Optimizing bevacizumab dosing in glioblastoma: less is more
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Compared to traditional chemotherapies, where dose limiting toxicities represent the maximum possible dose, monoclonal antibody therapies are used at doses well below maximum tolerated dose. However, there has been little effort to ascertain whether there is a submaximal dose at which the efficacy/complication ratio is maximized. Thus, despite the general practice of using Bevacizumab (BEV) at dosages of 10 mg/kg every other week for glioma patients, there has not been much prior work examining whether the relatively high complication rates reported with this agent can be decreased by lowering the dose without impairing efficacy. We assessed charts from 80 patients who received BEV for glioblastoma to survey the incidence of complications relative to BEV dose. All patients were treated with standard upfront chemoradiation. The toxicity was graded based on the NCI CTCAE, version 4.03. The rate of BEV serious related adverse events was 12.5% (n = 10/80). There were no serious adverse events (≥grade 3) when the administered dose was (<3 mg/kg/week), compared to a 21% incidence in those who received higher doses (≥3 mg/kg/week) (P < 0.01). Importantly, the three patient deaths attributable to BEV administration occurred in patients receiving higher doses. Patients who received lower doses also had a better survival rate, although this did not reach statistical significance [median OS 39 for low dose group vs. 17.3 for high dose group (P = 0.07)]. Lower rates of serious BEV related toxicities are noted when lower dosages are used without diminishing positive clinical impact. Further work aimed at optimizing BEV dosage is justified.
KeywordsGlioblastoma Bevacizumab dose Adverse events Outcomes
All listed authors contributed to the study design, data analysis, and writing the manuscript. In addition, AA and PT did the data collection.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
This article does not contain any studies with human participants performed by any of the authors. Our study protocol was approved by the institutional review board (IRB:6208;8) for retrospective analysis.
- 1.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 CrossRefPubMedGoogle Scholar
- 2.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 CrossRefPubMedGoogle Scholar
- 3.Vredenburgh JJ, Desjardins A, Herndon JE 2nd, Marcello J, Reardon DA, Quinn JA, Rich JN, Sathornsumetee S, Gururangan S, Sampson J, Wagner M, Bailey L, Bigner DD, Friedman AH, Friedman HS (2007) Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J Clin Oncol 25(30):4722–4729. doi: 10.1200/JCO.2007.12.2440 CrossRefPubMedGoogle Scholar
- 5.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 CrossRefPubMedGoogle Scholar
- 6.Dowlati A, Robertson K, Radivoyevitch T, Waas J, Ziats NP, Hartman P, Abdul-Karim FW, Wasman JK, Jesberger J, Lewin J, McCrae K, Ivy P, Remick SC (2005) Novel Phase I dose de-escalation design trial to determine the biological modulatory dose of the antiangiogenic agent SU5416. Clin Cancer Res 11(21):7938–7944. doi: 10.1158/1078-0432.CCR-04-2538 CrossRefPubMedGoogle Scholar
- 9.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 CrossRefPubMedPubMedCentralGoogle Scholar
- 10.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 CrossRefPubMedGoogle Scholar
- 14.Stark-Vance V (2005) Bevacizumab and CPT-11 in the treatment of relapsed malignant glioma. Neuro-Oncology 7(3):369–369Google Scholar
- 16.Vredenburgh JJ, Desjardins A, Herndon JE 2nd, Dowell JM, Reardon DA, Quinn JA, Rich JN, Sathornsumetee S, Gururangan S, Wagner M, Bigner DD, Friedman AH, Friedman HS (2007) Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma. Clin Cancer Res 13(4):1253–1259. doi: 10.1158/1078-0432.CCR-06-2309 CrossRefPubMedGoogle Scholar
- 19.Raizer JJ, Grimm S, Chamberlain MC, Nicholas MK, Chandler JP, Muro K, Dubner S, Rademaker AW, Renfrow J, Bredel M (2010) A phase 2 trial of single-agent bevacizumab given in an every-3-week schedule for patients with recurrent high-grade gliomas. Cancer 116(22):5297–5305. doi: 10.1002/cncr.25462 CrossRefPubMedGoogle Scholar
- 24.Reck M, von Pawel J, Zatloukal P, Ramlau R, Gorbounova V, Hirsh V, Leighl N, Mezger J, Archer V, Moore N, Manegold C (2009) Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil. J Clin Oncol 27(8):1227–1234. doi: 10.1200/JCO.2007.14.5466 CrossRefPubMedGoogle Scholar
- 25.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 Neuro-Oncol 107(2):351–358. doi: 10.1007/s11060-011-0748-5 CrossRefGoogle Scholar
- 27.Keunen O, Johansson M, Oudin A, Sanzey M, Rahim SAA, Fack F, Thorsen F, Taxt T, Bartos M, Jirik R, Miletic H, Wang JA, Stieber D, Stuhr L, Moen I, Rygh CB, Bjerkvig R, Niclou SP (2011) Anti-VEGF treatment reduces blood supply and increases tumor cell invasion in glioblastoma. Proc Natl Acad Sci USA 108(9):3749–3754. doi: 10.1073/pnas.1014480108 CrossRefPubMedPubMedCentralGoogle Scholar
- 29.Bag AK, Kim H, Gao Y, Bolding M, Warren PP, Fathallah-Shaykh HM, Gurler D, Markert JM, Fiveash J, Beasley TM, Khawaja A, Friedman GK, Chapman PR, Nabors LB, Han XS (2015) Prolonged treatment with bevacizumab is associated with brain atrophy: a pilot study in patients with high-grade gliomas. J Neuro-Oncol 122(3):585–593. doi: 10.1007/s11060-015-1751-z CrossRefGoogle Scholar