Effect of angiotensin system inhibitors on survival in newly diagnosed glioma patients and recurrent glioblastoma patients receiving chemotherapy and/or bevacizumab
- 512 Downloads
Given prior studies that suggest the use of angiotensin system inhibitors (ASIs) is associated with prolonged overall survival (OS) in glioblastoma (GBM) patients, we evaluated the effect of ASIs in glioma patients receiving chemotherapy and/or bevacizumab (BEV). Using retrospective IRB-approved electronic chart review of newly diagnosed WHO grade 2–4 glioma patients from the Kaiser Permanente Tumor Registry of Northern California, we evaluated the impact of ASIs on OS by Cox proportional hazard model analysis for subgroups who received cytotoxic therapy, cytotoxic therapy with BEV, or BEV alone, as well as those with recurrent GBM (rGBM). Of the 1186 glioma patients who received chemotherapy ASI exposure improved OS (HR 0.82; 95% CI 0.71, 0.93; p = 0.003). When stratified by BEV exposure, a sub-analysis revealed further OS advantage for the BEV group (HR 0.75, 95% CI 0.62, 0.90; p = 0.002). In a second cohort of 181 rGBM patients who received BEV in varying dosages, ASI exposure conferred an OS advantage (HR 0.649; 95% CI 0.46, 0.92; p = 0.016). Moreover, patients with ASI exposure who received low-dose BEV treatment (AUCBEV < 3.6 mg wk/kg) had a significantly longer OS (median = 99 weeks; 95% CI 44.3, 205) than those without ASI (median OS = 55.6 weeks; 95% CI 37.7–73.7; p = 0.032). ASI use is associated with longer OS in glioma patients. Further survival advantage with ASI use was observed in rGBM patients receiving low-dose bevacizumab. These data warrant prospective evaluation of adding ASI to low-dose BEV treatment in GBM patients to improve the outcome of standard therapies.
KeywordsAvastin Bevacizumab Drug dose Angiotensin receptor blockers Glioma Glioblastoma Retrospective analysis
Angiotensin converting enzyme
Angiotensin receptor blocker
Angiotensin II receptor 1
Angiotensin system inhibitor
Central nervous system
Newly diagnosed glioblastoma
Non-small-cell lung cancer
Progression free survival
Renal cell carcinoma
Vascular endothelial growth factor
We thank Dr. D. G. Duda for his scientific input. This study was supported, in part, by NIH- P01CA080124 (to R.K.J.) and NIH-F31HL126449 (to M.D.).
No reagents or funding from these companies were used in these studies.
Compliance with ethical standards
Conflict of interest
V.A.L. received consulting fees from Orbus Therapeutics, Inc., Nativis, Inc., and Bristol-Myers Squibb. R.K.J. received consultant fees from Ophthotech, SPARC, SynDevRx and XTuit. R.K.J owns equity in Enlight, SPARC, SynDevRx and XTuit, and serves on the Board of Directors of XTuit and Boards of Trustees of Tekla Healthcare Investors, Tekla Life Sciences Investors, Tekla Healthcare Opportunities Fund and Tekla World Healthcare Fund. R.K.J only had access to de-identified data.
- 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, European Organisation for R, Treatment of Cancer Brain T, Radiotherapy G, National Cancer Institute of Canada Clinical Trials G (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996. doi: 10.1056/NEJMoa043330 CrossRefPubMedGoogle Scholar
- 2.Levin VA, Silver P, Hannigan J, Wara WM, Gutin PH, Davis RL, Wilson CB (1990) Superiority of post-radiotherapy adjuvant chemotherapy with CCNU, procarbazine, and vincristine (PCV) over BCNU for anaplastic gliomas: NCOG 6G61 final report. Int J Radiat Oncol Biol Phys 18:321–324CrossRefPubMedGoogle Scholar
- 3.Lu-Emerson C, Duda DG, Emblem KE, Taylor JW, Gerstner ER, Loeffler JS, Batchelor TT, Jain RK (2015) Lessons from anti–vascular endothelial growth factor and anti–vascular endothelial growth factor receptor trials in patients with glioblastoma. J Clin Oncol. doi: 10.1200/jco.2014.55.9575 PubMedPubMedCentralGoogle Scholar
- 5.Huang Y, Yuan J, Righi E, Kamoun WS, Ancukiewicz M, Nezivar J, Santosuosso M, Martin JD, Martin MR, Vianello F, Leblanc P, Munn LL, Huang P, Duda DG, Fukumura D, Jain RK, Poznansky MC (2012) Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy. Proc Natl Acad Sci USA 109:17561–17566. doi: 10.1073/pnas.1215397109 CrossRefPubMedPubMedCentralGoogle Scholar
- 7.Lorgis V, Maura G, Coppa G, Hassani K, Taillandier L, Chauffert B, Apetoh L, Ladoire S, Ghiringhelli F (2012) Relation between bevacizumab dose intensity and high-grade glioma survival: a retrospective study in two large cohorts. J Neurooncol 107:351–358. doi: 10.1007/s11060-011-0748-5 CrossRefPubMedGoogle Scholar
- 12.Chauhan VP, Martin JD, Liu H, Lacorre DA, Jain SR, Kozin SV, Stylianopoulos T, Mousa AS, Han X, Adstamongkonkul P, Popovic Z, Huang P, Bawendi MG, Boucher Y, Jain RK (2013) Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels. Nat Commun 4:2516. doi: 10.1038/ncomms3516 CrossRefPubMedPubMedCentralGoogle Scholar
- 13.Menter AR, Carroll NM, Sakoda LC, Delate T, Hornbrook MC, Jain RK, Kushi LH, Quinn VP, Ritzwoller DP (2016) Effect of angiotensin system inhibitors on survival in patients receiving chemotherapy for advanced non-small-cell lung cancer. Clin Lung Cancer. doi: 10.1016/j.cllc.2016.07.008 PubMedGoogle Scholar
- 14.Lombardi G, Zustovich F, Farina P, Fiduccia P, Della Puppa A, Polo V, Bertorelle R, Gardiman MP, Banzato A, Ciccarino P, Denaro L, Zagonel V (2013) Hypertension as a biomarker in patients with recurrent glioblastoma treated with antiangiogenic drugs: a single-center experience and a critical review of the literature. Anticancer Drugs 24:90–97. doi: 10.1097/CAD.0b013e32835aa5fd CrossRefPubMedGoogle Scholar
- 16.Lu-Emerson C, Duda DG, Emblem KE, Taylor JW, Gerstner ER, Loeffler JS, Batchelor TT, Jain RK (2015) Lessons from anti-vascular endothelial growth factor and anti-vascular endothelial growth factor receptor trials in patients with glioblastoma. J Clin Oncol 33:1197–1213. doi: 10.1200/JCO.2014.55.9575 CrossRefPubMedPubMedCentralGoogle Scholar
- 17.Liu TT, Achrol AS, Mitchell LA, Rodriguez SA, Feroze A, Kim C, Chaudhary N, Gevaert O, Stuart JM, Harsh GR, Chang SD, Rubin DL, Michael IV (2016) Magnetic resonance perfusion image features uncover an angiogenic subgroup of glioblastoma patients with poor survival and better response to antiangiogenic treatment. Neuro Oncol. doi: 10.1093/neuonc/now270 Google Scholar
- 18.Batchelor TT, Gerstner ER, Emblem KE, Duda DG, Kalpathy-Cramer J, Snuderl M, Ancukiewicz M, Polaskova P, Pinho MC, Jennings D, Plotkin SR, Chi AS, Eichler AF, Dietrich J, Hochberg FH, Lu-Emerson C, Iafrate AJ, Ivy SP, Rosen BR, Loeffler JS, Wen PY, Sorensen AG, Jain RK (2013) Improved tumor oxygenation and survival in glioblastoma patients who show increased blood perfusion after cediranib and chemoradiation. Proc Natl Acad Sci USA 110:19059–19064. doi: 10.1073/pnas.1318022110 CrossRefPubMedPubMedCentralGoogle Scholar
- 20.McKay RR, Rodriguez GE, Lin X, Kaymakcalan MD, Hamnvik OP, Sabbisetti VS, Bhatt RS, Simantov R, Choueiri TK (2015) Angiotensin system inhibitors and survival outcomes in patients with metastatic renal cell carcinoma. Clin Cancer Res 21:2471–2479. doi: 10.1158/1078-0432.CCR-14-2332 CrossRefPubMedPubMedCentralGoogle Scholar
- 22.Murphy JE, Wo JY-L, Ferrone C, Jiang W, Yeap BY, Blaszkowsky LS, Kwak EL, Allen JN, Clark JW, Faris JE, Zhu AX, Goyal L, Mamon HJ, Lillemoe KD, Ryan DP, DeLaney TF, Fernandez-del Castillo C, Boucher Y, Hong TS (2017) TGF-B1 inhibition with losartan in combination with FOLFIRINOX (F-NOX) in locally advanced pancreatic cancer (LAPC): Preliminary feasibility and R0 resection rates from a prospective phase II study. J Clin Oncol 35(suppl 4S):386CrossRefGoogle Scholar
- 25.Arrieta O, Guevara P, Escobar E, Garcia-Navarrete R, Pineda B, Sotelo J (2005) Blockage of angiotensin II type I receptor decreases the synthesis of growth factors and induces apoptosis in C6 cultured cells and C6 rat glioma. Br J Cancer 92:1247–1252. doi: 10.1038/sj.bjc.6602483 CrossRefPubMedPubMedCentralGoogle Scholar