Skip to main content
SpringerLink
Log in

A systematic review of tumor treating fields therapy for high-grade gliomas

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

Abstract

Introduction

Tumor treating fields (TTF) is a unique treatment modality that utilizes alternating electric fields to deliver therapy. Treatment effects have been assessed in patients with newly diagnosed and recurrent glioblastoma in clinical trials and retrospective studies. While the results of these studies led to FDA approval for both populations, a portion of the neuro-oncology and neurosurgery community remains skeptical of TTF. Thus, this review aims to systematically summarize and evaluate prior studies investigating the efficacy and safety of TTF in patients with high-grade gliomas.

Methods

A systematic review of the literature was performed according to PRISMA guidelines from database inception through February 2019. To be included, studies must have investigated the efficacy of TTF in adult high-grade glioma patients.

Results

In total, 852 studies were initially identified, 9 of which met final inclusion criteria. In total, 1191 patients were identified who received TTF. Included studies consisted of two pilot clinical trials, two randomized clinical trials, and five retrospective studies. In randomized clinical trials, TTF improved survival for newly diagnosed glioblastoma patients but not for recurrent glioblastoma patients. Adverse skin reactions were the primary adverse effect associated with TTF.

Conclusion

While TTF has been evaluated for safety and efficacy in a number of studies, concerns remain regarding study design, quality of life, and cost of therapy. Further investigation is needed regarding the therapy, and ongoing trials are already underway to provide more data regarding therapy outcomes and interactions in combination regimens.

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

Fig. 1

Similar content being viewed by others

Data availability

All data collected during this study are included in the manuscript and supplementary information files.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Code availability

Not applicable.

References

  1. Grossman SA, Ye X, Piantadosi S et al (2010) Survival of patients with newly diagnosed glioblastoma treated with radiation and temozolomide on research studies in the United States. Clin Cancer Res Off J Am Assoc Cancer Res 16:2443–2449. https://doi.org/10.1158/1078-0432.CCR-09-3106

    Article  CAS  Google Scholar 

  2. Ostrom QT, Cote DJ, Ascha M et al (2018) Adult glioma incidence and survival by race or ethnicity in the United States from 2000 to 2014. JAMA Oncol 4:1254–1262. https://doi.org/10.1001/jamaoncol.2018.1789

    Article  PubMed  PubMed Central  Google Scholar 

  3. Stupp R, Mason WP, van den Bent MJ et al (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 

  4. Koshy M, Villano JL, Dolecek TA et al (2012) Improved survival time trends for glioblastoma using the SEER 17 population-based registries. J Neurooncol 107:207–212. https://doi.org/10.1007/s11060-011-0738-7

    Article  PubMed  Google Scholar 

  5. Gilbert MR, Wang M, Aldape KD et al (2013) Dose-dense temozolomide for newly diagnosed glioblastoma: a randomized phase III clinical trial. J Clin Oncol Off J Am Soc Clin Oncol 31:4085–4091. https://doi.org/10.1200/JCO.2013.49.6968

    Article  CAS  Google Scholar 

  6. Gilbert MR, Dignam JJ, Armstrong TS et al (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 

  7. Chinnaiyan P, Won M, Wen PY et al (2018) A randomized phase II study of everolimus in combination with chemoradiation in newly diagnosed glioblastoma: results of NRG Oncology RTOG 0913. Neuro-Oncology 20:666–673. https://doi.org/10.1093/neuonc/nox209

    Article  CAS  PubMed  Google Scholar 

  8. Vartanian A, Singh SK, Agnihotri S et al (2014) GBM’s multifaceted landscape: highlighting regional and microenvironmental heterogeneity. Neuro-Oncology 16:1167–1175. https://doi.org/10.1093/neuonc/nou035

    Article  PubMed  PubMed Central  Google Scholar 

  9. Oberoi RK, Parrish KE, Sio TT et al (2016) Strategies to improve delivery of anticancer drugs across the blood–brain barrier to treat glioblastoma. Neuro-Oncology 18:27–36. https://doi.org/10.1093/neuonc/nov164

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kanner AA, Wong ET, Villano JL, Ram Z (2014) Post hoc analyses of intention-to-treat population in phase III comparison of NovoTTF-100ATM system versus best physician’s choice chemotherapy. Semin Oncol 41:S25–S34. https://doi.org/10.1053/j.seminoncol.2014.09.008

    Article  PubMed  Google Scholar 

  12. Stupp R, Wong ET, Kanner AA et al (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 

  13. Stupp R, Taillibert S, Kanner A et al (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  PubMed Central  Google Scholar 

  14. Mehta M, Wen P, Nishikawa R et al (2017) Critical review of the addition of tumor treating fields (TTFields) to the existing standard of care for newly diagnosed glioblastoma patients. Crit Rev Oncol Hematol 111:60–65. https://doi.org/10.1016/j.critrevonc.2017.01.005

    Article  CAS  PubMed  Google Scholar 

  15. Wick W (2016) TTFields: where does all the skepticism come from? Neuro-Oncology 18:303–305. https://doi.org/10.1093/neuonc/now012

    Article  PubMed  PubMed Central  Google Scholar 

  16. Burri SH, Gondi V, Brown PD, Mehta MP (2018) The evolving role of tumor treating fields in managing glioblastoma: guide for oncologists. Am J Clin Oncol 41:191. https://doi.org/10.1097/COC.0000000000000395

    Article  PubMed  Google Scholar 

  17. Moher D, Liberati A, Tetzlaff J et al (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 6:e1000097. https://doi.org/10.1371/journal.pmed.1000097

    Article  PubMed  PubMed Central  Google Scholar 

  18. Sterne JAC, Savović J, Page MJ et al (2019) RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ 366:l4898. https://doi.org/10.1136/bmj.l4898

    Article  PubMed  Google Scholar 

  19. Sterne JA, Hernán MA, Reeves BC et al (2016) ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ 355:i4919. https://doi.org/10.1136/bmj.i4919

    Article  PubMed  PubMed Central  Google Scholar 

  20. (2016) OCEBM Levels of Evidence. In: CEBM. https://www.cebm.net/2016/05/ocebm-levels-of-evidence/. Accessed 31 Dec 2019

  21. Wong ET, Lok E, Gautam S, Swanson KD (2015) Dexamethasone exerts profound immunologic interference on treatment efficacy for recurrent glioblastoma. Br J Cancer 113:232–241. https://doi.org/10.1038/bjc.2015.238

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Mrugala MM, Engelhard HH, Dinh Tran D et al (2014) Clinical practice experience with NovoTTF-100ATM system for glioblastoma: the patient registry dataset (PRiDe). Semin Oncol 41:S4–S13. https://doi.org/10.1053/j.seminoncol.2014.09.010

    Article  PubMed  Google Scholar 

  23. Kirson ED, Schneiderman RS, Dbalý V et al (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 

  24. Toms SA, Kim CY, Nicholas G, Ram Z (2019) Increased compliance with tumor treating fields therapy is prognostic for improved survival in the treatment of glioblastoma: a subgroup analysis of the EF-14 phase III trial. J Neurooncol 141:467–473. https://doi.org/10.1007/s11060-018-03057-z

    Article  CAS  PubMed  Google Scholar 

  25. Wong ET, Lok E, Swanson KD (2015) Clinical benefit in recurrent glioblastoma from adjuvant NovoTTF-100A and TCCC after temozolomide and bevacizumab failure: a preliminary observation. Cancer Med 4:383–391. https://doi.org/10.1002/cam4.421

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Lu G, Rao M, Zhu P et al (2019) Triple-drug therapy with bevacizumab, irinotecan, and temozolomide plus tumor treating fields for recurrent glioblastoma: a retrospective study. Front Neurol. https://doi.org/10.3389/fneur.2019.00042

    Article  PubMed  PubMed Central  Google Scholar 

  27. 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 

  28. Gallego O (2015) Nonsurgical treatment of recurrent glioblastoma. Curr Oncol 22:e273–e281. https://doi.org/10.3747/co.22.2436

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Taphoorn MJB, Dirven L, Kanner AA et al (2018) Influence of treatment with tumor-treating fields on health-related quality of life of patients with newly diagnosed glioblastoma: a secondary analysis of a randomized clinical trial. JAMA Oncol 4:495–504. https://doi.org/10.1001/jamaoncol.2017.5082

    Article  PubMed  PubMed Central  Google Scholar 

  30. Halasz LM, Mitin T (2018) Tumor-treating fields: answering the concern about quality of life. JAMA Oncol 4:504–505. https://doi.org/10.1001/jamaoncol.2017.5062

    Article  PubMed  Google Scholar 

  31. Dua P, Heiland MF, Kracen AC, Deshields TL (2017) Cancer-related hair loss: a selective review of the alopecia research literature. Psychooncology 26:438–443. https://doi.org/10.1002/pon.4039

    Article  PubMed  Google Scholar 

  32. Hesketh PJ, Batchelor D, Golant M et al (2004) Chemotherapy-induced alopecia: psychosocial impact and therapeutic approaches. Support Care Cancer 12:543–549. https://doi.org/10.1007/s00520-003-0562-5

    Article  PubMed  Google Scholar 

  33. Zhang I, Knisely JPS (2016) Tumor treating fields—effective, but at what cost? Transl Cancer Res 5:S1349–S1353. https://doi.org/10.21037/11292

    Article  Google Scholar 

  34. Bernard-Arnoux F, Lamure M, Ducray F et al (2016) The cost-effectiveness of tumor-treating fields therapy in patients with newly diagnosed glioblastoma. Neuro-Oncology 18:1129–1136. https://doi.org/10.1093/neuonc/now102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Lamers LM, Stupp R, van den Bent MJ et al (2008) Cost-effectiveness of temozolomide for the treatment of newly diagnosed glioblastoma multiforme. Cancer 112:1337–1344. https://doi.org/10.1002/cncr.23297

    Article  CAS  PubMed  Google Scholar 

  36. Garside R, Pitt M, Anderson R et al (2007) The effectiveness and cost-effectiveness of carmustine implants and temozolomide for the treatment of newly diagnosed high-grade glioma: a systematic review and economic evaluation. Health Technol Assess Winch Engl. https://doi.org/10.3310/hta11450

    Article  Google Scholar 

  37. Schiff D, Schrag D (2016) Living in a material world: tumor-treating fields at the top of the charts. Neuro-Oncology 18:1033–1034. https://doi.org/10.1093/neuonc/now138

    Article  PubMed  PubMed Central  Google Scholar 

  38. Hayes MJ, Prasad V (2019) Association between conflict of interest and published position on tumor-treating fields for the treatment of glioblastoma. J Cancer Policy 21:100189. https://doi.org/10.1016/j.jcpo.2019.100189

    Article  Google Scholar 

Download references

Funding

None.

Author information

Authors and Affiliations

  1. Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA

    Pavan P. Shah, Taija White, Adham M. Khalafallah & Debraj Mukherjee

  2. Department of Neurology, Brain Cancer Program, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA

    Carlos G. Romo

  3. Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, 20892, USA

    Carlos G. Romo

  4. Welch Medical Library, Johns Hopkins University, Baltimore, MD, 21205, USA

    Carrie Price

Authors
  1. Pavan P. Shah
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Taija White
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Adham M. Khalafallah
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Carlos G. Romo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Carrie Price
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Debraj Mukherjee
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Debraj Mukherjee.

Ethics declarations

Conflict of interest

All authors declare that they have no conflict of interest.

Ethical approval

Not applicable.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This study was performed in accordance with PRISMA guidelines (http://www.prisma-statement.org/).

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shah, P.P., White, T., Khalafallah, A.M. et al. A systematic review of tumor treating fields therapy for high-grade gliomas. J Neurooncol 148, 433–443 (2020). https://doi.org/10.1007/s11060-020-03563-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11060-020-03563-z

Keywords

Search

Navigation