Inclusion Criteria:

• Age ≥18 years

• Histologically or cytologically confirmed gastrointestinal malignancy (colon, rectal, gastric, esophageal, or other GI cancer) for which fluoropyrimidine therapy (5-FU or capecitabine) is indicated, either as single agent or in combination with other systemic therapy.

• Planned initiation of 5-FU (infusional or bolus-based) or oral capecitabine therapy, either as standard chemotherapy or as a radiosensitizer.

• ECOG Performance Status (PS) 0, 1, or 2.

• Ability to return to Mayo Clinic for baseline and follow-up EndoPAT testing, ECG, Holter monitoring, and blood draws.

• Provide written informed consent.

• Adequate baseline hemodynamic status: systolic blood pressure ≥120 mmHg and resting heart rate ≥70 beats/minute (to ensure safety for potential vasodilator therapy in Phase II).

Exclusion Criteria:

• Current or planned treatment with long-acting nitrates or calcium channel blockers at the time of fluoropyrimidine initiation.

• Known hypersensitivity or contraindication to nitrates or calcium channel blockers.

• Baseline systolic blood pressure <120 mmHg or resting heart rate <70 beats/minute.

• History of myocardial infarction ≤6 months prior to registration, or symptomatic  heart failure (decompensated or NYHA III-IV) requiring ongoing therapy.

• Recent acute coronary syndrome or coronary revascularization within 3 months of enrollment

• High-grade AV block without pacemaker

• Use of PDE-5 inhibitors (e.g. sildenafil (Viagra)) within 48 hours of enrollment3.28 Uncontrolled intercurrent illness including but not limited to: unstable angina, symptomatic arrhythmias, uncontrolled infection, or psychiatric/social conditions limiting compliance with study requirements.

• Physical inability to undergo EndoPAT testing (e.g., digital amputation, severe hand deformity, or other limiting condition).

• Pregnant or nursing persons.

• Concurrent enrollment in another interventional clinical trial that, in the opinion of the investigator, would interfere with study endpoints.

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 12/30/2025. Questions regarding updates should be directed to the study team contact.