Bevacizumab-induced tumor calcifications as a surrogate marker of outcome in patients with glioblastoma. Neuro Oncol

Dr. Senckenberg Institute of Neurooncology, Goethe-University Hospital Frankfurt, Frankfurt, Germany.
Neuro-Oncology (Impact Factor: 5.56). 09/2011; 13(9):1020-9. DOI: 10.1093/neuonc/nor099
Source: PubMed


Therapy-induced calcifications in glioblastoma are rarely recognized. They may represent regressive changes in the tumor tissue, but their occurrence and possible predictive or prognostic value have not been systematically assessed. The observation of hyperintense lesions on precontrast T1-weighted magnetic resonance images (MRIs) in 2 index patients with glioblastoma after therapy with bevacizumab, subsequently identified as calcifications on computed tomographs (CTs), prompted us to prospectively screen for these radiographic changes. Therefore, 36 patients with recurrent glioblastoma prospectively treated with bevacizumab in an observational trial were examined every 8 weeks by MRI and, if clinically necessary, by CT. In 22 patients (61.1%), T1 hyperintense lesions became apparent after bevacizumab treatment. The median time to detection of these lesions was 55 days. In 14 (63.6%) of 22 patients, CTs were available and confirmed the existence of tumor calcifications. No substantial changes in T1 hyperintense lesions or calcifications were recognized on additional MRI or CT scans. Interestingly, the patients with therapy-induced T1 hyperintense lesions had better durations of progression-free survival than patients without these changes (median, 5.8 vs 3.5 months; P< .001), and the duration of overall survival was also superior (median, 9.7 vs 5.0 months; P= .006). There was a striking correlation between the appearance of therapy-induced T1 hyperintense lesions and overall response to bevacizumab. Therefore, this phenomenon is a rather early and time-limited event during the first weeks of treatment and appears to be response related. In summary, T1 hyperintense lesions are common in patients with glioblastoma who have been exposed to bevacizumab, may represent a novel biomarker of response and outcome, and seem to correspond to tumor calcifications.

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Available from: Oliver Bähr, Apr 17, 2014
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    • "Initial results suggest that glioblastoma patients with oligodendroglial components have prolonged survival and show better response to temozolomide [20], [21], [22], [23]. Furthermore, a recent report suggests that formation of calcifications in patients with glioblastoma after therapy with bevacizumab is associated with the response to therapy and improved outcome [24]. Therefore, the presence of calcifications in glioblastoma may represent an important biomarker for therapy decision, treatment response, and outcome. "
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    ABSTRACT: The application of susceptibility weighted imaging (SWI) in brain tumor imaging is mainly used to assess tumor-related "susceptibility based signals" (SBS). The origin of SBS in glioblastoma is still unknown, potentially representing calcifications or blood depositions. Reliable differentiation between both entities may be important to evaluate treatment response and to identify glioblastoma with oligodendroglial components that are supposed to present calcifications. Since calcifications and blood deposits are difficult to differentiate using conventional MRI, we investigated whether a new post-processing approach, quantitative susceptibility mapping (QSM), is able to distinguish between both entities reliably. SWI, FLAIR, and T1-w images were acquired from 46 patients with glioblastoma (14 newly diagnosed, 24 treated with radiochemotherapy, 8 treated with radiochemotherapy and additional anti-angiogenic medication). Susceptibility maps were calculated from SWI data. All glioblastoma were evaluated for the appearance of hypointense or hyperintense correlates of SBS on the susceptibility maps. 43 of 46 glioblastoma presented only hyperintense intratumoral SBS on susceptibility maps, indicating blood deposits. Additional hypointense correlates of tumor-related SBS on susceptibility maps, indicating calcification, were identified in 2 patients being treated with radiochemotherapy and in one patient being treated with additional anti-angiogenic medication. Histopathologic reports revealed an oligodendroglial component in one patient that presented calcifications on susceptibility maps. QSM provides a quantitative, local MRI contrast, which reliably differentiates between blood deposits and calcifications. Thus, quantitative susceptibility mapping appears promising to identify rare variants of glioblastoma with oligodendroglial components non-invasively and may allow monitoring the role of calcification in the context of different therapy regimes.
    PLoS ONE 03/2013; 8(3):e57924. DOI:10.1371/journal.pone.0057924 · 3.23 Impact Factor
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    • "Herein it should be raised that there is no imaging ‘gold standard’ to detect tumor infiltration and even the FLAIR sequence may fail to show histopathological paths of tumor invasion. FLAIR is influenced by T1- and T2-relaxation times and both may be changed especially under therapy [52]. On the other hand the sensitivity of MRS to detect pathologies in normal appearing brain tissue has been shown for brain tumors [53], [54]. "
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    ABSTRACT: Metabolic changes upon antiangiogenic therapy of recurrent glioblastomas (rGBMs) may provide new biomarkers for treatment efficacy. Since in vitro models showed that phospholipid membrane metabolism provides specific information on tumor growth we employed in-vivo MR-spectroscopic imaging (MRSI) of human rGBMs before and under bevacizumab (BVZ) to measure concentrations of phosphocholine (PCho), phosphoethanolamine (PEth), glycerophosphocholine (GPC), and glyceroethanolamine (GPE). (1)H and (31)P MRSI was prospectively performed in 32 patients with rGBMs before and under BVZ therapy at 8 weeks intervals until tumor progression. Patients were dichotomized into subjects with long overall survival (OS) (>median OS) and short OS (<median OS) survival time from BVZ-onset. Metabolite concentrations from tumor tissue and their ratios were compared to contralateral normal-appearing tissue (control). Before BVZ, (1)H-detectable choline signals (total GPC and PCho) in rGBMs were elevated but significance failed after dichotomizing. For metabolite ratios obtained by (31)P MRSI, the short-OS group showed higher PCho/GPC (p = 0.004) in rGBMs compared to control tissue before BVZ while PEth/GPE was elevated in rGBMs of both groups (long-OS p = 0.04; short-OS p = 0.003). Under BVZ, PCho/GPC and PEth/GPE in the tumor initially decreased (p = 0.04) but only PCho/GPC re-increased upon tumor progression (p = 0.02). Intriguingly, in normal-appearing tissue an initial PEth/GPE decrease (p = 0.047) was followed by an increase at the time of tumor progression (p = 0.031). An elevated PCho/GPC ratio in the short-OS group suggests that it is a negative predictive marker for BVZ efficacy. These gliomas may represent a malignant phenotype even growing under anti-VEGF treatment. Elevated PEth/GPE may represent an in-vivo biomarker more sensitive to GBM infiltration than MRI.
    PLoS ONE 03/2013; 8(3):e56439. DOI:10.1371/journal.pone.0056439 · 3.23 Impact Factor
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    ABSTRACT: Background Standard pre- and postcontrast (T1 + C) anatomical MR imaging is proving to be insufficient for accurately monitoring bevacizumab treatment response in recurrent glioblastoma (GBM). We present a novel imaging biomarker that detects abnormal tumor vasculature exhibiting both arterial and venous perfusion characteristics. We hypothesized that a decrease in the extent of this abnormal vasculature after bevacizumab treatment would predict treatment efficacy and overall survival.Methods Dynamic susceptibility contrast perfusion MRI was gathered in 43 patients with high-grade glioma. Independent component analysis separated vasculature into arterial and venous components. Voxels with perfusion characteristics of both arteries and veins (ie, arterio-venous overlap [AVOL]) were measured in patients with de novo untreated GBM and patients with recurrent high-grade glioma before and after bevacizumab treatment. Treated patients were separated on the basis of an increase or decrease in AVOL volume (+/-ΔAVOL), and overall survival following bevacizumab onset was then compared between +/-ΔAVOL groups.ResultsAVOL in untreated GBM was significantly higher than in normal vasculature (P < .001). Kaplan-Meier survival curves revealed a greater median survival (348 days) in patients with GBM with a negative ΔAVOL after bevacizumab treatment than in patients with a positive change (197 days; hazard ratio, 2.51; P < .05). Analysis of patients with combined grade III and IV glioma showed similar results, with median survivals of 399 days and 153 days, respectively (hazard ratio, 2.71; P < .01). Changes in T1+C volume and ΔrCBV after treatment were not significantly different across +/-ΔAVOL groups, and ΔAVOL was not significantly correlated with ΔT1+C or ΔrCBV.Conclusions The independent component analysis dynamic susceptibility contrast-derived biomarker AVOL adds additional information for determining bevacizumab treatment efficacy.
    Neuro-Oncology 02/2013; 15(4). DOI:10.1093/neuonc/nos323 · 5.56 Impact Factor
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