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The role of bevacizumab in the treatment of glioblastoma

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Abstract

Bevacizumab has been used in patients with GBM as a salvage therapy since its approval in the United States for recurrent GBM in 2009. In order to review the therapeutic effect of bevacizumab in the primary and recurrent clinical setting we have performed a systematic analysis of data from the published literature. Weighted median progression free survival and overall survival were calculated and compared to standard therapy or other experimental therapies. A qualitative analysis of the limited studies on health related quality of life and effects on steroid requirements was also undertaken. We found that the available literature supports the use of bevacizumab for prolonging PFS and OS in the recurrent setting either alone or in combination with a cytotoxic agent (P < 0.05), but does not support its use in the primary setting (P > 0.05). The survival advantage of bevacizumab compared to experimental therapy at recurrence is limited to 4 months. There is no additional benefit reported to date in health-related quality of life with the use of bevacizumab, although it may reduce steroid requirements. On average there is one side-effect event per patient and 74% of these events are grade 3 toxicity or higher. Further studies investigating the role of bevacizumab in combination with cytotoxic agents at recurrence are awaited.

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References

  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 (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352(10):987–996. doi:10.1056/NEJMoa043330

    Article  CAS  PubMed  Google Scholar 

  2. Quick J, Gessler F, Dutzmann S, Hattingen E, Harter PN, Weise LM, Franz K, Seifert V, Senft C (2014) Benefit of tumor resection for recurrent glioblastoma. J Neurooncol 117(2):365–372. doi:10.1007/s11060-014-1397-2

    Article  CAS  PubMed  Google Scholar 

  3. Seystahl K, Gramatzki D, Roth P, Weller M (2016) Pharmacotherapies for the treatment of glioblastoma—current evidence and perspectives. Expert Opin Pharmacother 17(9):1259–1270. doi:10.1080/14656566.2016.1176146

    Article  CAS  PubMed  Google Scholar 

  4. Gilbert MR, Dignam JJ, Armstrong TS, Wefel JS, Blumenthal DT, Vogelbaum MA, Colman H, Chakravarti A, Pugh S, Won M, Jeraj R, Brown PD, Jaeckle KA, Schiff D, Stieber VW, Brachman DG, Werner-Wasik M, Tremont-Lukats IW, Sulman EP, Aldape KD, Curran WJ Jr, Mehta MP (2014) A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med 370(8):699–708. doi:10.1056/NEJMoa1308573

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Kreisl TN, Kim L, Moore K, Duic P, Royce C, Stroud I, Garren N, Mackey M, Butman JA, Camphausen K, Park J, Albert PS, Fine HA (2009) Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol 27(5):740–745. doi:10.1200/jco.2008.16.3055

    Article  CAS  PubMed  Google Scholar 

  6. Friedman HS, Prados MD, Wen PY, Mikkelsen T, Schiff D, Abrey LE, Yung WK, Paleologos N, Nicholas MK, Jensen R, Vredenburgh J, Huang J, Zheng M, Cloughesy T (2009) Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol 27(28):4733–4740. doi:10.1200/JCO.2008.19.8721

    Article  CAS  PubMed  Google Scholar 

  7. Chinot OL, Wick W, Mason W, Henriksson R, Saran F, Nishikawa R, Carpentier AF, Hoang-Xuan K, Kavan P, Cernea D, Brandes AA, Hilton M, Abrey L, Cloughesy T (2014) Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med 370(8):709–722. doi:10.1056/NEJMoa1308345

    Article  CAS  PubMed  Google Scholar 

  8. Bengtsson H (2016) matrixStats: functions that apply to rows and Columns of matrices (and to Vectors). R package version 0.51.0 edn

  9. Team RC (2013) R: a language and environment for statistical computing. R Foundation for Statistical Copmuting, Vienna

  10. Vredenburgh JJ, Desjardins A, Kirkpatrick JP, Reardon DA, Peters KB, Herndon JE 2nd, Marcello J, Bailey L, Threatt S, Sampson J, Friedman A, Friedman HS (2012) Addition of bevacizumab to standard radiation therapy and daily temozolomide is associated with minimal toxicity in newly diagnosed glioblastoma multiforme. Int J Radiat Oncol Biol Phys 82(1):58–66. doi:10.1016/j.ijrobp.2010.08.058

    Article  CAS  PubMed  Google Scholar 

  11. Vredenburgh JJ, Desjardins A, Reardon DA, Peters KB, Herndon JE 2nd, Marcello J, Kirkpatrick JP, Sampson JH, Bailey L, Threatt S, Friedman AH, Bigner DD, Friedman HS (2011) The addition of bevacizumab to standard radiation therapy and temozolomide followed by bevacizumab, temozolomide, and irinotecan for newly diagnosed glioblastoma. Clin Cancer Res 17(12):4119–4124. doi:10.1158/1078-0432.CCR-11-0120

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Lai A, Tran A, Nghiemphu PL, Pope WB, Solis OE, Selch M, Filka E, Yong WH, Mischel PS, Liau LM, Phuphanich S, Black K, Peak S, Green RM, Spier CE, Kolevska T, Polikoff J, Fehrenbacher L, Elashoff R, Cloughesy T (2011) Phase II study of bevacizumab plus temozolomide during and after radiation therapy for patients with newly diagnosed glioblastoma multiforme. J Clin Oncol 29(2):142–148. doi:10.1200/JCO.2010.30.2729

    Article  CAS  PubMed  Google Scholar 

  13. Narayana A, Gruber D, Kunnakkat S, Golfinos JG, Parker E, Raza S, Zagzag D, Eagan P, Gruber ML (2012) A clinical trial of bevacizumab, temozolomide, and radiation for newly diagnosed glioblastoma. J Neurosurg 116(2):341–345. doi:10.3171/2011.9.JNS11656

    Article  CAS  PubMed  Google Scholar 

  14. Hainsworth JD, Shih KC, Shepard GC, Tillinghast GW, Brinker BT, Spigel DR (2012) Phase II study of concurrent radiation therapy, temozolomide, and bevacizumab followed by bevacizumab/everolimus as first-line treatment for patients with glioblastoma. Clin Adv Hematol Oncol 10 (4):240–246

    PubMed  Google Scholar 

  15. Hofland KF, Hansen S, Sorensen M, Engelholm S, Schultz HP, Muhic A, Grunnet K, Ask A, Costa JC, Kristiansen C, Thomsen C, Poulsen HS, Lassen U (2014) Neoadjuvant bevacizumab and irinotecan versus bevacizumab and temozolomide followed by concomitant chemoradiotherapy in newly diagnosed glioblastoma multiforme: a randomized phase II study. Acta Oncol 53(7):939–944. doi:10.3109/0284186X.2013.879607

    Article  CAS  PubMed  Google Scholar 

  16. van Linde ME, Verhoeff JJ, Richel DJ, van Furth WR, Reijneveld JC, Verheul HM, Stalpers LJ (2015) Bevacizumab in combination with radiotherapy and temozolomide for patients with newly diagnosed glioblastoma multiforme. Oncologist 20(2):107–108. doi:10.1634/theoncologist.2014-0418

    Article  PubMed  PubMed Central  Google Scholar 

  17. Verhoeff JJ, Lavini C, van Linde ME, Stalpers LJ, Majoie CB, Reijneveld JC, van Furth WR, Richel DJ (2010) Bevacizumab and dose-intense temozolomide in recurrent high-grade glioma. Ann Oncol 21(8):1723–1727. doi:10.1093/annonc/mdp591

    Article  CAS  PubMed  Google Scholar 

  18. Hasselbalch B, Lassen U, Hansen S, Holmberg M, Sorensen M, Kosteljanetz M, Broholm H, Stockhausen MT, Poulsen HS (2010) Cetuximab, bevacizumab, and irinotecan for patients with primary glioblastoma and progression after radiation therapy and temozolomide: a phase II trial. Neuro Oncol 12(5):508–516. doi:10.1093/neuonc/nop063

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Sathornsumetee S, Desjardins A, Vredenburgh JJ, McLendon RE, Marcello J, Herndon JE, Mathe A, Hamilton M, Rich JN, Norfleet JA, Gururangan S, Friedman HS, Reardon DA (2010) Phase II trial of bevacizumab and erlotinib in patients with recurrent malignant glioma. Neuro Oncol 12(12):1300–1310. doi:10.1093/neuonc/noq099

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Desjardins A, Reardon DA, Coan A, Marcello J, Herndon JE 2nd, Bailey L, Peters KB, Friedman HS, Vredenburgh JJ (2012) Bevacizumab and daily temozolomide for recurrent glioblastoma. Cancer 118(5):1302–1312. doi:10.1002/cncr.26381

    Article  CAS  PubMed  Google Scholar 

  21. Reardon DA, Desjardins A, Peters KB, Gururangan S, Sampson JH, McLendon RE, Herndon JE 2nd, Bulusu A, Threatt S, Friedman AH, Vredenburgh JJ, Friedman HS (2012) Phase II study of carboplatin, irinotecan, and bevacizumab for bevacizumab naive, recurrent glioblastoma. J Neurooncol 107(1):155–164. doi:10.1007/s11060-011-0722-2

    Article  CAS  PubMed  Google Scholar 

  22. Moller S, Grunnet K, Hansen S, Schultz H, Holmberg M, Sorensen M, Poulsen HS, Lassen U (2012) A phase II trial with bevacizumab and irinotecan for patients with primary brain tumors and progression after standard therapy. Acta Oncol 51(6):797–804. doi:10.3109/0284186X.2012.681063

    Article  CAS  PubMed  Google Scholar 

  23. Soffietti R, Trevisan E, Bertero L, Cassoni P, Morra I, Fabrini MG, Pasqualetti F, Lolli I, Castiglione A, Ciccone G, Ruda R (2014) Bevacizumab and fotemustine for recurrent glioblastoma: a phase II study of AINO (Italian Association of Neuro-Oncology). J Neurooncol 116(3):533–541. doi:10.1007/s11060-013-1317-x

    Article  CAS  PubMed  Google Scholar 

  24. Lassen U, Sorensen M, Gaziel TB, Hasselbalch B, Poulsen HS (2013) Phase II study of bevacizumab and temsirolimus combination therapy for recurrent glioblastoma multiforme. Anticancer Res 33(4):1657–1660

    CAS  PubMed  Google Scholar 

  25. Lee EQ, Reardon DA, Schiff D, Drappatz J, Muzikansky A, Grimm SA, Norden AD, Nayak L, Beroukhim R, Rinne ML, Chi AS, Batchelor TT, Hempfling K, McCluskey C, Smith KH, Gaffey SC, Wrigley B, Ligon KL, Raizer JJ, Wen PY (2015) Phase II study of panobinostat in combination with bevacizumab for recurrent glioblastoma and anaplastic glioma. Neuro Oncol 17(6):862–867. doi:10.1093/neuonc/nou350

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Taal W, Oosterkamp HM, Walenkamp AM, Dubbink HJ, Beerepoot LV, Hanse MC, Buter J, Honkoop AH, Boerman D, de Vos FY, Dinjens WN, Enting RH, Taphoorn MJ, van den Berkmortel FW, Jansen RL, Brandsma D, Bromberg JE, van Heuvel I, Vernhout RM, van der Holt B, van den Bent MJ (2014) Single-agent bevacizumab or lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOB trial): a randomised controlled phase 2 trial. Lancet Oncol 15(9):943–953. doi:10.1016/S1470-2045(14)70314-6

    Article  CAS  PubMed  Google Scholar 

  27. Odia Y, Iwamoto FM, Moustakas A, Fraum TJ, Salgado CA, Li A, Kreisl TN, Sul J, Butman JA, Fine HA (2016) A phase II trial of enzastaurin (LY317615) in combination with bevacizumab in adults with recurrent malignant gliomas. J Neurooncol 127(1):127–135. doi:10.1007/s11060-015-2020-x

    Article  CAS  PubMed  Google Scholar 

  28. Fadul CE, Kingman LS, Meyer LP, Cole BF, Eskey CJ, Rhodes CH, Roberts DW, Newton HB, Pipas JM (2008) A phase II study of thalidomide and irinotecan for treatment of glioblastoma multiforme. J Neurooncol 90(2):229–235. doi:10.1007/s11060-008-9655-9

    Article  CAS  PubMed  Google Scholar 

  29. Weller M, Tabatabai G, Kastner B, Felsberg J, Steinbach JP, Wick A, Schnell O, Hau P, Herrlinger U, Sabel MC, Wirsching HG, Ketter R, Bahr O, Platten M, Tonn JC, Schlegel U, Marosi C, Goldbrunner R, Stupp R, Homicsko K, Pichler J, Nikkhah G, Meixensberger J, Vajkoczy P, Kollias S, Husing J, Reifenberger G, Wick W, Group DS (2015) MGMT promoter methylation is a strong prognostic biomarker for benefit from dose-intensified temozolomide rechallenge in progressive glioblastoma: the director trial. Clin Cancer Res 21(9):2057–2064. doi:10.1158/1078-0432.CCR-14-2737

    Article  CAS  PubMed  Google Scholar 

  30. 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. New Engl J Med 352 (10):987–996. doi:10.1056/NEJMoa043330

    Article  CAS  PubMed  Google Scholar 

  31. Malmstrom A, Gronberg BH, Marosi C, Stupp R, Frappaz D, Schultz H, Abacioglu U, Tavelin B, Lhermitte B, Hegi ME, Rosell J, Henriksson R, Nordic Clinical Brain Tumour Study G (2012) Temozolomide versus standard 6-week radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: the Nordic randomised, phase 3 trial. Lancet Oncol 13(9):916–926. doi:10.1016/S1470-2045(12)70265-6

    Article  PubMed  Google Scholar 

  32. 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 (2013) Dose-dense temozolomide for newly diagnosed glioblastoma: a randomized phase III clinical trial. J Clin Oncol 31(32):4085–4091. doi:10.1200/JCO.2013.49.6968

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Rosenthal MA, Gruber ML, Glass J, Nirenberg A, Finlay J, Hochster H, Muggia FM (2000) Phase II study of combination taxol and estramustine phosphate in the treatment of recurrent glioblastoma multiforme. J Neurooncol 47(1):59–63

    Article  CAS  PubMed  Google Scholar 

  34. See SJ, Levin VA, Yung WK, Hess KR, Groves MD (2004) 13-cis-retinoic acid in the treatment of recurrent glioblastoma multiforme. Neuro Oncol 6(3):253–258. doi:10.1215/S1152851703000607

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Groves MD, Puduvalli VK, Chang SM, Conrad CA, Gilbert MR, Tremont-Lukats IW, Liu TJ, Peterson P, Schiff D, Cloughesy TF, Wen PY, Greenberg H, Abrey LE, DeAngelis LM, Hess KR, Lamborn KR, Prados MD, Yung WK (2007) A North American brain tumor consortium (NABTC 99-04) phase II trial of temozolomide plus thalidomide for recurrent glioblastoma multiforme. J Neurooncol 81(3):271–277. doi:10.1007/s11060-006-9225-y

    Article  CAS  PubMed  Google Scholar 

  36. Puduvalli VK, Giglio P, Groves MD, Hess KR, Gilbert MR, Mahankali S, Jackson EF, Levin VA, Conrad CA, Hsu SH, Colman H, de Groot JF, Ritterhouse MG, Ictech SE, Yung WK (2008) Phase II trial of irinotecan and thalidomide in adults with recurrent glioblastoma multiforme. Neuro Oncol 10(2):216–222. doi:10.1215/15228517-2007-060

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Wick W, Gorlia T, Bendszus M, Sahm F, Taal W, Taphoorn M, Domont J, Idbaih A, Campone M, Clement PM, Stupp R, Fabbro M, Le Rhun E, Dubois F, Klein M, Platten M, Weller M, Golfinopoulos V, Van Den Bent MJ (2016) EORTC 26101 phase III trial exploring the combination of bevacizumab and lomustine in patients with first progression of a glioblastoma. J Clin Oncol 34 (suppl; abstr 2001)

  38. Taphoorn MJ, Henriksson R, Bottomley A, Cloughesy T, Wick W, Mason WP, Saran F, Nishikawa R, Hilton M, Theodore-Oklota C, Ravelo A, Chinot OL (2015) Health-related quality of life in a randomized phase III study of bevacizumab, temozolomide, and radiotherapy in newly diagnosed glioblastoma. J Clin Oncol 33(19):2166–2175. doi:10.1200/JCO.2014.60.3217

    Article  CAS  PubMed  Google Scholar 

  39. Herrlinger U, Schafer N, Steinbach JP, Weyerbrock A, Hau P, Goldbrunner R, Friedrich F, Rohde V, Ringel F, Schlegel U, Sabel M, Ronellenfitsch MW, Uhl M, Maciaczyk J, Grau S, Schnell O, Hanel M, Krex D, Vajkoczy P, Gerlach R, Kortmann RD, Mehdorn M, Tuttenberg J, Mayer-Steinacker R, Fietkau R, Brehmer S, Mack F, Stuplich M, Kebir S, Kohnen R, Dunkl E, Leutgeb B, Proescholdt M, Pietsch T, Urbach H, Belka C, Stummer W, Glas M (2016) Bevacizumab plus irinotecan versus temozolomide in newly diagnosed o6-Methylguanine-DNA methyltransferase nonmethylated glioblastoma: the randomized glarius trial. J Clin Oncol 34(14):1611–1619. doi:10.1200/JCO.2015.63.4691

    Article  CAS  PubMed  Google Scholar 

  40. Dirven L, van den Bent MJ, Bottomley A, van der Meer N, van der Holt B, Vos MJ, Walenkamp AM, Beerepoot LV, Hanse MC, Reijneveld JC, Otten A, de Vos FY, Smits M, Bromberg JE, Taal W, Taphoorn MJ, Dutch Neuro-Oncology G (2015) The impact of bevacizumab on health-related quality of life in patients treated for recurrent glioblastoma: results of the randomised controlled phase 2 BELOB trial. Eur J Cancer 51(10):1321–1330. doi:10.1016/j.ejca.2015.03.025

    Article  CAS  PubMed  Google Scholar 

  41. Zang J, Xiang C, He J (2013) Synthesis of median survival time in meta-analysis. Epidemiology 24(2):337–338. doi:10.1097/EDE.0b013e318282a66c

    Article  PubMed  Google Scholar 

  42. Brandes AA, Mason W, Pichler J, Nowak AK, Gil M, Saran F, Revil C, Lutiger B, Carpentier AF (2014) Can bevacizumab prolong survival for glioblastoma patients through multiple lines of therapy? Future Oncol 10(7):1137–1145. doi:10.2217/fon.14.75

    Article  CAS  PubMed  Google Scholar 

  43. Gu B, Gao W, Chu H, Gao J, Fu Z, Ding H, Lv J, Wu Q (2016) Adverse events risk associated with anti-VEGFR agents in the treatment of advanced nonsmall-cell lung cancer: a meta-analysis. Medicine (Baltimore) 95(48):e3752. doi:10.1097/MD.0000000000003752

    Article  CAS  Google Scholar 

  44. Lai XX, Xu RA, Yu-Ping L, Yang H (2016) Risk of adverse events with bevacizumab addition to therapy in advanced non-small-cell lung cancer: a meta-analysis of randomized controlled trials. OncoTargets Ther 9:2421–2428. doi:10.2147/OTT.S96156

    Article  Google Scholar 

  45. Nagpal S, Harsh G, Recht L (2011) Bevacizumab improves quality of life in patients with recurrent glioblastoma. Chemother Res Pract 2011:602812. doi:10.1155/2011/602812

    PubMed  PubMed Central  Google Scholar 

  46. Nghiemphu PL, Liu W, Lee Y, Than T, Graham C, Lai A, Green RM, Pope WB, Liau LM, Mischel PS, Nelson SF, Elashoff R, Cloughesy TF (2009) Bevacizumab and chemotherapy for recurrent glioblastoma: a single-institution experience. Neurology 72(14):1217–1222. doi:10.1212/01.wnl.0000345668.03039.90

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Diaz, R.J., Ali, S., Qadir, M.G. et al. The role of bevacizumab in the treatment of glioblastoma. J Neurooncol 133, 455–467 (2017). https://doi.org/10.1007/s11060-017-2477-x

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