FMISO-PET in Brain Tumors and SCS Effect

Study Overview
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Brief Summary
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The aim of this study is to assess, with 18F-FMISO PET, hypoxia in high grade gliomas and changes by spinal cord stimulation in a subset of patients. Additionally, the potential correlation with pathological, imaging and clinical parameters will be analyzed.

Detailed Description
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Tumour ischaemia-hypoxia decreases the efficacy of radio-chemotherapy. Polarographic probe (and some 18F-FMISO-PET) studies have demonstrated prognostic value. Additionally hypoxia modification may increase survival. However, in high grade gliomas (HGG) there are not well established methods to evaluate and modify tumor hypoxia. We have previously described how spinal cord stimulation (SCS) can modify oxygenation, blood flow and metabolism in malignant gliomas. The aim of this study is to assess with 18F-FMISO PET: hypoxia in HGG and changes by spinal cord stimulation in a subset of patients. Additionally, the potential correlation with pathological, imaging and clinical parameters will be analyzed. 18F-FMISO PET will be performed in 20 patients with diagnosis of HGG: after surgery/biopsy and before radical treatment with 3D radiotherapy and temozolomide. A subset of 10 patients undergo two studies with 18F- FMISO-PET (one with SCS off and one with SCS on). In these patients, SCS will be connected from 1 hour before to 1 hour after each radiotherapy session, and in the day-time during the days of adjuvant temozolomide. 18F-FMISO PET results will not be taking into account for patient management. Patients will be followed at least until the end of adjuvant temozolomide (6 months after the end of concurrent radiochemotherapy).

Official Title
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Positron Emission Tomography With Fluoro-misonidazole (PET-FMISO) in High Grade Gliomas: Assessment of Tumor Hypoxia and Effect of Spinal Cord Stimulation

Conditions
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Malignant Glioma

Intervention / Treatment
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* Drug: 18F-FMISO
* Procedure: PET without SCS
* Device: SCS
* Procedure: PET without/with SCS
* Radiation: Radiotherapy
* Drug: Temozolomide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with pathologically confirmed (first presentation or relapsed) high grade glioma (Grade III or Grade IV according WHO criteria) proposed for radical treatment with 3D radiotherapy and temozolomide. Patients 18-75 years old. Karnofsky >= 60% and ECOG =< 2. Signed informed consent. Exclusion Criteria: Clinical or psychological contraindications to fly (if 18F-FMISO-PET is realized in Madrid) or to SCS-placement (only for this subset). Pregnant or breastfeeding women and women of fertile age who are not using a safe contraceptive method or do not intend to use one during the trial. Safe contraceptive methods are oral or parenteral contraceptive treatments or barrier methods: masculine or feminine condom, diaphragm and/or intrauterine device (IUD) or withdrawal over the course of the study. Serious co-existing or concurrent illness, including any of the following: uncontrolled or severe infection, heart, liver or kidney disease Lung thromboembolism. Another malignancy in the last 5 years other than basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix. Patients with life expectancy <3 months. Patients with any of the following: creatinine > 2 mg/dl, neutrophils <1.5 * 10^9/L, platelets <100 * 10^9/L or hemoglobin <8.5 g/dL. Contraindications to receive radiotherapy or chemotherapy Clinical or psychological contraindications for placement of spinal cord stimulation devices (only for that specific subset of patients). Patients who are unable or unwilling to meet the protocol study. Patients who do not meet all the inclusion criteria.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Arm-A: 18F-FMISO-PET without SCS<br>One 18F-FMISO-PET study for assessment of tumor hypoxia before radiotherapy and Temozolomide, without spinal cord stimulation. | Drug: 18F-FMISO<br>* 18F-FMISO-PET scanning, for tumor hypoxia assessment before radio-chemotherapy.<br>* Other names: FMISO;Procedure: PET without SCS<br>* PET-scanning using 18F-fluoromisonidazole without SCS<br>* Other names: Positron emission tomography scanning;Radiation: Radiotherapy<br>* Standard radiation therapy<br>* Other names: Radiation therapy;Drug: Temozolomide<br>* Standard treatment with concurrent and adjuvant Temozolomide.<br>* Other names: Temcad;|
| Other: Arm-B: 18F-FMISO-PET without/with SCS<br>Two 18F-FMISO-PET studies for assessment of tumor hypoxia before radiotherapy and Temozolomide: one without and one with spinal cord stimulation | Drug: 18F-FMISO<br>* 18F-FMISO-PET scanning, for tumor hypoxia assessment before radio-chemotherapy.<br>* Other names: FMISO;Procedure: PET without SCS<br>* PET-scanning using 18F-fluoromisonidazole without SCS<br>* Other names: Positron emission tomography scanning;Device: SCS<br>* Electrical stimulation of spinal cord, minimally invasive neurosurgical technique used to treat refractory pain and ischemic syndromes.<br>* Other names: Spinal Cord Stimulation;Procedure: PET without/with SCS<br>* Second PET-scanning using 18F-fluoromisonidazole: without/with SCS<br>* Other names: Positron emission tomography scanning;Radiation: Radiotherapy<br>* Standard radiation therapy<br>* Other names: Radiation therapy;Drug: Temozolomide<br>* Standard treatment with concurrent and adjuvant Temozolomide.<br>* Other names: Temcad;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tumor hypoxia measurement using 18F-FMISO-PET (hypoxic volume and tumor/muscle ratio). Baseline measurement. | Tumor hypoxia will be measured in 20 patients with HGG using 18F-FMISO-PET: after biopsy or surgery and before the commencement of radio-chemotherapy. It will be assessed the prevalence and extent of significant hypoxia in HGG. | 18F-FMISO-PET between 1 and 3 weeks before the commencement of radio-chemotherapy | 
| Change from baseline tumor hypoxia using 18F-FMISO-PET (hypoxic volume and tumor/muscle ratio) during SCS. | A subset of 10 patients will undergo a second 18F-FMISO-PET study during spinal cord stimulation to evaluate changes by SCS between 1 and 7 days after the first 18F-FMISO-PET study (and before the commencement of radio-chemotherapy). | 2nd 18F-FMISO-PET between 1 and 7 days after the 1st 18F-FMISO-PET | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Correlation between 18F-FMISO-PET values and pathological tumor parameters | To analyze the correlation of 18F-FMISO-PET with histological parameters and tumor expression of: CD31 (vascular density), VEGF (vascular endothelial growth factor) and VEGFR (angiogenesis), EGFR (epidermal growth factor receptor), Ki-67 (proliferation index) and hypoxic markers | Week 0 (at the commencement of radio-chemotherapy). | 
| Correlation with Karnofsky scale. | To analyze the correlation with performance status using the Karnofsky scale. | At 0, 2 and 9 months after the commencement of the radio-chemotherapy. | 
| Correlation with the ECOG (Eastern Cooperative Oncology Group) performance status scale | To analyze the correlation with performance status using the ECOG (WHO) scale. | At 0, 2 and 9 months after the commencement of the radio-chemotherapy | 
| Correlation with the Quality of Life Questionnaire QLQ-C30 (EORTC) | To analyze the correlation with quality of life using the QLQ-C30 (EORTC) questionnaire. | At 0, 2 and 9 months after the commencement of the radio-chemotherapy. | 
| Overall survival. | To analyze the correlation with overall survival. | At 9 months after the commencement of the radio-chemotherapy. | 
| Radiological response to treatment | To analyze the correlation between 18F-FMISO-PET values and radiological response to treatment | 9 months after the commencement of radio-chemotherapy | 
| Radiological location of tumor relapse or progression | To analyze the correlation between 18F-FMISO-PET values and the radiological location of tumor relapse or progression | 9 months after the commencement of radio-chemotherapy | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Anaplastic Astrocytoma, Brain Tumors, Cancer Imaging, Fluoromisonidazole, FMISO PET, Glioblastoma, High Grade Glioma, Hypoxia Modification, Positron Emission Tomography, Radiation-Sensitizing Agents, Spinal Cord Stimulation, Tumor Hypoxia Measurement