Treatment of high-grade glioma with radiolabeled peptides.

The management of high-grade glioma (HGG) patients in clinical routine represents a challenging task. HGG has a poor prognosis because of early recurrence or therapy-refractory disease following first-line standard therapy, which includes a multidisciplinary approach involving radical surgical resection followed by external beam radiation therapy in combination with chemotherapy. Glioma cells are known to express specific receptors or glycoproteins on their surface which can be used as biological targets for treatment. The application of radiopharmaceuticals consisting of a targeting and an effector domain has led to the introduction of new treatment approaches, aiming at a tumor-specific treatment sparing normal brain tissue. One of these new modalities is the peptide receptor radionuclide therapy (PRRT). Peptides labeled with radioactive nuclides can bind directly to the tumor cells and deliver high doses of radioactivity directly to the tumor tissue. This article reviews the literature for PRRT in HGG.

ADC histograms predict response to anti-angiogenic therapy in patients with recurrent high-grade glioma.

INTRODUCTION: The purpose of this study is to evaluate apparent diffusion coefficient (ADC) maps to distinguish anti-vascular and anti-tumor effects in the course of anti-angiogenic treatment of recurrent high-grade gliomas (rHGG) as compared to standard magnetic resonance imaging (MRI). METHODS: This retrospective study analyzed ADC maps from diffusion-weighted MRI in 14 rHGG patients during bevacizumab/irinotecan (B/I) therapy. Applying image segmentation, volumes of contrast-enhanced lesions in T1 sequences and of hyperintense T2 lesions (hT2) were calculated. hT2 were defined as regions of interest (ROI) and registered to corresponding ADC maps (hT2-ADC). Histograms were calculated from hT2-ADC ROIs. Thereafter, histogram asymmetry termed "skewness" was calculated and compared to progression-free survival (PFS) as defined by the Response Assessment Neuro-Oncology (RANO) Working Group criteria. RESULTS: At 8-12 weeks follow-up, seven (50%) patients showed a partial response, three (21.4%) patients were stable, and four (28.6%) patients progressed according to RANO criteria. hT2-ADC histograms demonstrated statistically significant changes in skewness in relation to PFS at 6 months. Patients with increasing skewness (n = 11) following B/I therapy had significantly shorter PFS than did patients with decreasing or stable skewness values (n = 3, median percentage change in skewness 54% versus -3%, p = 0.04). CONCLUSION: In rHGG patients, the change in ADC histogram skewness may be predictive for treatment response early in the course of anti-angiogenic therapy and more sensitive than treatment assessment based solely on RANO criteria.

Management of recurrent malignant glioma--neurosurgical strategies.

There is currently no standard for neurosurgical interventions in patients with recurrent high grade gliomas. An individualized approach is recommended as well for decision-making as for planning an intervention with resection of the outmost possible amount of tumor tissue while preserving neurological function and thus quality of life. Recent technical developments of imaging and of neuronavigation and visualization of tumor tissue with in vivo fluorescence with 5-Ala have proved helpful in improving symptoms and prolonging survival times also for patients with recurrent malignant gliomas.

Axl and growth arrest-specific gene 6 are frequently overexpressed in human gliomas and predict poor prognosis in patients with glioblastoma multiforme.

PURPOSE: The receptor tyrosine kinase Axl has recently been identified as a critical element in the invasive properties of glioma cell lines. However, the effect of Axl and its ligand growth arrest--specific gene 6 (Gas6) in human gliomas is still unknown. EXPERIMENTAL DESIGN: Axl and Gas6 expression was studied in 42 fresh-frozen and 79 paraffin-embedded glioma specimens by means of reverse transcription-PCR and immunohistochemistry. The prognostic value of Axl and Gas6 expression was evaluated using a population-based tissue microarray derived from a cohort of 55 glioblastoma multiforme (GBM) patients. RESULTS: Axl and Gas6 were detectable in gliomas of malignancy grades WHO 2 to 4. Moderate to high Axl mRNA expression was found in 61%, Axl protein in 55%, Gas6 mRNA in 81%, and Gas6 protein in 74% of GBM samples, respectively. GBM patients with high Axl expression and Axl/Gas6 coexpression showed a significantly shorter time to tumor progression and an association with poorer overall survival. Comparative immunohistochemical studies showed that Axl staining was most pronounced in glioma cells of pseudopalisades and reactive astrocytes. Additionally, Axl/Gas6 coexpression was observed in glioma cells and tumor vessels. In contrast, Axl staining was not detectable in nonneoplastic brain tissue and Gas6 was strongly expressed in neurons. CONCLUSIONS: In human gliomas, Axl and Gas6 are frequently overexpressed in both glioma and vascular cells and predict poor prognosis in GBM patients. Our results indicate that specific targeting of the Axl/Gas6 signaling pathway may represent a potential new approach for glioma treatment.

In vitro investigation on the pH dependence of the absorption and fluorescence properties of the photosensitizer mTHPC.

Fluorescence excitation efficiency is of great importance for photodynamic diagnosis. Because usually a difference in the interstitial pH between normal and tumor tissue occurs, it is necessary to assess the impact of pH on the fluorescence emission intensity of the photosensitizer meta-tetrahydroxyphenylchlorin (mTHPC) in this context. The results obtained by in vitro fluorescence measurements clearly indicate that pH values below 6 lead to a significant decrease in the fluorescence intensity. In the physiological range of pH 6.5-7.2, however, no pH dependence was found. Besides the decrease in the fluorescence intensity of mTHPC for pH < 6, changes in the spectral shape of the absorption were found. These changes can be utilized for "dual-wavelength ratio imaging," using mTHPC as a pH-sensitive indicator with the excitation pair 405 nm/436 nm in the range of pH 3.5-6.

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.

O-(2-18F-fluoroethyl)-L-tyrosine PET predicts failure of antiangiogenic treatment in patients with recurrent high-grade glioma.

UNLABELLED: The objective of this study was to compare MRI response assessment with metabolic O-(2-(18)F-fluoroethyl)-L-tyrosine ((18)F-FET) PET response evaluation during antiangiogenic treatment in patients with recurrent high-grade glioma (rHGG). METHODS: Eleven patients with rHGG were treated biweekly with bevacizumab-irinotecan. MR images and (18)F-FET PET scans were obtained at baseline and at follow-up 8-12 wk after treatment onset. MRI treatment response was evaluated by T1/T2 volumetry according to response assessment in neurooncology (RANO) criteria. For (18)F-FET PET evaluation, an uptake reduction of more than 45% calculated with a standardized uptake value of more than 1.6 was defined as a metabolic response (receiver-operating-characteristic curve analysis). MRI and (18)F-FET PET volumetry results and response assessment were compared with each other and in relation to progression-free survival (PFS) and overall survival (OS). RESULTS: At follow-up, MR images showed partial response in 7 of 11 patients (64%), stable disease in 2 of 11 patients (18%), and tumor progression in 2 of 11 patients (18%). In contrast, (18)F-FET PET revealed 5 of 11 metabolic responders (46%) and 6 of 11 nonresponders (54%). MRI and (18)F-FET PET showed that responders survived significantly longer than did nonresponders (10.24 vs. 4.1 mo, P = 0.025, and 7.9 vs. 2.3 mo, P = 0.015, respectively). In 4 patients (36.4%), diagnosis according to RANO criteria and (18)F-FET PET was discordant. In these cases, PET was able to detect tumor progression earlier than was MRI. CONCLUSION: In rHGG patients undergoing antiangiogenic treatment, (18)F-FET PET seems to be predictive for treatment failure in that it contributes important information to response assessment based solely on MRI and RANO criteria.

Photodynamic diagnosis and therapy and the brain.

Photodynamic techniques such as photodynamic diagnosis (PDD), fluorescence-guided tumour resection (FGR) and photodynamic therapy (PDT) are currently undergoing intensive clinical investigations as adjuvant treatment for malignant brain tumours. The following chapter provides an overview on the current clinical data and trials of PDT as well as photosensitizers, technical developments and indications for photodynamic application in neurosurgery. Besides many clinical phase I/II trials for PDT for malignant brain tumours, there are only few controlled clinical trials following tumour resection. Variations in treatment protocols, variation of photosensitizers and light dose make the evaluation scientifically difficult; however there is a clear trend towards prolonging median survival after one single photodynamic treatment as compared to standard therapeutic regimens. According to the meta analysis the median survival after PDT for primary glioblastoma multiforme (WHO grade IV) was 22 months and for recurrent GBM was 9 months as compared to standard conventional treatment, in which it is 15 and 3 months, respectively. Fluorescence-guided resection of the tumour demonstrated significant greater reduction of tumour burden. The combination of PDD/ FGR and intraoperative PDT ("to see and to treat") offers an exciting approach to the treatment of malignant brain tumours. PDT was generally well tolerated and side effects consisted of occasionally increased intracranial pressure and prolonged skin sensitivity against direct sunlight.

Response of recurrent high-grade glioma to treatment with (90)Y-DOTATOC.

UNLABELLED: The treatment of patients with high-grade malignant glioma still represents an unsolved clinical problem. We report the treatment of 3 patients who had World Health Organization grade IV recurrent glioblastoma: a 23-y-old woman and 2 men aged 61 and 62 y. METHODS: All 3 patients were treated with the somatostatin receptor radiopharmaceutical (90)Y-labeled [1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid(0)-d-Phe(1),Tyr(3)]octreotide (DOTATOC). A cumulated dose of 1.7-2.2 GBq given in 3 or 4 cycles was locally injected into a previously implanted catheter system. RESULTS: Treatment was successful in all 3 patients, with only minor side effects reported. After treatment, MRI and PET showed complete remission in one patient and partial remission in the other patients. These findings correlated well with clinical improvement and improved quality of life. CONCLUSION: Receptor-mediated radionuclide therapy by locally injected (90)Y-DOTATOC is feasible and well tolerated. This approach represents an attractive strategy for the treatment of locally recurring or progressing glioblastoma.

[Surgical intervention in patients with malignant glioma]. / Neurochirurgische Therapie maligner Gliome.

Glial tumors occur at an incidence from 2 to 10/ 100.000 (Japan vs. Sweden) and building up to 50 % of all patients suffering from brain tumors. 50 % of those are again malignant gliomas Grade III and Grade IV. Despite all therapeutic approaches the median survival for glioblastomas is 15 months and for anaplastic gliomas Grade III 30 months. After diagnosis, preferably by MRI, a neurosurgical procedure is performed under microsurgical guidelines mostly by means of neuronavigation and intraoperative guidance. Depending on the preoperative diagnosis and localisation of the pathologic lesion an open craniotomy or a stereotactic biopsy is performed. This allows the histological verification and decompression and cytoreduction. A gros total safe removal preserving neurological function is the most important goal of surgery. Tumor removal in eloquent areas such as speech area is performed under local anesthesia as an awake operation. Age, Karnofsky performance status, histology as well as radical removal have a significant influence on overall survival. Adjuvant radiotherapy and chemotherapy with Temozolemide have further improved the outcome significantly. The 2-year survival has reached 28 % in most recent studies. Further experimental therapies in controlled trials, such as intratumoral convection-enhanced instillation of immunotoxins and radiopeptids, photodynamic therapy and direct instillation of new formulations of chemotherapeutic drugs (e. g. nanoparticles) are promising new approaches. New developments in the treatment of patients harboring malignant brain tumors allow an individual neurooncological treatment concept to be established to enhance overall survival and quality of life.