The purpose of this FOA is to encourage transdisciplinary research to improve traditional assessment of acute- and late-term cognitive changes following cancer treatment for non-central nervous system malignancies. Complaints of persistent cognitive deficits are common among the increasing population of cancer survivors, particularly those who have undergone adjuvant chemotherapy, hormone and/or molecularly-targeted cancer treatments. Systemically-treated cancer patients experience cognitive impairment during treatment, upon completion of regimens, and often as part of long-term survivorship. However, the specific nature and underlying mechanisms causing the cognitive impairments are often unclear. By leveraging advances in cognitive neuroscience, fundamental knowledge about the specific underlying mechanisms responsible for cognitive impairment may be obtained.
This FOA encourages transdisciplinary research that will apply cognitive neuroscience theory and task paradigms, developed in the last three decades, for improved measurement and assessment of acute- and late-term cognitive changes following cancer treatment. With the application of cognitive neuroscience tasks for the longitudinal assessment of cancer patients (prior to the start of treatment, during treatment, and following treatment over time), we can more specifically measure cognitive impairment and its prevalence.
In the absence of precise measurement, clinicians and survivors will remain uncertain about the nature of the cognitive difficulties and modes for remediation. Knowing whether a patient’s complaint, for example, about failing memory reflects poor attention and/or poor retrieval, can reduce uncertainty, inform care planning, and suggest possible accommodation strategies. The incorporation of cognitive neuroscience task paradigms into clinical assessment approaches has the potential to change cancer care planning. Traditional neuropsychological batteries, which are time consuming and complicated to administer, have been a barrier to widespread adoption of surveillance and clinical assessment of cognition in cancer patients and survivors exposed to systemic treatments.
This FOA is suitable for transdisciplinary research efforts where proof-of-principle of the proposed technology or methodology has already been established and supportive preliminary data are available. This FOA runs in parallel with an FOA of identical scientific scope, PAR-16-213, which utilizes the Exploratory/Developmental Grant (R21) mechanism.
The Clinical Problem: As the number of cancer survivors in the U.S. increases—from the current 14.5 million to an estimated 19 million in the next decade—the need to minimize chronic and late cancer treatment-related cognitive impairment becomes more urgent. Approximately one-third of patients with non-central nervous system malignancies treated with adjuvant chemotherapy experience clinically significant cognitive difficulties that persist for months or years following treatment. Survivors often report problems with memory, attention, verbal fluency, processing speed, multi-tasking, planning, and following directions. Complaints tend to be associated with exposure to chemotherapy agents, such as fluorouracil, cyclophosphamide, docetaxel and doxorubicin, regardless of whether these agents can cross the blood-brain barrier. Evidence of chemotherapy drugs causing cognitive impairment in patients is supported by preclinical findings and structural and functional neuroimaging studies that have documented gray and white matter volume changes. Studies implicate the neurotoxic effects of cytokine dysregulation, direct neurotoxic injury, and oxidative stress, and have ruled out diagnosable affective disorders as primary causes of the cognitive complaints. Furthermore, when anxiety or depressive symptomatologies are associated with cognitive complaints, the cause and effect are often ambiguous. There are reports, and plausible biological basis, of cognitive complaints after receipt of hormonal (tamoxifen, anastrosole) and molecular-targeted therapies. As treatment of early-stage cancers (e.g., breast cancer with low Onco DX scores) shifts away from conventional chemotherapy agents and toward adjuvant chemotherapy and molecularly-targeted treatments, cognitive effects of these targeted therapies also require empirical attention.
A better understanding of cancer treatment-associated cognitive impairment is important because cognitive difficulties can have a profound and pervasive impact on quality of life. Survivors may experience difficulty engaging in treatment decision making, resuming employment, and managing basic activities of daily living. Older survivors, many of whom live independently and need to work to support themselves, may suffer economic hardship if they are unable to return to work, and social isolation if they are unable to resume previous social roles.
What is Needed: If we are to understand and address cancer treatment-associated cognitive impairment, we must first be able to accurately and precisely evaluate it. Self-reports of cognitive functioning and traditional neuropsychological tests are the primary sources of current assessment. Patient-reported outcomes can identify general deficits but were not intended to identify the component processes underlying these complaints. Self-reports have intrinsic limitations (e.g., a patient reporting to her physician, “I am forgetting things I just heard,” may conclude this is due to a memory defect, which in fact may be due to an attentional deficit).
Traditional clinical neuropsychological test batteries may not be able to distinguish, for example, which aspects of executive function are affected (e.g., processing speed, planning, response inhibition) nor parse which facets of memory (e.g., encoding, storage [working-memory, short-term memory], and retrieval) are responsible for poor performance on a traditional clinical neuropsychological test. Poor performance may be due to a single impaired subcomponent or multiple sub-component cognitive processes, but the batteries lack the specificity to determine. Traditional neuropsychological tests also tend be insensitive to less severe, but still debilitating cognitive impairments, such as those observed in chemotherapy patients (when compared to patients of blunt trauma or stroke).
Recent developments in assessment such as the NIH Toolbox Cognitive Battery and the Cambridge Neuropsychological Test Automated Battery represent improvements and are briefer than traditional neuropsychological batteries, but were validated on the traditional measures, and share the same imprecision for several cognitive domains. The later limitation is not surprising, given that the neuropsychological tests were originally developed several decades ago, to diagnose severe brain pathology, such as dementia and traumatic brain injury. The types of cognitive impairments associated with chemotherapy are typically more subtle in comparison.
Preclinical models assessing effects of chemotherapy, immunotherapy, and/or molecularly-targeted agents in tumor-free and/or tumor-bearing animals with cognitive-science informed paradigms may also be informative.
Opportunity to Leverage Cognitive Neuroscience: Task paradigms and tools developed in cognitive neuroscience in the last 30 years (e.g., cognitive neuroscience task paradigms, computational modeling, and electrophysiological techniques), have the potential to measure discrete cognitive processes and parse which subcomponent processes underlie cognitive complaints. In addition to their higher precision, these cognitive neuroscience paradigms may require considerably less time and are easier to administer than traditional clinical neuropsychological batteries ¾a significant potential asset for dissemination and implementation within the clinical setting.
With the exception of fMRI research on default mode network connectivity, modern cognitive neuroscience approaches have not been applied to diagnose cancer treatment-associated cognitive impairment (although these approaches have been used in brain imaging studies with cancer patients in a few studies). However, research on other brain disorders, such as autism, Parkinson’s disease, and attention deficit hyperactivity disorder (ADHD), has been informed by cognitive neuroscience tasks. For example, ADHD has long been characterized as a disorder of attentional processes, but with only a vague understanding of which attentional processes were impaired. However, recent cognitive neuroscience-based studies found that children with ADHD were normal with respect to visual selective attention but had difficulty keeping track of what they should have been looking for.
The success of cognitive neuroscience techniques in identifying the component processes of other neurologic disorders serves as a proof-of-principle that cognitive neuroscience task paradigms can elucidate specific components of cognition, impaired as a function of adjuvant cancer treatments, which are the source of patients’ complaints. This research can inform care planning and accommodation strategies for clinical populations.
This initiative seeks to produce a better understanding of the specific components of cognition affected by adjuvant cancer treatments for non-CNS malignancies by leveraging cognitive neuroscience approaches in assessment. Some projects might build on the extant evidence from early-stage breast cancer patients, while other projects may extend cognitive neuroscience tasks to other non-CNS malignancies (e.g., lymphoma, prostate cancer) for which cognitive complaints also have been reported. Other projects may propose to use preclinical animal models with translational relevance to identify specific components of cancer treatment cognitive impairment.
Projects that are suitable for this FOA are likely to include study design features that enable improved understanding of the acute- and late-term cognitive changes following exposure to adjuvant chemotherapy and molecularly-targeted treatments, including hormonal therapy, for non-central nervous system tumors. Prospective longitudinal designs with a pre-treatment baseline assessment prior to initiation of a first line adjuvant therapy regimen and repeated assessments over an appropriate time period are essential to evaluate acute and late-term changes.
Possible comparison groups to control for patient status and age might involve cancer patients not receiving chemotherapy and/or healthy aged-matched controls. The choice of comparison group will depend on the cancer site, stage, and treatment regimen chosen for study depending on the specific aims and hypotheses of the project. Researchers may study the effects of traditional chemotherapy; however, molecular targeted therapies are becoming more common in cancer care and may be associated with cognitive complaints.
Structural and/or functional neuroimaging may be included to test whether cognitive neuroscience task performance predicts gray and white matter damage and alterations in neural connectivity. Inclusion of traditional clinical neuropsychological assessment and/or tools, such as NIH Cognitive Toolbox or Cambridge Neuropsychological Test Automated Battery, is encouraged to compare performance with results from cognitive neuroscience paradigms. Inclusion of quality of life and functional outcomes to assess the predictive validity of cognitive neuroscience task performance as a function of cancer treatments may also be considered.
Projects that assess a broad range of cognitive ability via outreach/recruitment to understudied and demographically diverse samples (e.g., low socioeconomic status or educational attainment, rural, and race/ethnicity) are encouraged.
This FOA encourages transdisciplinary research projects that leverage advances in cognitive science, neuroscience and neuroimaging, and integrates expertise from diverse disciplines such as medical oncology, cancer epidemiology, neuropsychology, psychometrics, human development and aging, preclinical models of human cancer, statistical modeling, systems biology, genetics, and behavioral science.
Examples of research questions that fall within the scope of this FOA follow but are not limited to:
- Which specific cognitive functions are impaired following chemotherapy and/or molecular-targeted therapies for non-central nervous system malignancies? Alternatively, are impairments generalized across all or most cognitive domains?
- What impairment differences are found with cognitive neuroscience task paradigms versus patient-reported outcomes, traditional clinical neuropsychological test batteries, and/or tests derived from them such as the NIH Toolbox Cognitive Battery?
- To what extent does performance on cognitive neuroscience task paradigms predict reduction in gray matter volume, white matter integrity, and neural connectivity (measured via structural and functional neuroimaging) better than patient-reported outcomes, traditional clinical neuropsychological test batteries, and/or NIH Toolbox?
- To what extent can reliable and sensitive cognitive neuroscience task paradigms be integrated into the standard of cancer care for persons undergoing treatment for non-CNS malignancies?
- To what extent does poor performance on cognitive neuroscience task paradigms predict acute and late term indices of quality of life and functional outcomes better than traditional clinical neuropsychological testing or variants thereof?
- If cognitive neuroscience task paradigms are administered at several time points, what kinds of trajectories of cognitive change are detected (e.g., transient impairment, delayed impairment, improvements followed by reversals, or chronic long-term impairment) in persons treated for non-CNS malignancies?
- To what degree can advances made in the Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia (CNTRICS) initiative be leveraged to improve cognitive assessment of cancer-treatment associated impairment in patients with non-CNS malignancies?
- To what extent can preclinical research using translationally relevant animal models expand our mechanistic understanding of the impact of systemic treatments for non-CNS malignancies (e.g., chemotherapy, targeted therapies, biologics) on brain function and structure, cognition, and behavior?
Deadlines: October 13, 2016; April 11, 2017; October 10, 2017; April 11, 2018; October 10, 2018; April 11, 2019
Filed Under: Funding Opportunities