Antiangiogenic therapy using bevacizumab in recurrent high-grade glioma: impact on local control and patient survival

Narayana, Ashwatha; Kelly, Patrick; Golfinos, John G.; Parker, Erik C.; Johnson, Glyn; Knopp, Edmond A.; Zagzag, David; Fischer, Ingeborg; Raza, Shahzad; Medabalmi, Praveen; Eagan, Patricia; Gruber, Michael L.

doi:10.3171/2008.4.17492

Cited by 216 publications

(175 citation statements)

References 25 publications

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“…The frequency of distant recurrences in this patient series was 23%. Of note, 20% distant recurrences had been found in an analysis of the recurrence patterns at DRAFT-final first progression of the non-BEV-containing EORTC 26981/22981/NCIC CE.3 trial [23] and prior data suggested a frequency of distant failure of between 20 and 30% with BEV [11,19,20]. Therefore, a controlled analysis should ask the question whether distant recurrences are more frequent in BEV-treated patients versus patients with similar clinical characteristics who have not been exposed to BEV or another antiangiogenic treatment in the observation period.…”

Section: Distant or Diffuse Recurrence May Be A Feature Of Late-stagementioning

confidence: 93%

“…For BEV, various patient series have suggested an increase in diffusely or distantly recurring tumors [11,19]. This gliomatosis-like phenotype or remote spread is best depicted on fluid-attenuated inversion recovery (FLAIR) MRI sequences [11].…”

Section: Introductionmentioning

confidence: 99%

“…It may happen that despite persistent reduction in contrast enhancement an increase in non-enhancing T2 or FLAIR signal alterations suggestive of infiltrative tumor develops [11,19,20]. This dissociation is called "discordance" between the information gathered on T1+c and T2 images [20,21].…”

Section: Introductionmentioning

confidence: 99%

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Patterns of Progression in Malignant Glioma Following Anti-VEGF Therapy: Perceptions and Evidence

Wick

Weiler

et al. 2011

Curr Neurol Neurosci Rep

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Antiangiogenic treatment has recently become an integral part of modern cancer therapy targeting the vasculature of numerous aggressive malignancies including glioblastoma. There is preclinical evidence that antiangiogenic therapies promote glioma cell invasiveness. In clinical series, upon progression on antiangiogenic therapy with the vascular endothelial growth factor-directed antibody bevacizumab (BEV), glioblastoma has been reported to display a more infiltrative pattern of recurrence. This distant spread at recurrence or progression and a gliomatosis cerebri-like growth pattern is best detectable on fluid-attenuated inversion recovery MRI. The frequency of up to 20% to 30% of such a pattern in BEV-treated patients is higher than expected to occur without BEV. Older reports and common clinical knowledge estimate the frequency of diffuse or distant spread in recurrent glioblastoma at 10%. This observation stimulated two streams of research. One is to overcome this often insidious adverse effect of antiangiogenic treatment, to optimize antiangiogenic therapies and to face this major challenge, integrating antiangiogenic with anti-invasive mechanisms into one combined treatment concept. The second is questioning a specific property of antiangiogenic therapy to induce diffuse or distant spread. Here, alternative hypotheses of increased awareness and better imaging as well as invasiveness being part of the natural course of the disease have been tested. Without doubt, migration and invasiveness are major obstacles to successful glioma therapy, notably local therapies, both in the natural course of the disease and in the concept of "evasive resistance." However, clinical analyses of case series, matched pairs analyses, and follow-up on the BRAIN trial (A Study to Evaluate Bevacizumab Alone or in Combination with Irinotecan for Treatment of Glioblastoma Multiforme), which led to accelerated approval of BEV for recurrent glioblastoma in the United States, have not supported a specific propensity of BEV to induce diffuse growth or distant spread at recurrence.

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Section: Distant or Diffuse Recurrence May Be A Feature Of Late-stagementioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

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Patterns of Progression in Malignant Glioma Following Anti-VEGF Therapy: Perceptions and Evidence

Wick

Weiler

et al. 2011

Curr Neurol Neurosci Rep

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“…to evaluate for patterns of recurrence, ie, multifocal or diffuse (or worsening) infiltration on FLAIR sequence. 12,17,24,25 Multifocal recurrence was defined as new sites of contrast-enhanced tumor remote from the original site without an obvious connection observed on FLAIR sequences, whereas diffuse infiltration was defined as the progression of nonenhancing tumor, which lead to Original Article 6.4…”

Section: Assessmentsmentioning

confidence: 99%

“…The activity of bevacizumab alone or in combination with irinotecan for recurrent HGG has been investigated and has produced response rates that range from 35% to 60% and PFS6 rates of 40% to 60% (Table 1). [11][12][13][14][15][16][17][18][19][20][21][22] The current study was a prospective phase 2 trial of single-agent bevacizumab for the treatment of patients with recurrent HGG on an every-3-week schedule to assess PFS, OS, and safety. In addition, outcomes based on VEGFA and VEGFR2 tumor expression were assessed.…”

mentioning

confidence: 99%

A phase 2 trial of single‐agent bevacizumab given in an every‐3‐week schedule for patients with recurrent high‐grade gliomas

Raizer

Grimm

Chamberlain

et al. 2010

Cancer

139

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BACKGROUND:The authors evaluated a 3-week schedule of bevacizumab in patients with recurrent high-grade glioma (HGG). METHODS: Patients received bevacizumab 15 mg/kg every 3 weeks and were evaluated every 6 weeks until tumor progression. Tissue correlates were used to quantify tumor content of vascular endothelial growth factor A (VEGFA) and vascular endothelial growth factor receptor-2 (VEGFR2). RESULTS: Of 61 patients who were treated (35 men and 26 women; median age, 52 years; age range, 21-78 years), 50 patients had glioblastoma multiforme (GBM), and 11 patients had anaplastic glioma (AG). The median number of previous chemotherapies was 2 (range, 1-5 previous chemotherapies), and 16 patients had received !3 previous chemotherapies. The median number of bevacizumab doses was 4 (range, 1-20 doses), and 45% of patients received >5 doses. The toxicities observed were primarily grade 1 and 2, and the most common were fatigue, hypertension, and headache. One grade 2 intratumoral bleed and 1 bowel perforation were reported. For patients with GBM, the 6-month progression-free survival rate was 25%, the median time to tumor progression was 10.8 weeks, and the median overall survival was 25.6 weeks. The best response included a partial response in 15 patients (24.5%) and stable disease in 31 patients (50.8%) patients; radiographic recurrence patterns included increased changes in fluid attenuation inversion recovery (24%) and multifocal recurrence (20%). The median survival after bevacizumab failure was 10 weeks. The ratio of tumor VEGFA/VEGFR2 was increased in patients aged >55 years; an increased VEGFA/VEGFR2 ratio was correlated nonsignificantly with decreased survival (P ¼ .052). CONCLUSIONS: An every-3-week schedule of bevacizumab had antitumor activity and was relatively nontoxic for patients with recurrent HGG. The predictive value of VEGFA/VEGFR2 in tumor will require validation in a larger patient cohort. Cancer 2010;116:5297-305.

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Bevacizumab does not increase the risk of remote relapse in malignant glioma

Wick

Dörner

Schäfer

et al. 2011

Annals of Neurology

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Preclinical evidence and uncontrolled clinical studies suggest an increased risk for distant spread and development of a gliomatosislike phenotype at recurrence or progression of malignant glioma patients treated with bevacizumab (BEV), an antibody to vascular endothelial growth factor (VEGF). Here we asked whether BEV treatment of recurrent malignant glioma increases the risk of distant or diffuse tumor spread at further recurrence. BEV-treated patients were compared with matched pairs of patients treated without anti-VEGF regimens. T1 contrast-enhanced (T1+c) and fluid-attenuated inversion recovery (FLAIR) images were analyzed using a novel automated tool of image analysis. At the start of the study, 20.5% of BEV-treated and 22.7% of non-BEV-treated patients had displayed distant or diffuse recurrence. Distant or diffuse recurrences were observed in 22% (BEV) and 18% (non-BEV) on T1+c and in 25% and 18% on FLAIR (p > 0.05). The correlation between changes on T1+c and FLAIR at progression was high. The risk of distant or diffuse recurrence at the time of failure of BEV-containing treatments was not higher than with anti-VEGF-free regimens, arguing against a specific property of BEV that promotes distant tumor growth or a gliomatosislike phenotype at recurrence.

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Antiangiogenic therapy using bevacizumab in recurrent high-grade glioma: impact on local control and patient survival

Abstract: Antiangiogenic therapy using bevacizumab appears to improve survival in patients with recurrent high-grade glioma. A possible change in the invasiveness of the tumor following therapy is worrisome and must be closely monitored.

Cited by 216 publications

References 25 publications

Patterns of Progression in Malignant Glioma Following Anti-VEGF Therapy: Perceptions and Evidence

Patterns of Progression in Malignant Glioma Following Anti-VEGF Therapy: Perceptions and Evidence

A phase 2 trial of single‐agent bevacizumab given in an every‐3‐week schedule for patients with recurrent high‐grade gliomas

Bevacizumab does not increase the risk of remote relapse in malignant glioma

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