Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

All Conditions

Prostatic Neoplasms

Genital Neoplasms, Male

Urogenital Neoplasms

Genital Diseases

Genital Diseases, Male

Urogenital Diseases

Prostatic Diseases

Male Urogenital Diseases

All Drugs and Chemicals

Androgens

Hormones

Prolactin Release-Inhibiting Factors

Androgen Antagonists

Prostate cancer patients or survivors who have a treatment history that includes androgen deprivation therapy. This includes 1) orchiectomy (surgical castration), 2) luteinizing hormone-releasing hormone (LHRH) agonists (also called LHRH analogs or Gonadotrophin-releasing hormone (GnRH) agonists), 3) LHRH antagonist, 4) CYP17 inhibitor, or 5) anti-androgen.

Prostate cancer patients or survivors who have never been treated with androgen deprivation therapy.

Individuals with no history of prostate caner androgen deprivation therapy. Free of known clinical cardiovascular disease

Non-invasive assessment of left ventricle structure and function

Transthoracic Echocardiography

Continuously monitored for 5-30 minutes via finger photoplethysmography

Arterial blood pressure

Incremental exercise test to 85% predicted maximal heart rate on a recumbent cycle ergometer

Submaximal Exercise

Carl J Ade, PhD

The aim of this project is to determine whether androgen deprivation therapy (ADT) decreases left ventricular function in prostate cancer patients. If found successful, this may lead to improved cardiovascular health via treatment and/or lifestyle interventions in prostate cancer populations.

Prostate Cancer is the second most common cancer among American men. Approximately 1 in 7 men will be diagnosed with prostate cancer during his lifetime. In prostate cancer patients alone, hypotestosteronemia, caused by prostate cancer treatment is associated with visceral adiposity, insulin resistance, metabolic syndrome, decreased high-density lipoprotein, increased low-density lipoprotein, increased triglycerides, loss of muscle mass, erectile disfunction, and a loss of microvascular endothelial function. Recently, several population-based studies have reported an association between androgen deprivation therapy and an increased risk of cardiovascular events, that include myocardial infarction and cardiovascular mortality. Given this link and the growing evidence that androgen-deprivation therapy adversely affects traditional risk factors, it is essential to better understand the role this type of treatment has on cardiac structure and function. As such, the manifestation of cardiovascular toxicities with prostate cancer treatment will initially be subclinical (left ventricular function changes in asymptomatic individuals) compared to clinical (including coronary symptoms or heart failure) and may develop subacutely (during treatment) or chronically.

Effect of Androgen Deprivation Therapy on Cardiovascular Function in Prostate Cancer

Effect of Androgen Deprivation Therapy on Left Ventricular Function in Prostate Cancer Patients and Survivors

measure of left ventricular systolic function

measure of left ventricular systolic and diastolic function

measure of cardiac function at rest and during submaximal exercise

Kansas State University

Assistant Professor

Skin and Connective Tissue Diseases

Digestive System Diseases

Breast Neoplasms

Head and Neck Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Antineoplastic Agents

Vasodilator Agents

Fluorouracil

Acetylcholine

Comprised of newly diagnosed cancer patients 21 years or older who have received 5-FU chemotherapy within the past 30 days or are scheduled to receive 5-FU chemotherapy.

Comprised of newly diagnosed cancer patients 21 years or older who have received chemotherapy other than 5-FU within the past 30 days or are scheduled to receive chemotherapy other than 5-FU.

Age, biological sex, and prior health history (excluding cancer diagnosis) matched control for cancer patients

Cancer survivors who have not received cancer therapy during the past year but previously received 5-Fluorouracil chemotherapy.

Measured using an automated non-invasive finger cuff that obtains beat-by-beat blood pressure measurements via finger photoplesmography. Briefly, changes in artery diameter are detected through infrared light in the finger cuff. (Finometer Pro, FMS, The Netherlands).

Assessed non-invasively in the forearm skin via Laser Doppler flowmetry in response to locally delivered acetylcholine and norepinepherine or phenylepherine via iontophoresis.

Skin microcirculatory blood flow

A GE Ultrasound System will be used to non-invasively assess brachial artery blood flow prior to and following a standard flow mediated dilation protocol.

Brachial artery blood flow

A venous blood sample from the antecubital vein or a vein in the back of the hand will be taken via venipuncure by a nurse or a certified phlebotomist at the beginning of the experimental visit. These blood samples will be analyzed for the presence of reactive oxygen species and inflammatory markers.

Venous blood draw

Steve T Hammond

Carl J Ade, Ph.D.

The primary aim of this study is to investigate potential differences in vascular function between patients receiving 5-Fluorouracil (5-FU) chemotherapy, patients receiving chemotherapies other than 5-FU, cancer survivors who were treated with 5-FU, and an age and sex matched control. 5-FU is the third most commonly administered chemotherapeutic agent and its use is associated with the second most occurrences of cardiotoxicity. Despite the known cardiotoxic effects of 5-FU, it's effects on the human vasculature are not well understood.

To achieve the goals of this project Laser Doppler flowmetry (LDF) will be used to assess blood flow within the skin microcirculation of the forearm in cancer patients who have received 5-Fluoruracil within the past 30 days (Experimental Group), cancer patients receiving radiotherapy and/or chemotherapy other than 5-Fluorouracil, and an age and sex matched control (Control Group). LDF utilizes a small (\~3 cm) non-invasive sensor placed on the skin. The sensor shines light into the skin, and upon contact with red blood cells (RBCs), the light is reflected and scattered. This information is used to evaluate microvascular blood flow and has previously been used in clinical populations.

Although cancer continues to be one of the leading causes of death each year, advancements in cancer treatments and detection have improved patient prognosis across a large number of cancer types. This trend of improved survival rates has made apparent the significant risk of chemotherapy on the cardiovascular system in such a way that cardiotoxicity has become a prime concern in cancer survivors. Indeed, cardiotoxic events have been related to numerous chemotherapy types, including the commonly used 5-Fluorouracil (5-FU). 5-FU is the third most commonly administered form of chemotherapy used in the treatment of solid malignancies. Despite undeniable effectiveness in treating cancer, administration of 5-FU is associated with the second highest incidence of cardiotoxicity out of all chemotherapeutic agents.

Such cardiotoxic manifestations typically appear in the form of chest pain, angina during rest and/or exertion, and acute coronary syndromes, however, other events such as arrythmias, myocarditis, pericarditis, heart failure, or even death have been reported following 5-FU administration. While multiple mechanisms are believed to lead to 5-FU cardiotoxicity, the effects 5-FU has on the vasculature seem to be of particular importance. Initial findings suggest these drugs have a direct toxic effect on the vascular endothelium and smooth muscle, likely through increases in reactive oxygen species (ROS). ROS are known to adversely affect endothelium independent and dependent factors which influence vascular tone. Along with increased ROS, decreases in antioxidant capacity following 5-FU therapy lead to increased vasospasms and altered vasodilator/constrictor responses. Indeed, both coronary artery vasospasms and brachial artery vasoconstriction have been found to occur in some groups directly after injection of 5-FU.

Although the primary signaling pathways for 5-FU induced cardiotoxicity are well documented, many of these studies have been conducted in animal models. Previous work has demonstrated substantial vascular dysfunction in current cancer patients undergoing adjuvant systematic chemotherapy when compared to healthy controls, however, alike investigations specifically focused on vascular dysfunction in patients receiving 5-FU have yet to be conducted. To investigate such mechanisms, microvascular reactivity will be measured with laser Doppler flowmetry combined with iontophoresis of acetylcholine in cancer patients currently undergoing treatment with 5-Fluorouracil, patients receiving chemotherapy treatments other than 5-Fluorouracil, cancer survivors previously treated with 5-Fluorouracil, and age and sex matched controls.

Venous blood samples (5-7 mL) from the antecubital vein or a vein in the back of the hand will be taken via venipuncure by a nurse or a certified phlebotomist at the beginning of the experimental visit. These blood samples will be analyzed for the presence of reactive oxygen species and inflammatory markers.

Microvascular Function in Patients Undergoing 5-Fluorouracil Chemotherapy

Measured once in each group following administration of vasodilatory (Acetylcholine) and vasoconstrictive (Norepinepherine or Phenylephrine) substances.

Systolic, diastolic, and mean arterial pressure will be measured continuously over the course of the visit for each group.

Immune System Diseases

Blood and Lymph Conditions

Rare Diseases

Hypersensitivity

Lymphoma

Lymphosarcoma

Anti-Infective Agents

Antihypertensive Agents

Nitric Oxide Donors

Hydrogen Peroxide

Nitroprusside

Breast cancer or lymphoma patients currently undergoing anthracycline-based chemotherapy treatment. Patients are eligible if they have completed at least 1 cycle of chemotherapy. Free of known clinical cardiovascular disease.

Individuals with history of breast cancer or lymphoma (1-5 years removed from last date of chemotherapy) who have a treatment history of anthracycline-based chemotherapy. Free of known clinical cardiovascular disease.

Individuals with no history of caner or chemotherapy. Free of known clinical cardiovascular disease

Continuously monitored for 5-30 minutes via finger photoplesmography

Assessment of carotid artery cross sectional area and intima-media thickness. Assessment of brachial artery diameter

Vascular Ultrasound

Evaluation of oxidative stress via serum lipid hydroperoxide

Venous blood sample

Assessed non-invasively in the forearm skin via Laser Doppler flowmetry in response to locally delivered acetylcholine (ACh) and sodium nitroprusside (SNP) via iontophoresis.

The overall goal of this project is to determine the effects of anti-cancer chemotherapy on reflex control of blood pressure and vascular function. Recent data have demonstrated that cardiovascular disease-related mortality is the 2nd cause of morbidity and mortality for 7-year cancer survivors treated with chemotherapy. This anti-cancer treatment-mediated cardiotoxicity is a progressive process that begins at the molecular level, progresses to myocardial injury and left ventricular dysfunction, cumulating as heart failure and cardiovascular disease-related mortality. In parallel to these cardiac-specific changes, chemotherapy has also been shown to increase the risk for vascular-related abnormalities. However, the impact of adjuvant treatments on the function and structure of the peripheral vascular system remains poorly understood. With normal aging, two of the most important vascular adaptations to arteries, which strongly contribute to the increased risk of vascular-related and general cardiovascular disease, are an increase in large artery stiffness and dysfunction of the vascular endothelium. Therefore, the overall goal of this project is to determine the effects of anthracycline-based chemotherapy on large and small artery function and structure. The central hypothesis is that this type of cancer therapy results in negative vascular consequences as determined by non-invasive evaluation of spontaneous blood pressure control, carotid artery stiffness, and vascular endothelium-dependent vasodilation.

This observational study is designed to increase our understanding of the vascular changes that occur during and following anti-cancer chemotherapy and provide insight into new methods that will decrease cardiovascular disease risk in those treated for cancer.

Cancer remains one of the leading causes of death in modern society. Breast cancer is a prevalent type of cancer in most societies, but due to increasing rates of detection coupled with advanced therapies, of the ≈230,000 people newly diagnosed each year with breast cancer, approximately 90% are expected to live beyond 5 years. Despite the trend in improved cancer-related morality, cancer survivors are at a significantly increased risk for cardiovascular disease (CVD) morbidity and mortality. As such, approximately $800 million is spent annually in providing cardiovascular care for female cancer survivors alone. In a recent study, Daher et al. (2012) reported a Framingham Risk Score of 8.4 and a 10-year risk of general CVD of 7.6% in men and women cancer survivors older than 30 yrs. More importantly, they also determined that the mean vascular age of cancer survivors was 8 years greater than their chronological age, suggesting that sub-clinical manifestation of CVD may be present within the vasculature of some cancer survivors.

The definition and scientific study of cardiotoxicity has, to date, primarily focused solely on the myocardial injury related to adjuvant cancer therapy and the National Cancer Institute has defined it as "toxicity that affects the heart" (http://www.cancer.gov/dictionary/). However, cancer survivors are also at risk for vascular-related abnormalities. Despite this risk, the impact of adjuvant treatments on the function and structure of the peripheral vascular system is still poorly understood. With normal aging, two of the most important vascular adaptations to arteries, which strongly contribute to the increased risk of vascular-related and general CVD, are an increase in large artery stiffness and dysfunction of the vascular endothelium \[15, 16\]. In subjects receiving anthracycline chemotherapy, Chaosuwannaki et al. (2010), Miza-Stec et al. (2013), and Draft et al. (2013) independently demonstrated significant increases in aortic stiffness 4-6 mo following treatment. Likewise, carotid intima-media thickness has been shown to increase within 6 mo of treatment with chemotherapy. This is critical given that arterial stiffness and intima-media thickness both are independently associated with increased risk of cardiovascular disease. In addition, carotid artery stiffness is a key determinant of the sympathetic baroreflex sensitivity in older men and women. This information suggests that decreases in baroreflex sensitivity may be occurring following chemotherapy treatment, which is important given it is a primary mechanism through which the autonomic nervous system regulates arterial blood pressure and that a low baroreflex sensitivity is associated with cardiovascular morbidity and mortality. Specific Aim 1 will address this question.

The vascular endothelium is the first physiological barrier encountered by intravenously administered chemotherapy. Unfortunately, the effects of adjuvant therapy on endothelial function have primarily been studied in childhood cancer survivors or following a single treatment session. Chow et al. (2006) observed a decreased brachial artery flow-mediated dilation (FMD), a measurement of endothelial-dependent dilation, ≈20 mo following anthracycline-based chemotherapy. Similarly, Vaughn et at. (2008) demonstrated a decreased FMD in long-term survivors of testicular cancer. In addition, several reports have demonstrated a decrease in arterial reactivity to various biological vasodilators (e.g., sodium nitroprusside, acetylcholine) following acute chemotherapy and radiation. In contrast to these studies, Jones et al. (2007) reported no difference in FMD in breast cancer patients ≈20 mo post-treatment compared to healthy controls. Increasing our understanding of the effects of chemotherapy on endothelial function is essential, especially since it can be the initial step in the development of cardiovascular disease.

Recently, the skin microcirculation has been used as a model circulation to evaluate the changes in vascular health in a variety of diseases including hypertension, renal disease, diabetes, atherosclerosis, coronary artery disease, and heart failure. This work has been facilitated, in part, by its easy accessibility and high responsiveness to biological vasodilators. Given the paucity of information on endothelial health in cancer patients undergoing anthracycline chemotherapy evaluation of the skin microcirculation provides a non-invasive and useful method of increasing our understanding of cardiotoxicity. Specific Aim 2 will address this problem.

Specific Aim 1: Evaluate the changes in spontaneous blood pressure control and arterial stiffness in patients treated with anthracycline-based chemotherapy.

Hypothesis 1a: Spontaneous baroreflex sensitivity will be significantly decreased in cancer patients and cancer survivors treated with anthracycline-based chemotherapy.

Hypothesis 1b: Changes in baroreflex control of blood pressure will be related to increases in carotid artery stiffness and cardiac changes in left ventricular ejection time.

Specific Aim 2: Evaluate the changes in macrovascular and microvascular vascular function.

Hypothesis 2a: Treatment with anthracycline-based chemotherapy will significantly decrease endothelium-dependent vasodilation in both the large brachial artery and the small microvascular capillaries in the skin.

Hypothesis 2b: Changes in vascular function will be associated with molecular markers of endothelial function and oxidative stress.

The Effects of Anthracycline-based Chemotherapy on Peripheral Vascular Function

The Effects of Anthracycline-based Chemotherapy on Spontaneous Baroreflex Sensitivity, Carotid Artery Stiffness, and Endothelial-dependent Vascular Function.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Effect of Androgen Deprivation Therapy on Cardiovascular Function in Prostate Cancer	NCT03275181	Prostate Cancer	Transthoracic E... Arterial blood ... Submaximal Exer...	21 Years - 80 Years	Kansas State University
Microvascular Function in Patients Undergoing 5-Fluorouracil Chemotherapy	NCT04042298	Gastrointestina... Head and Neck C... Breast Cancer Chemotherapy Ef... 5-Fluorouracil ...	Arterial blood ... Skin microcircu... Brachial artery... Venous blood dr...	21 Years -	Kansas State University
The Effects of Anthracycline-based Chemotherapy on Peripheral Vascular Function	NCT03062878	Breast Cancer Lymphoma Chemotherapy Ef...	Arterial blood ... Vascular Ultras... Venous blood sa... Skin microcircu...	21 Years -	Kansas State University
Microvascular Function in Patients Undergoing 5-Fluorouracil Chemotherapy	NCT04042298	Gastrointestina... Head and Neck C... Breast Cancer Chemotherapy Ef... 5-Fluorouracil ...	Arterial blood ... Skin microcircu... Brachial artery... Venous blood dr...	21 Years -	Kansas State University
Effect of Androgen Deprivation Therapy on Cardiovascular Function in Prostate Cancer	NCT03275181	Prostate Cancer	Transthoracic E... Arterial blood ... Submaximal Exer...	21 Years - 80 Years	Kansas State University

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