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

S A Toms, C Y Kim, G Nicholas, Z Ram, S A Toms, C Y Kim, G Nicholas, Z Ram

Abstract

Background: Tumor treating fields (TTFields) is a non-invasive, antimitotic therapy. In the EF-14 phase 3 trial in newly diagnosed glioblastoma, TTFields plus temozolomide (TTFields/TMZ) improved progression free (PFS) and overall survival (OS) versus TMZ alone. Previous data indicate a ≥ 75% daily compliance improves outcomes. We analyzed compliance data from TTFields/TMZ patients in the EF-14 study to correlate TTFields compliance with PFS and OS and identify potential lower boundary for compliance with improved clinical outcomes.

Methods: Compliance was assessed by usage data from the NovoTTF-100A device and calculated as percentage per month of TTFields delivery. TTFields/TMZ patients were segregated into subgroups by percent monthly compliance. A Cox proportional hazard model controlled for sex, extent of resection, MGMT methylation status, age, region, and performance status was used to investigate the effect of compliance on PFS and OS.

Results: A threshold value of 50% compliance with TTFields/TMZ improved PFS (HR 0.70, 95% CI 0.47-1.05) and OS (HR 0.67, 95% CI 0.45-0.99) versus TMZ alone with improved outcome as compliance increased. At compliance > 90%, median survival was 24.9 months (28.7 months from diagnosis) and 5-year survival rate was 29.3%. Compliance was independent of gender, extent of resection, MGMT methylation status, age, region and performance status (HR 0.78; p = 0.031; OS at compliance ≥ 75% vs. < 75%).

Conclusion: A compliance threshold of 50% with TTFields/TMZ correlated with significantly improved OS and PFS versus TMZ alone. Patients with compliance > 90% showed extended median and 5-year survival rates. Increased compliance with TTFields therapy is independently prognostic for improved survival in glioblastoma.

Trial registration: ClinicalTrials.gov NCT00916409.

Keywords: Compliance; Glioblastoma; Monthly usage; Tumor treating fields.

Conflict of interest statement

S. A. Toms, C. Y. Kim and G. Nicholas have nothing to disclose. Z. Ram reports a research grant (principal investigator and consultant) with Novocure, Ltd. and ownership interest (stock) in Novocure, Ltd.

Figures

Fig. 1
Fig. 1
Forest plots show the effect of treatment compliance with TTFields plus TMZ on PFS and OS. A threshold value of 50% compliance with TTFields plus TMZ was needed to show a significant extension of OS compared to TMZ alone. Both PFS and OS were extended with treatment compliance levels > 50%. A trend in favor of longer PFS and OS was seen with higher rates of treatment compliance
Fig. 2
Fig. 2
Newly diagnosed GBM patients had maximal treatment benefit from TTFields plus TMZ with compliance rates > 90% with a median overall survival of 24.9 months (28.7 months from diagnosis)
Fig. 3
Fig. 3
The annual survival rate was highest for newly diagnosed GBM patients with compliance rates > 90% with a 29.3% survival rate over 5 years from randomization

References

    1. 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-oncology. 2017;19:v1–v88. doi: 10.1093/neuonc/nox158.
    1. Koshy M, Villano JL, Dolecek TA, Howard A, Mahmood U, Chmura SJ, Weichselbaum RR, McCarthy BJ. Improved survival time trends for glioblastoma using the SEER 17 population-based registries. J Neuro-oncol. 2012;107:207–212. doi: 10.1007/s11060-011-0738-7.
    1. 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.
    1. 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.
    1. Hottinger AF, Pacheco P, Stupp R. Tumor treating fields: a novel treatment modality and its use in brain tumors. Neuro-oncology. 2016;18:1338–1349. doi: 10.1093/neuonc/now182.
    1. 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.
    1. Kirson ED, Dbaly 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. Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors. Proc Natl Acad Sci USA. 2007;104:10152–10157. doi: 10.1073/pnas.0702916104.
    1. Kirson ED, Schneiderman RS, Dbaly V, Tovarys F, Vymazal J, Itzhaki A, Mordechovich D, Gurvich Z, Shmueli E, Goldsher D, Wasserman Y, Palti Y. Chemotherapeutic treatment efficacy and sensitivity are increased by adjuvant alternating electric fields (TTFields) BMC Med Phys. 2009;9:1. doi: 10.1186/1756-6649-9-1.
    1. 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–S41. doi: 10.1053/j.seminoncol.2014.09.006.
    1. Gera N, Yang A, Holtzman TS, Lee SX, Wong ET, Swanson KD. Tumor treating fields perturb the localization of septins and cause aberrant mitotic exit. PLoS ONE. 2015;10:e0125269. doi: 10.1371/journal.pone.0125269.
    1. Silginer M, Weller M, Stupp R, Roth P. Biological activity of tumor-treating fields in preclinical glioma models. Cell Death Dis. 2017;8:e2753. doi: 10.1038/cddis.2017.171.
    1. Porat Y, Shteingauz A, Giladi M, Schneiderman RS, Voloshin T, Munster M, Blat R, Kirson ED, Weinberg U, Palti Y. Abstract 3315: cancer cells upregulate autophagy as a survival mechanism in response to tumor treating fields (TTFields) Cancer Res. 2017;77:3315–3315. doi: 10.1158/1538-7445.AM2017-3315.
    1. Shteingauz A, Porat Y, Voloshin T, Schneiderman RS, Munster M, Zeevi E, Kaynan N, Gotlib K, Giladi M, Kirson ED, Weinberg U, Kinzel A, Palti Y. AMPK-dependent autophagy upregulation serves as a survival mechanism in response to tumor treating fields (TTFields) Cell Death Dis. 2018;9:1074. doi: 10.1038/s41419-018-1085-9.
    1. Karanam NK, Srinivasan K, Ding L, Sishc B, Saha D, Story MD. 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. 2017;8:e2711. doi: 10.1038/cddis.2017.136.
    1. Kim EH, Song HS, Yoo SH, Yoon M. Tumor treating fields inhibit glioblastoma cell migration, invasion and angiogenesis. Oncotarget. 2016;7:65125–65136.
    1. Giladi M, Voloshin T, Shteingauz A, Munster M, Blat R, Porat Y, Schneiderman RS, Cahal S, Itzhaki A, Kirson E, Weinberg U, Palti Y. Alternating electric fields (TTFields) induce immunogenic cell death resulting in enhanced antitumor efficacy when combined with anti-PD-1 therapy. J Immunol. 2016;196:75.26.
    1. 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. Mitotic spindle disruption by alternating electric fields leads to improper chromosome segregation and mitotic catastrophe in cancer cells. Sci Rep. 2015;5:18046. doi: 10.1038/srep18046.
    1. Giladi M, Munster M, Schneiderman RS, Voloshin T, Porat Y, Blat R, Zielinska-Chomej K, Haag P, Bomzon Z, Kirson ED, Weinberg U, Viktorsson K, Lewensohn R, Palti Y. Tumor treating fields (TTFields) delay DNA damage repair following radiation treatment of glioma cells. Radiat Oncol (London) 2017;12:206. doi: 10.1186/s13014-017-0941-6.
    1. Kim EH, Kim YH, Song HS, Jeong YK, Lee JY, Sung J, Yoo SH, Yoon M. Biological effect of an alternating electric field on cell proliferation and synergistic antimitotic effect in combination with ionizing radiation. Oncotarget. 2016;7:62267–62279.
    1. Stupp R, Wong ET, Kanner AA, Steinberg D, Engelhard H, Heidecke V, Kirson ED, Taillibert S, Liebermann F, Dbaly 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. NovoTTF-100A versus physician’s choice chemotherapy in recurrent glioblastoma: a randomised phase III trial of a novel treatment modality. Eur J Cancer (Oxford, England: 1990) 2012;48:2192–2202. doi: 10.1016/j.ejca.2012.04.011.
    1. 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(Suppl 6):S25–S34. doi: 10.1053/j.seminoncol.2014.09.008.
    1. Vymazal J, Wong ET. Response patterns of recurrent glioblastomas treated with tumor-treating fields. Semin Oncol. 2014;41(Suppl 6):S14–S24. doi: 10.1053/j.seminoncol.2014.09.009.
    1. Mrugala MM, Engelhard HH, Dinh Tran D, Kew Y, Cavaliere R, Villano JL, Annenelie Bota D, Rudnick J, Love Sumrall A, Zhu JJ, Butowski N. Clinical practice experience with NovoTTF-100A system for glioblastoma: the patient registry dataset (PRiDe) Semin Oncol. 2014;41(Suppl 6):S4S13.
    1. Stupp R, Taillibert S, Kanner A, et al. 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.
    1. Stupp R, Taillibert S, Kanner AA, Kesari S, Steinberg DM, Toms SA, Taylor LP, Lieberman F, Silvani A, Fink KL, Barnett GH, Zhu JJ, 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. Maintenance therapy with tumor-treating fields plus temozolomide vs temozolomide alone for glioblastoma: a randomized clinical trial. JAMA. 2015;314:2535–2543. doi: 10.1001/jama.2015.16669.
    1. Taphoorn MJB, Dirven L, Kanner AA, Lavy-Shahaf G, Weinberg U, Taillibert S, Toms SA, Honnorat J, Chen TC, Sroubek J, David C, Idbaih A, Easaw JC, Kim CY, Bruna J, Hottinger AF, Kew Y, Roth P, Desai R, Villano JL, Kirson ED, Ram Z, Stupp R. 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. 2018;4:495–504. doi: 10.1001/jamaoncol.2017.5082.
    1. National Comprehensive Cancer Network (NCCN) Guidelines® (2018) Central nervous system cancers (version 1.2018) . Accessed 20th June 2018
    1. Murphy J, Bowers ME, Barron L. Optune(R): practical nursing applications. Clin J Oncol Nurs. 2016;20:S14–S19. doi: 10.1188/16.CJON.S1.14-19.
    1. McCue DA, Lohr LK, Pick AM. Improving adherence to oral cancer therapy in clinical practice. Pharmacotherapy. 2014;34:481–494. doi: 10.1002/phar.1399.
    1. Lacouture ME, Davis ME, Elzinga G, Butowski N, Tran D, Villano JL, DiMeglio L, Davies AM, Wong ET. 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. 2014;41(Suppl 4):S1–S14. doi: 10.1053/j.seminoncol.2014.03.011.
    1. Wang R, Lagakos SW, Ware JH, Hunter DJ, Drazen JM. Statistics in medicine—reporting of subgroup analyses in clinical trials. N Engl J Med. 2007;357:2189–2194. doi: 10.1056/NEJMsr077003.
    1. Liau LM, Ashkan K, Tran DD, Campian JL, Trusheim JE, Cobbs CS, Heth JA, Salacz M, Taylor S, D’Andre SD, Iwamoto FM, Dropcho EJ, Moshel YA, Walter KA, Pillainayagam CP, Aiken R, Chaudhary R, Goldlust SA, Bota DA, Duic P, Grewal J, Elinzano H, Toms SA, Lillehei KO, Mikkelsen T, Walbert T, Abram SR, Brenner AJ, Brem S, Ewend MG, Khagi S, Portnow J, Kim LJ, Loudon WG, Thompson RC, Avigan DE, Fink KL, Geoffroy FJ, Lindhorst S, Lutzky J, Sloan AE, Schackert G, Krex D, Meisel HJ, Wu J, Davis RP, Duma C, Etame AB, Mathieu D, Kesari S, Piccioni D, Westphal M, Baskin DS, New PZ, Lacroix M, May SA, Pluard TJ, Tse V, Green RM, Villano JL, Pearlman M, Petrecca K, Schulder M, Taylor LP, Maida AE, Prins RM, Cloughesy TF, Mulholland P, Bosch ML. First results on survival from a large phase 3 clinical trial of an autologous dendritic cell vaccine in newly diagnosed glioblastoma. J Transl Med. 2018;16:142. doi: 10.1186/s12967-018-1507-6.
    1. Desjardins A, Gromeier M, Herndon JE, 2nd, Beaubier N, Bolognesi DP, Friedman AH, Friedman HS, McSherry F, Muscat AM, Nair S, Peters KB, Randazzo D, Sampson JH, Vlahovic G, Harrison WT, McLendon RE, Ashley D, Bigner DD. Recurrent glioblastoma treated with recombinant poliovirus. N Engl J Med. 2018

Source: PubMed

Sponsorer og samarbeidspartnere

Medisinsk tilstand

Legemiddelintervensjoner

3
Abonnere