Do statins, ACE inhibitors or sartans improve outcome in primary glioblastoma?

Abstract

Glioblastomas are malignant brain tumors with poor prognosis. Lately, data from clinical studies assessing the role of co-medications in different cancer types suggested reduced mortality and potential anti-tumor activity for statins, angiotensin-I converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (sartans). Here, we analysed the association of co-treatment with statins, ACEI or sartans with outcome in a cohort of 810 patients enrolled in the phase III CENTRIC and phase II CORE trials on the role of the integrin antagonist, cilengitide, in newly diagnosed glioblastoma with or without O6-methylguanine DNA methyltransferase (MGMT) promoter methylation. Progression-free survival (PFS) and overall survival (OS) were analysed for each medication in the pooled patient group. No association was found for co-medication with either drug for PFS or OS. Median OS was 22.1 (statins) versus 22.2 (control) months (HR 1.06, 95% CI 0.81–1.39, p = 0.69), 20.4 (ACEI) versus 22.6 (control) months (HR 1.25, 95% CI 0.96–1.62, p = 0.10), and 21.7 (sartans) versus 22.3 (control) months (HR 0.86, 95% CI 0.61–1.21, p = 0.38). None of the comparisons showed a signal for different PFS or OS when analyses were controlled for MGMT promoter methylation or treatment group (TMZ/RT → TMZ vs. RT + CIL + TMZ → TMZ + CIL). This secondary analysis of two large glioblastoma trials thus was unable to detect evidence for an association of the use of statins, ACEI or sartans with outcome in patients with newly diagnosed glioblastoma. These data challenge the rationale for prospective studies on the possible role of these non-tumor-specific drugs within the concept of drug repurposing.

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Acknowledgements

The authors thank the EORTC Cancer Research Fund (ECRF) for providing the data of the CENTRIC study.

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Correspondence to Caroline Happold.

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Conflict of interest

CHa has received honoraria for advisory board participation from MSD. CHi is employee of Merck KGaA. DAR has received lab support from Acerta, Agenus, Celldex, EMD Serono, Acerta, Inovio, Midatech and Tragara, and honoraria for lectures or advisory board from Abbvie, Agenus, Amgen, Bristol Myers Squibb, Cavion, Celldex, EMD Serono, Genentech/Roche, Juno Pharmaceuticals, Merck, Midatech, Inovio, Momenta Pharmaceuticals, Novartis, Novocure, Oxigene, Regeneron, Stemline Therapeutics. RS has received honoraria for advisory board participation and consulting from Roche, Merck KGaA, MSD, Merck, Pfizer, Ipsen, Novartis and AbbVie. MW has received research grants from Acceleron, Actelion, Bayer, Isarna, Merck, Sharp & Dohme, Merck (EMD, Darmstadt), Novocure, OGD2, Piqur and Roche and honoraria for lectures or advisory board participation or consulting from Abbvie, BMS, Celldex, Immunocellular Therapeutics, Magforce, Merck, Sharp & Dohme, Merck (EMD, Darmstadt), Novocure, Pfizer, Roche, Teva and Tocagen.​ TG, LBN, SCE, and MP declare no conflict of interest.

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11060_2018_2786_MOESM1_ESM.pdf

Supplementary Figure 1 Prognostic significance of continued use (defined as captured medication intake at study baseline and at first visit after completion of radiochemotherapy) of statins (A,B), ACEI (C,D) or sartans (E,F) for PFS (A,C,E) and OS (B,D,F) (PDF 55 KB)

11060_2018_2786_MOESM2_ESM.pdf

Supplementary Figure 2 Prognostic significance of baseline use of statins vs. no statins in the patient cohort with documented hyperlipidemia only (A), or of ACEI and sartans vs. none of these drugs in the patient cohort with documented hypertension only (B) (PDF 44 KB)

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Happold, C., Gorlia, T., Nabors, L.B. et al. Do statins, ACE inhibitors or sartans improve outcome in primary glioblastoma?. J Neurooncol 138, 163–171 (2018). https://doi.org/10.1007/s11060-018-2786-8

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Keywords

  • Glioblastoma
  • Statins
  • ACEI
  • Sartans
  • Survival