M. C. Chamberlain and S. K. Johnston collected and analyzed the data for this article.
Bevacizumab for recurrent alkylator-refractory anaplastic oligodendroglioma
Version of Record online: 5 FEB 2009
Copyright © 2009 American Cancer Society
Volume 115, Issue 8, pages 1734–1743, 15 April 2009
How to Cite
Chamberlain, M. C. and Johnston, S. (2009), Bevacizumab for recurrent alkylator-refractory anaplastic oligodendroglioma. Cancer, 115: 1734–1743. doi: 10.1002/cncr.24179
- Issue online: 6 APR 2009
- Version of Record online: 5 FEB 2009
- Manuscript Accepted: 17 OCT 2008
- Manuscript Revised: 27 AUG 2008
- Manuscript Received: 22 JUL 2008
- recurrent anaplastic oligodendroglioma;
A retrospective evaluation of single agent bevacizumab was carried out in adults with recurrent alkylator-refractory 1p19q codeleted anaplastic oligodendrogliomas (AO) with an objective of determining progression-free survival (PFS). There is no standard therapy for alkylator-resistant AO, and hence a need exists for new therapies.
Twenty-two patients aged 24 to 60 years with recurrent AO were treated. All patients had previously been treated with surgery, radiotherapy, adjuvant chemotherapy (temozolomide, 17; carmustine wafers, 4; carmustine, 1), and 1 salvage regimen (procarbazine, lomustine, and vincristine, 15; temozolomide, 6; carmustine wafers, 1). Eleven patients underwent repeat surgery. Patients were treated at second recurrence with bevacizumab, once every 2 weeks, defined as a single cycle. Neurological evaluation was performed every 2 weeks, and neuroradiographic assessment was made after the initial 2 cycles of bevacizumab and subsequently after every 4 cycles of bevacizumab.
A total of 391 cycles of bevacizumab (median, 14.5 cycles; range, 2-39 cycles) were administered. Bevacizumab-related toxicity included fatigue (14 patients; 4 grade 3), leukopenia (9; 1 grade 3), anemia (5; 0 grade 3), hypertension (5; 1 grade 3), deep vein thrombosis (4; 1 grade 3), and wound dehiscence (2; 1 grade 3). Fifteen (68%) patients demonstrated a partial radiographic response, 1 (5.0%) demonstrated stable disease, and 6 (27%) demonstrated progressive disease after 2 cycles of bevacizumab. Time to tumor progression ranged from 1 to 18 months (median, 6.75 months). Survival ranged from 3 to 19 months (median, 8.5 months). Six-month and 12-month PFS were 68% and 23%, respectively.
Bevacizumab demonstrated efficacy and acceptable toxicity in this cohort of adults with recurrent 1p19q codeleted alkylator-refractory AO. Cancer 2009. © 2009 American Cancer Society.
The treatment of recurrent anaplastic oligodendroglial tumors (anaplastic oligodendroglioma [AO], anaplastic oligoastrocytoma [AOA]) like all high grade gliomas (HGG) is problematic, as only partially effective therapeutic modalities are available, and there is a lack of a standard therapy for recurrence. These therapies include chemotherapy, radioactive implants, stereotactic radiotherapies, targeted therapy, and reoperation.1-27 Chemotherapy for recurrent HGG is of modest benefit, primarily because response to chemotherapy is of limited duration. In an analysis of 8 institutional phase 2 studies of chemotherapy for recurrent HGG, Wong reported that response rates in recurrent anaplastic astrocytomas were 14%, and progression-free survival (PFS) at 6 months (PFS-6) was 31%.13 Those drugs most active are the nitrosoureas, such as carmustine (BCNU) and lomustine (CCNU), in addition to temozolomide (TMZ), procarbazine, cis-retinoic acid, and platinum compounds.1, 2, 4, 5, 10-12, 14, 17, 23-27 Bevacizumab, with or without irinotecan (CPT-11), has activity in recurrent glioblastoma (GBM), and a small data set exists for activity as well in recurrent anaplastic gliomas.28-34
The objective of this single institution retrospective analysis was to observe whether bevacizumab as a single agent, given every 2 weeks, could significantly delay progression in patients with neuroradiographically recurrent 1p19q codeleted AO/AOA as determined by PFS-6. Twenty-two adult patients with recurrent supratentorial AO/AOA previously treated with surgery, radiotherapy, and alkylator-based chemotherapy (TMZ and PCV [procarbazine, CCNU, and vincristine]) were retrospectively evaluated.
MATERIALS AND METHODS
The retrospective analysis was performed at the University of Washington and the University of South Florida, H. Lee Moffitt Cancer Center and Research Institute. The trial commenced in January 2005 and closed in March 2008. The retrospective analysis was conducted without industry support, and approval and funding for off-label use of bevacizumab was obtained from the patients' insurance carrier. Patients were apprised of the nonstandard care treatment and agreed to bevacizumab treatment after disclosure of potential risks and benefits.
Objectives and Endpoints
The objective was to determine the efficacy of bevacizumab in the treatment of patients with TMZ-refractory recurrent 1p19q codeleted AO/AOA. The primary endpoint was PFS-6. Secondary endpoints included overall survival (OS), time to progression, and response. Toxicity was evaluated in all eligible patients receiving at least 1 cycle of bevacizumab.
Patients were required to have a histologically proven 1p19q codeleted AO or AOA that was recurrent neuroradiographically. Patients must have progressed after definitive radiotherapy and alkylator-based chemotherapy (TMZ and nitrosoureas). Patients may have had no more than 1 salvage chemotherapy regimen. At least 4 (if prior TMZ treatment), 6 (if prior PCV/BCNU treatment), or 12 (if prior carmustine wafers treatment) weeks must have elapsed since the last dose of chemotherapy, and patients must have recovered from the adverse effects of prior therapy. Patients could not have received prior bevacizumab therapy. Patients were required to have radiographically measurable intracranial disease wherein recurrent tumor was bidimensionally measurable (at least 1 cm × 1 cm) by cranial contrast-enhanced magnetic resonance imaging (MRI). Histological confirmation of tumor recurrence was not required for entry into the study. Pregnant or lactating women were not permitted to participate. Patients of childbearing potential were required to implement adequate contraceptive measures during participation in this study. Patients must have had a Karnofsky performance status ≥60 and a life expectancy >3 months.
Adequate hematologic, renal, and hepatic functions were required and were defined by the following: absolute granulocyte count >1500/dL or white blood cell count >4000/dL, platelet count >100,000/dL, total bilirubin level <1.8 mg/dL, transaminase level <4× the upper limit of normal, and creatinine concentration <1.8 mg/dL (or creatinine clearance ≥60 mL/m2/1.73).
All patients were aware of the neoplastic nature of their disease and willingly agreed to participate after being informed of the procedures to be used, experimental nature of the therapy, alternatives, potential benefits, side effects, risk, and discomforts. Patients with carcinomatous meningitis were not eligible. No serious concurrent medical illnesses or active infection could be present that would jeopardize the ability of the patient to receive bevacizumab therapy. Patients could not have an active concomitant malignancy except skin cancer (squamous cell or basal cell). Patients could range in age from 18 to 80 years.
Bevacizumab (Avastin; Genentech Pharmaceuticals, South San Francisco, Calif) was administered as a single agent to all patients at a dose of 10 mg/kg regardless of antiepileptic drug use. Bevacizumab was administered intravenously over 30 minutes on a single day.28-34 Concurrent dexamethasone was permitted for control of neurologic signs and symptoms. Bevacizumab was administered without premedication or prechemotherapy hydration. No posthydration intravenous fluids were administered. In patients having undergone re-resection, bevacizumab commenced 4 to 6 weeks after surgery and after establishment of normal craniotomy wound healing.
A cycle of therapy was operationally defined as 14 days, during which bevacizumab was administered on Day 1. Treatment with bevacizumab was repeated every 14 days from Day 1, provided that all hematologic toxicity from the previous cycle had resolved to grade 2 or less, and all nonhematologic toxicity had recovered to either grade 1 or less. If recovery had not occurred by Day 14, the subsequent cycle of bevacizumab was delayed until these criteria were met. All toxicities including hematologic because of bevacizumab therapy were rated according to the National Institutes of Health Common Toxicity Criteria (version 3.0).
No bevacizumab dose escalations were permitted. Dose reduction for toxicity was by 25% in patients with grade ≥3 toxicity, and only 1 dose reduction was allowed. Patients having grade 3 toxicity of any type after 1 dose reduction discontinued bevacizumab, as did patients delayed more than 2 weeks from the next scheduled chemotherapy.
Method of Evaluation
Laboratory tests (complete blood counts, basic metabolic panel, and urinary protein to creatinine ratio) were obtained biweekly, and neurological examination was performed every other week. Contrast-enhanced cranial MRI was performed after the initial 2 cycles of bevacizumab and thereafter every 8 weeks (and after 4 subsequent cycles of bevacizumab).
Neuroradiographic response criteria as defined by Macdonald et al were used.21, 28-34 Complete response (CR) was defined as the disappearance of all enhancing (contrast-enhancing tumor volume [CTV]) or nonenhancing tumor (MRI-defined fluid-attenuated inversion recovery tumor volume [FTV]) on consecutive MRI scans at least 1 month apart, with the patient off corticosteroids and neurologically stable or improved. Partial response (PR) was defined as a >50% reduction in the size of tumor (CTV; FTV) on consecutive MRI scans at least 1 month apart, with the corticosteroid dose stable or decreased and the patient neurologically stable or improved. Progressive disease (PD) was defined as a >25% increase in the size of tumor (CTV; FTV) or any new tumor on MRI scans, or the patient neurologically worse with a stable or increased corticosteroid dose. Stable disease (SD) was defined as all other situations. SD response as with CR and PR required a confirmation MRI scan 1 month after documenting best response.
In patients with SD, PR, or CR, 4 additional cycles of bevacizumab was to be administered, after which patients were assessed again as described. Patients were continued on bevacizumab therapy until documentation of PD, at which time patients were removed from bevacizumab treatment and were either monitored or offered alternative therapy.
PFS and OS were defined as the time from the first day of treatment with bevacizumab until progression or death (PFS) or death (OS). Patients were removed from bevacizumab treatment if there was progressive disease, development of unacceptable toxicity, patient refusal, or noncompliance with protocol requirements.
The objective of this retrospective analysis was to determine whether single agent bevacizumab could significantly delay progression in patients with recurrent AO/AOA. Historical values were obtained from analysis of a database of 350 patients with recurrent HGG (125 anaplastic gliomas [AG]) treated on consecutive prospective phase II trials, in which PFS-6 was 31% for AG.13 The authors recognize that this comparison is only partially relevant, as the trials by Wong analyzed only anaplastic astrocytoma and not AO and AOA. Nonetheless, there are no other published data sets regarding outcome of recurrent AO/AOA. The median survival, time to progression, and the associated 95% confidence intervals (CIs) were computed. Kaplan-Meier plots were constructed to display the estimated probabilities of overall survival and time to progression.35-39
Twenty-two patients (13 men; 9 women) aged 24 to 60 years (median, 51 years), with recurrent 1p19q codeleted (by fluorescence in situ hybridization [FISH]) AO/AOA (original pathology including FISH analysis was reviewed and confirmed in all cases by the participating institutions) were treated with bevacizumab (Table 1). Recurrent AO/AOA was defined by objective neuroradiographic progression (>25% increase in tumor size), as compared with prior baseline neuroradiographic images using the criteria reported by Macdonald.21 All neuroradiography was locally reviewed by 2 neuroradiologists blinded to treatment and by the participating neuro-oncologist (M.C.C.). All patients underwent cranial MRI demonstrating progressive disease within 2 weeks of bevacizumab administration. Eleven (50%) patients underwent a reoperation (subtotal in all but 1) in which repeat tumor histology was consistent with 1p19q codeleted AO or AOA. Notwithstanding reoperation, residual disease was measurable (median tumor volume 2 cm2) in all patients. The single patient with a complete re-resection subsequently progressed and had radiographically measurable disease.
|Patient||Sex||Age, y||Tumor Location||Adjuvant Therapy||Prior Salvage Therapy||Bevacizumab Salvage Therapy|
|Surgery||Radiation, Gy||Chemotherapy Cycles (Best Response)||Chemotherapy Cycles (Best Response)/ Repeat Surgery||No. of Cycles||Response/ Duration, mo||Survival, mo|
|1||M||24||R Frontal||STR||60||TMZ 12 (PR)||PCV 2 (SD)||6||SD/3||5|
|2||M||28||R Parietal||GTR||60||TMZ 6 (SD)||PCV 1 (PD)||13||PR/6||8|
|3||W||29||L Frontal||GTR||59||TMZ 6 (SD)||PCV 2 (SD)||20||PR/9||10|
|4||M||35||L Parietal||STR||60||TMZ 12 (SD)||PCV 1 (PD)/STR x1||18||PR/8||10|
|5||M||42||Bifrontal||Bx||60||TMZ 12 (PR)||PCV 4 (PR)||13||PR/6||7|
|6||M||43||L Frontal||GTR||60||Carmustine wafers 1 (SD)||TMZ 6 (SD)||2||PD/2||4|
|7||W||47||L Occipital||STR||60||BCNU 6 (PR)||TMZ 5 (SD)/STR x1||3||PD/1.5||3|
|8||M||47||L Frontal||GTR||59||TMZ 6 (SD)||PCV 3 (SD)||13||PR/6||7|
|9||W||48||R Frontotemporal||STR||59||TMZ 12 (PR)||PCV 4 (PR)/STR x1||26||PR/12||14|
|10||M||49||L Frontal||GTR||60||Carmustine wafers 1 (SD)||TMZ 4 (SD)||16||PR/7.5||9|
|11||W||50||R Temporal||GTR||60||TMZ 6 (SD)||PCV 3 (PR)/STR x1||13||PR/6||8|
|12||W||52||R Parietal||Bx||60||TMZ 12 (SD)||PCV 4 (SD)/STR x1||3||PD/1.5||3|
|13||M||52||L Parietal||Bx||60||TMZ 12 (SD)||PCV 1 (PD)/STR x1||19||PD/8.5||10|
|14||M||53||R Temporal||GTR||59||Carmustine wafers 1 (SD)||TMZ 6 (PR)/STR x1||23||PR/10.5||12|
|15||W||54||R Frontoparietal||STR||60||TMZ 12 (PR)||Carmustine wafers 1 (SD)/GTR x1||8||SD/4||5|
|16||M||56||R Frontal||GTR||60||TMZ 6 (SD)||PCV 1 (PD)||17||PR/8||10|
|17||W||56||L Frontal||GTR||60||Carmustine wafers 1 (SD)||TMZ 8 (PR)/STR x1||30||PR/14||15|
|18||M||57||R Temporal||GTR||60||TMZ 6 (SD)||PCV 4 (PR)||19||PR/8.5||10|
|19||M||58||R Parietal||STR||60||TMZ 12 (PR)||PCV 2 (PD)/STR x1||30||PR/14||15|
|20||W||59||L Frontotemporal||STR||60||TMZ 12 (SD)||PCV 2 (PD)||39||PR/18||19|
|21||M||59||R Frontal||GTR||60||TMZ 6 (SD)||PCV 1 (PD)/STR x1||2||PD/1||3|
|22||W||60||L Parietal||Bx||59.4||TMZ 12 (PR)||TMZ 6 (SD)||3||PD/1.5||3|
Patients presented at the time of tumor recurrence with the following signs and symptoms: increased intracranial pressure as manifested by increasing headache (n = 16), worsening seizures (n = 10), altered mental status (n = 4), progressive hemiparesis (n = 4), new onset homonymous hemianopsia (n = 1), and gait ataxia (n = 1). Patient performance status using the Karnofsky scale ranged from 60 to 100 (median, 80) at the time of documented tumor recurrence and initiation of bevacizumab therapy. Tumor locations are delineated in Tables 1 and 2. Pathology (reviewed by a panel of 2 neuropathologists) showed all tumors to be AO/AOA by World Health Organization criteria.
|Variables||No. of Patients||%|
|Median (range)||51 (24-60)|
|Location of tumor|
|Extent of initial surgery|
|Reoperation at recurrence|
|No. of cycles of bevacizumab|
|Median (range)||14.5 (2-39)|
|Best response to bevacizumab treatment|
Prior treatment is shown in Tables 1 and 2. All patients had previously been treated with up-front limited-field radiotherapy using conventional fractionated radiotherapy in which 1.8 to 2.0 grays (Gy) was administered daily, with a median tumor dose of 60 Gy (range, 59-60 Gy). No patients were treated with stereotactic radiotherapy.
All patients were treated with bevacizumab after failure of alkylator-based therapy (Table 1 and 2) as demonstrated by neuroradiographic progression (in all patients) or clinical disease progression (60% of patients). All patients began bevacizumab at second recurrence with a median time to initiation of bevacizumab after initial surgery of 52 months, with a range of 16 to 113 months. A total of 391 cycles of bevacizumab were administered. A minimum of 2 cycles of bevacizumab was administered to each patient, with a median of 14.5 cycles (range, 2-39 cycles). Bevacizumab was administered at the prescribed dose in all patients. No other antiglioma agents aside from dexamethasone were used during the study. Oral dexamethasone was used concurrently in 14 patients and was increased in 6 patients with clinical disease progression. Dexamethasone dose was decreased in 15 patients with a neuroradiographic response and as patient clinical status permitted.
Six patients received cyclophosphamide chemotherapy after progression on bevacizumab, although none responded and all progressed rapidly and died of complications of their primary brain tumor (median survival, 2 months). No patient after demonstrating progression on bevacizumab-only therapy continued on bevacizumab when changed to cyclophosphamide.
Toxicity was recorded for all grades for all patients by type using the National Cancer Institute common toxicity criteria (version 3.0). Table 3 lists all grade 2 to 5 toxicity observed with each figure representing the sum of the highest grade of toxicity attained, per toxicity, per cycle for all patients. A total of 391 treatment cycles were administered, of which there were 9 grade 3 adverse events (AEs) in 9 (41%) patients and no grade 4 or 5 AEs. There were no treatment-related transfusions, episodes of febrile neutropenia, or treatment-related deaths. Two patients developed asymptomatic small intratumoral hemorrhages, and in both bevacizumab therapy was continued without evidence of hemorrhagic progression by serial magnetic resonance images. One patient with a craniotomy wound dehiscence requiring surgery prematurely terminated bevacizumab therapy.
|Toxicity||Grade 2||Grade 3||Grade 4||Grade 5||Total|
|Infection without neutropenia||2||1||0||0||3|
All patients were assessable for response and survival. After 2 cycles of bevacizumab, 6 (27%) patients demonstrated progressive disease and discontinued therapy. Fifteen (68%) patients received ≥13 cycles of therapy. At the conclusion of bevacizumab, Karnofsky performance status ranged from 40 to 70, with a median of 60 in the entire study group. PFS ranged from 3 to 18 months (Fig. 1), with an estimated median of 8.0 months (95% CI, 7.03-8.97). Patients who failed to respond to bevacizumab were offered alternative or supportive therapy. Survival in the entire cohort ranged from 3 months to 19 months, with an estimated median of 8.0 months (95% CI, 6.28-9.72) (Fig. 1). The probability of survival at 6 and 12 months was 68% and 23%. All patients have died, and all deaths were directly attributable to the effects of progressive intracranial tumor.
No (0%) patient demonstrated a complete response, 14 (64%) patients demonstrated a neuroradiographic partial response (95% CI, 44%-84%), and 1 (5%) patient demonstrated stable disease (95% CI, −4%-13%). In patients with a neuroradiographic response or stable disease (16; 73%), median time to tumor progression was 8 months (range, 3-18 months; 95% CI, 7.02-8.97). Fifteen (68%) patients were able to reduce dexamethasone dose, and in 10 (45%) patients, dexamethasone was discontinued.
There was no association observed between response to bevacizumab and response to the prior alkylator-based regimens. In addition, no difference was seen in the pretreatment tumor volume in patients with either a bevacizumab partial response or stable disease as compared with patients with progressive disease.
How best to manage recurrent AO/AOA remains ill-defined notwithstanding a variety of studies. Most studies, however, are small nonrandomized trials comparing outcome to historical controls (similar to the present retrospective analysis). Only a minority of patients with recurrent AO/AOA (only 1 in the present study notwithstanding 50% of patients underwent re-resection) are candidates for image-verified complete or near complete re-resection followed by carmustine wafer implantation.26 Therefore, the majority of patients if desirous of further therapy are offered chemotherapy. PCV has been used in TMZ-refractory AO/AOA in an European Organization for Research and Treatment of Cancer trial with response rates of 17% and PFS-6 of 25%.40, 41 By way of comparison, in the present analysis all patients had in addition to TMZ chemotherapy been treated with a nitrosourea (BCNU, carmustine wafers, or PCV), and consequently at time of recurrence, an alternative non–alkylator-based therapy was attractive. CPT-11 (Camptosar, Pfizer Pharmaceuticals, Princeton, NJ) has been used for recurrent AO with response rates of 23% and 33% PFS-6, results again less compelling than the present study.24, 42-47 Similarly, carboplatin (with or without teniposide) has been used in several trials for recurrent AO with response rates of 9% to 13% and 35% PFS-6, results less robust than the present analysis.14, 15, 48, 49
The present retrospective analysis was directed at the 1p19q codeleted AO/AOA population who had failed prior alkylator-based chemotherapy (both TMZ and nitrosoureas) and for whom further treatment appeared warranted. Treatment with bevacizumab did not require histological proof of recurrent AO/AOA, and the possibility of radiation necrosis as opposed to recurrent tumor is possible. This appears unlikely for the following reasons. No patient received stereotactic radiotherapy, and the risk of radiation necrosis is <5% in patients treated with standard fractionated radiotherapy. Furthermore, 11 (50%) patients underwent 2-deoxy-2[F-18]fluoro-D-glucose positron emission tomography, and 10 (45%) patients underwent magnetic resonance spectroscopy in which recurrent viable tumor was radiographically confirmed. Lastly, histopathology was reconfirmed in 11 (50%) patients who underwent reoperation. The retrospective analysis did not require re-examination of histology, and therefore a proportion of patients assumed to have AO/AOA may have progressed to glioblastoma. Therefore the present cohort may be evaluating both patients with AO/AOA and those with secondary glioblastoma.
Although multiple antiangiogenic strategies are being explored, with respect to antiglioma based therapy, only 2 have entered clinical practice, ligand-based antagonist therapy using monoclonal antibodies such as bevacizumab and receptor-based antagonist therapy with tyrosine kinase inhibitors such as AZD2171.28-34, 50 The use of bevacizumab has been predominantly with cytotoxic chemotherapy (CPT-11 or carboplatin) based on 2 concepts: interruption of vascular endothelial growth factor (VEGF) signaling leading to sensitization or reversal of cytotoxic drug resistance, and improvement in cytotoxic drug vascular access through vascular normalization and decrease in tumor interstitial pressure. This combinatorial rationale is compelling for non-neural cancers, for example colorectal, nonsmall cell lung, and breast cancer, although it has not been convincingly demonstrated for HGG.34
The available data for antiangiogenic therapy in HGG are most robust for ligand-based VEGF antagonism and are based on several single institution studies, many of which are retrospective.28-34 With 1 exception, these studies have used combinatorial therapy and treated predominantly GBM (among a total of 344 patients treated, 45 [13%] were AG). Data regarding response rates and survival for AG treated with bevacizumab are difficult to determine, as outcome is often reported for both GBM and AG. On the basis of the 2 largest studies using bevacizumab for recurrent AG (n = 30), response rates vary with complete response to bevacizumab plus therapy in 0%, partial response in 34% to 67%, and stable disease in 25% to 30% of patients.31, 33 PFS varies as well (median, 30 weeks; PFS-6, 32%-56%). These results with bevacizumab can be compared with TMZ for recurrent TMZ-naive AG (response rate, 35%; PFS-6, 44%; median overall survival, 13.6 months) and an aggregate series of 8 phase II trials for recurrent AG (pre-TMZ) from the M. D. Anderson Cancer Center (response rate, 14%; PFS-6, 31%; median overall survival, 47 weeks).13, 16 In the present analysis and compared with the abovementioned historical controls, bevacizumab therapy improved both response rate (68%) and PFS-6 (68%) in patients with recurrent alkylator-refractory AO/AOA, but had no clear survival benefit (median overall survival, 8 months). Bevacizumab therapy therefore appears to increase response of recurrent AG by 2-fold without a clear benefit with respect to PFS or OS. Notwithstanding the limited literature, based on these data and historical comparisons, bevacizumab plus therapy has become the current treatment of choice for recurrent AG. In a provocative phase II study comparing bevacizumab with or without CPT-11 in patients with recurrent GBM (the only randomized trial in recurrent gliomas), results suggest similar outcomes between treatment arms, raising the question of what added value is provided by CPT-11.34 The authors recognize that these data remain preliminary, as they have been published only in abstract form and may change upon publication.
In these various studies including the present study, toxicity of bevacizumab plus therapy have been modest and comprised primarily of low grade bleeding (epistaxis, vaginal, or oral cavity), proteinuria, impaired wound healing, and hypertension.28-34 The majority of antiangiogenic side effects appear to be a consequence of on-target actions of this class of agents and reflect disruption of VEGF in normal tissue. Rare serious side effects include gastrointestinal perforation, intratumoral hemorrhage, and craniotomy or central venous line wound dehiscence (each with <1% incidence). The high incidence of deep vein thrombosis and pulmonary embolism in patients with HGG confounds separation as an independent toxicity of antiangiogenic therapies, although antiangiogenic therapy may aggravate this thrombogenic predisposition.51-54 A retrospective review of bevacizumab plus therapy in patients with recurrent HGG suggests that concurrent use of anticoagulation appears safe without an apparent increased risk of hemorrhage.33
In conclusion, bevacizumab as a single agent used at this dose and schedule in patients with previously treated alkylator chemotherapy–refractory recurrent 1p19q codeleted AO appears of benefit (as determined by response rate and PFS-6) for recurrent alkylator-refractory AO/AOA. Regarding the primary endpoint (PFS-6), the results exceed the 20% threshold for success, assuming a 20% improvement as compared with the database reported by Wong (anaplastic astrocytoma: expected 31%; observed 68%).13 More problematic, however, is the lack of OS benefit with bevacizumab for recurrent AG. A prospective trial evaluating bevacizumab for recurrent AG using quality of life endpoints as well as traditional outcome measures is required to determine whether an advantage for bevacizumab therapy exists compared with alternative chemotherapy strategies.
Conflict of Interest Disclosures
The authors report no conflict of interest.
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