Clinical trial NCT04042298: Microvascular Function in Patients Undergoing 5-Fluorouracil Chemotherapy
Official title: Microvascular Function in Patients Undergoing 5-Fluorouracil Chemotherapy
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Gastrointestinal Cancer
Head and Neck Cancer
Breast Cancer
Chemotherapy Effect
5-Fluorouracil Toxicity
Lead sponsor: Kansas State University
Sponsor class: OTHER
First posted: 2019-08-01
Enrollment: 106
Sex: ALL
Minimum age (years): 21
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Newly diagnosed cancer patients who have received (or are scheduled to receive) 5-FU chemotherapy within the past 30 days (n=26) will enter the study soon after initiation of treatment. Newly diagnosed cancer patients receiving cancer treatment other than 5-FU (n=26; chemotherapy, radiotherapy, etc.) will enter into the study soon after initiation of treatment. Cancer survivors (n=26) who have previously received 5-FU but not within the year proceeding enrollment will be entered into the study. Age, sex, and health (n=26; excluding cancer) matched controls will be included in the study.

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Cutaneous (skin) blood flow (%) following administration of vasoactive substances
timeFrame: 1 day
measure: Brachial artery flow mediated dilation (FMD)
timeFrame: 1 day
Secondary outcomes:
measure: Arterial blood pressure
timeFrame: 1 day
Other outcomes:
Locations:
city: Manhattan
country: United States
facility: Lafene Health Center
state: Kansas
Study officials:
References:
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citation: 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.