Vasodilator Therapy With Isosorbide Mononitrate or Diltiazem to Reduce Vasotoxicity in Patients With Gastrointestinal Cancer Receiving Fluoropyrimidine Therapy

Inclusion Criteria:

* REGISTRATION: Age ≥ 18 years
* REGISTRATION: 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
* REGISTRATION: Planned initiation of 5-FU (infusional) or oral capecitabine therapy, either as standard chemotherapy or as a radiosensitizer
* REGISTRATION: Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2
* REGISTRATION: Ability to return to Mayo Clinic for baseline and follow-up EndoPAT testing, electrocardiogram (ECG), Holter monitoring, and blood draws
* REGISTRATION: Provide written informed consent
* REGISTRATION: 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)
* RANDOMIZATION: Completed all phase I baseline and follow-up assessments, including EndoPAT, ECG, high-sensitivity cardiac troponin T (hs-TnT), and Holter monitoring
* RANDOMIZATION: Demonstrated a ≥ 20% decline in reactive hyperemia index (RHI) from baseline at either phase I follow-up assessment as measured by EndoPAT
* RANDOMIZATION: Adequate hemodynamic status prior to randomization: systolic blood pressure ≥ 120 mmHg and resting heart rate ≥ 70 beats/minute
* RANDOMIZATION: Ability to tolerate and comply with study medication (isosorbide mononitrate, diltiazem, or placebo) per investigator assessment
* RANDOMIZATION: Willingness to initiate study medication 5 days before and continue through the assigned fluoropyrimidine treatment cycle
* RANDOMIZATION: Provide written informed consent for randomization phase

Exclusion Criteria:

* REGISTRATION: Current or planned treatment with long-acting nitrates or calcium channel blockers at the time of fluoropyrimidine initiation
* REGISTRATION: Known hypersensitivity or contraindication to nitrates or calcium channel blockers
* REGISTRATION: Baseline systolic blood pressure \< 120 mmHg or resting heart rate \< 70 beats/minute
* REGISTRATION: History of myocardial infarction ≤ 6 months prior to registration, or symptomatic heart failure \[decompensated or New York Heart Association (NYHA) III-IV\] requiring ongoing therapy
* REGISTRATION: Recent acute coronary syndrome or coronary revascularization within 3 months of enrollment
* REGISTRATION: High-grade atrioventricular (AV) block without pacemaker
* REGISTRATION: Use of PDE-5 inhibitors \[e.g. sildenafil (Viagra)\] within 48 hours of enrollment
* REGISTRATION: Uncontrolled intercurrent illness including but not limited to: unstable angina, symptomatic arrhythmias, uncontrolled infection, or psychiatric/social conditions limiting compliance with study requirements
* REGISTRATION: Physical inability to undergo EndoPAT testing (e.g., digital amputation, severe hand deformity, or other limiting condition)
* REGISTRATION: Pregnant or nursing persons
* REGISTRATION: Concurrent enrollment in another interventional clinical trial that, in the opinion of the investigator, would interfere with study endpoints