Microvascular Function in Patients Undergoing 5-Fluorouracil Chemotherapy

NCT ID: NCT04042298

Last Updated: 2025-09-02

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

COMPLETED

Total Enrollment

62 participants

Study Classification

OBSERVATIONAL

Study Start Date

2019-06-25

Study Completion Date

2023-06-01

Brief Summary

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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.

Detailed Description

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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.

Conditions

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Gastrointestinal Cancer Head and Neck Cancer Breast Cancer Chemotherapy Effect 5-Fluorouracil Toxicity

Study Design

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Observational Model Type

CASE_CONTROL

Study Time Perspective

PROSPECTIVE

Study Groups

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5-FU Chemotherapy (Experimental)

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.

Arterial blood pressure

Intervention Type OTHER

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).

Skin microcirculatory blood flow

Intervention Type OTHER

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

Brachial artery blood flow

Intervention Type OTHER

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.

Venous blood draw

Intervention Type OTHER

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.

Non-5-FU Chemotherapy (Sub-Control)

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.

Arterial blood pressure

Intervention Type OTHER

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).

Skin microcirculatory blood flow

Intervention Type OTHER

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

Brachial artery blood flow

Intervention Type OTHER

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.

Venous blood draw

Intervention Type OTHER

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.

Age/Sex matched Control (Control)

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

Arterial blood pressure

Intervention Type OTHER

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).

Skin microcirculatory blood flow

Intervention Type OTHER

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

Brachial artery blood flow

Intervention Type OTHER

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.

Venous blood draw

Intervention Type OTHER

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.

5-FU Chemotherapy Cancer Survivor (Survivor)

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

Arterial blood pressure

Intervention Type OTHER

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).

Skin microcirculatory blood flow

Intervention Type OTHER

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

Brachial artery blood flow

Intervention Type OTHER

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.

Venous blood draw

Intervention Type OTHER

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.

Interventions

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Arterial blood pressure

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).

Intervention Type OTHER

Skin microcirculatory blood flow

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

Intervention Type OTHER

Brachial artery 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.

Intervention Type OTHER

Venous blood draw

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.

Intervention Type OTHER

Eligibility Criteria

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Inclusion Criteria

* Give voluntary consent to participate in the study
* (Group 1) Current cancer treatment includes 5-FU
* (Group 2) Current cancer treatment does not include 5-FU
* (Group 3) Cancer survivor previously treated with 5-FU but has not received cancer treatment in the year proceeding enrollment.
* (Group 4) Age, sex, and health matched (excluding cancer) control for Group 1

Exclusion Criteria

* (Groups 1, 2, and 4) Have received cancer treatment outside of the past year
* Not met above criteria
* Pregnant, breastfeeding, or planning to become pregnant
* Unable to provide informed consent
Minimum Eligible Age

21 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

Yes

Sponsors

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Kansas State University

OTHER

Sponsor Role lead

Responsible Party

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Carl Ade, M.S., Ph.D.

Assistant Professor

Responsibility Role PRINCIPAL_INVESTIGATOR

Locations

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Lafene Health Center

Manhattan, Kansas, United States

Site Status

Countries

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United States

References

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Yeh ET, Bickford CL. Cardiovascular complications of cancer therapy: incidence, pathogenesis, diagnosis, and management. J Am Coll Cardiol. 2009 Jun 16;53(24):2231-47. doi: 10.1016/j.jacc.2009.02.050.

Reference Type BACKGROUND
PMID: 19520246 (View on PubMed)

Sara JD, Kaur J, Khodadadi R, Rehman M, Lobo R, Chakrabarti S, Herrmann J, Lerman A, Grothey A. 5-fluorouracil and cardiotoxicity: a review. Ther Adv Med Oncol. 2018 Jun 18;10:1758835918780140. doi: 10.1177/1758835918780140. eCollection 2018.

Reference Type BACKGROUND
PMID: 29977352 (View on PubMed)

Taniyama Y, Griendling KK. Reactive oxygen species in the vasculature: molecular and cellular mechanisms. Hypertension. 2003 Dec;42(6):1075-81. doi: 10.1161/01.HYP.0000100443.09293.4F. Epub 2003 Oct 27.

Reference Type BACKGROUND
PMID: 14581295 (View on PubMed)

Polk A, Vistisen K, Vaage-Nilsen M, Nielsen DL. A systematic review of the pathophysiology of 5-fluorouracil-induced cardiotoxicity. BMC Pharmacol Toxicol. 2014 Sep 4;15:47. doi: 10.1186/2050-6511-15-47.

Reference Type BACKGROUND
PMID: 25186061 (View on PubMed)

Luwaert RJ, Descamps O, Majois F, Chaudron JM, Beauduin M. Coronary artery spasm induced by 5-fluorouracil. Eur Heart J. 1991 Mar;12(3):468-70. doi: 10.1093/oxfordjournals.eurheartj.a059919.

Reference Type BACKGROUND
PMID: 2040332 (View on PubMed)

Sudhoff T, Enderle MD, Pahlke M, Petz C, Teschendorf C, Graeven U, Schmiegel W. 5-Fluorouracil induces arterial vasocontractions. Ann Oncol. 2004 Apr;15(4):661-4. doi: 10.1093/annonc/mdh150.

Reference Type BACKGROUND
PMID: 15033676 (View on PubMed)

Sutterfield SL, Caldwell JT, Post HK, Lovoy GM, Banister HR, Ade CJ. Lower cutaneous microvascular reactivity in adult cancer patients receiving chemotherapy. J Appl Physiol (1985). 2018 Oct 1;125(4):1141-1149. doi: 10.1152/japplphysiol.00394.2018. Epub 2018 Aug 9.

Reference Type BACKGROUND
PMID: 30091663 (View on PubMed)

Other Identifiers

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Pro9646

Identifier Type: -

Identifier Source: org_study_id

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