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Purpose: PET with somatostatin receptor ligand [68Ga]Ga-DOTA-D-Phe1-Tyr3-octreotide ([68Ga]Ga-DOTA-TOC) is an established method in radiotherapy planning because of the improved detection and delineation of meningioma tissue. We investigated the diagnostic accuracy of supplementary [68Ga]Ga-DOTA-TOC PET in patients with a 3-month postoperative MRI reporting gross-total resection (GTR). Experimental Design: Thirty-seven patients with a histologically proven meningioma and GTR on postoperative MRI were prospectively referred to [68Ga]Ga-DOTA-TOC PET. Detection and volume measurements of [68Ga]Ga-DOTA-TOC-avid lesions in relation to the primary tumor site were recorded. Residual tumor in suspicious lesions suggested by [68Ga]Ga-DOTA-TOC PET was verified by (i) tumor recurrence/progression on subsequent MRI scans according to the Response Assessment of Neuro-Oncology criteria, (ii) subsequent histology, and (iii) follow-up [68Ga]Ga-DOTA-TOC PET scan. Results: Twenty-three PET scans demonstrated [68Ga]Ga-DOTA-TOC-avid lesions suspicious of residual meningioma, where 18 could be verified by (i) tumor progression on subsequent MRI scans (n = 6), (ii) histologic confirmation (n = 3), and (iii) follow-up [68Ga]Ga-DOTA-TOC PET scans confirming the initial PET findings (n = 9) after an overall median follow-up time of 17 months (range, 9–35 months). In contrast, disease recurrence was seen in only 2 of 14 patients without [68Ga]Ga-DOTA-TOC-avid lesions (P < 0.0001). The sensitivity, specificity, and diagnostic accuracy of [68Ga]Ga-DOTA-TOC PET in detecting meningioma residue was 90% [95% confidence interval (CI), 67–99], 92% (95% CI, 62–100), and 90% (95% CI, 74–98; P < 0.0001), respectively. Conclusions: The majority of patients with GTR on 3-month postoperative MRI may have small unrecognized meningioma residues that can be detected using [68Ga]Ga-DOTA-TOC PET.

BACKGROUND Bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor A (VEGF-A), has demonstrated activity in the treatment of recurrent malignant glioma. High response rates have been observed, but particularly in WHO grade 3 gliomas, efforts to identify predictors of clinical response have been limited. Predictive markers and prognostic models are required in order to individualize treatment for this patient population. The primary endpoint of this study was to identify predictive biomarkers associated with response to bevacizumab therapy. The secondary endpoint was to identify prognostic factors associated with progression-free survival (PFS) and overall survival (OS). METHODS A total of 62 consecutive, recurrent grade 3 glioma patients were retrospectively evaluated. Eligible patients from our center had a WHO performance status of 0-2 and were administered bevacizumab and irinotecan between December 2005 and November 2014 according to a previously published clinical protocol. Baseline factors screened for potential prognostic and predictive value included: Age, gender, PS, WHO grade 3 diagnosis, tumor size and location, multifocal disease, extent of resection, number of prior chemotherapy regiments, response to prior chemotherapy, first-line treatment, number of previous recurrences, neurological deficit, corticosteroid use, necrosis, vascular proliferation, neutrophil-to-lymphocyte ratio, and expression of p53, EGFR, MIB-1, MGMT, IDH1 and ATRX. Candidate factors with p-values below 5% were considered for multivariate analysis. Prognostic models were generated by logistic regression and Cox regression, modelling response and survival endpoints. RESULTS Twenty-two patients (35.5%) demonstrated a response according to the RANO criteria. Responders had significantly prolonged OS (p = 0.007) and trended toward longer PFS (p = 0.067) as compared to non-responders (OS: 12.4 vs 4.3 months, PFS: 5.6 vs 3.2 months). Presence of necrosis (OR: 0.17, CI: 0.04-0.68, p = 0.012) and a WHO performance status (PS) of more than 1 (OR: 0.04, CI: 0.002-0.89, p = 0.042) were more common in non-responders than responders. Female gender (HR: 0.48, CI: 0.28-0.82, p = 0.008) and a PS of 0-1 (HR: 0.20, CI: 0.10-0.41, p < 0.0001) were identified as positive prognostic factors for PFS. Immunohistochemical p53 negativity (HR: 0.47, CI: 0.26-0.87, p = 0.016) and low PS (HR: 0.17, CI: 0.07-0.39, p < 0.0001) correlated with extended OS and these factors were included in a prognostic model. CONCLUSIONS A favorable baseline PS and absence of necrosis were positively associated with response to bevacizumab treatment in recurrent grade 3 glioma patients. Low PS, female gender and p53 negativity are prognostic of improved outcome in this patient group. Citation Format: Anders Toft, Thomas Urup, Ib J. Christensen, Signe R. Michaelsen, Babloo S. Lukram, Kirsten Grunnet, Michael Kosteljanetz, Vibeke A. Larsen, Ulrik Lassen, Helle Broholm, Hans S. Poulsen. Prognostic and predictive biomarkers in recurrent WHO grade 3 malignant glioma patients treated with bevacizumab and irinotecan. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B3.

Background: Bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor A (VEGF-A), has proven activity in treatment of recurrent high-grade glioma. High response rates have been demonstrated, but particularly in WHO grade 3 malignant gliomas, efforts to identify predictors of clinical response have been limited. Predictive biomarkers and prognostic models are required in order to individualize treatment for this patient population. The primary end-point of this study was identification of prognostic and potentially predictive clinical and paraclinical factors of response. The secondary end-point was to identify prognostic factors associated with progression-free survival (PFS) and overall survival (OS). Materials and methods: A total of 64 recurrent grade 3 glioma patients treated with bevacizumab and irinotecan were retrospectively evaluated. Eligible patients from our center had a WHO performance status of 0-2 and were administered bevacizumab and irinotecan between December 2005 and November 2014 according to a previously published clinical protocol. The possibly relevant prognostic baseline factors screened for included: Age, gender, WHO grade 3 diagnosis, tumor size and location, multifocal disease, extent of resection, number of prior chemotherapy regiments, response to prior chemotherapy, first-line treatment, number of previous recurrences, neurological deficit, corticosteroid use, performance status, necrosis, vascular proliferation, neutrophil-to-lymphocyte ratio, and expression of p53, EGFR, Mib-1, MGMT, IDH-1 and ATRX. Candidate factors were subjected to univariate analysis and factors with P-values below 0.10 were considered for multivariate analysis. Prognostic models were generated by logistic regression and Cox regression, modeling response and survival end-points. P-values below 0.05 were considered statistically significant. Results will be presented. Citation Format: Anders Toft, Thomas Urup, Kirsten Grunnet, Ib J. Christensen, Signe R. Michaelsen, Helle Broholm, Vibeke A. Larsen, Michael Kosteljanetz, Ulrik Lassen, Hans S. Poulsen. Prognostic and predictive biomarkers of clinical response to Bevacizumab in recurrent WHO grade 3 malignant glioma patients. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5310. doi:10.1158/1538-7445.AM2015-5310