- Department of Neurosurgery, University of Tsukuba, Tsukuba, Ibaraki, Japan.
Masahide Matsuda, Department of Neurosurgery, University of Tsukuba, Tsukuba, Ibaraki, Japan.
DOI:10.25259/SNI_959_2022Copyright: © 2022 Surgical Neurology International This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-Share Alike 4.0 License, which allows others to remix, transform, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.
How to cite this article: Masahide Matsuda, Hidehiro Kohzuki, Takao Tsurubuchi, Eiichi Ishikawa. Timing of bevacizumab administration after biopsy for unresectable newly diagnosed glioblastoma. 16-Dec-2022;13:583
How to cite this URL: Masahide Matsuda, Hidehiro Kohzuki, Takao Tsurubuchi, Eiichi Ishikawa. Timing of bevacizumab administration after biopsy for unresectable newly diagnosed glioblastoma. 16-Dec-2022;13:583. Available from: https://surgicalneurologyint.com/surgicalint-articles/12058/
Background: Recent studies have revealed that bevacizumab (BEV) can improve the survival of patients with newly diagnosed unresectable glioblastoma (GBM) with poor performance status. For patients who develop early clinical deterioration, early initiation of BEV would be beneficial. However, the safety and feasibility of early initiation of BEV remain to be determined because of the lack of studies addressing adverse events associated with BEV initiation
Methods: Thirty-one consecutive patients with newly diagnosed GBM who underwent biopsy followed by BEV administration were investigated. The relationships between the timing of BEV administration and treatment response, survival outcome, and adverse events were analyzed.
Results: Response rates based on the RANO criteria and overall survival times were similar between the early and standard BEV groups. No wound dehiscence was observed in the early BEV group, and only one case was observed in the standard BEV group. Patients in the early BEV group were more likely to have undergone biopsy with a smaller skin incision than those in the standard BEV group. Equivalent treatment effects of BEV were achieved in patients who developed early clinical deterioration and those without clinical deterioration.
Conclusion: Early BEV administration is effective in controlling early clinical deterioration and does not increase the risk of wound-healing complications. Further studies with larger numbers of patients are needed to validate our results.
Keywords: Bevacizumab, Biopsy, Newly diagnosed glioblastoma, Timing, Wound complication
Several randomized and clinical trials have demonstrated that the addition of bevacizumab (BEV), a humanized monoclonal antibody that inhibits vascular endothelial growth factor (VEGF) signaling, to standard chemoradiotherapy improves progression-free survival but not overall survival (OS) in patients with newly diagnosed glioblastoma (GBM).[
The manufacturer’s recommendation states that BEV should not be initiated for at least 28 days following major surgery because of the risk of wound-healing complications.[
We investigated 31 consecutive patients with newly diagnosed GBM who underwent biopsy followed by BEV administration at the University of Tsukuba Hospital between December 2014 and December 2019. The surgical procedures for tumor biopsy included open biopsy via small craniotomy, endoscopic biopsy, and stereotactic needle biopsy; the most suitable method was chosen based on tumor characteristics, such as location and vascularity. Endoscopic and stereotactic needle biopsies were performed through a burr hole with a minimal skin incision. Open biopsy through small craniotomy required a large incision with a linear or curved shape, especially in cases of forehead craniotomy, and a larger skin incision was needed from a cosmetic point of view.
All patients received concurrent radiotherapy and temozolomide after the histopathological diagnosis of GBM was confirmed by biopsy. Patients with GBM treated at our institute received one of two postoperative chemoradiotherapy protocols. In the conventional protocol, a total dose of 60.0 Gy was administered in daily fractions of 2.0 Gy 5 times/week concomitant with 75 mg/m2 temozolomide daily. For elderly patients with a low Karnofsky Performance Status (KPS) score, the elderly protocol was generally administered, in which a total radiation dose of 45.0 Gy was administered in daily fractions of 3.0 Gy 5 times/ week concomitant with 50 mg/m2 temozolomide daily.
All patients received BEV at a dose of 10 mg/kg intravenously every other week. BEV was initiated on or after 28 ± 1 days following biopsy for patients without clinical deterioration (standard BEV group), whereas for patients showing early clinical deterioration, BEV was initiated <27 days after biopsy (early BEV group). Treatment response was assessed according to the Response Assessment in Neuro-Oncology (RANO) criteria. The study protocol was approved by the ethics committee of the University of Tsukuba Hospital (number R01-202).
Statistical analyses were performed using SPSS, version 26 (SPSS, Inc.). The primary outcome to investigate the prognostic value of the timing of BEV administration was OS, which was defined as the time from surgery to death. Survival probabilities were calculated using the Kaplan– Meier method, and differences among patient groups were evaluated using the log-rank test. Differences in normally distributed continuous variables were analyzed using Student’s t-test, and differences in non-normally distributed continuous variables were analyzed using the Mann– Whitney U test. Differences in categorical variables were evaluated using Fisher’s exact test or the Chi-square test. Statistical significance was set at P < 0.05.
The characteristics of the 31 patients are shown in
Eighteen (58.1%) patients received BEV on or after 28 ± 1 days following biopsy (standard BEV group), and 13 (41.9%) received BEV <27 days after biopsy (early BEV group). The clinical and treatment characteristics of patients in the early and standard BEV groups are summarized in
According to the RANO criteria, the response rates were similar in both treatment groups: In the early BEV group, 5 patients (38.5%) had partial response (PR), 6 (46.2%) had stable disease (SD), and 2 (15.4%) had progressive disease (PD), whereas in the standard BEV group, 5 patients (27.8%) had PR, 11 (61.1%) had SD, and 2 (11.1%) had PD. The median OS for all patients was 10.3 months (95% confidence interval [CI], 9.3–11.2). The results of the analysis based on the Kaplan–Meier method are shown in
Adverse events that fulfilled the criteria for Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or higher toxicities related to the administration of BEV are summarized in
A 50-year-old man was referred to our hospital because of a suspected brain tumor. Magnetic resonance imaging (MRI) revealed a heterogeneously enhancing mass in the corpus callosum [
Axial T1-weighted images with gadolinium (a) Preoperative magnetic resonance imaging (MRI). MRI demonstrated a heterogeneously enhancing tumor located in the corpus callosum. (b) MRI the day after the biopsy surgery MRI showed mild enlargement of the heterogeneously enhancing tumor. (c) MRI 11 days after initial administration of bevacizumab MRI showed shrinkage of the heterogeneously enhancing tumor.
In the present study, we retrospectively analyzed the timing of BEV administration in patients with newly diagnosed GBM who underwent biopsy to assess the risks and benefits of early BEV administration. No increase in wound-healing complications was observed in patients who received BEV 13–23 days after biopsy (early BEV group) compared to those who received BEV more than 26 days after biopsy (standard BEV group). In addition, equivalent treatment effects were achieved in patients who developed early clinical deterioration and those without clinical deterioration, suggesting the effectiveness of early BEV initiation in controlling early clinical deterioration.
To date, the utility of adding BEV to standard chemoradiotherapy in patients with newly diagnosed GBM remains to be demonstrated, as represented by the lack of OS prolongation in two large, randomized, and clinical trials.[
Because VEGF plays a crucial role in wound healing and tumor angiogenesis, its inhibition by BEV has the potential to affect the healing of surgical wounds. The incidences of wound complications at the craniotomy site in patients with newly diagnosed GBM or recurrent GBM were 1.5–6.9% and 4–6%, respectively, when BEV was initiated after surgery in prospective clinical trials.[
Notably, the incidence of wound complications did not increase in patients who received early BEV administration.
Regarding the timing of BEV initiation after surgery, the drug manufacturer recommends postponing administration of BEV for at least 28 days following surgery.[
In the present study, the sizes of the surgical wound were different between the early and standard BEV groups, although the difference was not statistically significant. Notably, patients in the early BEV group were more likely to undergo surgery with a small skin incision. This may reflect a preoperative premonition based on tumor characteristics of the urgent need of early BEV initiation due to early clinical deterioration. In a previous review article, Bose et al. proposed different timings of BEV initiation based on the type of preceding surgery.[
The present study has several limitations. First, due to its retrospective nature and potential bias in the sample, the rate of complications may be slightly underestimated. Second, this study also involved a relatively small sample size, which limit the generalizability of the findings. Although these limitations should be recognized and considered, the present findings offer useful insights into the efficacy of early BEV initiation for controlling early clinical deterioration. Further investigations with a larger number of patients are required to validate the utility of early BEV initiation.
We demonstrated that early BEV administration (13– 23 days after surgery) does not increase the risk of wound-healing complications when the wound condition is good. Initiation of BEV at least 14 days after surgery can be tolerated by patients who develop early clinical deterioration to accomplish the initial chemoradiotherapy and continue subsequent maintenance chemotherapy. Further studies with larger numbers of patients are needed to validate our results.
Institutional Review Board (IRB) permission obtained for the study.
This work was supported in part by Grants-in-Aid for Scientific Research (KAKENHI) to MM (No. JP 21K09170) from the Japan Society for the Promotion of Science.
There are no conflicts of interest.
The views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Journal or its management. The information contained in this article should not be considered to be medical advice; patients should consult their own physicians for advice as to their specific medical needs.
1. , editors. Avastin [Package Insert]. South San Francisco, CA: Genentech Inc; p.
2. , editors. U.S. BL 125085/169 Amendment: Bevacizumab-Genentech, Inc. p.
3. Abrams DA, Hanson JA, Brown JM, Hsu FP, Delashaw JB, Bota DA. Timing of surgery and bevacizumab therapy in neurosurgical patients with recurrent high grade glioma. J Clin Neurosci. 2015. 22: 35-9
4. Bose D, Meric-Bernstam F, Hofstetter W, Reardon DA, Flaherty KT, Ellis LM. Vascular endothelial growth factor targeted therapy in the perioperative setting: Implications for patient care. Lancet Oncol. 2010. 11: 373-82
5. Chinot OL, Wick W, Mason W, Henriksson R, Saran F, Nishikawa R. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med. 2014. 370: 709-22
6. Clark AJ, Butowski NA, Chang SM, Prados MD, Clarke J, Polley MY. Impact of bevacizumab chemotherapy on craniotomy wound healing. J Neurosurg. 2011. 114: 1609-16
7. Erinjeri JP, Fong AJ, Kemeny NE, Brown KT, Getrajdman GI, Solomon SB. Timing of administration of bevacizumab chemotherapy affects wound healing after chest wall port placement. Cancer. 2011. 117: 1296-301
8. Friedman HS, Prados MD, Wen PY, Mikkelsen T, Schiff D, Abrey LE. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol. 2009. 27: 4733-40
9. Gilbert MR, Dignam JJ, Armstrong TS, Wefel JS, Blumenthal DT, Vogelbaum MA. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med. 2014. 370: 699-708
10. Gutin PH, Iwamoto FM, Beal K, Mohile NA, Karimi S, Hou BL. Safety and efficacy of bevacizumab with hypofractionated stereotactic irradiation for recurrent malignant gliomas. Int J Radiat Oncol Biol Phys. 2009. 75: 156-63
11. Hata N, Yoshimoto K, Hatae R, Kuga D, Akagi Y, Sangatsuda Y. Add-on bevacizumab can prevent early clinical deterioration and prolong survival in newly diagnosed partially resected glioblastoma patients with a poor performance status. Onco Targets Ther. 2017. 10: 429-37
12. Lai A, Tran A, Nghiemphu PL, Pope WB, Solis OE, Selch M. Phase II study of bevacizumab plus temozolomide during and after radiation therapy for patients with newly diagnosed glioblastoma multiforme. J Clin Oncol. 2011. 29: 142-8
13. Tonnesen MG, Feng X, Clark RA. Angiogenesis in wound healing. J Investig Dermatol Symp Proc. 2000. 5: 40-6
14. Yonezawa H, Hirano H, Uchida H, Habu M, Hanaya R, Oyoshi T. Efficacy of bevacizumab therapy for unresectable malignant glioma: A retrospective analysis. Mol Clin Oncol. 2017. 6: 105-10