PURPOSE: Tumor Treating Fields (TTFields) therapy, an electric field-based cancer treatment, became FDA-approved for patients with newly diagnosed glioblastoma (GBM) in 2015 based on the randomized controlled EF-14 study. Subsequent approvals worldwide and increased adoption over time have raised the question of whether a consistent survival benefit has been observed in the real-world setting, and whether device usage has played a role. METHODS: We conducted a literature search to identify clinical studies evaluating overall survival (OS) in TTFields-treated patients. Comparative and single-cohort studies were analyzed. Survival curves were pooled using a distribution-free random-effects method. RESULTS: Among nine studies, seven (N = 1430 patients) compared the addition of TTFields therapy to standard of care (SOC) chemoradiotherapy versus SOC alone and were included in a pooled analysis for OS. Meta-analysis of comparative studies indicated a significant improvement in OS for patients receiving TTFields and SOC versus SOC alone (HR: 0.63; 95% CI 0.53-0.75; p < 0.001). Among real-world post-approval studies, the pooled median OS was 22.6 months (95% CI 17.6-41.2) for TTFields-treated patients, and 17.4 months (95% CI 14.4-21.6) for those not receiving TTFields. Rates of gross total resection were generally higher in the real-world setting, irrespective of TTFields use. Furthermore, for patients included in studies reporting data on device usage (N = 1015), an average usage rate of ≥ 75% was consistently associated with prolonged survival (p < 0.001). CONCLUSIONS: Meta-analysis of comparative TTFields studies suggests survival may be improved with the addition of TTFields to SOC for patients with newly diagnosed GBM.

Department of Radiation Oncology West Cancer Center Germantown TN USA

Na Homolce Hospital Prague Czech Republic

Novocure GmBH Munich Germany

Novocure Inc New York NY USA

Novocure Ltd Haifa Israel

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Stupp R, Taillibert S, Kanner A, Read W, Steinberg D, Lhermitte B, Toms S, Idbaih A, Ahluwalia MS, Fink K, Di Meco F, Lieberman F, Zhu JJ, Stragliotto G, Tran D, Brem S, Hottinger A, Kirson ED, Lavy-Shahaf G, Weinberg U, Kim CY, Paek SH, Nicholas G, Bruna J, Hirte H, Weller M, Palti Y, Hegi ME, Ram Z. Effect of Tumor-Treating Fields Plus maintenance temozolomide vs maintenance temozolomide alone on survival in patients with glioblastoma: a randomized clinical trial. JAMA. 2017;318:2306–2316. doi: 10.1001/jama.2017.18718. PubMed DOI PMC

Ostrom QT, Price M, Neff C, Cioffi G, Waite KA, Kruchko C, Barnholtz-Sloan JS. CBTRUS Statistical Report: primary brain and other Central Nervous System Tumors diagnosed in the United States in 2015–2019. Neuro Oncol. 2022;24:v1–v95. doi: 10.1093/neuonc/noac202. PubMed DOI PMC

Ostrom QT, Gittleman H, Liao P, Vecchione-Koval T, Wolinsky Y, Kruchko C, Barnholtz-Sloan JS. CBTRUS Statistical Report: primary brain and other central nervous system tumors diagnosed in the United States in 2010–2014. Neuro Oncol. 2017;19:v1–v88. doi: 10.1093/neuonc/nox158. PubMed DOI PMC

Birzu C, French P, Caccese M, Cerretti G, Idbaih A, Zagonel V, Lombardi G. Recurrent glioblastoma: from molecular landscape to new treatment perspectives. Cancers. 2020;13:47. doi: 10.3390/cancers13010047. PubMed DOI PMC

Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, 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. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352:987–996. doi: 10.1056/NEJMoa043330. PubMed DOI

Rivera AL, Pelloski CE, Gilbert MR, Colman H, De La Cruz C, Sulman EP, Bekele BN, Aldape KD. MGMT promoter methylation is predictive of response to radiotherapy and prognostic in the absence of adjuvant alkylating chemotherapy for glioblastoma. Neuro Oncol. 2010;12:116–121. doi: 10.1093/neuonc/nop020. PubMed DOI PMC

Hegi ME, Diserens A-C, Gorlia T, Hamou M-F, de Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L, Bromberg JEC, Hau P, Mirimanoff RO, Cairncross JG, Janzer RC, Stupp R. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005;352:997–1003. doi: 10.1056/NEJMoa043331. PubMed DOI

Gilbert MR, Wang M, Aldape KD, Stupp R, Hegi ME, Jaeckle KA, Armstrong TS, Wefel JS, Won M, Blumenthal DT, Mahajan A, Schultz CJ, Erridge S, Baumert B, Hopkins KI, Tzuk-Shina T, Brown PD, Chakravarti A, Curran WJ, Jr, Mehta MP. Dose-dense temozolomide for newly diagnosed glioblastoma: a randomized phase III clinical trial. J Clin Oncol. 2013;31:4085–4091. doi: 10.1200/jco.2013.49.6968. PubMed DOI PMC

Hanif F, Muzaffar K, Perveen K, Malhi SM, Simjee Sh U. Glioblastoma multiforme: a review of its epidemiology and pathogenesis through clinical presentation and treatment. Asian Pac J Cancer Prev. 2017;18:3–9. doi: 10.22034/apjcp.2017.18.1.3. PubMed DOI PMC

Mun EJ, Babiker HM, Weinberg U, Kirson ED, Von Hoff DD. Tumor-treating Fields: a fourth modality in cancer treatment. Clin Cancer Res. 2018;24:266–275. doi: 10.1158/1078-0432.CCR-17-1117. PubMed DOI

Kirson ED, Gurvich Z, Schneiderman R, Dekel E, Itzhaki A, Wasserman Y, Schatzberger R, Palti Y. Disruption of cancer cell replication by alternating electric fields. Cancer Res. 2004;64:3288–3295. doi: 10.1158/0008-5472.CAN-04-0083. PubMed DOI

Voloshin T, Schneiderman RS, Volodin A, Shamir RR, Kaynan N, Zeevi E, Koren L, Klein-Goldberg A, Paz R, Giladi M, Bomzon Z, Weinberg U, Palti Y. Tumor Treating Fields (TTFields) hinder cancer cell motility through regulation of microtubule and actin dynamics. Cancers. 2020;12:3016. doi: 10.3390/cancers12103016. PubMed DOI PMC

Voloshin T, Kaynan N, Davidi S, Porat Y, Shteingauz A, Schneiderman RS, Zeevi E, Munster M, Blat R, Tempel Brami C, Cahal S, Itzhaki A, Giladi M, Kirson ED, Weinberg U, Kinzel A, Palti Y. Tumor-treating fields (TTFields) induce immunogenic cell death resulting in enhanced antitumor efficacy when combined with anti-PD-1 therapy. Cancer Immunol Immunother. 2020;69:1191–1204. doi: 10.1007/s00262-020-02534-7. PubMed DOI PMC

Barsheshet Y, Voloshin T, Brant B, Cohen G, Koren L, Blatt R, Cahal S, Haj Khalil T, Zemer Tov E, Paz R, Klein-Goldberg A, Tempel-Brami C, Jacobovitch S, Volodin A, Kan T, Koltun B, David C, Haber A, Giladi M, Weinberg U, Palti Y. Tumor Treating Fields (TTFields) concomitant with immune checkpoint inhibitors are therapeutically effective in non-small cell lung cancer (NSCLC) in vivo model. Int J Mol Sci. 2022;23:14073. doi: 10.3390/ijms232214073. PubMed DOI PMC

Giladi M, Weinberg U, Schneiderman RS, Porat Y, Munster M, Voloshin T, Blatt R, Cahal S, Itzhaki A, Onn A, Kirson ED, Palti Y. 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. 2014;41(Suppl 6):S35–41. doi: 10.1053/j.seminoncol.2014.09.006. PubMed DOI

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

Voloshin T, Munster M, Blatt R, Shteingauz A, Roberts PC, Schmelz EM, Giladi M, Schneiderman RS, Zeevi E, Porat Y, Bomzon Z, Urman N, Itzhaki A, Cahal S, Kirson ED, Weinberg U, Palti Y. Alternating electric fields (TTFields) in combination with paclitaxel are therapeutically effective against ovarian cancer cells in vitro and in vivo. Int J Cancer. 2016;139:2850–2858. doi: 10.1002/ijc.30406. PubMed DOI PMC

Mumblat H, Martinez-Conde A, Braten O, Munster M, Dor-On E, Schneiderman RS, Porat Y, Voloshin T, Davidi S, Blatt R, Shteingauz A, Tempel Brami C, Zeevi E, Lajterer C, Shmueli Y, Danilov S, Haber A, Giladi M, Weinberg U, Kinzel A, Palti Y. Tumor Treating Fields (TTFields) downregulate the Fanconi Anemia-BRCA pathway and increase the efficacy of chemotherapy in malignant pleural mesothelioma preclinical models. Lung Cancer. 2021;160:99–110. doi: 10.1016/j.lungcan.2021.08.011. PubMed DOI

Kessler AF, Frömbling GE, Gross F, Hahn M, Dzokou W, Ernestus RI, Löhr M, Hagemann C. Effects of tumor treating fields (TTFields) on glioblastoma cells are augmented by mitotic checkpoint inhibition. Cell Death Discov. 2018;4:12. doi: 10.1038/s41420-018-0079-9. PubMed DOI PMC

Toms SA, Kim CY, Nicholas G, Ram Z. 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. 2019;141:467–473. doi: 10.1007/s11060-018-03057-z. PubMed DOI PMC

Ballo MT, Urman N, Lavy-Shahaf G, Grewal J, Bomzon Z, Toms S. Correlation of tumor treating fields dosimetry to survival outcomes in newly diagnosed glioblastoma: a large-scale numerical simulation-based analysis of data from the phase 3 EF-14 randomized trial. Int J Radiat Oncol Biol Phys. 2019;104:1106–1113. doi: 10.1016/j.ijrobp.2019.04.008. PubMed DOI

Moser JC, Salvador E, Deniz K, Swanson K, Tusynski J, Carlson KW, Karanam NK, Patel CB, Story M, Lou E, Hagemann C. The mechanisms of action of Tumor Treating Fields. Cancer Res. 2022 doi: 10.1158/0008-5472.Can-22-0887. PubMed DOI PMC

Chen D, Le SB, Hutchinson TE, Calinescu AA, Sebastian M, Jin D, Liu T, Ghiaseddin A, Rahman M, Tran DD. Tumor Treating Fields dually activate STING and AIM2 inflammasomes to induce adjuvant immunity in glioblastoma. J Clin Invest. 2022;132:e149258. doi: 10.1172/jci149258. PubMed DOI PMC

Lacouture M, Anadkat MJ, Ballo MT, Iwamoto F, Jeyapalan SA, La Rocca RV, Schwartz M, Serventi JN, Glas M. Prevention and management of dermatologic adverse events associated with Tumor Treating Fields in patients with glioblastoma. Front Oncol. 2020;10:1045. doi: 10.3389/fonc.2020.01045. PubMed DOI PMC

Trusheim J, Dunbar E, Battiste J, Iwamoto F, Mohile N, Damek D, Bota DA, Connelly J. A state-of-the-art review and guidelines for tumor treating fields treatment planning and patient follow-up in glioblastoma. CNS Oncol. 2017;6:29–43. doi: 10.2217/cns-2016-0032. PubMed DOI PMC

Glas M, Ballo MT, Bomzon Z, Urman N, Levi S, Lavy-Shahaf G, Jeyapalan S, Sio TT, DeRose PM, Misch M, Taillibert S, Ram Z, Hottinger AF, Easaw J, Kim CY, Mohan S, Stupp R. The impact of Tumor Treating Fields on glioblastoma progression patterns. Int J Radiat Oncol Biol Phys. 2022;112:1269–1278. doi: 10.1016/j.ijrobp.2021.12.152. PubMed DOI

Tierney JF, Stewart LA, Ghersi D, Burdett S, Sydes MR. Practical methods for incorporating summary time-to-event data into meta-analysis. Trials. 2007;8:16. doi: 10.1186/1745-6215-8-16. PubMed DOI PMC

Ballo MT, Qualls KW, Michael LM, Sorenson JM, Baughman B, Karri-Wellikoff S, Pandey M. Determinants of tumor treating field usage in patients with primary glioblastoma: a single institutional experience. Neurooncol Adv. 2022;4:vdac150. doi: 10.1093/noajnl/vdac150. PubMed DOI PMC

Wells G, Shea B, O’Connell D, Peterson j, Welch V, Losos M, Tugwell P (2000) The Newcastle–Ottawa Scale (NOS) for Assessing the Quality of Non-Randomized Studies in Meta-Analysis. https://www.ohri.ca/programs/clinical_epidemiology/oxford.asp. Accessed 13 Mar 2023

Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327:557–560. doi: 10.1136/bmj.327.7414.557. PubMed DOI PMC

West SL, Gartlehner G, Mansfield AJ, Poole C, Tant E, Lenfestey N, Lux LJ, Amoozegar J, Morton SC, Carey TC, Viswanathan M, Lohr KN (2010) AHRQ methods for Effective Health Care. Comparative effectiveness review methods: clinical heterogeneity. Agency for Healthcare Research and Quality (US), Rockville (MD) PubMed

Combescure C, Foucher Y, Jackson D. Meta-analysis of single-arm survival studies: a distribution-free approach for estimating summary survival curves with random effects. Stat Med. 2014;33:2521–2537. doi: 10.1002/sim.6111. PubMed DOI

Vymazal J, Kazda T, Novak T, Slanina P, Sroubek J, Klener J, Hrbac T, Syrucek M, Rulseh AM. Eighteen years’ experience with tumor treating fields in the treatment of newly diagnosed glioblastoma. Front Oncol. 2023;12:1014455. doi: 10.3389/fonc.2022.1014455. PubMed DOI PMC

Chen C, Xu H, Song K, Zhang Y, Zhang J, Wang Y, Sheng X, Chen L, Qin Z. Tumor treating Fields combine with temozolomide for newly diagnosed glioblastoma: a retrospective analysis of chinese patients in a single center. J Clin Med. 2022 doi: 10.3390/jcm11195855. PubMed DOI PMC

Shi W, Blumenthal DT, Oberheim Bush NA, Kebir S, Lukas RV, Muragaki Y, Zhu JJ, Glas M. Global post-marketing safety surveillance of Tumor Treating Fields (TTFields) in patients with high-grade glioma in clinical practice. J Neurooncol. 2020;148:489–500. doi: 10.1007/s11060-020-03540-6. PubMed DOI PMC

Korshoej AR, Lukacova S, Lassen-Ramshad Y, Rahbek C, Severinsen KE, Guldberg TL, Mikic N, Jensen MH, Cortnum SOS, von Oettingen G, Sørensen JCH. OptimalTTF-1: enhancing tumor treating fields therapy with skull remodeling surgery. A clinical phase I trial in adult recurrent glioblastoma. Neurooncol Adv. 2020;2:vdaa121. doi: 10.1093/noajnl/vdaa121. PubMed DOI PMC

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

Vymazal J, Wong ET. Response patterns of recurrent glioblastomas treated with tumor-treating fields. Semin Oncol. 2014;41(Suppl 6):S14–24. doi: 10.1053/j.seminoncol.2014.09.009. PubMed DOI

Olubajo F, Thorpe A, Davis C, Sinha R, Crofton A, Mills SJ, Williams M, Jenkinson MD, Price SJ, Watts C, Brodbelt AR. Tumour treating fields in glioblastoma: is the treatment tolerable, effective, and practical in UK patients? Br J Neurosurg. 2022;36:770–776. doi: 10.1080/02688697.2022.2028722. PubMed DOI

Magouliotis DE, Asprodini EK, Svokos KA, Tasiopoulou VS, Svokos AA, Toms SA. Tumor-treating fields as a fourth treating modality for glioblastoma: a meta-analysis. Acta Neurochir (Wien) 2018;160:1167–1174. doi: 10.1007/s00701-018-3536-6. PubMed DOI

Shah PP, White T, Khalafallah AM, Romo CG, Price C, Mukherjee D. A systematic review of tumor treating fields therapy for high-grade gliomas. J Neurooncol. 2020;148:433–443. doi: 10.1007/s11060-020-03563-z. PubMed DOI

Regev O, Merkin V, Blumenthal DT, Melamed I, Kaisman-Elbaz T. Tumor-treating Fields for the treatment of glioblastoma: a systematic review and meta-analysis. Neurooncol Pract. 2021;8:426–440. doi: 10.1093/nop/npab026. PubMed DOI PMC

Liu Y, Strawderman MS, Warren KT, Richardson M, Serventi JN, Mohile NA, Milano MT, Walter KA. Clinical efficacy of Tumor Treating Fields for newly diagnosed glioblastoma. Anticancer Res. 2020;40:5801–5806. doi: 10.21873/anticanres.14597. PubMed DOI

Krigers A, Pinggera D, Demetz M, Kornberger LM, Kerschbaumer J, Thomé C, Freyschlag CF. The routine application of Tumor-Treating Fields in the treatment of glioblastoma WHO° IV. Front Neurol. 2022;13:900377. doi: 10.3389/fneur.2022.900377. PubMed DOI PMC

Pandey M, Xiu J, Mittal S, Zeng J, Saul M, Kesari S, Azadi A, Newton H, Deniz K, Ladner K, Sumrall A, Korn WM, Lou E. Molecular alterations associated with improved outcome in patients with glioblastoma treated with Tumor-Treating Fields. Neurooncol Adv. 2022;4:vdac096. doi: 10.1093/noajnl/vdac096. PubMed DOI PMC

Nishikawa R, Yamasaki F, Arakawa Y, Muragaki Y, Narita Y, Tanaka S, Yamaguchi S, Mukasa A, Kanamori M. Safety and efficacy of tumour-treating fields (TTFields) therapy for newly diagnosed glioblastoma in japanese patients using the Novo-TTF System: a prospective post-approval study. Jpn J Clin Oncol. 2023 doi: 10.1093/jjco/hyad1001. PubMed DOI PMC

She L, Gong X, Su L, Liu C. Effectiveness and safety of tumor-treating fields therapy for glioblastoma: a single-center study in a chinese cohort. Front Neurol. 2022;13:1042888. doi: 10.3389/fneur.2022.1042888. PubMed DOI PMC