Kirsten Grunnet

Bevacizumab plus irinotecan in the treatment patients with progressive recurrent malignant brain tumours

Material and Methods. We retrospectively determined the efficacy and safety of a combination of bevacizumab and irinotecan in a consecutive series of 52 heavily pre-treated patients with recurrent high-grade brain tumours. Patients received bevacizumab (10 mg/kg) and irinotecan [340 mg/m2 for those receiving enzyme-inducing antiepileptic drugs (EIAEDs) and 125 mg/m2 for those not receiving EIAEDs] every 2 weeks. Fifty-two patients were included and 47 were evaluable for response. Results. Complete or partial response was observed in 25% of all cases (30% response in grade IV glioma and 15% in grade III glioma). Estimated median progression-free survival (PFS) for both grade IV and grade III glioma was 22 weeks. The 6-month PFS was 32% for all patients, 40% for grade IV glioma and 33% for grade III glioma. Estimated median overall survival was 30 weeks for all patients, 28 weeks for grade IV glioma and 32 weeks for grade III glioma. Four patients discontinued treatment because of unmanageable toxicity: cerebral haemorrhage, cardiac arrhythmia, intestinal perforation and diarrhoea, the latter resulting in death. Discussion. We conclude that the combination of bevacizumab and irinotecan shows acceptable safety and is a clinically relevant choice of therapy in heavily pre-treated patients with recurrent high-grade brain tumours.

A phase II trial with bevacizumab and irinotecan for patients with primary brain tumors and progression after standard therapy

Abstract The combination of irinotecan and bevacizumab has shown efficacy in the treatment of recurrent glioblastoma multiforme (GBM). A prospective, phase II study of 85 patients with various recurrent brain tumors was carried out. Primary endpoints were progression free survival (PFS) and response rate. Material and methods. Patients with recurrent primary brain tumors with performance status 0–2 were eligible. Intravenous bevacizumab 10 mg/kg and irinotecan 125/340 mg/m2 were administered every 14 days. Evaluation was carried out every eight weeks using MRI and Macdonald response criteria. Treatment was continued until progression. Results. In total 85 patients were included with the following histologies: GBM (n = 32), glioma WHO gr. III (n = 33), glioma WHO gr. II (n = 12) and others (n = 8). Patients received a median of four cycles. ORR (overall response rate) for glioblastoma was 25% and 59% achieved stable disease (SD). Median PFS was 5.2 months. For grade III gliomas ORR was 21% and 45% had SD. Median PFS was 3.7 months. No objective responses occurred in grade II gliomas. In the non-glioma population, one PR as well as several long PFS times were observed. Discussion and conclusion. The combination of bevacizumab and irinotecan is well tolerated and moderately efficacious in glioblastoma and glioma WHO gr. III. A majority of patients achieve at least disease stabilization. Prolonged progression-free survival in non-glioma patients warrants further research.

Prospective evaluation of angiogenic, hypoxic and EGFR-related biomarkers in recurrent glioblastoma multiforme treated with cetuximab, bevacizumab and irinotecan

Hasselbalch B, Eriksen JG, Broholm H, Christensen IJ, Grunnet K, Horsman MR, Poulsen HS, Stockhausen M‐T, Lassen U. Prospective evaluation of angiogenic, hypoxic and EGFR‐related biomarkers in recurrent glioblastoma multiforme treated with cetuximab, bevacizumab and irinotecan. APMIS 2010; 118: 585–94.

Neoadjuvant bevacizumab and irinotecan versus bevacizumab and temozolomide followed by concomitant chemoradiotherapy in newly diagnosed glioblastoma multiforme: A randomized phase II study

Abstract Background. Surgery followed by radiotherapy and concomitant and adjuvant temozolomide is standard therapy in newly diagnosed glioblastoma multiforme (GBM). Bevacizumab combined with irinotecan produces impressive response rates in recurrent GBM. In a randomized phase II study, we investigated the efficacy of neoadjuvant bevacizumab combined with irinotecan (Bev-Iri) versus bevacizumab combined with temozolomide (Bev-Tem) before, during and after radiotherapy in newly diagnosed GBM. Material and methods. After surgery, patients were randomized to Bev-Iri or Bev-Tem for eight weeks, followed by standard radiotherapy (60 Gy/30 fractions) and concomitant Bev-Iri or Bev-Tem followed by adjuvant Bev-Iri or Bev-Tem for another eight weeks. Bev-Iri: Bevacizumab and irinotecan were given every 14 days before, during and after radiotherapy. Bev-Tem: Bevacizumab was given as in Bev-Iri and temozolomide was given for five days every four weeks before and after radiotherapy and once daily during radiotherapy. The primary endpoint was response after neoadjuvant chemotherapy and a pre-specified response rate of 30% or more was considered of interest for future studies. Secondary endpoints were progression-free survival (PFS) and toxicity. Results. The response rate was 32% (95% CI 17–51%) for Bev-Tem (n = 32) and 23% (95% CI 9–44%) for Bev-Iri (n = 31) (p = 0.56). Median PFS was 7.7 and 7.3 months for Bev-Tem and Bev-Iri, respectively. Hematological toxicity was more frequent with Bev-Tem including one death from febrile neutropenia whereas non-hematological toxicity was manageable. Conclusions. Only the Bev-Tem arm met the pre-specified level of activity of interest. Our results did not indicate any benefit from Bev-Iri in first-line therapy as opposed to Bev-Tem in terms of response and PFS.

Assessment of Quantitative and Allelic MGMT Methylation Patterns as a Prognostic Marker in Glioblastoma

Methylation of the O6-methylguanine-DNA methyltransferase (MGMT) gene is a predictive and prognostic marker in newly diagnosed glioblastoma patients treated with temozolomide but how MGMT methylation should be assessed to ensure optimal detection accuracy is debated. We developed a novel quantitative methylation-specific PCR (qMSP) MGMT assay capable of providing allelic methylation data and analyzed 151 glioblastomas from patients receiving standard of care treatment (Stupp protocol). The samples were also analyzed by immunohistochemistry (IHC), standard bisulfite pyrosequencing, and genotyped for the rs1690252 MGMT promoter single nucleotide polymorphism. Monoallelic methylation was observed more frequently than biallelic methylation, and some cases with monoallelic methylation expressed the MGMT protein whereas others did not. The presence of MGMT methylation was associated with better overall survival (p = 0.006; qMSP and p = 0.002; standard pyrosequencing), and the presence of the protein was associated with worse overall survival (p = 0.009). Combined analyses of qMSP and standard pyrosequencing or IHC identified additional patients who benefited from temozolomide treatment. Finally, low methylation levels were also associated with better overall survival (p = 0.061; qMSP and p = 0.02; standard pyrosequencing). These data support the use of both MGMT methylation and MGMT IHC but not allelic methylation data as prognostic markers in patients with temozolomide-treated glioblastoma.

Angiotensinogen and HLA class II predict bevacizumab response in recurrent glioblastoma patients

Bevacizumab combination therapy is among the most frequently used treatments in recurrent glioblastoma and patients who achieve response to bevacizumab have improved survival as well as quality of life. Accordingly, the aim of this study was to identify predictive biomarkers for bevacizumab response in recurrent glioblastoma patients.

Development and validation of a prognostic model for recurrent glioblastoma patients treated with bevacizumab and irinotecan

Abstract Background Predictive markers and prognostic models are required in order to individualize treatment of recurrent glioblastoma (GBM) patients. Here, we sought to identify clinical factors able to predict response and survival in recurrent GBM patients treated with bevacizumab (BEV) and irinotecan. Material and methods A total of 219 recurrent GBM patients treated with BEV plus irinotecan according to a previously published treatment protocol were included in the initial population. Prognostic models were generated by means of multivariate logistic and Cox regression analysis. Results In multivariate analysis, corticosteroid use had a negative predictive impact on response at first evaluation (OR 0.45; 95% CI 0.22–0.93; p = 0.03) and at best response (OR 0.51; 95% CI 0.26–1.02; p = 0.056). Three significant (p < 0.05) prognostic factors associated with reduced progression-free survival and overall survival (OS) were identified. These factors were included in the final model for OS, namely corticosteroid use (HR 1.70; 95% CI 1.18–2.45; p = 0.004), neurocognitive deficit (HR 1.40; 95% CI 1.04–1.89; p = 0.03) and multifocal disease (HR 1.56; 95% CI 1.15–2.11; p < 0.0001). Based on these results a prognostic index able to calculate the probability for OS at 6 and 12 months for the individual patient was established. The predictive value of the model for OS was validated in a separate patient cohort of 85 patients. Discussion and conclusion A prognostic model for OS was established and validated. This model can be used by physicians to risk stratify the individual patient and together with the patient decide whether to initiate BEV relapse treatment.

Biomarkers in Recurrent Grade III Glioma Patients Treated with Bevacizumab and Irinotecan

ABSTRACT Predictive biomarkers and prognostic models are required to identify recurrent grade III glioma patients who benefit from existing treatment. In this study of 62 recurrent grade III glioma patients, a range of clinical and paraclinical factors are tested for association with progression-free survival, overall survival, and response to bevacizumab and irinotecan therapy. Significant factors from univariate screening are included in multivariate analysis. Biomarkers previously advanced as predictive or prognostic in the first-line setting did not affect outcome in this patient cohort. Based on the optimized model for overall survival, comprising performance status and p53 expression, a prognostic index is established.

Abstract A25: Predictive biomarkers for bevacizumab response in recurrent glioblastoma patients

BACKGROUND: Bevacizumab (BEV) plus chemotherapy has shown high response rates in recurrent glioblastoma (GBM) and patients who achieve response have an improved overall survival as well as quality of life. Recent retrospective analysis of the randomized phase III trial, AVAglio, indicate that patients with the proneural GBM subtype have a survival benefit when treated with BEV in combination with standard treatment. However, no validated biomarkers able to predict BEV response have been identified and the biology reflecting a clinical BEV response is poorly understood. The primary objective of this study was to evaluate the predictive and prognostic value of GBM subtypes in recurrent GBM patients treated with BEV therapy. The secondary objective was to identify biomarkers able to predict response to BEV therapy in recurrent GBM patients. METHODS: A total of 90 recurrent GBM patients treated with BEV combination treatment according to a previously published treatment protocol were included. Inclusion criteria: BEV plus irinotecan treatment in the period between May 2005-2011; available GBM tissue (according to WHO); response evaluable (RANO). RNA from tumor tissue was analyzed by the NanoString platform covering 800 genes. Raw data was assigned to molecular subtypes for each of the samples using the PAMR classifier model, previously trained on the AVAglio dataset. In order to identify novel candidate biomarkers able to predict response, differentially expressed genes (fold-change difference > 1.5) between patients responding versus progressing on BEV were identified using a t-test. Biomarkers significantly (P Citation Format: Thomas Urup, Signe Regner Michaelsen, Lars Ronn Olsen, Anders Toft, Ib Jarle Christensen, Kirsten Grunnet, Helle Broholm, Michael Kosteljanetz, Shohreh Issazadeh-Navikas, Hans Skovgaard Poulsen, Ulriik Lassen. Predictive biomarkers for bevacizumab response in recurrent glioblastoma patients. [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 A25.

Abstract B3: Prognostic and predictive biomarkers in recurrent WHO grade 3 malignant glioma patients treated with bevacizumab and irinotecan

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 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.