Journal of Neuro-Oncology

, Volume 135, Issue 1, pp 99–105 | Cite as

Optimizing bevacizumab dosing in glioblastoma: less is more

  • Abdulrazag Ajlan
  • Piia Thomas
  • Abdulrahman Albakr
  • Seema Nagpal
  • Lawrence Recht
Clinical Study

Abstract

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.

Keywords

Glioblastoma Bevacizumab dose Adverse events Outcomes 

Notes

Authors’ contribution

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.

Ethical approval

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.

Supplementary material

11060_2017_2553_MOESM1_ESM.docx (24 kb)
Supplementary material 1 (DOCX 23 KB)
11060_2017_2553_MOESM2_ESM.docx (24 kb)
Supplementary material 2 (DOCX 23 KB)
11060_2017_2553_MOESM3_ESM.png (469 kb)
Supplementary material 3—50-year-old male who presented with seizures. All magnetic resonance imaging (MRI) are axial T1 with gadolinium. (A) MRI showed left frontal enhancing lesion. The patient underwent left frontal craniotomy and gross total resection of the enhancing portion. The pathology reveled glioblastoma WHO grade IV. (B) Post.operative (Post.op) MRI showing the resection cavity. He received standard 6 weeks of radiation and daily Temozolomide followed by monthly Temozolomide. (C) His follow-up MRI, 5 months following surgery, showed new enhancement concerning for tumor progression. He underwent another surgical resection. The pathology showed tumor progression. (D) Post.op MRI showing the second resection. He was started on Lomustine (CCNU). (E) Follow-up MRI, 2 months following surgery, showed evidence of second progression. At that point, Bevacizumab (BEV) was added at 7.5 mg/kg every 2 weeks (3.25 mg/kg/week). (F) Two months follow-up MRI after BEV initiation showed decrease in the enhancement. The patient’s seizures were controlled and he had a KPS of 90. At that point, BEV dose was reduced to 7.5 mg/kg every 3 weeks (2.5 mg/kg/week). (G) Five months follow-up MRI after BEV initiation. At that point he was clinically stable. (H) Eight months follow-up MRI after BEV initiation showed progression. At that point, he was symptomatic and severely impaired. The patient elected to proceed with palliation and therefore all treatments were held. He deceased 2 months after starting hospice care. He survived 18 months after his first surgical resection. (PNG 469 KB)
11060_2017_2553_MOESM4_ESM.png (956 kb)
Supplementary material 4—60-year-old woman who presented to us with headache and dysphasia. (A) Magnetic resonance imaging (MRI) showed left temporal enhancing lesion. She underwent left temporal craniotomy and gross total resection of the enhancing portion. The pathology reveled glioblastoma WHO grade IV. (B) Post.operative MRI showing the resection cavity. She received chemoradiation followed by monthly Temozolomide. (C) Two months follow-up MRI showed new enhancement. No change in treatment was done at that point. (D) Follow-up MRI, 4 months following chemoradiation surgery, showed progression of the enhancement. Bevacizumab (BEV) was added to the treatment at the dose 5 mg/kg every 3 weeks (1.67 mg/kg/week). (E) Follow-up MRI, 2 months following initiation of BEV, showed reduction of the enhancement and the surrounding T2 changes. (F) Follow-up MRI, 4 months on BEV, showed reduction of surrounding T2 changes. At that point BEV was reduced to 5 mg/kg every 4 weeks (1.25 mg/kg/week). (G) Follow-up MRI, 9 months following BEV initiation, showed stable enhancement. At that time, her BEV was stopped and she completed 7 cycles of Temozolomide. (H) Follow-up MRI, 7 months after stopping BEV, showed increased enhancement and surrounding T2 changes. She was having more headaches. BEV was restarted at 5 mg/kg every 2 weeks (2.5 mg/kg/week). Her follow-up MRIs showed reduction of the enhancing lesion. The BEV dose was reduced to 5 mg/kg every 3 weeks, then to 5mg/kg every 4 weeks (1.25 mg/kg/week). (I) Her last follow-up MRI, 6 months after restarting BEV, showed stable response. At that point, she was clinically stable. (PNG 956 KB)

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Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  1. 1.Department of NeurosurgeryStanford University School of MedicineStanfordUSA
  2. 2.Department of NeurologyStanford University School of MedicineStanfordUSA
  3. 3.Department of NeurosurgeryKing Saud UniversityRiyadhSaudi Arabia

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