoma with data suggesting that they prolong disease-free survival and overall survival. Novocure has marketed a device that generates these fields via externally placed electrodes. Incorporation of electric field therapy into GBM treatment has been somewhat slow, due to concerns about cost, practicality of its usage from a patient perspective, and hesitation of the medical and scientific community to embrace its unconventional mechanism. However, clinical trials have demonstrated this therapy has relatively minor side effects and high patient compliance. In this review, we explore the current state of this technology and discuss the benefits and limitations of tumor treating fields.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Ostrom QT, Bauchet L, Davis FG, Deltour I, Fisher JL, Langer CE, Pekmezci M, Schwartzbaum JA, Turner MC, Walsh KM, Wrensch MR, Barnholtz-Sloan JS (2014) The epidemiology of glioma in adults: a state of the science review. Neuro Oncology 16:896–913. https://doi.org/10.1093/neuonc/nou087

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Sarkar A, Chiocca EA, Glioblastoma, Astrocytoma M (2012) Glioblastoma and malignant astrocytoma. Brain Tumors. https://doi.org/10.1016/B978-0-443-06967-3.00021-1

    Google Scholar 

  3. Zhu P, Du XL, Lu G, Zhu J-J (2017) Survival benefit of glioblastoma patients after FDA approval of temozolomide concomitant with radiation and bevacizumab: a population-based study. Oncotarget 8:44015–44031. https://doi.org/10.18632/oncotarget.17054

    PubMed  PubMed Central  Google Scholar 

  4. Woernle CM, Péus D, Hofer S, Rushing EJ, Held U, Bozinov O, Krayenbühl N, Weller M, Regli L (2015) Efficacy of surgery and further treatment of progressive glioblastoma. World Neurosurg 84:301–307. https://doi.org/10.1016/j.wneu.2015.03.018

    Article  PubMed  Google Scholar 

  5. Johnson DR, O’Neill BP (2012) Glioblastoma survival in the United States before and during the temozolomide era. J Neurooncol 107:359–364. https://doi.org/10.1007/s11060-011-0749-4

    Article  CAS  PubMed  Google Scholar 

  6. Walid MS (2008) Prognostic factors for long-term survival after glioblastoma. Perm J 12:45–48

    PubMed  PubMed Central  Google Scholar 

  7. Hottinger AF, Pacheco P, Stupp R (2016) Tumor treating fields: a novel treatment modality and its use in brain tumors. Neuro Oncology 18:1338–1349. https://doi.org/10.1093/neuonc/now182

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Aoki T, Hashimoto N, Matsutani M (2007) Management of glioblastoma. Expert Opin Pharmacother 8:3133–3146. https://doi.org/10.1517/14656566.8.18.3133

    Article  CAS  PubMed  Google Scholar 

  9. Hottinger AF, Stupp R, Homicsko K (2014) Standards of care and novel approaches in the management of glioblastoma multiforme. Chin J Cancer 33:32–39. https://doi.org/10.5732/cjc.013.10207

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Park JK, Hodges T, Arko L, Shen M, Dello Iacono D, McNabb A, Olsen Bailey N, Kreisl TN, Iwamoto FM, Sul J, Auh S, Park GE, Fine HA, Black PM (2010) Scale to predict survival after surgery for recurrent glioblastoma multiforme. J Clin Oncol 28:3838–3843. https://doi.org/10.1200/JCO.2010.30.0582

    Article  PubMed  PubMed Central  Google Scholar 

  11. Brown T, Brennan M, Li M, Church E, Brandmeir N, Rakszawski K, Patel A, Rizk E, Suki D, Sawaya R, Glantz M (2016) Association of the extent of resection with survival in glioblastoma: a systematic review and meta-analysis. JAMA Oncol 2:1460–1469. https://doi.org/10.1001/jamaoncol.2016.1373

    Article  PubMed  Google Scholar 

  12. Vogelbaum MA (2012) Does extent of resection of a glioblastoma matter? Clin Neurosurg 59:79–81. https://doi.org/10.1227/NEU.0b013e31826b2e75

    Article  PubMed  Google Scholar 

  13. Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJB, Janzer RC, Ludwin SK, Allgeier A, Fisher B, Belanger K, Hau P, Brandes AA, Gijtenbeek J, Marosi C, Vecht CJ, Mokhtari K, Wesseling P, Villa S, Eisenhauer E, Gorlia T, Weller M, Lacombe D, Cairncross JG, Mirimanoff R-O (2017) Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 10:459–466. https://doi.org/10.1016/S1470-2045(09)70025-7

    Article  Google Scholar 

  14. Keime-Guibert F, Chinot O, Taillandier L, Cartalat-Carel S, Frenay M, Kantor G, Guillamo JS, Jadaud E, Colin P, Bondiau PY, Menei P, Loiseau H, Bernier V, Honnorat J, Barrie M, Mokhtari K, Mazeron JJ, Bissery A, Delattre JY, Association of French-Speaking Neuro-Oncologists (2007) Radiotherapy for glioblastoma in the elderly. N Engl J Med 356:1527–1535. https://doi.org/10.1056/NEJMoa065901

    Article  CAS  PubMed  Google Scholar 

  15. Perry JR, Laperriere N, O’Callaghan CJ, Brandes AA, Menten J, Phillips C, Fay M, Nishikawa R, Cairncross JG, Roa W, Osoba D, Rossiter JP, Sahgal A, Hirte H, Laigle-Donadey F, Franceschi E, Chinot O, Golfinopoulos V, Fariselli L, Wick A, Feuvret L, Back M, Tills M, Winch C, Baumert BG, Wick W, Ding K, Mason WP (2017) Short-course radiation plus temozolomide in elderly patients with glioblastoma. N Engl J Med 376:1027–1037. https://doi.org/10.1056/NEJMoa1611977

    Article  CAS  PubMed  Google Scholar 

  16. Taillibert S, Le Rhun E, Chamberlain MC (2015) Tumor treating fields. Curr Opin Neurol 28:659–664. https://doi.org/10.1097/WCO.0000000000000250

    Article  CAS  PubMed  Google Scholar 

  17. Lok E, San P, Hua V, Phung M, Wong ET (2017) Analysis of physical characteristics of tumor treating fields for human glioblastoma. Cancer Med 6:1286–1300. https://doi.org/10.1002/cam4.1095

    Article  PubMed  PubMed Central  Google Scholar 

  18. Mun EJ, Babiker HM, Weinberg U, Kirson ED, Von Hoff DD, Tumor treating fields: a fourth modality in cancer treatment. Clin Cancer Res (2017). https://doi.org/10.1158/1078-0432.CCR-17-1117

    Google Scholar 

  19. Weaver JC, Chizmadzhev YA (1996) Theory of electroporation: a review. Bioelectrochem Bioenergy 41:135–160. https://doi.org/10.1016/S0302-4598(96)05062-3

    Article  CAS  Google Scholar 

  20. Holzapfel C, Vienken J, Zimmermann U (1982) Rotation of cells in an alternating electric field theory and experimental proof. J Membr Biol 67:13–26. https://doi.org/10.1007/BF01868644

    Article  CAS  PubMed  Google Scholar 

  21. Sugar IP, Neumann E (1984) Stochastic model for electric field-induced membrane pores electroporation. Biophys Chem 19:211–225. https://doi.org/10.1016/0301-4622(84)87003-9

    Article  CAS  PubMed  Google Scholar 

  22. Giladi M, Schneiderman RS, Porat Y, Munster M, Itzhaki A, Mordechovich D, Cahal S, Kirson ED, Weinberg U, Palti Y (2014) Mitotic disruption and reduced clonogenicity of pancreatic cancer cells in vitro and in vivo by tumor treating fields. Pancreatology 14:54–63. https://doi.org/10.1016/j.pan.2013.11.009

    Article  PubMed  Google Scholar 

  23. Berjano EJ (2006) Theoretical modeling for radiofrequency ablation: state-of-the-art and challenges for the future. Biomed Eng Online 5:24. https://doi.org/10.1186/1475-925X-5-24

    Article  PubMed  PubMed Central  Google Scholar 

  24. Atroshi I, Gummesson C, Johnsson R, Ornstein E (2003) Diagnostic properties of nerve conduction tests in population-based carpal tunnel syndrome. BMC Musculoskelet Disord 4:9. https://doi.org/10.1186/1471-2474-4-9

    Article  PubMed  PubMed Central  Google Scholar 

  25. Alanko T, Puranen L, Hietanen M (2011) Assessment of exposure to intermediate frequency electric fields and contact currents from a plasma ball. Bioelectromagnetics 32:644–651. https://doi.org/10.1002/bem.20675

    Article  PubMed  Google Scholar 

  26. Kirson ED (2004) Disruption of cancer cell replication by alternating electric fields. Cancer Res 64:3288–3295. https://doi.org/10.1158/0008-5472.CAN-04-0083

    Article  CAS  PubMed  Google Scholar 

  27. Giladi M, Schneiderman RS, Voloshin T, Porat Y, Munster M, Blat R, Sherbo S, Bomzon Z, Urman N, Itzhaki A, Cahal S, Shteingauz A, Chaudhry A, Kirson ED, Weinberg U, Palti Y (2015) Mitotic spindle disruption by alternating electric fields leads to improper chromosome segregation and mitotic catastrophe in cancer cells. Sci Rep 5:18046. https://doi.org/10.1038/srep18046

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Giladi M, Weinberg U, Schneiderman RS, Porat Y, Munster M, Voloshin T, Blatt R, Cahal S, Itzhaki A, Onn A, Kirson ED, Palti Y (2014) Alternating electric fields (tumor-treating fields therapy) can improve chemotherapy treatment efficacy in non-small cell lung cancer both in vitro and in vivo. Semin Oncol 41:S35–S41. https://doi.org/10.1053/j.seminoncol.2014.09.006

    Article  PubMed  Google Scholar 

  29. Kirson ED, Dbalý V, Tovaryš 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 (2007) Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors. Proc Natl Acad Sci USA 104:10152–10157. https://doi.org/10.1073/pnas.0702916104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kirson ED, Giladi M, Gurvich Z, Itzhaki A, Mordechovich D, Schneiderman RS, Wasserman Y, Ryffel B, Goldsher D, Palti Y (2009) Alternating electric fields (TTFields) inhibit metastatic spread of solid tumors to the lungs. Clin Exp Metastasis 26:633–640. https://doi.org/10.1007/s10585-009-9262-y

    Article  PubMed  PubMed Central  Google Scholar 

  31. Kirson ED, Schneiderman RS, Dbalý V, Tovarys F, Vymazal J, Itzhaki A, Mordechovich D, Gurvich Z, Shmueli E, Goldsher D, Wasserman Y, Palti Y (2009) Chemotherapeutic treatment efficacy and sensitivity are increased by adjuvant alternating electric fields (TTFields). BMC Med Phys 9:1. https://doi.org/10.1186/1756-6649-9-1

    Article  PubMed  PubMed Central  Google Scholar 

  32. Schneiderman RS, Shmueli E, Kirson ED, Palti Y (2010) TTFields alone and in combination with chemotherapeutic agents effectively reduce the viability of MDR cell sub-lines that over-express ABC transporters. BMC Cancer 10:229. https://doi.org/10.1186/1471-2407-10-229

    Article  PubMed  PubMed Central  Google Scholar 

  33. Stupp R, Wong ET, Kanner AA, Steinberg D, Engelhard H, Heidecke V, Kirson ED, Taillibert S, Liebermann F, Dbalý V, Ram Z, Villano JL, Rainov N, Weinberg U, Schiff D, Kunschner L, Raizer J, Honnorat J, Sloan A, Malkin M, Landolfi JC, Payer F, Mehdorn M, Weil RJ, Pannullo SC, Westphal M, Smrcka M, Chin L, Kostron H, Hofer S, Bruce J, Cosgrove R, Paleologous N, Palti Y, Gutin PH (2012) NovoTTF-100A versus physician’s choice chemotherapy in recurrent glioblastoma: a randomised phase III trial of a novel treatment modality. Eur J Cancer 48:2192–2202. https://doi.org/10.1016/j.ejca.2012.04.011

    Article  PubMed  Google Scholar 

  34. Lacouture ME, Elizabeth Davis M, Elzinga G, Butowski N, Tran D, Villano JL, Dimeglio L, Davies AM, Wong ET (2014) Characterization and management of dermatologic adverse events with the NovoTTF-100A system, a novel anti-mitotic electric field device for the treatment of recurrent glioblastoma. Semin Oncol 41:S1–S14. https://doi.org/10.1053/j.seminoncol.2014.03.011

    Article  PubMed  Google Scholar 

  35. Stupp R, Taillibert S, Kanner AA, Kesari S, Steinberg DM, Toms SA, Taylor LP, Lieberman F, Silvani A, Fink KL, Barnett GH, Zhu J-J, Henson JW, Engelhard HH, Chen TC, Tran DD, Sroubek J, Tran ND, Hottinger AF, Landolfi J, Desai R, Caroli M, Kew Y, Honnorat J, Idbaih A, Kirson ED, Weinberg U, Palti Y, Hegi ME, Ram Z (2015) Maintenance therapy with tumor-treating fields plus temozolomide vs temozolomide alone for glioblastoma. Jama 314:2535. https://doi.org/10.1001/jama.2015.16669

    Article  CAS  PubMed  Google Scholar 

  36. Zhu J-J, Demireva P, Kanner AA, Pannullo S, Mehdorn M, Avgeropoulos N, Salmaggi A, Silvani A, Goldlust S, David C, Benouaich-Amiel A (2017) Health-related quality of life, cognitive screening, and functional status in a randomized phase III trial (EF-14) of tumor treating fields with temozolomide compared to temozolomide alone in newly diagnosed glioblastoma. J Neurooncol. https://doi.org/10.1007/s11060-017-2601-y

    PubMed Central  Google Scholar 

  37. Stupp R, Ram Z (2017) OS07.9 Standard of care temozolomide chemotherapy ± tumor treating fields (TTFields) in newly diagnosed glioblastoma. Final results of the phase III EF-14 clinical trial. Neuro Oncol 19:iii15. https://doi.org/10.1093/neuonc/nox036.050

    Article  Google Scholar 

  38. Stupp R, Hegi ME, Idbaih A, Steinberg DM, Lhermitte B, Read W, Toms SA, Barnett GH, Nicholas G, Kim C-Y, Fink K, Salmaggi A, Lieberman FS, Zhu J-J, Taylor L, Stragliotto G, Hottinger AF, Kirson ED, Weinberg U, Palti Y, Ram Z (2017) Abstract CT007: tumor treating fields added to standard chemotherapy in newly diagnosed glioblastoma (GBM): final results of a randomized, multi-center, phase III trial. Cancer Res 77:CT007 LP-CT007. http://cancerres.aacrjournals.org/content/77/13_Supplement/CT007.abstract

  39. Stupp R, Taillibert S, Kanner A, Read W, Steinberg DM, Lhermitte B, Toms S, Idbaih A, Ahluwalia MS, Fink K, Di Meco F, Lieberman F, Zhu J-J, Stragliotto G, Tran DD, Brem S, Hottinger AF, Kirson ED, Lavy-Shahaf G, Weinberg U, Kim C-Y, Paek S-H, Nicholas G, Burna J, Hirte H, Weller M, Palti Y, Hegi ME, Ram Z (2017) Effect of tumor-treating fields plus maintenance temozolomide vs maintenance temozolomide alone on survival in patients with glioblastoma: a randomized clinical trial. JAMA 318:2306–2316. https://doi.org/10.1001/jama.2017.18718

    Article  CAS  PubMed  Google Scholar 

  40. Kelly C, Majewska P, Ioannidis S, Raza MH, Williams M (2017) Estimating progression-free survival in patients with glioblastoma using routinely collected data. J Neurooncol 135:621–627. https://doi.org/10.1007/s11060-017-2619-1

    Article  PubMed  PubMed Central  Google Scholar 

  41. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJB, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996. https://doi.org/10.1056/NEJMoa043330

    Article  CAS  PubMed  Google Scholar 

  42. Mrugala MM, Engelhard HH, Dinh Tran D, Kew Y, Cavaliere R, Villano JL, Annenelie Bota D, Rudnick J, Love Sumrall A, Zhu J-J, Butowski N (2017) Clinical practice experience with NovoTTF-100A system for glioblastoma: the patient registry dataset (PRiDe). Semin Oncol 41:S4–S13. https://doi.org/10.1053/j.seminoncol.2014.09.010

    Article  Google Scholar 

  43. Gilbert MR, Dignam JJ, Armstrong TSTS., Wefel JS, Blumenthal DT, Vogelbaum MA, Colman H, Chakravarti A, Pugh SL, Won M, Jeraj R, Brown PD, Jaeckle KA, Schiff D, Stieber VW, Brachman DG, Werner-Wasik M, Tremont-Lukats IW, Sulman EP, Aldape KD, Curran WJJ, Mehta MP (2014) A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med 370:699–708. https://doi.org/10.1056/NEJMoa1308573

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Narita Y (2015) Bevacizumab for glioblastoma. Ther Clin Risk Manag 11:1759–1765. https://doi.org/10.2147/TCRM.S58289

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Ansstas G, Tran DD (2016) Treatment with tumor-treating fields therapy and pulse dose bevacizumab in patients with bevacizumab-refractory recurrent glioblastoma: a case series. Case Rep Neurol 8:1–9. https://doi.org/10.1159/000442196

    Article  PubMed  PubMed Central  Google Scholar 

  46. Jackson C, Ruzevick J, Brem H, Lim M, Manuscript A (2013) Vaccine strategies for glioblastoma: progress and future directions. Immunotherapy 5:155–167. https://doi.org/10.2217/imt.12.155

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Novocure, Optune, Instruction for Use, 1st ed., Novocure, 2016. doi:QSD-QR-703

  48. Lukas RV, Ratermann KL, Wong ET, Villano JL (2017) Skin toxicities associated with tumor treating fields: case based review. J Neurooncol. https://doi.org/10.1007/s11060-017-2612-8

    Google Scholar 

  49. Zhang I, Knisely JPS (2016) Tumor treating fields—effective, but at what cost? Transl Cancer Res 5:S1349–S1353. https://doi.org/10.21037/tcr.2016.12.45

    Article  Google Scholar 

  50. Bernard-Arnoux F, Lamure M, Ducray F, Aulagner G, Honnorat J, Armoiry X (2016) The cost-effectiveness of tumor-treating fields therapy in patients with newly diagnosed glioblastoma. Neuro Oncol 18:1129–1136. https://doi.org/10.1093/neuonc/now102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Korshoej AR, Hansen FL, Thielscher A, Von Oettingen GB, Christian J, Hedemann S (2017) Impact of tumor position, conductivity distribution and tissue homogeneity on the distribution of tumor treating fields in a human brain: a computer modeling study. PLoS ONE 12:e0179214. https://doi.org/10.1371/journal.pone.0179214

    Article  PubMed  PubMed Central  Google Scholar 

  52. Chang E, Pohling C, Beygui N, Patel CB, Rosenberg J, Ha DH, Gambhir SS (2017) Synergistic inhibition of glioma cell proliferation by Withaferin A and tumor treating fields. J Neurooncol. https://doi.org/10.1007/s11060-017-2534-5

    Google Scholar 

  53. Wong ET, Lok E, Swanson KD, An evidence-based review of alternating electric fields therapy for malignant gliomas. Curr Treat Options Oncol (2015). https://doi.org/10.1007/s11864-015-0353-5

    PubMed Central  Google Scholar 

  54. Karanam NK, Srinivasan K, Ding L, Sishc B, Saha D, Story MD (2017) Tumor-treating fields elicit a conditional vulnerability to ionizing radiation via the downregulation of BRCA1 signaling and reduced DNA double-strand break repair capacity in non-small cell lung cancer cell lines. Cell Death Dis 8:e2711. https://doi.org/10.1038/cddis.2017.136

    Article  PubMed  PubMed Central  Google Scholar 

  55. Holtzman T, IMST-26 (2016) Tumor treating fields exposure of tumor cells induce activation phenotype in immune cells. Neuro Oncology 18:vi92. https://doi.org/10.1093/neuonc/now212.382

    Article  Google Scholar 

Download references

Funding

Jonathan Rick and Ankush Chandra are supported by the Howard Hughes Medical Institute.

Author information

Authors and Affiliations

  1. Department of Neurosurgery, University of California at San Francisco (UCSF), 505 Parnassus Avenue Room M779, San Francisco, CA, 94143-0112, USA

    Jonathan Rick, Ankush Chandra & Manish K. Aghi

  2. Wayne State University School of Medicine, 540 East Canfield, Detroit, MI, 48201, USA

    Ankush Chandra

Authors
  1. Jonathan Rick
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ankush Chandra
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Manish K. Aghi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jonathan Rick.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest.

Research involving human and animals participants

No experiments were performed on animal or human subjects by the authors.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rick, J., Chandra, A. & Aghi, M.K. Tumor treating fields: a new approach to glioblastoma therapy. J Neurooncol 137, 447–453 (2018). https://doi.org/10.1007/s11060-018-2768-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11060-018-2768-x

Keywords

Search

Navigation