Fluoropyrimidine Chemotherapy and the Risk of Death and Cardiovascular Events in Patients With Gastrointestinal Cancer

Abstract

Background: Fluoropyrimidine chemotherapy is administered first-line for many gastrointestinal cancers. However, patients with cardiovascular disease commonly receive alternative treatment due to cardiotoxicity concerns.

Objectives: This study sought to assess the risks of all-cause mortality and acute cardiovascular events with fluoropyrimidine treatment.

Methods: We conducted an observational cohort study applying a target trial emulation framework to linked national cancer, cardiac, and hospitalization registry data from the Virtual Cardio-Oncology Research Initiative. Adults diagnosed with tumors eligible for fluoropyrimidine-based chemotherapy as first-line therapy were included. All-cause mortality and a composite of hospitalization for acute cardiovascular events (acute coronary syndrome, heart failure, cardiac arrhythmia, cardiac intervention, cardiac arrest, and cardiac death) were compared in patients treated with fluoropyrimidine-based chemotherapy vs alternative management. Adjusted, weighted pooled logistic regression models were used to estimate the 1-year risk difference (RD).

Results: Among 103,110 patients (mean age 69.7 years, 59% male), the absolute risk of death at 1 year was significantly lower in fluoropyrimidine-treated patients (RD: -7.7%; 95% CI: -8.7% to -6.7%) with a small increased risk of acute cardiovascular events (RD: 0.9%; 95% CI: 0.0% to 1.9%). This was primarily due to arrhythmias (RD: 0.8%; 95% CI: 0.1% to 1.6%) and cardiac arrest (RD: 0.3%; 95% CI: 0.1% to 0.5%), with no increased risk of acute coronary syndromes including in the subgroup of patients with pre-existing coronary artery disease.

Conclusions: The markedly improved overall survival with fluoropyrimidines in patients with gastrointestinal cancer significantly outweighs the small risk of cardiac arrhythmia and arrest. Oncologists should take this into consideration for decision making to avoid undue clinical conservatism, particularly in patients with cardiovascular disease.

Keywords: 5-fluorouracil; arrhythmia; capecitabine; cardiotoxicity; gastrointestinal cancer; outcomes; risk prediction; sudden death; target trial emulation; vasospasm.

Graphical abstract

Figure 1

Selection of Patients From NCRD for the Target Trial Emulation There were 206,756 patients with new gastrointestinal tumor diagnosed between 2014 and 2018 in the National Cancer Registration Dataset (NCRD) database. After exclusion, 103,110 patients were eligible for the trial emulation. All patients were cloned and assigned with both treatment strategies. HES = Hospital Episode Statistics.

Figure 2

Weighted, Standardized Cumulative Incidence Curves Graphs showing weighted, standardized cumulative incidence curves for (A) all-cause mortality and (B) composite cardiovascular events, comparing patients on fluoropyrimidine vs no fluoropyrimidine.

Figure 3

1-Year Absolute Risk Differences With 95% CIs Graphs showing 1-year absolute risk differences with 95% CIs from calculated weighted, standardized cumulative incidence for (A) all-cause mortality and (B) composite cardiovascular events, comparing patients on fluoropyrimidine vs no fluoropyrimidine.

Central Illustration

Real-World Survival Benefit and Cardiovascular Risk With Fluoropyrimidine Treatment Among Patients With Gastrointestinal Cancers Real-world observational data of 103,110 patients with gastrointestinal cancers from England were used to emulate a target trial to evaluate the survival benefit and cardiovascular risk with fluoropyrimidine treatment. There was a 7.7% lower absolute risk difference for all-cause mortality and a 0.9% higher absolute risk difference for cardiovascular events at 1 year after the cancer diagnosis comparing fluoropyrimidine vs no fluoropyrimidine.