A Study of Cognitive Changes in Patients Receiving Brain Radiation

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Brief Title

A Study of Cognitive Changes in Patients Receiving Brain Radiation

Official Title

A Prospective Pilot Study of Cognitive Changes in Patients Receiving Partial Brain Radiation: Development of a Radiation Dose-toxicity Model for Neuroanatomic Targets

Brief Summary

      Cranial radiation therapy (RT), commonly used to treat benign and malignant brain tumors, can
      lead to cognitive impairments in domains not related to neuroanatomic structures directly
      impacted by the tumor. The study will prospectively enroll 58 patients with benign and
      low-grade brain tumors who will undergo partial brain RT, with either conventionally
      fractionated or hypofractionated schedules. Subjects will receive MRI scans at baseline and 6
      months. Given the role of the limbic system in key cognitive functions affected by RT,
      researchers have a particular interest in characterizing MRI changes in the limbic system and
      thalamus in relation to memory and related processes.

      Specific Aims:

        1. To examine objective neurocognitive changes over time. The investigators hypothesize
           that they will see RT-induced neurocognitive impairment in up to 50% of patients after
           cranial RT.

        2. To examine changes in brain tissue (via MRI) induced by off-target RT in patients with
           benign and low-grade brain tumors. The investigators specifically hypothesize that
           comapping of RT dose and MRI changes in the thalamus and limbic system (i.e., thalamic
           nuclei, hippocampus, fornix, hypothalamus/mammillary bodies, limbic lobe, cingulum) will
           be most distorted by off-target RT.

        3. To examine the relationship between MRI changes for key neuroanatomic structures
           identified in Aim 1 with objective neurocognitive testing. The investigators hypothesize
           that cognitive decline will be correlated with damage revealed by MRI to limbic and
           thalamic structures.

      This research will help to define which neuroanatomic structures are most at risk from
      RT-induced damage and will help ultimately establish new dose constraint guidelines for
      important structures to improve cognitive outcomes.
    

Detailed Description

      Cranial radiation therapy (RT), commonly used to treat benign and malignant brain tumors, can
      lead to cognitive impairments in domains not related to neuroanatomic structures directly
      impacted by the tumor. This suggests that off-target RT, even at low doses, may have a
      negative cognitive impact by affecting neuroanatomic targets proximal or distal to the tumor.
      While constraints to minimize brain necrosis, ototoxicity, and optic neuropathy are
      well-established, RT dose tolerances for cognitive changes in key domains (memory, attention,
      executive function, and processing speed) that occur in RT-treated patients are poorly
      characterized. There is accumulating evidence that consideration of neuroanatomic targets
      could better explain cranial RT-mediated cognitive change. Additionally, a recent cooperative
      group phase III trial has shown that conformal avoidance of the hippocampus with whole brain
      RT can reduce cognitive impairment. Unfortunately, 60% of patients still had cognitive
      impairment at 6 months even with hippocampal avoidance, implying that other structures and
      networks are involved in cognitive deficits from RT and efforts to identify those structures
      are warranted. A major obstacle in the field has been difficulty identifying sites of
      off-target tissue damage that could impact cognition after RT. Given the role of the limbic
      system in key cognitive functions affected by RT, the investigators have a particular
      interest in characterizing changes in limbic system and thalamus in relation to memory and
      related processes.

      The investigators plan to examine RT effects on neuroanatomic structures in the limbic system
      and thalamus as well as candidate structures identified systematically using magnetic
      resonance imaging (MRI). The investigators propose to prospectively enroll 58 patients with
      benign and low-grade brain tumors who will undergo partial brain RT, either conventionally
      fractionated or hypofractionated.

      Neurocognitive testing will be obtained at baseline, 3, and 6 months after RT using a battery
      of tests to assess visual and verbal memory, attention, executive function, and processing
      speed. Brain MRI, including high resolution T1 images, diffusion tensor imaging (DTI), and
      resting functional MRI (fMRI) sequences, will be evaluated at baseline and 6 months after RT.

      This pilot study will provide preliminary data to identify key areas impacted by RT that can
      be followed up in future research.

      Aim 1: To examine objective neurocognitive changes over time. Based on prior data, the
      investigators hypothesize that they will see RT-induced neurocognitive impairment in up to
      50% of patients after cranial RT. The investigators will evaluate neurocognitive testing
      changes using a composite global deficit z-score (primary endpoint) as well as z-score
      changes in cognitive domains of verbal and visual memory, attention, executive function and
      processing speed.

      Aim 2: To examine changes in brain tissue (via MRI) induced by off-target RT in patients with
      benign and low-grade brain tumors. The investigators hypothesize that a detailed brain tissue
      injury mapping of off-target RT doses from pre to post-RT and reconstructed structural and
      functional connectivity (DTI and fMRI) will provide data on the relationship between RT dose
      and MRI changes in specific structures. The investigators specifically hypothesize that
      co-mapping of RT dose and MRI changes in the thalamus and limbic system (i.e., thalamic
      nuclei, hippocampus, fornix, hypothalamus/mammillary bodies, limbic lobe, cingulum) will be
      most distorted by off-target RT.

      Aim 3: To examine the relationship between MRI changes for key neuroanatomic structures with
      neurocognitive testing. The investigators hypothesize that RT will impact several neuronal
      networks sub-serving multiple cognitive domains and cognitive decline (Aim 2) will be
      correlated with damage revealed by MRI to limbic and thalamic structures (Aim 1). This
      approach will allow identification of brain structures most associated with domain-specific
      cognitive impairment.

      There is critical need for well-designed longitudinal studies that examine the impact of RT
      on neuroanatomic structures. Many of the studies that evaluate cognition with RT do not take
      into account neuroanatomic dose distributions. Even within the literature that evaluates
      neuroanatomic targets, there has not been a systematic approach to evaluation of
      neuroanatomic targets by RT. This research will help to define which neuroanatomic structures
      are most at risk from RT-induced damage and will help ultimately establish new dose
      constraint guidelines for important structures to improve cognitive outcomes.
    


Study Type

Observational


Primary Outcome

Change in global cognitive function

Secondary Outcome

 Correlation of change in fractional anisotropy (FA) on diffusion tensor imaging (DTI) in the thalamus and limbic system with RT dose

Condition

Brain Tumor Adult


Study Arms / Comparison Groups

 All participants
Description:  Participants will receive standard of care partial brain radiation therapy at discretion of their radiation oncologist

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information



Estimated Enrollment

58

Start Date

October 16, 2018

Completion Date

December 1, 2020

Primary Completion Date

December 1, 2020

Eligibility Criteria

        Inclusion Criteria:

          -  >18 years old patients with brain tumors including low grade gliomas, meningiomas,
             acoustic neuromas, pituitary adenomas, craniopharyngiomas, hemangiopericytomas, pineal
             tumors, and other benign or slow-growing brain tumors

          -  Pathologic diagnosis will be required for gliomas, but not for other tumor types
             (though it will be recorded if available)

          -  Within 3 months prior to registration, patients must have a post gadolinium
             contrast-enhanced three dimensional spoiled gradient (SPGR), magnetization-prepared
             rapid gradient echo (MP-RAGE), or turbo field echo (TFE) MRI scan and an axial
             T2/FLAIR sequence. To yield acceptable image quality with the smallest possible axial
             slice thickness, , the imaging protocol should include the standard brain tumor
             protocol sequences: long DTI, sagittal SPGR, and brainlab sequences, resting
             functional MRI or their equivalent.

          -  Patients will need to be planned to receive fractionated radiation therapy or
             stereotactic radiation therapy, either fractionated or single fraction (enrollment
             must occur prior to radiation therapy so that baseline neurocognitive evaluation can
             be done)

          -  Surgical excision and/or chemotherapy treatment prior to enrollment is allowed

          -  Concurrent chemotherapy with radiation is allowed

          -  Antiepileptic drugs use, seizures, steroids, anticholinergic medications will be
             recorded but patients will not be excluded

          -  Hydrocephalus will be recorded, but patients will not be excluded

        Exclusion Criteria:

          -  Prior cranial radiation therapy

          -  Other active malignancy

          -  Contraindication to MRI imaging such as implanted metal devices or foreign bodies

          -  Contraindication to gadolinium contrast administration during MR imaging such as
             allergy or insufficient renal function

          -  Intractable seizures while on adequate anticonvulsant therapy-more than 1 seizure per
             month for the past 2 months

          -  Life expectancy <6 months due to other severe comorbidity

          -  Due to limitations in our ability to test patients in languages other than English,
             patients will have to be English-speaking

          -  Diagnosis of pre-existing dementia (clinically significant as defined by a neurologist
             or other provider), neurodegenerative, or neuro-inflammatory conditions as made by an
             appropriate health care professional such as a neurologist

          -  Inability to participate in neuro-cognitive testing

          -  Significant aphasia leading to difficulty participating in neuro-cognitive testing
      

Gender

All

Ages

18 Years - N/A


Contacts

, 585-275-9990, [email protected]

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT04390906

Organization ID

RSRB00070001


Responsible Party

Principal Investigator

Study Sponsor

University of Rochester

Collaborators

 National Center for Advancing Translational Science

Study Sponsor

, , 


Verification Date

May 2020