This study is examining the effects of standard of care cancer treatment as well as a medication called Sildenafil, on the cancer associated fatigue, cognition and the gut microbiome.
Cancer related cognitive impairment (CRCI) severely impacts neurocognitive function and is characterized by deficits in memory, learning, processing speed, and executive function. This cognitive impairment commonly referred to as "brain fog" or "chemo-brain," often co-occurs with central and peripheral fatigue. Symptoms typically begin acutely with the initiation of therapy, and persist chronically throughout prolonged treatment. Despite advancements in cytotoxic chemotherapies, CRCI plagues 75% of breast cancer patients during treatment, and development of new therapeutic options have been hampered by an incomplete understanding of the underlying mechanisms that cause CRCI. Although the etiology is not clear, CRCI is known to be associated with oxidative stress, increased inflammation, and disruption to the blood-brain barrier (BBB). Importantly, the endothelial cells of the BBB protect the central nervous system (CNS) from harmful and inflammatory bloodborne factors. Similarly, endothelial and epithelial barriers in the gut prevent microbial invasion and resulting regional and systemic inflammatory signaling. Thus, gut and brain barriers regulate exposure of the CNS to inflammatory factors and represent an important source of communication in the gut-brain axis. Research suggests that cytotoxic chemotherapeutic agents compromise both brain and gut endothelial and epithelial barrier integrity, leading to extravasation of toxins and immune cells into the CNS, causing neuroinflammation and CRCI. This study proposes that sildenafil, a phosphodiesterase-5 (PDE-5) inhibitor, will preserve barrier integrity during chemotherapy by downregulating oxidative and nitrosative stress that leads to endothelial dysfunction via multiple pathways. Thus, the goal of this project is to interrogate how chemotherapy-induced brain and gut barrier dysfunction mediate CRCI, neurotoxicity, and neuro- and systemic inflammation. Outcomes will be measured at baseline and throughout standard of care treatment, specifically after neoadjuvant chemotherapy, surgery, radiation treatment, chemotherapy treatment and after 24 weeks of endocrine treatment.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
SUPPORTIVE_CARE
Masking
NONE
Enrollment
30
Sildenafil, 50mg, daily
The University of Texas Medical Branch
Galveston, Texas, United States
Fatigue and Cognition as measured by the Fatigue and Altered Cognition Scale at baseline
The Fatigue and Altered Cognition Scale (FACS) is a joint project from University of Texas Medical Branch and Texas A\&M University. The FACS is a 20 question assessment designed to access perceived fatigue and cognition. There are 2 subscales used to calculate a total score. The subscales are: Fatigue and Altered Cognition. The total score is calculated by adding the subscales together. The range of the total score is 0-100, with a higher score indicating more fatigue and altered cognition.
Time frame: Baseline
Fatigue and Cognition as measured by the Fatigue and Altered Cognition Scale after neoadjuvant chemotherapy treatment
The Fatigue and Altered Cognition Scale (FACS) is a joint project from University of Texas Medical Branch and Texas A\&M University. The FACS is a 20 question assessment designed to access perceived fatigue and cognition. There are 2 subscales used to calculate a total score. The subscales are: Fatigue and Altered Cognition. The total score is calculated by adding the subscales together. The range of the total score is 0-100, with a higher score indicating more fatigue and altered cognition.
Time frame: through neoadjuvant chemotherapy treatment completion, average of 20 weeks from baseline
Fatigue and Cognition as measured by the Fatigue and Altered Cognition Scale after surgery
The Fatigue and Altered Cognition Scale (FACS) is a joint project from University of Texas Medical Branch and Texas A\&M University. The FACS is a 20 question assessment designed to access perceived fatigue and cognition. There are 2 subscales used to calculate a total score. The subscales are: Fatigue and Altered Cognition. The total score is calculated by adding the subscales together. The range of the total score is 0-100, with a higher score indicating more fatigue and altered cognition.
Time frame: through completion of surgery, average of 24 weeks from baseline
Fatigue and Cognition as measured by the Fatigue and Altered Cognition Scale after radiation treatment
The Fatigue and Altered Cognition Scale (FACS) is a joint project from University of Texas Medical Branch and Texas A\&M University. The FACS is a 20 question assessment designed to access perceived fatigue and cognition. There are 2 subscales used to calculate a total score. The subscales are: Fatigue and Altered Cognition. The total score is calculated by adding the subscales together. The range of the total score is 0-100, with a higher score indicating more fatigue and altered cognition.
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Time frame: through radiation treatment completion, average of 30 weeks from baseline
Fatigue and Cognition as measured by the Fatigue and Altered Cognition Scale after chemotherapy treatment
The Fatigue and Altered Cognition Scale (FACS) is a joint project from University of Texas Medical Branch and Texas A\&M University. The FACS is a 20 question assessment designed to access perceived fatigue and cognition. There are 2 subscales used to calculate a total score. The subscales are: Fatigue and Altered Cognition. The total score is calculated by adding the subscales together. The range of the total score is 0-100, with a higher score indicating more fatigue and altered cognition.
Time frame: through chemotherapy treatment completion, average of 50 weeks from baseline
Fatigue and Cognition as measured by the Fatigue and Altered Cognition Scale after 24 weeks of endocrine treatment
The Fatigue and Altered Cognition Scale (FACS) is a joint project from University of Texas Medical Branch and Texas A\&M University. The FACS is a 20 question assessment designed to access perceived fatigue and cognition. There are 2 subscales used to calculate a total score. The subscales are: Fatigue and Altered Cognition. The total score is calculated by adding the subscales together. The range of the total score is 0-100, with a higher score indicating more fatigue and altered cognition.
Time frame: through 24 weeks of endocrine treatment, average of 74 weeks from baseline
Perceived Cognition measured by the Functional Assessment of Cancer Therapy - Cognitive (FACT-Cog) at baseline
The FACT-Cog is a self-administered measure of perceived cognitive impairment for patients undergoing cancer therapy. The FACT-Cog (version 3) contains 37 items which quantify 4 subscale domains using a 5 point Likert-type scale including: perceived cognitive impairments, impact of perceived cognitive impairments on quality of life, comments from others and perceived cognitive abilities. Perceived cognitive impairments subscale will be reported (range: 0-72, with a higher score indicating better quality of life).
Time frame: baseline
Perceived Cognition measured by the Functional Assessment of Cancer Therapy - Cognitive (FACT-Cog) after neoadjuvant chemotherapy treatment
The FACT-Cog is a self-administered measure of perceived cognitive impairment for patients undergoing cancer therapy. The FACT-Cog (version 3) contains 37 items which quantify 4 subscale domains using a 5 point Likert-type scale including: perceived cognitive impairments, impact of perceived cognitive impairments on quality of life, comments from others and perceived cognitive abilities. Perceived cognitive impairments subscale will be reported (range: 0-72, with a higher score indicating better quality of life).
Time frame: through neoadjuvant chemotherapy treatment completion, average of 20 weeks from baseline
Perceived Cognition measured by the Functional Assessment of Cancer Therapy - Cognitive (FACT-Cog) after surgery
The FACT-Cog is a self-administered measure of perceived cognitive impairment for patients undergoing cancer therapy. The FACT-Cog (version 3) contains 37 items which quantify 4 subscale domains using a 5 point Likert-type scale including: perceived cognitive impairments, impact of perceived cognitive impairments on quality of life, comments from others and perceived cognitive abilities. Perceived cognitive impairments subscale will be reported (range: 0-72, with a higher score indicating better quality of life).
Time frame: through completion of surgery, average of 24 weeks from baseline
Perceived Cognition measured by the Functional Assessment of Cancer Therapy - Cognitive (FACT-Cog) after radiation treatment
The FACT-Cog is a self-administered measure of perceived cognitive impairment for patients undergoing cancer therapy. The FACT-Cog (version 3) contains 37 items which quantify 4 subscale domains using a 5 point Likert-type scale including: perceived cognitive impairments, impact of perceived cognitive impairments on quality of life, comments from others and perceived cognitive abilities. Perceived cognitive impairments subscale will be reported (range: 0-72, with a higher score indicating better quality of life).
Time frame: through radiation treatment completion, average of 30 weeks from baseline
Perceived Cognition measured by the Functional Assessment of Cancer Therapy - Cognitive (FACT-Cog) after chemotherapy treatment
The FACT-Cog is a self-administered measure of perceived cognitive impairment for patients undergoing cancer therapy. The FACT-Cog (version 3) contains 37 items which quantify 4 subscale domains using a 5 point Likert-type scale including: perceived cognitive impairments, impact of perceived cognitive impairments on quality of life, comments from others and perceived cognitive abilities. Perceived cognitive impairments subscale will be reported (range: 0-72, with a higher score indicating better quality of life).
Time frame: through chemotherapy treatment completion, average of 50 weeks from baseline
Perceived Cognition measured by the Functional Assessment of Cancer Therapy - Cognitive (FACT-Cog) after 24 weeks of endocrine therapy treatment
The FACT-Cog is a self-administered measure of perceived cognitive impairment for patients undergoing cancer therapy. The FACT-Cog (version 3) contains 37 items which quantify 4 subscale domains using a 5 point Likert-type scale including: perceived cognitive impairments, impact of perceived cognitive impairments on quality of life, comments from others and perceived cognitive abilities. Perceived cognitive impairments subscale will be reported (range: 0-72, with a higher score indicating better quality of life).
Time frame: through 24 weeks of endocrine treatment, average of 74 weeks from baseline
Perceptual Fatigue as measured by the MD Anderson Brief Fatigue Inventory (BFI) at baseline
Perceptual fatigue will be assessed using the Brief Fatigue Inventory (BFI), a 9-item questionnaire that assesses perceptual fatigue as well as fatigue interferences (e.g. interference with enjoyment of life). The scores from all 9 questions can be average to calculate a Global Fatigue Score, with a range from 0 to 10, with a higher score indicating more fatigue.
Time frame: baseline
Perceptual Fatigue as measured by the MD Anderson Brief Fatigue Inventory (BFI) after neoadjuvant chemotherapy treatment
Perceptual fatigue will be assessed using the Brief Fatigue Inventory (BFI), a 9-item questionnaire that assesses perceptual fatigue as well as fatigue interferences (e.g. interference with enjoyment of life). The scores from all 9 questions can be average to calculate a Global Fatigue Score, with a range from 0 to 10, with a higher score indicating more fatigue.
Time frame: through neoadjuvant chemotherapy treatment completion, average of 20 weeks from baseline
Perceptual Fatigue as measured by the MD Anderson Brief Fatigue Inventory (BFI) after surgery
Perceptual fatigue will be assessed using the Brief Fatigue Inventory (BFI), a 9-item questionnaire that assesses perceptual fatigue as well as fatigue interferences (e.g. interference with enjoyment of life). The scores from all 9 questions can be average to calculate a Global Fatigue Score, with a range from 0 to 10, with a higher score indicating more fatigue.
Time frame: through completion of surgery, average of 24 weeks from baseline
Perceptual Fatigue as measured by the MD Anderson Brief Fatigue Inventory (BFI) after radiation treatment
Perceptual fatigue will be assessed using the Brief Fatigue Inventory (BFI), a 9-item questionnaire that assesses perceptual fatigue as well as fatigue interferences (e.g. interference with enjoyment of life). The scores from all 9 questions can be average to calculate a Global Fatigue Score, with a range from 0 to 10, with a higher score indicating more fatigue.
Time frame: through radiation treatment completion, average of 30 weeks from baseline
Perceptual Fatigue as measured by the MD Anderson Brief Fatigue Inventory (BFI) after chemotherapy treatment
Perceptual fatigue will be assessed using the Brief Fatigue Inventory (BFI), a 9-item questionnaire that assesses perceptual fatigue as well as fatigue interferences (e.g. interference with enjoyment of life). The scores from all 9 questions can be average to calculate a Global Fatigue Score, with a range from 0 to 10, with a higher score indicating more fatigue.
Time frame: through chemotherapy treatment completion, average of 50 weeks from baseline
Perceptual Fatigue as measured by the MD Anderson Brief Fatigue Inventory (BFI) after 24 weeks of endocrine treatment
Perceptual fatigue will be assessed using the Brief Fatigue Inventory (BFI), a 9-item questionnaire that assesses perceptual fatigue as well as fatigue interferences (e.g. interference with enjoyment of life). The scores from all 9 questions can be average to calculate a Global Fatigue Score, with a range from 0 to 10, with a higher score indicating more fatigue.
Time frame: through 24 weeks of endocrine treatment, average of 74 weeks from baseline
Quantify absolute abundance of gut microbiome using using metagenomic analysis at baseline
Metagenomic analysis using a custom PCR array will be performed on stool samples to identify associated changes in microbiome absolute abundance at the genus and species level.
Time frame: baseline
Quantify absolute abundance of gut microbiome using metagenomic analysis after neoadjuvant chemotherapy treatment
Metagenomic analysis using a custom PCR array will be performed on stool samples to identify associated changes in microbiome absolute abundance at the genus and species level.
Time frame: through neoadjuvant chemotherapy treatment completion, average of 20 weeks from baseline
Quantify absolute abundance of gut microbiome using metagenomic analysis after surgery
Metagenomic analysis using a custom PCR array will be performed on stool samples to identify associated changes in microbiome absolute abundance at the genus and species level.
Time frame: through completion of surgery, average of 24 weeks from baseline
Quantify absolute abundance of gut microbiome using metagenomic analysis after radiation treatment
Metagenomic analysis using a custom PCR array will be performed on stool samples to identify associated changes in microbiome absolute abundance at the genus and species level.
Time frame: through radiation treatment completion, average of 30 weeks from baseline
Quantify absolute abundance of gut microbiome using metagenomic analysis after chemotherapy treatment
Metagenomic analysis using a custom PCR array will be performed on stool samples to identify associated changes in microbiome absolute abundance at the genus and species level.
Time frame: through chemotherapy treatment completion, average of 50 weeks from baseline
Quantify absolute abundance of gut microbiome using metagenomic analysis after 24 weeks of endocrine treatment
Metagenomic analysis using a custom PCR array will be performed on stool samples to identify associated changes in microbiome absolute abundance at the genus and species level.
Time frame: through 24 weeks of endocrine treatment, average of 74 weeks from baseline
Fold change in relative abundance of gut microbiome using using metatranscriptomic analysis from baseline to after neoadjuvant chemotherapy treatment
Metatranscriptomic analysis using a RNA seq will be performed on stool samples to identify associated fold changes in which genes are turned on and off
Time frame: through neoadjuvant chemotherapy treatment completion, average of 20 weeks from baseline
Fold change in relative abundance of gut microbiome using using metatranscriptomic analysis from baseline to after surgery
Metatranscriptomic analysis using a RNA seq will be performed on stool samples to identify associated fold changes in which genes are turned on and off
Time frame: through completion of surgery, average of 24 weeks from baseline
Fold change in relative abundance of gut microbiome using using metatranscriptomic analysis from baseline to after radiation treatment
Metatranscriptomic analysis using a RNA seq will be performed on stool samples to identify associated fold changes in which genes are turned on and off
Time frame: through radiation treatment completion, average of 30 weeks from baseline
Fold change in relative abundance of gut microbiome using using metatranscriptomic analysis from baseline to after chemotherapy treatment
Metatranscriptomic analysis using a RNA seq will be performed on stool samples to identify associated fold changes in which genes are turned on and off
Time frame: through chemotherapy treatment completion, average of 50 weeks from baseline
Fold change in relative abundance of gut microbiome using using metatranscriptomic analysis from baseline to after 24 weeks of endocrine treatment
Metatranscriptomic analysis using a RNA seq will be performed on stool samples to identify associated fold changes in which genes are turned on and off
Time frame: through 24 weeks of endocrine treatment, average of 74 weeks from baseline