Silvia Hofer

NovoTTF-100A versus physician's choice chemotherapy in recurrent glioblastoma: A randomised phase III trial of a novel treatment modality

PURPOSE NovoTTF-100A is a portable device delivering low-intensity, intermediate frequency electric fields via non-invasive, transducer arrays. Tumour Treatment Fields (TTF), a completely new therapeutic modality in cancer treatment, physically interfere with cell division. METHODS Phase III trial of chemotherapy-free treatment of NovoTTF (20-24h/day) versus active chemotherapy in the treatment of patients with recurrent glioblastoma. Primary end-point was improvement of overall survival. RESULTS Patients (median age 54 years (range 23-80), Karnofsky performance status 80% (range 50-100) were randomised to TTF alone (n=120) or active chemotherapy control (n=117). Number of prior treatments was two (range 1-6). Median survival was 6.6 versus 6.0 months (hazard ratio 0.86 [95% CI 0.66-1.12]; p=0.27), 1-year survival rate was 20% and 20%, progression-free survival rate at 6 months was 21.4% and 15.1% (p=0.13), respectively in TTF and active control patients. Responses were more common in the TTF arm (14% versus 9.6%, p=0.19). The TTF-related adverse events were mild (14%) to moderate (2%) skin rash beneath the transducer arrays. Severe adverse events occurred in 6% and 16% (p=0.022) of patients treated with TTF and chemotherapy, respectively. Quality of life analyses favoured TTF therapy in most domains. CONCLUSIONS This is the first controlled trial evaluating an entirely novel cancer treatment modality delivering electric fields rather than chemotherapy. No improvement in overall survival was demonstrated, however efficacy and activity with this chemotherapy-free treatment device appears comparable to chemotherapy regimens that are commonly used for recurrent glioblastoma. Toxicity and quality of life clearly favoured TTF.

A specific miRNA signature in the peripheral blood of glioblastoma patients

J. Neurochem. (2011) 118, 449–457.

Pathway Analysis of Glioblastoma Tissue after Preoperative Treatment with the EGFR Tyrosine Kinase Inhibitor Gefitinib—A Phase II Trial

Amplification of the epidermal growth factor receptor (EGFR) gene is one of the most common oncogenic alterations in glioblastoma (45%) making it a prime target for therapy. However, small molecule inhibitors of the EGFR tyrosine kinase showed disappointing efficacy in clinical trials for glioblastoma. Here we aimed at investigating the molecular effects of the tyrosine kinase inhibitor gefitinib on the EGFR signaling pathway in human glioblastoma. Twenty-two patients selected for reoperation of recurrent glioblastoma were treated within a phase II trial for 5 days with 500 mg gefitinib before surgery followed by postoperative gefitinib until recurrence. Resected glioblastoma tissues exhibited high concentrations of gefitinib (median, 4.1 μg/g), 20 times higher than respective plasma. EGFR-pathway activity was evaluated with phosphorylation-specific assays. The EGFR was efficiently dephosphorylated in treated patients as compared to a control cohort of 12 patients. However, no significant effect on 12 pathway constituents was detected. In contrast, in vitro treatment of a glioblastoma cell line, BS-153, with endogenous EGFRwt amplification and EGFRvIII expression resulted not only in dephosphorylation of the EGFR, but also of key regulators in the pathway such as AKT. Treating established xenografts of the same cell line as an in vivo model showed dephosphorylation of the EGFR without affecting downstream signal transductors, similar to the human glioblastoma. Taken together, gefitinib reaches high concentrations in the tumor tissue and efficiently dephosphorylates its target. However, regulation of downstream signal transducers in the EGFR pathway seems to be dominated by regulatory circuits independent of EGFR phosphorylation. Mol Cancer Ther; 10(6); 1102–12. ©2011 AACR.

Local Targeting of Malignant Gliomas by the Diffusible Peptidic Vector 1,4,7,10-Tetraazacyclododecane-1-Glutaric Acid-4,7,10-Triacetic Acid-Substance P

Purpose: Malignant glial brain tumors consistently overexpress neurokinin type 1 receptors. In classic seed-based brachytherapy, one to several rigid 125I seeds are inserted, mainly for the treatment of small low-grade gliomas. The complex geometry of rapidly proliferating high-grade gliomas requires a diffusible system targeting tumor-associated surface structures to saturate the tumor, including its margins. Experimental Design: We developed a new targeting vector by conjugating the chelator 1,4,7,10-tetraazacyclododecane-1-glutaric acid-4,7,10-triacetic acid to Arg1 of substance P, generating a radiopharmaceutical with a molecular weight of 1,806 Da and an IC50 of 0.88 ± 0.34 nmol/L. Cell biological studies were done with glioblastoma cell lines. neurokinin type-1 receptor (NK1R) autoradiography was done with 58 tumor biopsies. For labeling, 90Y was mostly used. To reduce the “cross-fire effect” in critically located tumors, 177Lut and 213Bi were used instead. In a pilot study, we assessed feasibility, biodistribution, and early and long-term toxicity following i.t. injection of radiolabeled 1,4,7,10-tetraazacyclododecane-1-glutaric acid-4,7,10-triacetic acid substance P in 14 glioblastoma and six glioma patients of WHO grades 2 to 3. Results: Autoradiography disclosed overexpression of NK1R in 55 of 58 gliomas of WHO grades 2 to 4. Internalization of the peptidic vector was found to be specific. Clinically, the radiopharmeutical was distributed according to tumor geometry. Only transient toxicity was seen as symptomatic radiogenic edema in one patient (observation period, 7-66 months). Disease stabilization and/or improved neurologic status was observed in 13 of 20 patients. Secondary resection disclosed widespread radiation necrosis with improved demarcation. Conclusions: Targeted radiotherapy using diffusible peptidic vectors represents an innovative strategy for local control of malignant gliomas, which will be further assessed as a neoadjuvant approach.

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

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. Ann Neurol 2010;69:586–592

Clinical outcome with bevacizumab in patients with recurrent high-grade glioma treated outside clinical trials

Abstract Background. Patients with recurrent high-grade glioma (HGG) have a poor prognosis and there is no defined standard of care. High levels of vascular endothelial growth factor (VEGF) expressed in HGG make the anti-VEGF monoclonal antibody bevacizumab (BEV) of particular interest. Patients and methods. In an ongoing registry data were collected from patients who have received BEV for the treatment of recurrent HGG. The primary objective was the identification of any clinical benefit as assessed by change in Karnofsky Performance Score (KPS), decreased steroid use and duration of treatment. Results. Two hundred and twenty-five patients with HGG were included (176 glioblastoma; 49 anaplastic glioma; median age 52 years). KPS improved in 10% of patients and remained stable in 68%. Steroids were stopped in 37.6% of patients. Median duration of treatment was 5.5 months; 19.1% of patients were treated for more than 12 months. Median overall survival from beginning of BEV treatment was 8.5 months. At the time of analysis, 169 patients (75.1%) had died and 56 patients (24.9%) were alive. Only 21 patients (9.3%) discontinued treatment due to toxicity. Conclusions. Our data reveal valuable palliation with preservation of KPS and an option for steroid withdrawal in patients treated with BEV, supporting the role of this therapy in late-stage disease.

Gefitinib concentrations in human glioblastoma tissue.

well investigated and studies analyzing drug concentrations in human tumor tissue, especially in the brain, are scarce. In our institution, we have the opportunity to directly measure anticancer drug concentrations in glioblastoma (GBM) tumor tissue in correlation to plasma concentration. GBM patients with a relapse, however in good performance status are offered secondary surgery where appropriate and participation in a prospective trial with gefitinib [1]. Gefitinib is currently under scrutiny for the treatment of high grade glioma [2]. At least 5 days before re-operation, patients receive gefitinib 500 mg daily continuously until tumor progression or intolerable side effects. Patients on cytochrome P450 isoenzyme CYP3A4-inducing antiepileptic drugs (EIAE) have to change to a nonenzyme-inducing drug, due to predicted ensuing interactions of EIAE with gefitinib metabolism, reducing its systemic availability. The trial is approved by the local ethic committee and is registered within the National Library of Medicine Clinical Trials Database (www.clinicaltrials.gov, NCT00250887). Here we report on surprisingly high tumor tissue levels of gefitinib from the first seven patients (Table 1). Tumor tissue and blood samples were snap frozen immediately upon removal and stored at –70 C for analysis (Laboratory Analytico Medinet B.V., Breda, NL). High performance liquid chromatography coupled to tandem mass spectroscopy was performed to determine drug concentrations, as described previously [3]. To our knowledge this is the first consecutive series of gefitinib concentrations in human brain tumor tissue. We suggest, that higher drug exposure is not required to treat glioma patients. Further translational research will be performed with the tumor material to correlate responding patients to their tumor EGFR pathway activity and to define molecular markers predictive for response. Table 1 Gefitinib tumor and plasma concentrations

Spatial Heterogeneity of Low-Grade Gliomas at the Capillary Level: A PET Study on Tumor Blood Flow and Amino Acid Uptake

Many low-grade gliomas (World Health Organization grade II) respond to chemotherapy. Cerebral blood flow (CBF) and microvessel density may be critical for drug delivery. We used PET with 18F-fluoro-ethyl-l-tyrosine (FET) to measure the spatial distribution of the amino acid carrier, which is located at the brain capillaries, and 15O-H2O to measure tumor CBF. Methods: Seventeen patients with low-grade glioma were studied. Region-of-interest (ROI) analysis was used to quantify tumor tracer uptake, which was normalized to cerebellar uptake (tumor-to-cerebellum ratio). “Active” tumor was defined as tumor having a radioactivity concentration that was at least 110% of the cerebellar activity. This threshold provided measures of active tumor volume, global and peak tumor CBF, and 18F-FET uptake. Trace ROIs were applied to create voxelwise profiles of CBF and 18F-FET uptake across tumor and brain. Standard MRI sequences were used for spatial correlations. Results: Fourteen of 17 tumors showed increased global CBF and 18F-FET uptake. Active tumor volumes ranged between 3 and 270 cm3 for 18F-FET and between 1 and 41 cm3 for CBF. Global 18F-FET uptake in tumors corresponded to CBF increases (Spearman rank ρ = 0.771, P < 0.01). The volumes of increased CBF and 18F-FET uptake spatially coincided and were also correlated (ρ = 0.944, P < 0.01). Trace ROIs showed that irrespective of increased 18F-FET uptake at the tumor periphery, CBF increases were more confined to the tumor center. Within individual tumors, spatial heterogeneity was present. Particular tumors infiltrating the corpus callosum showed low CBF and 18F-FET uptake in this tumor region. The patterns observed with PET were not reflected on MRI of the tumors, all of which presented as homogeneous non–gadolinium-enhancing lesions. Conclusion: Low-grade gliomas are heterogeneous tumors with regard to the distribution of amino acid uptake and CBF. Both are coupled in the tumor center. At the tumor periphery, where tumor infiltration of surrounding brain occurs, CBF may be low irrespective of increased 18F-FET uptake. An ongoing study is investigating the effect of chemotherapy on these observations.

Glioblastoma in the Canton of Zurich, Switzerland revisited: 2005 to 2009.

A population‐based analysis of patients with glioma diagnosed between 1980 and 1994 in the Canton of Zurich in Switzerland confirmed the overall poor prognosis of glioblastoma. To explore changes in outcome, registry data were reevaluated for patients diagnosed between 2005 and 2009.

Patupilone (epothilone B) for recurrent glioblastoma: clinical outcome and translational analysis of a single-institution phase I/II trial.

Background: Patients with glioblastoma (GBM) inevitably develop recurrent or progressive disease after initial multimodal treatment and have a median survival of 6–9 months from time of progression. To date, there is no accepted standard treatment for GBM relapse or progression. Patupilone (EPO906) is a novel natural microtubule-stabilizing cytotoxic agent that crosses the blood-brain barrier and has been found to have preclinical activity in glioma models. Methods: This is a single-institution, early-phase I/II trial of GBM patients with tumor progression who qualified for second surgery with the goal of evaluating efficacy and safety of the single-agent patupilone (10 mg/m2, every 3 weeks). Patients received patupilone 1 week prior to second surgery and every 3 weeks thereafter until tumor progression or toxicity. Primary end points were progression-free survival (PFS) and overall survival (OS) at 6 months as well as patupilone concentration in tumor tissue. Secondary end points were toxicity, patupilone concentration in plasma and translational analyses for predictive biomarkers. Results: Nine patients with a mean age of 54.6 ± 8.6 years were recruited between June 2008 and April 2010. Median survival and 1-year OS after second surgery were 11 months (95% CI, 5–17 months) and 45% (95% CI, 14–76), respectively. Median PFS was 1.5 months (95% CI, 1.3–1.7 months) and PFS6 was 22% (95% CI, 0–46), with 2 patients remaining recurrence-free at 9.75 and 22 months. At the time of surgery, the concentration of patupilone in tumor tissue was 30 times higher than in the plasma. Tumor response was not predictable by the tested biomarkers. Treatment was generally well tolerated with no hematological, but cumulative, though reversible sensory neuropathy grade ≤3 was seen in 2 patients (22%) at 8 months and grade 4 diarrhea in the 2nd patient (11%). Non-patupilone-related peri-operative complications occurred in 2 patients resulting in discontinuation of patupilone therapy. There were no neurocognitive changes 3 months after surgery compared to baseline. Conclusions: In recurrent GBM, patupilone can be given safely pre- and postoperatively. The drug accumulates in the tumor tissue. The treatment results in long-term PFS in some patients. Patupilone represents a valuable novel compound which deserves further evaluation in combination with radiation therapy in patients with GBM.