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Chemotherapy-Related Cognitive Impairment

Cognition Disorders

Neurocognitive Disorders

Mental Disorders

Psychotic Disorders

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Drug-Related Side Effects and Adverse Reactions

Chemically-Induced Disorders

Without self-report cognitive impairment.

Jay F. Piccirillo, MD

The investigators overall research hypothesis is that systemic chemotherapy induces structural changes in the white matter of the brain as demonstrated with Diffusion Tensor Imaging (DTI) and functional changes in well-defined cortical neural networks as demonstrated by resting-state functional connectivity MRI (rs-fcMRI). The investigators believe these structural and functional changes are responsible for the cognitive symptoms associated with chemotherapy-induced cognitive impairment (CICI).

The Specific Aim for this study is:

To assess the impact of chemotherapy on structural white matter as defined by DTI and functional cognitive networks as defined by rs-fcMRI by comparing a sample of breast cancer survivors with self-reported CICI to breast cancer survivors without CICI.

Hypothesis: Post-chemotherapy breast cancer patients with self-reported CICI will have abnormal structural connections characterized by DTI-defined disruptions in fractional anisotropy (FA) and mean diffusivity (MD) and abnormal functional connectivity characterized by rs-fcMRI-defined disruptions in cognitive networks when compared to patients without self-reported CICI.

Chemotherapy has been linked to cognitive impairments among breast cancer patients, especially in the domains of executive function (planning and problem solving), attention, learning, and information processing. The etiology of these chemotherapy-associated impairments remains unknown, although recent neuroimaging studies suggest that disruption of white matter integrity may play a role. With continued use of chemotherapy in breast cancer patients, this study's novel use of functional neuroimaging will be significant to better inform practitioners and patients of potential consequences to anticipate and serve as a starting point in the development of therapeutic interventions.

Chemotherapy-Induced Cognitive Impairment

The Neurobiology of Chemotherapy-Induced Cognitive Impairment

As compared with the controls, the breast cancer patients will show decreased fractional anisotropy (FA) in the frontal and temporal white matter (WM) tracts and.

As compared with the controls, the breast cancer patients will show decreased functional integrity of the default mode network \[DMN\], associated with memory; the dorsal and ventral attention networks \[DAN/VAN\], involved in attention; and the Cognitive/Control network, involved in executive decision-making

As compared with the controls, the breast cancer patients will show increased mean diffusivity (MD) in frontal White Matter (WM).

Washington University Siteman Cancer Center

Barnes-Jewish Hospital

Professor

Memory Disorders

Computer-based Cognitive Training

Henry W Mahncke, PhD

The investigators hypothesize that continuous active interaction with environments that are demanding to sensory, cognitive, and motor systems, together with imbedded rewards for successful performance, will help improve memory and cognitive functioning in patients suffering from "chemobrain".

Breast cancer is the most common malignancy in women in the United States, with an estimated 211,240 new cases of invasive breast cancer diagnosed among women, and 1,700 diagnosed in men, in 2005. While cure rates have improved significantly, chemotherapy for breast cancer is associated with a number of negative side effects. One of which is a deficit in cognitive function, a condition commonly referred to as "chemobrain". While the debate about cognitive decline being a result of chemotherapy is still ongoing, there is clear evidence of cognitive decline in women with breast cancer post-chemotherapy. Cognitive decline is often reported to affect memory, attention, executive functioning and information processing speed.

Studies suggest that incidence of "chemobrain" ranges from 17% - 75% in women who have undergone chemotherapy.This cognitive impairment affects quality of life by impacting patients' ability to concentrate, make decisions and to fulfill family, career, and community responsibilities.

Although there is uncertainty about the mechanisms that can lead to this cognitive decline, there is a pressing need to identify interventions that will alleviate its symptoms and help breast cancer survivors recover their cognitive functioning and resume their roles and activities at the pre-cancer level.

Brain plasticity refers to the brain's capacity for physical and functional change; it is this capacity that explains how experience induces learning throughout life. On the basis of a growing body of literature in the fields of psychophysics, neurology, neuropsychology, and brain plasticity, we hypothesize that the brain processing machinery can be refined, elaborated, and strengthened through rigorous training and learning. The purpose of this study is to investigate if such training can improve cognitive functioning.

We hypothesize that continuous active interaction with environments that are demanding to sensory, cognitive, and motor systems, together with imbedded rewards for successful performance will help improve memory and cognitive functioning in patients suffering from "chemobrain".

Computer-Based Training in Patients With Post-Chemotherapy Cognitive Impairment

Computer-Based Training in Patients With Post-Chemotherapy Cognitive Impairment, A Pilot Study

Posit Science Corporation

Respiratory Tract (Lung and Bronchial) Diseases

Lung Neoplasms

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Study participants with advanced-stage lung cancer.

Surveys about symptoms, mood, and quality of life.

Questionnaire

Automated telephone system call once a week during therapy, rating of severity of symptoms and daily life interference done with numeric key pad. Post therapy is complete, a call every two weeks for up to six months.

Telephone Interactive System

For participating patients, 3 additional tablespoons of blood drawn at the beginning of each chemotherapy treatment (before treatment starts) and at the beginning of each cycle of treatment.

Blood Samples

Xin Shelley Wang, MD

Primary Objectives:

* To compare the severity of symptoms, their impact on affective and health-related functional status, and symptom interference among patients with advanced-stage lung cancer following initiation of chemotherapy by disease status, tumor response to chemotherapy, and adequacy of symptom management.
* To examine the relationship of disease-related and treatment-related physical symptoms to affective impairment and the patient's reported symptom interference and functional impairment.
* To compare symptom severity, adequacy of symptom management, and interference with affective status and health-related function by patient's minority status.
* To explore the serum level of inflammatory cytokines during chemotherapy among lung cancer patients.
* To measure DNA repair capacity (DRC) in lymphocyte cultures of all patients enrolled in the protocol at baseline (before treatment) and during each follow-up blood draw. The hypothesis is that patients with suboptimal DRC will do better with chemotherapy than patients with efficient DRC.
* To extract DNA and genotype for polymorphisms in genes involved in the nucleotide excision repair pathway and in those involved in response to pain (opioid receptors, dopamine receptors, COMT). We hypothesize that:

  1. Polymorphisms in NER genes that modulate DNA repair capacity will also effect response to chemotherapy and to outcome.
  2. Cytokine gene polymorphisms account for variations in symptom outcomes (specific symptoms and symptom clusters) before, during and after chemotherapy.
  3. The COMT val/met polymorphism affects the metabolism of catecholamines on the modulation of response to sustained pain.
  4. Dopamine receptor polymorphisms that result in decreased density of dopamine receptors will result in a deficit in the dopamine pathway. that will also affect response to pain.
* To evaluate neurocognitive function to determine the prevalence, severity, and pattern of cognitive symptoms.

One of the ways to learn about the symptoms of chemotherapy is by looking at how certain proteins called cytokines (found in the blood) change during therapy. Another way is to look at how symptoms change during treatment.

Before therapy starts, you will be asked to complete several questionnaires during a visit to the thoracic clinic at M. D. Anderson. These questionnaires measure physical and emotional (mental) symptoms. The questionnaires should take about 60 minutes to finish. You will also be asked to complete some cognitive (mental) questionnaires that take about 25 minutes to complete. During this visit, the research nurse will teach you how to use an interactive voice response telephone system for measuring symptoms. The research nurse will ask you the most convenient time for the telephone calls, and make sure the system is programmed to call you at that time. The date of the call will be at the same or close to the date of your weekly clinic visit.

Symptoms will be monitored weekly during chemotherapy treatment using this interactive voice response telephone system. The automated telephone system will call you once a week, and using the numeric key pad on your telephone, you will rate the severity of your symptoms and how much they interfere in your daily life. Once you complete therapy, the phone system will call every two weeks for up to six months. The information collected by these calls is only being used for this research study.

In addition to the telephone calls, the research nurse will arrange to meet you approximately every 6 weeks at your clinic visit. She will ask you to complete some surveys about your symptoms, mood, and quality of life. This meeting will take about 45 minutes. You will also be asked again to complete some cognitive (mental) questionnaires that take about 25 minutes to complete.

Research staff will also obtain from your medical record clinical information and lab values during your treatment period.

If you have agreed to participate in the companion caregiver study, the study staff will use your demographic and clinical data to study the influence of your symptoms on your caregiver's physical and mental health.

You are encouraged to report your symptoms to your treating physicians during the study, especially if you have any symptom that you rate greater than 7 on the 0 to 10 scale.

This is an investigational study. A total of up to 224 patients will take part in this multicenter study. Up to 112 will be enrolled at M. D. Anderson.

Study participants enrolled at M. D. Anderson will have additional serum drawn for cytokine analysis and DNA repair capacity. This blood will be drawn at the routine blood draws before treatment begins, and at the beginning of each treatment cycle.

Longitudinal Study of Multiple Symptoms in Advanced Lung Cancer

Longitudinal Study of the Prevalence, Severity, and Interference of Multiple Symptoms in Advanced Lung Cancer

IVR telephone system to collect longitudinal data on symptom patterns and severity using patient tumor response evaluation after 2-3 cycles chemotherapy and total weekly IVR assessment period at 18 weeks.

National Cancer Institute (NCI)

M.D. Anderson Cancer Center

Stereotypic Movement Disorder

Breast Diseases

Skin Diseases

Participants in the control group received standard information on treatment side-effects.

Before completing the study's online baseline survey (pre-chemotherapy), participants in the information group received standard information with additional written information about potential chemotherapy-related cognitive symptoms.

Before completing the study's online baseline survey (pre-chemotherapy), participants in the information+SA group (SA=self-affirmation) received standard and additional written information about potential chemotherapy-related cognitive symptoms with a subsequent self-affirmative text.

Written information about potential chemotherapy-related cognitive symptoms without self-affirmation

Written information about potential chemotherapy-related cognitive symptoms with self-affirmation

Enny Das, PhD

Sanne B Schagen, PhD

Gabe S Sonke, PhD, MD

Previous cross-sectional studies have shown that informing cancer patients about potential chemotherapy-related cognitive symptoms may negatively affect perceived cognitive symptoms and verbal memory performance. A multicenter, randomized study in newly diagnosed breast cancer patients receiving (neo) adjuvant chemotherapy was performed to evaluate this Adverse Information Effect (AIE) over time and investigated whether inviting patients to self-affirm can reduce such AIEs on perceived cognitive symptoms and cognitive test performance.

Rationale:

Although information about their treatment and its side-effects is requested by cancer patients, is vital for informed decision making and can positively impact patients' health outcomes and illness perceptions, this kind of information can also adversely impact perceived cognitive symptoms and cognitive test performance. Previous studies have shown that informing cancer patients about potential chemotherapy-related cognitive symptoms may negatively affect perceived cognitive symptoms and verbal memory performance. A multicenter, randomized study in newly diagnosed breast cancer patients receiving (neo) adjuvant chemotherapy was performed to evaluate this Adverse Information Effect (AIE) over time and investigated whether inviting patients to self-affirm can reduce such AIEs on perceived cognitive symptoms and cognitive test performance.

Main objectives and hypotheses:

The overall aim of the study was to investigate the occurrence and duration of AIEs on the perceived frequency of cognitive symptoms, the perceived severity of cognitive symptoms and cognitive performance in breast cancer patients, and to examine ways to reduce such AIEs. First, evaluated the effect of providing breast cancer patients with additional factual written information about potential chemotherapy-related cognitive symptoms before chemotherapy-initiation on perceived cognitive symptoms and cognitive performance was evaluated, and the duration of such effects was assessed. Building on previous findings that breast cancer patients showed an increase in perceived cognitive symptoms and a decrease in verbal memory performance after receiving cognitive side-effect information, it was hypothesized that communicating about potential chemotherapy-related cognitive symptoms will result in AIEs, and it was explored to what extent these AIEs persist over time. Second, this study aimed to translate the beneficial effects of self-affirmation to the oncology domain, and examined the efficacy of a text-integrated self-affirmation intervention in reducing the impact of AIEs on perceived cognitive symptoms and cognitive performance in breast cancer patients when communicating about chemotherapy-related cognitive symptoms. It was hypothesized that a textual self-affirmation intervention would reduce AIEs in breast cancer patients, building on evidence from health promotion and stereotype threat research outside the oncology domain that individuals' self-concepts can be affirmed via text-integrated health messages and that allowing individuals the opportunity for self-affirmation can reduce stereotype threat effects.

The main research questions were:

1. Does written information about potential chemotherapy-related cognitive symptoms presented only once before treatment-initiation affect short- and longer-term perceived cognitive symptoms (the perceived frequency and severity of cognitive symptoms) and cognitive performance (verbal memory performance, information processing speed, executive functioning) in newly diagnosed breast cancer patients scheduled for (neo) adjuvant chemotherapy?
2. Does providing newly diagnosed breast cancer patients with a text integrated self-affirmation intervention after being informed about potential chemotherapy-related cognitive symptoms reduce AIEs on short- and longer-term perceived cognitive symptoms and cognitive performance?

Study procedure and outcome measures:

Before (neo) adjuvant chemotherapy, 160 newly diagnosed breast cancer patients were randomly allocated to receive either standard information on side-effects (control condition), or standard information with additional information about chemotherapy-related cognitive symptoms (information condition), or standard and additional information with a subsequent self-affirmative text (information+SA condition; SA=self-affirmation). Online-questionnaires were completed before chemotherapy (baseline, T0), 6-months (T1) and 12-months (T2) later to measure the perceived frequency (MOS-cog) and severity (MDASI-cog) of cognitive symptoms. Patients also completed two online neuro-psychological tests (Trail Making Test; TMT, and 15 Words test) to measure verbal memory performance, information processing speed and executive functioning. Additionally, several potential underlying mechanisms and risk factors of AIEs were examined, such as cancer related distress and performance worries. Baseline-to-follow-up analyses were performed using a mixed-effects modeling approach to compare groups over time.

A multicenter, randomized, controlled, prospective, online survey study was conducted. Before completing the study's online baseline survey (pre-chemotherapy; T0), participants were randomly assigned by the online survey program to receive either: standard information on side-effects (control condition), or standard information with additional written information about chemotherapy-related cognitive symptoms (information condition), or standard and additional information with a subsequent self-affirmative text (information+SA condition; SA=self-affirmation). The online experimental texts were presented to patients once, directly after randomization at baseline. At six months (T1) and twelve months (T2) follow-up, all groups received identical general introductions and online surveys, without any experimental manipulations. Outside of the trial, all patients received treatment information from their medical oncologist according to local practice as part of their usual care.

Health care professionals were blinded to group assignment, but due to the nature of the study, patients were not. However, patients were not informed about the main outcomes and specific hypotheses of the study, or about the study's experimental conditions and the content of the texts that they did not receive until after T2.

Breast Cancer Patients' Cognitive Symptoms After Information About Chemotherapy-Related Cognitive Symptoms

Downsides of Being Well-Informed: Tracking and Preventing Chemotherapy-Related Cognitive Problems in Breast Cancer Patients

An adapted version of two items of the M. D. Anderson Symptom Inventory Multiple Myeloma module (MDASI-MM; part 1; Cleeland et al., 2000; Jones et al., 2013) to measure the expected severity of cognitive symptoms during the next weeks (range 0-10). Higher scores indicate expectations of more severe cognitive symptoms.

An adapted version of four items of the M. D. Anderson Symptom Inventory Multiple Myeloma module (MDASI-MM; part 1; Cleeland et al., 2000; Jones et al., 2013) to measure the expected severity of other cancer-related symptoms during the next weeks (range 0-10). Higher scores indicate expectations of more severe other cancer-related symptoms.

Five modified and translated items from the effort subscale of the Intrinsic Motivation Inventory (IMI; Ryan, 1982; Ryan \& Deci, 2000) to measure the levels of motivation during the neuropsychological tasks (range 1-5). Higher mean scores indicate higher levels of motivation.

Four modified and translated items derived from the test anxiety subscale of the Motivated Strategies for learning Questionnaire (Pintrich \& De Groot, 1990) to measure the levels of worrying about cognitive test performance (range 1-5). Higher mean scores denote higher levels of worries.

Seven items of the intrusion subscale of the Dutch version of the Impact of Events Scale (Horowitz, Wilner, \& Alvarez, 1979; Van der Ploeg et al., 2004) to assess the levels of intrusion of cancer related stressful thoughts (range 0-28). Higher sum scores indicate higher intrusion when confronted with the stressful experience of being treated for cancer.

Eight translated and adapted items derived from the 10-item Stigma Consciousness Questionnaire to measure the extent to which patients expect to be stereotyped by others (Brown \& Pinel, 2003; cf. Jacobs, Das, \& Schagen, 2017; range 1-5). Higher mean scores indicate higher levels of stigma consciousness.

Three adapted and translated items from the math identification subscale of the Social Identities and Attitudes Scale (SIAS; Picho \& Brown, 2011), to measure the extent to which participants identify with the domain of 'cognition' and the level of importance of their cognition (range 1-5). Higher mean scores indicate higher levels of domain identification.

Two newly developed items and four items derived and adapted from Doosje and colleagues (Doosje, Ellemers, \& Spears, 1995), Spears and colleagues (Spears, Doosje, \& Ellemers, 1997), and Quayle (2011) to measure the level of group identification, that is to what extent participants identify with other (ex) cancer patients (range 1-5). Higher mean scores indicate higher levels of group identification.

Information monitoring was measured by one item that asked patients how often during the past weeks they searched for health- and cancer related information (range 0-4). Higher scores indicate higher levels of information monitoring.

One item to indicate which information sources participants used (twelve options; for example information leaflets yes/no).

One item to assess what information content participants looked for (six options; for example information about chemotherapy side-effects yes/no).

At twelve months follow-up (T2), stereotype self-relevance was measured using one item that assessed perceived self-relevance of the chemotherapy-impairs-cognition stereotype: 'To what extent does the phenomena 'Chemo brain' apply to you?' (range 1-5). Higher scores indicate higher levels of self-relevance.

At twelve months follow-up (T2), two items asked participants to indicate the extent to which they attributed their own and others' cognitive symptoms to chemotherapy (range 1-5). Higher scores indicate higher levels of attribution of cognitive symptoms to chemotherapy.

Six items of the revised Medical Outcomes Study - cognitive functioning subscale (MOS-cog; Stewart \& Ware, 1992) to measure the perceived frequency of cognitive symptoms. Participants indicated the frequency of experiencing a range of day-to-day problems in six aspects of cognitive functioning during the past week (including today). Higher mean scores indicate better perceived cognitive functioning (range 0-100).

Two items of the M.D. Anderson Symptom Inventory Multiple Myeloma module (MDASI-MM part 1; Cleeland et al., 2000; Jones et al., 2013) to measure the perceived severity of cognitive symptoms. Patients reported the severity of two cognitive symptoms at their worst in the last 24 hours on a 0-10 scale, with 0 being 'not present' and 10 being 'as bad as you can imagine': difficulty remembering and difficulty paying attention (concentrating). Higher mean scores indicate more severe symptoms.

Online, adapted version of the Groningen Fifteen Words Test (Rey, 1964) measuring immediate recall (range 0-45), delayed recall (range 0-15) and recognition (range 0-30). Higher scores indicate better performance.

Online version of the Trail Making Test (TMT; Reitan \& Wolfson, 1985) part A and B (and TMT-B to TMT-A ratio B/A) to measure the speed of information processing and executive functioning. The score on each part represents the amount of time in seconds required to complete the task. Higher scores indicate worse information processing and executive functioning.

Dutch version of the Hospital Anxiety and Depression Scale (HADS; Spinhoven et al., 1997; Zigmond \& Snaith, 1983) to measure levels of anxiety. Higher sum scores (range 0-21) indicate higher levels of anxiety.

Dutch version of the Hospital Anxiety and Depression Scale (HADS; Spinhoven et al., 1997; Zigmond \& Snaith, 1983) to measure levels of depression. Higher sum scores (range 0-21) indicate higher levels of depression.

Twelve items of the thirteen-item core M. D. Anderson Symptom Inventory (MDASI; part 1; Cleeland et al., 2000) to measure the perceived severity of other cancer-related symptoms. Participants reported the severity of twelve symptoms at their worst in the last 24 hours hours on a 0-10 scale, with 0 being 'not present' and 10 being 'as bad as you can imagine.' Difficulty remembering was excluded. Higher mean scores indicate more severe symptoms.

Participants indicated on one item (range 1-5) at the end of the T2 survey whether they had knowledge about the potential cognitive side-effects of cancer treatment prior to the experiment to measure pre-existing knowledge. Higher scores indicate more pre-existing knowledge.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Chemotherapy-Induced Cognitive Impairment	NCT01578083	Cognitive Sympt...		35 Years - 70 Years	Washington University School of Medicine
Computer-Based Training in Patients With Post-Chemotherapy Cognitive Impairment	NCT00387062	Breast Cancer Cognitive Sympt... Memory Disorder...	Computer-based ...	21 Years -	Posit Science Corporation
Longitudinal Study of Multiple Symptoms in Advanced Lung Cancer	NCT00422500	Lung Cancer	Questionnaire Telephone Inter... Blood Samples	18 Years -	M.D. Anderson Cancer Center
Breast Cancer Patients' Cognitive Symptoms After Information About Chemotherapy-Related Cognitive Symptoms	NCT04813965	Breast Cancer Cognitive Sympt... Cognitive Decli...	Written informa... Written informa...	18 Years -	Radboud University Medical Center
Computer-Based Training in Patients With Post-Chemotherapy Cognitive Impairment	NCT00387062	Breast Cancer Cognitive Sympt... Memory Disorder...	Computer-based ...	21 Years -	Posit Science Corporation

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