Pilot Trial of Spectroscopic MRI-guided, Dose-Escalated Proton Radiation Therapy and Bevacizumab for Recurrent Glioblastoma
Overview
- Phase
- Not Applicable
- Intervention
- Intensity Modulated Proton Therapy (IMPT)
- Conditions
- Recurrent Glioblastoma
- Sponsor
- University of Miami
- Enrollment
- 96
- Locations
- 1
- Primary Endpoint
- Incidence of Grade 3 irreversible or any Grade 4/5 neurologic toxicity.
- Status
- Recruiting
- Last Updated
- 9 months ago
Overview
Brief Summary
The purpose of this research is to find hidden cancer with an experimental magnetic resonance imaging (MRI) scan called spectroscopic magnetic resonance imaging (sMRI). That spectroscopic MRI scan will be used to increase the area of the brain receiving radiation and then the dose of radiation in attempt to kill more of the cancer. Proton radiotherapy and bevacizumab (Avastin) are used to minimize the possible side effects of this approach.
Detailed Description
A common second course of radiation therapy for recurrent glioblastoma uses 35 Gy in 10 fractions to a small area defined by gadolinium enhancement on MRI. This is based in part on a recent cooperative group trial (RTOG 1205, NCT01730950) with concurrent bevacizumab resulting in very low toxicity and borderline progression free survival benefit. We hypothesize that radiation therapy would be more effective for recurrent glioblastoma when delivered to a larger area defined by spectroscopic MRI. The spectroscopic MRI can delineate occult microscopic disease not seen on clinical MRI. Our group was a partner in the multi-institutional spectroscopic MRI guided dose escalation pilot trial in the first line for glioblastoma (NCT03137888) showing safety and efficacy of planning radiation therapy based on spectroscopic MRI Choline to NAA (Cho:NAA) ratio maps. A local Cho:NAA ratio above 2 (Cho:NAA\>2) is known to correlate with high local GBM burden on pathology. In this study, we will use the same technique to target radiation therapy to recurrent glioblastoma in a larger area of the brain harboring microscopic tumor. We will start with the conventional radiation dose of 35 Gy in 10 fractions to the larger area defined by the spectroscopic MRI. If this is safe and feasible, we will perform a dose escalation to 40 Gy in 10 fractions to areas of gadolinium enhancement and sMRI Cho:NAA\>2 since existing data suggests that those areas harbor the highest risk of future progression. Use of proton radiotherapy to limit brain targeted outside of the treated regions and bevacizumab to prevent radiation toxicity are hypothesized to limit the side effects of this approach.
Investigators
Jonathan Bell
Associate Professor of Clinical
University of Miami
Eligibility Criteria
Inclusion Criteria
- •A. Recurrent glioblastoma (or variants such as gliosarcoma) based on one of the following criteria:
- •An area of MRI enhancement consistent with glioblastoma outside of the initial high dose radiation field.
- •Biopsy or resection proven recurrent glioblastoma.
- •Progressive glioblastoma based on advanced imaging (brain positron emission tomography (PET), perfusion MRI, or clinical MR Spectroscopy)
- •B. Pathology diagnosis of glioblastoma, or variants such as gliosarcoma, on initial and/or reresection by 2021 WHO glioblastoma criteria. Prior pathology reports or specimens can be reexamined and reclassified as glioblastoma based on current criteria.
- •C. Total area of recurrence on T1 post-contrast MRI (including all nodules of likely tumor) have a linear maximum measurement of 6 cm or less.
- •D. Patients must have received prior brain radiation therapy for glioma in conventional fractionation (1.8 - 2 Gy per fraction, total dose maximum 63 Gy).
- •E. Patients must have completed prior brain radiation four to six months or more prior to study treatment for recurrent tumors that are at least half based within the high dose (\> 46 Gy) radiation field.
- •For "marginal" or "out of field" radiation failures where at least half of the enhancing disease is outside of the prior high dose radiation field but there is field overlap, patients must have completed prior radiation at least four months or more prior to study treatment.
- •For "in field" radiation failures where at least half of the enhancing disease is within the prior high dose radiation field, patients must have completed prior radiation at least six months or more prior to study treatment.
Exclusion Criteria
- •A. Brain malignancies other than glioblastoma (or variants such as gliosarcoma) by WHO 2021 criteria (benign lesions like meningioma are allowed)
- •B. Glioma that has not previously undergone standard first line therapies including a first course of radiation therapy.
- •C. Glioma that has already undergone a second course of radiation therapy.
- •D. Multi-focal disease (separate enhancing nodules across multiple brain lobes). Note: Multiple nodules in the same region are allowed as long as the total linear diameter is 6 cm or less.
- •E. Patients who have had treatment with Bevacizumab in the past.
- •F. Patients who will receive chemotherapy concurrent with study therapy other than bevacizumab.
- •G. Patients with recurrent Glioblastoma (rGBM) based in the following anatomical regions known to have magnetic susceptibility or poor signal will be excluded: temporal lobe below the level of the floor of the third ventricle, orbitofrontal cortex, prefrontal cortex, medial frontal gyrus, brainstem, and cerebellum (these regions have known sMRI artifact).
- •H. Pregnant or breastfeeding patients.
- •I. Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 1 year. Non-invasive tumors are permissible (e.g., carcinoma in situ).
- •J. Severe active co-morbidities as follows:
Arms & Interventions
Cohort A: sMRI-Guided RT at 35 Gy in 10 fractions
Participants will receive a total dose of 3500 centigrays (cGY) (35Gy) of Spectroscopic Magnetic Resonance Imaging (sMRI)-guided radiation therapy delivered in 10 fractions, 350 cGy (3.5 Gy) to the Clinical Target Volume (CTV) by Intensity Modulated Proton Therapy (IMPT) simultaneous integrated boost technique. Participants will also receive Bevacizumab per standard of care, at treating physician's discretion. Initial dose will begin prior to first dose of radiation therapy (RT).
Intervention: Intensity Modulated Proton Therapy (IMPT)
Cohort A: sMRI-Guided RT at 35 Gy in 10 fractions
Participants will receive a total dose of 3500 centigrays (cGY) (35Gy) of Spectroscopic Magnetic Resonance Imaging (sMRI)-guided radiation therapy delivered in 10 fractions, 350 cGy (3.5 Gy) to the Clinical Target Volume (CTV) by Intensity Modulated Proton Therapy (IMPT) simultaneous integrated boost technique. Participants will also receive Bevacizumab per standard of care, at treating physician's discretion. Initial dose will begin prior to first dose of radiation therapy (RT).
Intervention: Bevacizumab
Cohort B: sMRI-Guided RT at 40 Gy in 10 fractions
Participants will receive a total dose of 4000 cGY (40Gy) of Spectroscopic Magnetic Resonance Imaging (sMRI)-guided radiation therapy delivered in 10 fractions, 400 cGy (4 Gy) to the Clinical Target Volume (CTV) by Intensity Modulated Proton Therapy (IMPT) simultaneous integrated boost technique. Participants will also receive Bevacizumab per standard of care, at treating physician's discretion. Initial dose will begin prior to first dose of radiation therapy (RT).
Intervention: Intensity Modulated Proton Therapy (IMPT)
Cohort B: sMRI-Guided RT at 40 Gy in 10 fractions
Participants will receive a total dose of 4000 cGY (40Gy) of Spectroscopic Magnetic Resonance Imaging (sMRI)-guided radiation therapy delivered in 10 fractions, 400 cGy (4 Gy) to the Clinical Target Volume (CTV) by Intensity Modulated Proton Therapy (IMPT) simultaneous integrated boost technique. Participants will also receive Bevacizumab per standard of care, at treating physician's discretion. Initial dose will begin prior to first dose of radiation therapy (RT).
Intervention: Bevacizumab
Outcomes
Primary Outcomes
Incidence of Grade 3 irreversible or any Grade 4/5 neurologic toxicity.
Time Frame: Up to 6 months
The incidence of irreversible Grade 3 or any Grade 4/5 neurologic adverse events (AEs) or serious adverse events (SAEs) in study participants will be assessed using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, per physician discretion. Incidence of these toxicities will be reported for both cohorts, Cohort A (sMRI-Guided RT at 35 Gy in 10 fractions) and Cohort B (sMRI-Guided RT at 40 Gy in 10 fractions).
Percentage of patients for whom sMRI-guided therapy is technically successful
Time Frame: About 60 days
The percentage of participants for whom sMRI-guided therapy is successful will be reported as the percentage of participants who show no significant residual tumor after protocol therapy.
Secondary Outcomes
- Health-Related Quality of Life (HRQOL) Scores: FACT-Br Questionnaire(Up to 2 years)
- Overall Survival (OS)(Up to 2 years)
- Comparison of Apparent Diffusion Coefficients (ADC) among MRI techniques(About 3 months)
- Progression-Free Survival (PFS)(Up to 2 years)
- Comparison of Cerebral Blood Volumes (CBV) among MRI techniques(About 3 months)
- Volume of enhancing disease at first progression compared to MRI volumes.(About 3 months)