Brain TumorsNCT01212237
Dose Response of Functionally Critical Brain Regions for Brain Radiotherapy
An observational study of Brain Tumors, run by Weill Medical College of Cornell University at 1 site in United States.
Trial summary
Normal tissue response is critical for brain radiotherapy, especially for dose escalation which carries with it an increased incidence of radiation-induced brain injury. Although radiation toxicity and limiting dose for anatomically critical structures of the brain have been well studied and documented, little is… Read more about this study
- Who is it for?
- Ages 18 to 80 years
- Conditions the study is for
- Brain Tumors
- What is being tested?
- fMRI Evaluation
- Type of treatment
- Surgery or procedure
- How many people
- 0 participants
- Where
- 1 siteUnited States
- Study dates
- 14 May 2012to 13 Apr 2013
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 80 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Study population: Patients with brain tumors (astrocytoma, meningioma, low grad glioma)
Who may be able to join
- 1. Histologically confirmed diagnosis of slow growing brain tumors that requires radiotherapy, e.g., meningioma, low grade glioma or anaplastic astrocytomas.
- 2. A diagnostic contrast enhanced CT/MRI demonstrating the lesion prior to registration.
- 3. Karnofsky performance status ≥60. 4. Ability to undergo MR imaging with the use of Gadolinium contrast. 5. Ability to undergo brain fMRI. 6. Patient must sign a study specific informed consent form. Patients who cannot provide consent due to cognitive impairment will not be enrolled in the study. The investigators will follow the recently published guidelines (Binder \& Guze, Am. J. Psy., 155, 1649-1650, 1998) to assess the subject's understanding of the procedure and his/her decision making capacity,.
Who cannot join
- 1. Any condition including allergy to Gadolinium contrast, metallic implants or cardiac pace makers that makes the candidate ineligible for MR imaging. These criteria will be determined by an MRI research screening form signed by the subject.
- 2. Any condition including taking anti-anxiety medicines such as Benzodiazepines or requiring sedative to overcome claustrophobia that makes the candidate ineligible brain fMRI.
- 3. Karnofsky performance status of ≤60 4. Prior history of radiation therapy to the brain 5. Pregnancy 6. Significant medical or neurological disorders that would affect the outcome of the evaluations and/or make a successful MRI/fMRI unduly difficult 7. Major psychiatric conditions, whether medicated or unmedicated, as such conditions can affect the validity of the evaluations
Trial locations and contacts
1 site in 1 country.
United States1 site
Weill Cornell Medical College
New York, New York, 10065
About this study
Official title: Phase I Study of Dose Response of Functionally Critical Brain Regions for Brain Radiotherapy
Normal tissue response is critical for brain radiotherapy, especially for dose escalation which carries with it an increased incidence of radiation-induced brain injury. Although radiation toxicity and limiting dose for anatomically critical structures of the brain have been well studied and documented, little is known for functionally critical brain regions and treatment of cognitive sequelae of cranial radiotherapy is limited. The objective of this clinical protocol is to accumulate preliminary data for future studies aiming to quantify dose response for functionally critical brain regions for brain radiotherapy. We plan to achieve this objective by correlating the radiation-induced complications and radiological changes with the radiation dose to the selected functionally critical brain regions for 25 patients. Each participating patient will receive brain fMRI to identify brain regions for processing visual, working memory and language functions. The image co-registration algorithm developed previously by our group will be used to co-register these regions on the CT scans for radiotherapy treatment planning for radiation dose calculation. Radiation-induced changes in cognitive functions will be evaluated using the modified mini mental status exam (3MS) and fMRI during the routine follow-up. The knowledge derived from this study might significantly improve the quality of life and allow safer dose escalation for patients receiving brain radiotherapy.
Read the detailed description
Research Question:
Our goal is to answer the following three research questions in this study:
- What is the dose response curve (degree of radiation complications/radiological changes vs. radiation dose) for brain regions involved in the processing of visual, language and working memory functions?
- What is the limiting dose for these functionally critical brain regions that can be applied to radiotherapy treatment planning to minimize (e.g., less than 5%) the possibility of radiation-induced injury?
- Can brain fMRI be used to guide the radiotherapy treatment planning to minimize the dose to functionally critical brain regions and evaluate treatment responses of these regions?
Research Method:
Imaging before radiotherapy: For each patient, active stimulation and resting fMRI examinations will be performed in addition to standard anatomic MRI for brain radiotherapy. Activation maps of regions involved in visual, language and working memory functions will be generated from the fMRI scans and the patient's responses on of the working memory task (i.e., the N-Back task) will be recorded during the fMRI studies. The MRI and fMRI will, combined, take approximately 90 minutes - 60 minutes for the standard MRI and 30 minutes for the fMRI. The activation maps will be overlaid onto the FLAIR MRI images, imported into the radiotherapy treatment planning system and co-registered with the simulation CT scan.
Radiotherapy and routine follow-up: Functionally critical areas in the fMRI activation maps will be separately contoured as critical organs but will not be considered for plan optimization. Dose volume histograms (DVHs) of functionally critically brain regions will be calculated and documented. Each patient will receive fractionated brain radiotherapy according to the treatment plan and will be followed up with every three months after radiotherapy.
Follow-up evaluations: The 3MS examination will be administered prior to initiation of treatment onset and every three months after treatment during routine follow-up to screen neuropsychological functions. Anatomic MRI (standard) and brain fMRI (research) will be acquired at 6 months after radiotherapy to determine the radiological and functional changes in regions involved in the processing of visual, language and working memory functions.
Minimizing the interference of tumor recurrence or progression: Two actions will be taken to minimize the interference of tumor recurrence or progression with the evaluation of performance alterations caused by radiation. First, patient inclusion will be restricted to patients with slow growing tumors, e.g., meningioma, low grade glioma and anaplastic astrocytoma so that the chance for tumor recurrence or progression is small. Secondly, patients who develop disease progression at any of the post-radiotherapy follow-ups will be excluded from the study, as it would not be possible to distinguish the effects of disease progression from radiotherapy side effects on the fMRI or the 3MS examination, and the findings would not be interpretable.
Dose Response Analysis: Logistic regression analysis will be used to assess the likelihood of complications to functionally critical brain regions as a function of radiation dose. The dependent variable will be the binary indicator that identifies patients' manifesting complications (decline of 3MS examination score and N-Back test, radiological/functional changes identified on MRI and fMRI) attributed to radiation exposure. The logistic regression model will include relevant subject level factors (e.g., age, gender, baseline Karnofsky performance status, tumor location, recent seizures, anti-epleptic medications) as covariates. The fitted logistic normal tissue complication probability (NTCP) model will permit estimation of the probability of significant complications associated with any radiation dose to the area, allowing the limiting dose to be calculated as the dose expected to induce complication with an acceptable probability (e.g., 5%).
Incorporation of limiting dose for radiotherapy treatment planning: The limiting dose from the above "Dose Response Analysis" will be used for IMRT re-planning considering the functionally critical brain regions. The optimization goal is to minimize the dose to functionally critical brain regions while maintaining similar PTV (planning target volume) coverage and keeping dose to the critical structures within accepted tolerance. DVHs of the functionally critical brain regions, PTV and all other critical structures will be compared for both treatment plans with and without considering the functionally critical brain regions. A Wilcoxon matched pair signed rank test will be performed to compare the plans in terms of calculated NTCP of critical organs. The McNemar test will be used to compare plans with and without dose constraints of functional areas in terms of yield rate (i.e., the proportion of patients for whom the IMRT plan was successfully devised).
The primary study endpoint of this study is normal tissue complication. The primary objective of this study is to determine the dose response curve and limiting dose for functionally critically brain regions for brain radiotherapy. The second objective of this study is to investigate the accuracy of active stimulation or resting state fMRI for avoidance of the functionally critical brain regions for radiotherapy treatment planning of brain tumors and for evaluating the treatment responses of these critical regions.
- Conditions
- Brain Tumors
- Being tested
- fMRI Evaluation
- Keywords
- glioma, meningioma, anaplastic astrocytoma
- Medical subject headings
- Brain Neoplasms, Glioma, Meningioma, Astrocytoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
fMRI EvaluationProcedure or surgery
Also called fMRI
Functional magnetic resonance imaging (fMRI) uses MR imaging to measure the tiny metabolic changes that take place in an active part of the brain. fMRIs are used for many reasons, for example, to determine precisely which part of the brain is handling critical functions such as thought, speech, movement and sensation, to help assess the effects of stroke, trauma or degenerative disease (such as Alzheimer's) on brain function, and to guide the planning of surgery and radiation therapy.
| Study group | Role | What they receive |
|---|---|---|
| fMRI Evaluation | All patients will undergo the following standard imaging and radiotherapy procedures will be performed for each patient:
1. Standard MRI for radiotherapy treatment planning which takes about 60 minutes.
2. Radiotherapy treatment simulation with CT.
3. Radiotherapy treatment planning
4. Radiotherapy treatment
5. Routine follow-up every 3 months after the radiotherapy.
Special Procedures.
The following special imaging and radiotherapy procedures will be performed for each patient:
1. fMRI (30 minutes)
2. The 3MS examination, administered every 3 months during routine follow-up for one year after the completion of the radiotherapy. Receives: Procedure: fMRI Evaluation |
What is being measured
The primary outcome is the main question the study is designed to answer.
fMRI to Measure Functional Changes of Criticial Brain Regions Over Time
fMRI screening at baseline and 6 months after the completion of radiation therapy to observe the original functionality of the brain (pre-radiation therapy) and the functionality of the brain after radiation therapy. If the radiation has damaged any functional areas, the difference in performance will be evident in the 6 month fMRI.
Measured: pre-radiation therapy and 6 months post radiation therapy
Secondary outcomes (1)
MMSE - expanded (Mini-Mental Status Examination)- to Document Changes in Functionality of Critical Brain Regions
The expanded MMSE (mini-mental status exam) routinely used to screen the overall cognitive functions of patients following brain radiotherapy. The MMSE will help to track brain function at a great interval than the fMRI. It will show changes in the brain over time.
Measured: pre-radiation therapy, 3, 6, 9, 12 months post-radiation therapy
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted30 Sep 2010 (estimated)
- Study start14 May 2012
- Primary completion13 Apr 2013
- Study completion13 Apr 2013
Why it stopped: There were no patients enrolled on this study.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Brain TumorsStudies of the same condition, open and under way.
- More trials run by Weill Medical College of Cornell UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Case-control
- Time perspective
- Prospective
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Lead sponsor
- Weill Medical College of Cornell University
- Sponsor type
- University, hospital or other
- Collaborators
- Memorial Sloan Kettering Cancer Center
- Responsible party
- Sponsor
- Investigators
- Jenghwa Chang, Ph.D., Principal investigator, Weill Medical College of Cornell University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01212237
- Sponsor's protocol ID
- 1003010928
- Status last verified
- Jul 2019
- First submitted
- 22 Jun 2010
- Last updated
- 29 Jul 2019
- Results posted
- No
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 29 Jul 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase I Study of Dose Response of Functionally Critical Brain Regions for Brain Radiotherapy
- ClinicalTrials.gov ID
- NCT01212237
- Acronym / sponsor ID
- 1003010928
- Conditions
- Brain Tumors
- Keywords
- glioma, meningioma, anaplastic astrocytoma
- Study type
- Observational
- Recruitment status
- WithdrawnReason stopped: There were no patients enrolled on this study.
- Enrolment
- 0 participants (actual)
- Lead sponsor
- Weill Medical College of Cornell UniversityUniversity, hospital or other
- Collaborators
- Memorial Sloan Kettering Cancer Center
- Study start
- 14 May 2012 (actual)
- Primary completion
- 13 Apr 2013 (actual)
- Study completion
- 13 Apr 2013 (actual)
- First posted
- 30 Sep 2010 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Normal tissue response is critical for brain radiotherapy, especially for dose escalation which carries with it an increased incidence of radiation-induced brain injury. Although radiation toxicity and limiting dose for anatomically critical structures of the brain have been well studied and documented, little is known for functionally critical brain regions and treatment of cognitive sequelae of cranial radiotherapy is limited. The objective of this clinical protocol is to accumulate preliminary data for future studies aiming to quantify dose response for functionally critical brain regions for brain radiotherapy. We plan to achieve this objective by correlating the radiation-induced complications and radiological changes with the radiation dose to the selected functionally critical brain regions for 25 patients. Each participating patient will receive brain fMRI to identify brain regions for processing visual, working memory and language functions. The image co-registration algorithm developed previously by our group will be used to co-register these regions on the CT scans for radiotherapy treatment planning for radiation dose calculation. Radiation-induced changes in cognitive functions will be evaluated using the modified mini mental status exam (3MS) and fMRI during the routine follow-up. The knowledge derived from this study might significantly improve the quality of life and allow safer dose escalation for patients receiving brain radiotherapy.
Detailed description
Research Question:
Our goal is to answer the following three research questions in this study:
- What is the dose response curve (degree of radiation complications/radiological changes vs. radiation dose) for brain regions involved in the processing of visual, language and working memory functions?
- What is the limiting dose for these functionally critical brain regions that can be applied to radiotherapy treatment planning to minimize (e.g., less than 5%) the possibility of radiation-induced injury?
- Can brain fMRI be used to guide the radiotherapy treatment planning to minimize the dose to functionally critical brain regions and evaluate treatment responses of these regions?
Research Method:
Imaging before radiotherapy: For each patient, active stimulation and resting fMRI examinations will be performed in addition to standard anatomic MRI for brain radiotherapy. Activation maps of regions involved in visual, language and working memory functions will be generated from the fMRI scans and the patient's responses on of the working memory task (i.e., the N-Back task) will be recorded during the fMRI studies. The MRI and fMRI will, combined, take approximately 90 minutes - 60 minutes for the standard MRI and 30 minutes for the fMRI. The activation maps will be overlaid onto the FLAIR MRI images, imported into the radiotherapy treatment planning system and co-registered with the simulation CT scan.
Radiotherapy and routine follow-up: Functionally critical areas in the fMRI activation maps will be separately contoured as critical organs but will not be considered for plan optimization. Dose volume histograms (DVHs) of functionally critically brain regions will be calculated and documented. Each patient will receive fractionated brain radiotherapy according to the treatment plan and will be followed up with every three months after radiotherapy.
Follow-up evaluations: The 3MS examination will be administered prior to initiation of treatment onset and every three months after treatment during routine follow-up to screen neuropsychological functions. Anatomic MRI (standard) and brain fMRI (research) will be acquired at 6 months after radiotherapy to determine the radiological and functional changes in regions involved in the processing of visual, language and working memory functions.
Minimizing the interference of tumor recurrence or progression: Two actions will be taken to minimize the interference of tumor recurrence or progression with the evaluation of performance alterations caused by radiation. First, patient inclusion will be restricted to patients with slow growing tumors, e.g., meningioma, low grade glioma and anaplastic astrocytoma so that the chance for tumor recurrence or progression is small. Secondly, patients who develop disease progression at any of the post-radiotherapy follow-ups will be excluded from the study, as it would not be possible to distinguish the effects of disease progression from radiotherapy side effects on the fMRI or the 3MS examination, and the findings would not be interpretable.
Dose Response Analysis: Logistic regression analysis will be used to assess the likelihood of complications to functionally critical brain regions as a function of radiation dose. The dependent variable will be the binary indicator that identifies patients' manifesting complications (decline of 3MS examination score and N-Back test, radiological/functional changes identified on MRI and fMRI) attributed to radiation exposure. The logistic regression model will include relevant subject level factors (e.g., age, gender, baseline Karnofsky performance status, tumor location, recent seizures, anti-epleptic medications) as covariates. The fitted logistic normal tissue complication probability (NTCP) model will permit estimation of the probability of significant complications associated with any radiation dose to the area, allowing the limiting dose to be calculated as the dose expected to induce complication with an acceptable probability (e.g., 5%).
Incorporation of limiting dose for radiotherapy treatment planning: The limiting dose from the above "Dose Response Analysis" will be used for IMRT re-planning considering the functionally critical brain regions. The optimization goal is to minimize the dose to functionally critical brain regions while maintaining similar PTV (planning target volume) coverage and keeping dose to the critical structures within accepted tolerance. DVHs of the functionally critical brain regions, PTV and all other critical structures will be compared for both treatment plans with and without considering the functionally critical brain regions. A Wilcoxon matched pair signed rank test will be performed to compare the plans in terms of calculated NTCP of critical organs. The McNemar test will be used to compare plans with and without dose constraints of functional areas in terms of yield rate (i.e., the proportion of patients for whom the IMRT plan was successfully devised).
The primary study endpoint of this study is normal tissue complication. The primary objective of this study is to determine the dose response curve and limiting dose for functionally critically brain regions for brain radiotherapy. The second objective of this study is to investigate the accuracy of active stimulation or resting state fMRI for avoidance of the functionally critical brain regions for radiotherapy treatment planning of brain tumors and for evaluating the treatment responses of these critical regions.
Study design
- Observational model
- Case-control
- Time perspective
- Prospective
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| fMRI Evaluation | – | Procedure: fMRI EvaluationAll patients will undergo the following standard imaging and radiotherapy procedures will be performed for each patient: 1. Standard MRI for radiotherapy treatment planning which takes about 60 minutes. 2. Radiotherapy treatment simulation with CT. 3. Radiotherapy treatment planning 4. Radiotherapy treatment 5. Routine follow-up every 3 months after the radiotherapy. Special Procedures. The following special imaging and radiotherapy procedures will be performed for each patient: 1. fMRI (30 minutes) 2. The 3MS examination, administered every 3 months during routine follow-up for one year after the completion of the radiotherapy. |
Who may qualify
- Ages
- 18 to 80 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- Patients with brain tumors (astrocytoma, meningioma, low grad glioma)
Key inclusion criteria (3 listed)
- 1. Histologically confirmed diagnosis of slow growing brain tumors that requires radiotherapy, e.g., meningioma, low grade glioma or anaplastic astrocytomas.
- 2. A diagnostic contrast enhanced CT/MRI demonstrating the lesion prior to registration.
- 3. Karnofsky performance status ≥60. 4. Ability to undergo MR imaging with the use of Gadolinium contrast. 5. Ability to undergo brain fMRI. 6. Patient must sign a study specific informed consent form. Patients who cannot provide consent due to cognitive impairment will not be enrolled in the study. The investigators will follow the recently published guidelines (Binder \& Guze, Am. J. Psy., 155, 1649-1650, 1998) to assess the subject's understanding of the procedure and his/her decision making capacity,.
Key exclusion criteria (3 listed)
- 1. Any condition including allergy to Gadolinium contrast, metallic implants or cardiac pace makers that makes the candidate ineligible for MR imaging. These criteria will be determined by an MRI research screening form signed by the subject.
- 2. Any condition including taking anti-anxiety medicines such as Benzodiazepines or requiring sedative to overcome claustrophobia that makes the candidate ineligible brain fMRI.
- 3. Karnofsky performance status of ≤60 4. Prior history of radiation therapy to the brain 5. Pregnancy 6. Significant medical or neurological disorders that would affect the outcome of the evaluations and/or make a successful MRI/fMRI unduly difficult 7. Major psychiatric conditions, whether medicated or unmedicated, as such conditions can affect the validity of the evaluations
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| fMRI EvaluationAlso: fMRIFunctional magnetic resonance imaging (fMRI) uses MR imaging to measure the tiny metabolic changes that take place in an active part of the brain. fMRIs are used for many reasons, for example, to determine precisely which part of the brain is handling critical functions such as thought, speech, movement and sensation, to help assess the effects of stroke, trauma or degenerative disease (such as Alzheimer's) on brain function, and to guide the planning of surgery and radiation therapy. | Procedure or surgery | fMRI Evaluation |
Primary outcome
fMRI to Measure Functional Changes of Criticial Brain Regions Over Time
Time frame: pre-radiation therapy and 6 months post radiation therapy
fMRI screening at baseline and 6 months after the completion of radiation therapy to observe the original functionality of the brain (pre-radiation therapy) and the functionality of the brain after radiation therapy. If the radiation has damaged any functional areas, the difference in performance will be evident in the 6 month fMRI.
1 secondary outcome
MMSE - expanded (Mini-Mental Status Examination)- to Document Changes in Functionality of Critical Brain Regions
Time frame: pre-radiation therapy, 3, 6, 9, 12 months post-radiation therapy
Results and safety
The study was withdrawn before enrolling participants, so there are no results.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 29 Jul 2019.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Jenghwa Chang, Ph.D. principal investigator
Weill Medical College of Cornell University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Brain Tumors, run by Weill Medical College of Cornell University at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 3 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: withdrawn, as of the sponsor's last update on 29 Jul 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study was withdrawn before enrolling participants, so there are no results.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
fMRI to Measure Functional Changes of Criticial Brain Regions Over Time (time frame: pre-radiation therapy and 6 months post radiation therapy). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 Jul 2019; AzTrials last refreshed its copy on 6 Nov 2026.