A Study of High-Dose Chemoradiation Using Biologically-Based Target Volume Definition in Patients With Glioblastoma

Study Overview
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Brief Summary
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This is a study to determine the safety and effectiveness of high-dose radiation therapy (RT) with concurrent temozolomide in patients with newly diagnosed glioblastoma.

Detailed Description
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After analysis demonstrated the improved prognostic value of identifying both hypercellular tumor (TVHCV) based on high b-value diffusion-weighted magnetic resonance imaging (DW-MRI) and hyperperfused tumor (TVCBV) based on dynamic contrast-enhanced MRI (DCE-MRI), the study was amended and later-enrolled patients boosted to both TVHCV and TVCBV.

Official Title
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Phase II Study of High Dose Radiotherapy and Concurrent Temozolomide Using Biologically-Based Target Volume Definition in Patients With Newly Diagnosed Glioblastoma

Conditions
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Glioma

Intervention / Treatment
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* Radiation: High Dose Radiation
* Drug: Temozolomide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Newly diagnosed histologically-confirmed supratentorial World Health Organization (WHO) grade IV gliomas including glioblastoma multiforme and gliosarcoma Age 18 or older Karnofsky performance status (a measure to quantify general well being and activities of daily life; scale ranges from 0 to 100 where 100 is perfect health) of greater than or equal to 70 Life expectancy of at least 12 weeks Adequate bone marrow reserve (hemoglobin greater than or equal to 10, absolute neutrophil count greater than or equal to 1500, platelets greater than or equal to 100,000); acceptable liver function (total bilirubin less than or equal to 2.0 mg/dl, ALT (Alanine Aminotransferase)/AST (Aspartate Aminotransferase) less than or equal to 5 times the normal range); acceptable renal function (serum creatinine less than or equal to 2.0 mg/dl). Eligibility level for hemoglobin may be reached by transfusion. Maximal contiguous volume of tumor based on high b-value diffusion MRI < 1/3 volume of brain Patients must be registered within 6 weeks of most recent resection. Patients must have signed a study-specific informed consent. Exclusion Criteria: Recurrent glioma, or tumor involving the brainstem or cerebellum. Prior low-grade glioma without prior RT, now with malignant progression are eligible. Prior use of Gliadel wafers or any other intratumoral or intracavitary treatment is not permitted. Prior chemotherapy for a different cancer is allowable, except for Temozolomide or Bevacizumab. Evidence of cerebrospinal fluid dissemination (positive cerebrospinal fluid cytology for malignancy or MRI findings consistent with CSF dissemination) Evidence of severe concurrent disease requiring treatment Prior invasive malignancy (except non-melanoma skin cancer) unless disease-free for a minimum of 3 years (for example, carcinoma in situ of breast, oral cavity or cervix are all permissible) Patients unable to undergo Magnetic Resonance Imaging exams (MRI) (i.e. patients with non-compatible devices such as cardiac pacemakers, other implanted electronic devices, metallic prostheses, or ferromagnetic prostheses (e.g. pins in artificial joints and surgical pins/clips) or unable to receive gadolinium for MRI, as per the standard UM Department of Radiology MRI screening criteria) Patients treated with previous cranial or head/neck radiotherapy leading to radiation field overlap Females of child-bearing potential must have a negative pregnancy test within 14 days prior to registration. Patients with reproductive potential must agree to use an effective contraceptive method during treatment.

Ages Eligible for Study
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Minimum Age: 18 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: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: High Dose Chemoradiation<br>Patients will receive high dose radiation based in part on advanced imaging, and concurrent temozolomide. Four weeks after the completion of chemoradiation, patients will receive adjuvant temozolomide. | Radiation: High Dose Radiation<br>* Radiation will be delivered once daily for a total of 30 fractions, five days per week.<br>Drug: Temozolomide<br>* Patients will receive concurrent temozolomide (75 mg/m^2 daily for 6 weeks). Adjuvant temozolomide will be given at 150-200 mg/m^2, D1-5 every 28 days for a minimum of six cycles and will be started approximately four weeks following completion of radiotherapy.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival at 12 Months | Percentage of patients alive at 12 months after completion of chemoradiation | 12 months after completion of chemoradiation | 
| Median Overall Survival | Median overall survival in months | Median follow-up time was 26 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Progression-free Survival | From start of RT until disease progression or death, or until date of last imaging follow-up, estimated using Kaplan-Meier. Progression is defined by any of the following: >= 25% increase in sum of the products of perpendicular diameters of enhancing lesions (compared with baseline if no decrease) on stable or increasing doses of corticosteroids; a significant increase in T2/FLAIR non-enhancing lesions on stable or increasing doses of corticosteroids compared with baseline scan or best response after initiation of therapy, not due to comorbid events; appearance of any new lesions; clear progression of non-measurable lesions; or definite clinical deterioration not attributable to causes other than tumor, or to decrease in corticosteroid dose. When pathologic confirmation was unavailable, progression was defined as worsening enhancement based on imaging with or without adjunctive advanced imaging including perfusion MRI or magnetic resonance spectroscopy, when clinically indicated. | Median follow-up time was 26 months | 
| Median Change in Tumor Volume From Baseline to Mid-radiation Treatment (Week 4) | Tumor volume will be measured by diffusion MRI and perfusion MRI before treatment start and at mid-treatment. | Baseline to Week 4 | 
| Percentage of Patients That Experienced Deterioration in Quality of Life (QOL) | Percentage of patients that experienced deterioration in QOL per the European Organization for Research and Treatment of Cancer, Quality of Life Questionnaire (EORTC QLQ-C30). EORTC QLQ-C30 is a 30-item questionnaire to assess the overall quality of life in cancer patients. EORTC QLQ-C30 includes functional scales (physical, role, cognitive, emotional, and social), global health status, symptom scales (fatigue, pain, nausea/vomiting), and other (dyspnea, appetite loss, insomnia, constipation/diarrhea, and financial difficulties). Most questions used 4-point scale (1 'Not at All' to 4 'Very Much'); 2 questions used 7-point scale (1 'Very Poor' to 7 'Excellent'). Scores are averaged, and transformed to 0-100 scale; higher score=better level of physical functioning. | Baseline to 1 and 7 months | 
| Percentage of Patients With Failure; Central or In-field vs. Marginal or Distant | Failures will be classified as central or in-field, marginal or distant based on previously published criteria. 1) central, in which 95% or more of the recurrent tumor volume (Vrecur) was within D95, the region treated to high dose (95% of the prescription dose); 2) in-field, in which 80% or more of Vrecur was within the D95 isodose surface; 3) marginal, when between 20 and 80% of Vrecur was inside the D95 surface; 4) outside, in which less than 20% of Vrecur was inside the D95 surface. | Median 26 months |