Bevacizumab for recurrent glioblastoma

Bevacizumab for recurrent glioblastoma

Bevacizumab(Avastin®)– a monoclonal antibody against VEGFFDA approved in May 2009 for progressive glioblastoma following prior treatment based on two trials: the BRAIN study, AVF3708g 1) and NCI 06-C-0064E 2).

Given as 10 mg/kg every 2 weeks until disease progression. The reported 6-month PFS rate was 36.0%. The median response durations were 3.9 months and 4.2 months from the two trials. The median OS was 9.3 months 3).

Side effects: gastrointestinal perforations, wound healing complications, hemorrhage, fistula formation, arterial thromboembolic events, hypertension.

Faltings et al. first reported the effect of rechallenging a patient with super-selective intra-arterial cerebral infusion (SIACI) of bevacizumab following disease progression after initial bevacizumab treatment and subsequent alternate clinical trial failure. There is a need to conduct further clinical trials to evaluate the benefits of rechallenge with SIACI versus IV bevacizumab for GBM, further exploring theories of bevacizumab resistance 4).

Some phase 2 trials had reported encouraging progression free survival with Bevacizumab in monotherapy or combined with chemotherapy in glioblastoma. However, phase 3 trials showed a significant improvement in progression free survival without a benefit in overall survival. To date, there are no predictive biomarker of response for Bevacizumab in glioblastoma 5)

There was interest in the role of bevacizumab, alone or in combination with cytotoxic drugs, but the results were conflicting 6) 7) 8) 9).

Given the highly vascular nature of GBM and its high expression of vascular endothelial growth factor and other angiogenic factors, recent investigation has turned to bevacizumab, an antivascular endothelial growth factor monoclonal antibody, for treatment of recurrent GBM. Phase 2 studies demonstrated the efficacy and safety of bevacizumab therapy for recurrent GBM, which led to its approval by the US Food and Drug Administration in 2009 for use in recurrent GBM. Since then, several new Phase 2 studies and retrospective series have demonstrated that bevacizumab significantly increased six-month progression-free survival in patients with recurrent GBM and may do so in new-onset GBM 10).

Further studies in recurrent disease are being conducted; preliminary results of a randomized trial showed favorable results with the combination with CCNU, and final results are awaited. Meanwhile, outside the realm of clinical trials, the current trend appears to be to reserve bevacizumab for use in recurrent disease, or for patients with moderate or severe neurologic symptoms, either in the newly diagnosed or recurrent setting. Further research efforts are needed to determine optimal candidates for this treatment from a molecular standpoint, as well as to develop imaging tools capable of accurately identifying response and progression, and to establish new drug combinations that could result in unquestionable clinical benefit and improved survival in these patients 11).

Monitoring response

In this setting, traditional anatomic MRI methods such as post-contrast T1-weighted and T2-weighted imaging are proving unreliable for monitoring response.

Standardized relative cerebral blood volume (rCBV) derived from dynamic susceptibility contrast MRI is predictive of overall survival (OS) and progression free survival (PFS) in patients with recurrent high-grade brain tumor treated with bevacizumab 12).

Overall survival

Trials on recurrent glioblastoma have shown that bevacizumab alone is able to increase response rate on MRI, median and 6-month progression-free survival (PFS), and modestly overall survival, allowing an improvement of neurological function and a reduction of steroids.

Any drug combination was not superior over bevacizumab alone. A synergistic effect of CCNU has been suggested when added to bevacizumab (BELOB trial), but excluded when added to cediranib (REGAL trial). Phase III trials on bevacizumab in newly diagnosed glioblastoma have shown an improvement of PFS of 3-4 months, but failed to prolong overall survival.

In a randomized trial of bevacizumab for newly diagnosed glioblastoma, the first-line use of bevacizumab did not improve overall survival. Progression-free survival was prolonged but did not reach the prespecified improvement target. (Funded by the National Cancer Institute; number, NCT00884741.) 13).

Unexplained is the observation that females had longer overall survival (OS) with BEV than males in patients with progressive glioblastoma 14).

Case series

Case reports



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. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol. 2009 Oct 1;27(28):4733-40. doi: 10.1200/JCO.2008.19.8721. Epub 2009 Aug 31. PubMed PMID: 19720927.

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. Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol. 2009; 27:740–745

Cohen MH, Shen YL, Keegan P, Pazdur R. FDA drug approval summary: bevacizumab (Avastin) as treatment of recurrent glioblastoma multiforme. Oncologist. 2009; 14:1131–1138

Faltings L, Kulason KO, Patel NV, Wong T, Fralin S, Li M, Schneider JR, Filippi CG, Langer DJ, Ortiz R, Boockvar JA. Rechallenging Recurrent Glioblastoma with Intra-Arterial Bevacizumab with Blood Brain Barrier Disruption Results in Radiographic Response: a Case Report. World Neurosurg. 2019 Jul 24. pii: S1878-8750(19)32043-1. doi: 10.1016/j.wneu.2019.07.137. [Epub ahead of print] PubMed PMID: 31351210.

Manneh Kopp RA, Sepúlveda-Sánchez JM, Ruano Y, Toldos O, Pérez Núñez A, Cantero D, Hilario A, Ramos A, de Velasco G, Sánchez-Gómez P, Hernández-Laín A. Correlation of radiological and immunochemical parameters with clinical outcome in patients with recurrent glioblastoma treated with Bevacizumab. Clin Transl Oncol. 2019 Mar 15. doi: 10.1007/s12094-019-02070-6. [Epub ahead of print] PubMed PMID: 30877636.

Lombardi G, Zustovich F, Farina P, et al. 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. 2012;24(1):90–97.

Reardon DA, Desjardins A, Peters KB, et al. Phase 2 study of carboplatin, irinotecan, and bevacizumab for recurrent glioblastoma after progression on bevacizumab therapy. Cancer. 2011;117(23):5351–5358.

Zustovich F, Lombardi G, Pastorelli D, et al. Bevacizumab and glioblastomas, a single-centre experience: how disease history and characteristics may affect clinical outcome. Anticancer Research. 2010;30(12):5213–5216.

Friedman HS, Prados MD, Wen PY, et al. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. Journal of Clinical Oncology. 2009;27(28):4733–4740.

Hanson JA, Hsu FP, Jacob AT, Bota DA, Alexandru D. Antivascular endothelial growth factor antibody for treatment of glioblastoma multiforme. Perm J. 2013 Fall;17(4):68-74. doi: 10.7812/TPP/13-081. PubMed PMID: 24361023; PubMed Central PMCID: PMC3854812.

Thomas AA, Omuro A. Current Role of Anti-Angiogenic Strategies for Glioblastoma. Curr Treat Options Oncol. 2014 Aug 31. [Epub ahead of print] PubMed PMID: 25173555.

Schmainda KM, Prah M, Connelly J, Rand SD, Hoffman RG, Mueller W, Malkin MG. Dynamic-susceptibility contrast agent MRI measures of relative cerebral blood volume predict response to bevacizumab in recurrent high-grade glioma. Neuro Oncol. 2014 Jan 15. [Epub ahead of print] PubMed PMID: 24431219.

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. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med. 2014 Feb 20;370(8):699-708. doi: 10.1056/NEJMoa1308573. PubMed PMID: 24552317.

Levin VA, Mendelssohn ND, Chan J, Stovall MC, Peak SJ, Yee JL, Hui RL, Chen DM. Impact of bevacizumab administered dose on overall survival of patients with progressive glioblastoma. J Neurooncol. 2015 Jan 11. [Epub ahead of print] PubMed PMID: 25575937.

Botulinum toxin

Botulinum toxin

Protein and neurotoxin produced by the bacterium Clostridium botulinum.

Side effects

It is the most acutely lethal toxin known, with an estimated human median lethal dose (LD-50) of 1.3–2.1 ng/kg intravenously or intramuscularly and 10–13 ng/kg when inhaled.

Botulinum toxin (BTX) can cause botulism, a serious and life-threatening illness in humans and animals. Three forms of botulinum toxin type A (Botox, Dysport and Xeomin) and one form of botulinum toxin type B (MyoBloc) are available commercially for various cosmetic and medical procedures.

Myogenic ptosis.


The standard modality for painful tic convulsif of treatment is microvascular decompression, which has shown greater effectiveness and control of symptoms in the long-term. However medical treatment, which includes percutaneous infiltration of botulinum toxin, has produced similar results at medium-term in the control of each individual clinical manifestation, but it must be considered as an alternative in the choice of treatment 1).

Botulinum toxin (Botox®): reduces transmission of calcitonin gene-related peptide (CGRP) producing a direct effect on the sensory nerve fibers.

Whiplash-associated disorders (WAD): Although botulinum toxin has not been evaluated in large long-term trials, these initial data are promising and suggest a role for this agent in the treatment of WAD. Additional study is needed to identify the subset of patients with WAD who are most likely to respond to treatment with botulinum toxin. 2).

Chronic cervical-associated headache

Fourteen subjects who received botulinum toxin A and 12 who received saline completed the study. At both 2 and 4 weeks post injection, the treatment group showed a significant improvement in pain and range of motion from preinjection levels (P<.01). The placebo group demonstrated no statistically significant changes at any posttreatment time. This study had quite a few placebo responders 3).

Piriformis syndrome.

Local injection of botulinum toxin: may work for retrocollis, is poor for lateral torticollis (must inject posterior cervicals and both SCM, and may cause temporary pharyngeal muscle dysfunction resulting in dysphagia), and is totally ineffective for anterocollis.

Local injection of botulinum toxin (Oculinum®) may be effective in treating HFS and/or blepharospasm 4) 5).

A total of 539 patients with hemifacial spasm (HFS) underwent MVD treatment in the Xinhua Hospital between January 2014 and June 2017. Among them, 83 patients had received botulinum toxin (BT) injection before surgery and were recorded as BT group. Eighty-three patients underwent acupuncture before surgery and were recorded as acupuncture group. Five patients received both BT injection and acupuncture before surgery and were recorded as mixed group. A total of 368 patients who had not received any treatment before surgery were recorded as simple MVD group. Zhang et al. calculated the immediate and long-term remission rates after surgery. Abnormal Muscle Response (AMR) and Compound Motor Action Potential (CMAP) monitoring were routinely performed during surgery.

Immediate remission rate after surgery was 96.4% (80/83) in BT group, 100% (83/83) in acupuncture group, 100% (5/5) in mixed group, and 95.1% (350/368) in simple MVD group, and the immediate remission rate of BT group is significantly higher than that of simple MVD group (p = 0.04). Long-term remission rate: the remission rates of the four groups were 94.0% (78/83), 97.6% (81/83), 100.0% (5/5) and 92.7%(341/368), respectively, and there is no statistical difference between them (p > 0.05). The amplitude of one branch or several branches of CMAP on the affected side was lower than the healthy side in BT or acupuncture treatment patients.

A preoperative BT injection or acupuncture treatment do not reduce the postoperative remission rate of HFS patients treated with MVD, and the amplitude of CMAP on the affected side was lower than the healthy side. 6).



Revuelta-Gutiérrez R, Velasco-Torres HS, Vales Hidalgo LO, Martínez-Anda JJ. [Painful tic convulsif: Case series and literature review]. Cir Cir. 2016 Nov – Dec;84(6):493-498. doi: 10.1016/j.circir.2015.08.012. Epub 2016 Jan 13. Spanish. PubMed PMID: 26774197.

Freund BJ, Schwartz M. Use of botulinum toxin in chronic whiplash-associated disorder. Clin J Pain. 2002 Nov-Dec;18(6 Suppl):S163-8. PubMed PMID: 12569964.

Freund BJ, Schwartz M. Treatment of chronic cervical-associated headache with botulinum toxin A: a pilot study. Headache. 2000 Mar;40(3):231-6. PubMed PMID: 10759926.

Dutton JJ, Buckley EG. Botulinum Toxin in the Management of Blepharospasm. Arch Neurol. 1986; 43:380–382

Kennedy RH, Bartley GB, Flanagan JC, et al. Treatment of Blepharospasm With Botulinum Toxin. Mayo Clin Proc. 1989; 64:1085–1090

Zhang WB, Min LZ, Zhong WX, Tao BB, Li B, Sun QY, Wang XQ. Surgical effect and electrophysiological study of patients with hemifacial spasm treated with botulinum toxin or acupuncture before microvascular decompression. Clin Neurol Neurosurg. 2019 Jul 12;184:105417. doi: 10.1016/j.clineuro.2019.105417. [Epub ahead of print] PubMed PMID: 31351214.



The Neurapheresis™ system (Minnetronix Inc, St. Paul, Minnesota) has been developed to filter CSF and remove blood products.

It has been hypothesized that early and rapid filtration of blood from cerebrospinal fluid (CSF) in post-subarachnoid hemorrhage patients may reduce hospital stay and related adverse events.

Khani et al. formulated a subject-specific computational fluid dynamics (CFD) model to parametrically investigate the impact of a novel dual-lumen catheter-based CSF filtration system, the NeurapheresisTM system (Minnetronix Neuro, Inc., St. Paul, MN), on intrathecal CSF dynamics. The operating principle of this system is to remove CSF from one location along the spine (aspiration port), externally filter the CSF routing the retentate to a waste bag, and return permeates (uncontaminated CSF) to another location along the spine (return port). The CFD model allowed parametric simulation of how the Neurapheresis system impacts intrathecal CSF velocities and steady-steady streaming under various Neurapheresis flow settings ranging from 0.5 to 2.0 ml/min and with a constant retentate removal rate of 0.2 ml/min. simulation of the Neurapheresis system was compared to a lumbar drain simulation with a typical CSF removal rate setting of 0.2 ml/min. Results showed that the Neurapheresis system at a maximum flow of 2.0 ml/min increased average steady-streaming CSF velocity 2X in comparison to lumbar drain (0.190 ± 0.133 versus 0.093 ± 0.107 mm/s, respectively). This effect was localized to the region within the Neurapheresis flow-loop. The mean velocities introduced by the flow-loop were relatively small in comparison to normal cardiac-induced CSF velocities 1).

It is being investigated for safety and feasibility in the ExtracorPoreal FILtration of subarachnoid hemorrhage via SpinaL CAtheteR (PILLAR) study. We report the first case using this novel device.

A 65-yr-old female presented with a ruptured left posterior communicating artery aneurysm. Following placement of a ventriculostomy and coil embolization of her aneurysm, the patient underwent placement of a lumbar dual lumen catheter for CSF filtration as part of the PILLAR study. In this case, a total of 9 h of filtration during 31 h of catheter indwelling resulted in 309.47 mL of processed CSF without complication. Computed tomography images demonstrated an interval reduction of subarachnoid hemorrhage immediately after filtration. The patient was discharged home on postbleed day 11 and at 30 d showed good recovery.

Safety of the Neurapheresis procedure was confirmed in this first case, and it will continue to evaluate the safety of the Neurapheresis system through the PILLAR trial 2).

Smilnak et al., provided the first publication demonstrating the direct ability to rapidly clear, both in vitro and in vivo, the otherwise slowly removed fungal pathogen that directly contributes to the morbidity and mortality seen in Cryptococcal Meningitis (CM) 3).



Khani M, Sass L, McCabe A, Zitella Verbick L, Lad SP, Sharp MK, Martin B. Impact of Neurapheresis system on intrathecal cerebrospinal fluid dynamics: a computational fluid dynamics study. J Biomech Eng. 2019 Jul 25. doi: 10.1115/1.4044308. [Epub ahead of print] PubMed PMID: 31343659.

Blackburn SL, Swisher CB, Grande AW, Rubi A, Verbick LZ, McCabe A, Lad SP. Novel Dual Lumen Catheter and Filtration Device for Removal of Subarachnoid hemorrhage: First Case Report. Oper Neurosurg (Hagerstown). 2018 Jun 5. doi: 10.1093/ons/opy151. [Epub ahead of print] PubMed PMID: 29873785.

Smilnak GJ, Charalambous LT, Cutshaw D, Premji AM, Giamberardino CD, Ballard CG, Bartuska AP, Ejikeme TU, Sheng H, Verbick LZ, Hedstrom BA, Pagadala PC, McCabe AR, Perfect JR, Lad SP. Novel Treatment of Cryptococcal Meningitis via Neurapheresis Therapy. J Infect Dis. 2018 Aug 24;218(7):1147-1154. doi: 10.1093/infdis/jiy286. PubMed PMID: 29788431; PubMed Central PMCID: PMC6107745.
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