This phase I/II trial compares the effect of drugs that causes widening of blood vessels as a result of smooth muscle relaxation (vasodilator therapy) with isosorbide mononitrate, diltiazem or placebo to reduce vasotoxicity in patients with gastrointestinal cancer receiving fluoropyrimidine therapy. Some patients develop chest pain (possibly even a heart attack, a drop in heart function, or a rhythm abnormality) during treatment with a class of cancer drugs known as fluoropyrimidines, which include 5-Fluorouracil (5-FU) and capecitabine. These side effects are believed to be due to the development of an abnormal reactivity of the blood vessels referred to as vasospasm. Vasotoxicity is damage or toxicity inflicted upon blood vessels (vascular system), often causing dysfunction, remodeling, or narrowing (vasoconstriction). It is a broad term used to describe the detrimental effects of certain agents, such as chemotherapy drugs. Researchers want to evaluate how often the reactivity of blood vessels becomes abnormal, during the treatment with 5-FU or capecitabine and how clinically relevant and controllable/preventable this phenomenon is in patients with gastrointestinal cancer.
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: 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
Sequential
Biospecimen Collection
Procedure/SurgeryUndergo blood sample collection
Capecitabine
DrugGiven IPO
Diltiazem Hydrochloride
DrugGiven PO
Electrocardiogram
Procedure/SurgeryUndergo ECG
Fluorouracil
DrugGiven IV
Holter Monitoring
DeviceUndergo Holter monitoring
Isosorbide Mononitrate
DrugGiven PO
Medical Device Usage and Evaluation
Other interventionUse EndoPAT
Placebo Administration
DrugGiven PO
Questionnaire Administration
Other interventionAncillary studies
Change in reactive hyperemia index (RHI)
Will be analyzed as a continuous variable and paired t-test or Wilcoxon signed-rank test will be used depending on parametric or non-parametric distribution of RHI values. Statistical significance is set at a p-value \< 0.05.
Proportion of patients with RHI decline ≥ 20%
Assessed from baseline (prechemotherapy) to follow-up assessments during and after fluoropyrimidine exposure. Will be analyzed as a continuous variable and paired t-test or Wilcoxon signed-rank test will be used depending on parametric or non-parametric distribution of RHI values. Statistical significance is set at a p-value \< 0.05.
Proportion of patients with absolute RHI ≤ 2.0
Assessed from baseline (prechemotherapy) to follow-up assessments during and after fluoropyrimidine exposure. Will be analyzed as a continuous variable and paired t-test or Wilcoxon signed-rank test will be used depending on parametric or non-parametric distribution of RHI values. Statistical significance is set at a p-value \< 0.05.
High-sensitivity troponin T (hsTnT) (indicator of myocardial ischemia)
Will be compared between patients with and without a decline in RHI ≥20% from baseline.
Presence of Holter abnormalities (ST-segment changes, arrhythmias)
Assessed using 48-hour continuous Holter monitoring. Will be compared between patients with and without a decline in RHI ≥20% from baseline.
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