Introduction
Fluoropyrimidines (FP), namely 5-fluorouracil (5-FU) and capecitabine, are widely used to treat solid malignancies, including those arising from gastrointestinal tract. In addition, FP are frequently used concurrently with radiotherapy, due to their radio-sensitizing properties. 5-FU and capecitabine are generally well tolerated, being myelosuppression, gastrointestinal, and skin toxicity (hand-foot syndrome) the most common adverse events, which vary according to dose and schedule (1).
Cardiotoxicity is a feared, uncommon toxicity of FP; although the most common manifestation of FP-induced cardiotoxicity (FIC) is unstable angina (2), other severe adverse cardiac events, including cardiomyopathy, myocarditis, and sudden cardiac death, have been reported (3). FIC typically occurs during the first few treatment cycles, which usually results in the discontinuation of treatment (4). As a consequence, FIC represents an important issue particularly in colorectal cancer (CRC) treatment, due to the central role of FP in the management of this disease, both in adjuvant and palliative settings. Patients with CRC that experienced FIC have a considerable reduction in their therapeutic options with a negative influence on prognosis (5).
Proposed mechanisms that underlie FIC include coronary artery vasospasms, vascular endothelial dysfunction, direct toxicity on the myocardium, and thrombogenicity due to altered blood rheology (6).
Coronary artery vasospasms are considered to be the main pathogenic mechanism (7), and it has been suggested that N-terminal (NT)-pro hormone BNP (proBNP) may act as a biomarker of FIC (8). The compound that may be responsible for these effects is fluoroacetate. 5-FU and capecitabine are catabolised by dehydro-pyrimidine dehydrogenase (DPYD) and in several steps degraded into α-fluoro-β-alanine, and then into fluoroacetate, a highly cardiotoxic and neurotoxic compound (9).
The reported incidence of cardiac symptoms and events varies greatly in the existing literature, with a range from 0–34.6% of patients (10). Serious cardiac events, including myocardial infarction, cardiogenic shock and cardiac arrest, occurred in 0–2% (11). No significant differences were observed in the incidence of cardiac events between capecitabine and 5-FU (11).
The identification of patients at risk for adverse cardiac events remains the major challenge, either due to the limited data on baseline cardiac risk factors or the lack of predictive biomarkers (10). Indeed, the correlation between cardiovascular (CV) risk factors, CV comorbidities and FIC remains unclear. Circulating biomarkers, such as proBNP and the cardiac structural proteins troponin I and T (TnI and TnT), useful for the diagnosis and prognosis of patients suffering from heart disease, have a limited role in the identification of FIC (10).
Other suitable and reliable plasma biomarkers could be represented by microRNAs (miRNA), small molecules of 20–22 nucleotides of non-coding RNA with a post-transcriptional regulation function. Different miRNAs are involved in CV diseases, including myocardial infarction, heart failure and cardiac hypertrophy. Certain of them, including miR-1, miR-133, miR-145, miR-208 and miR-499, abundantly expressed in the myocardium, have a diagnostic and prognostic role in cardiac damage (12,13). Consistent results were obtained for doxorubicin-treated patients with breast cancer: in particular, miR-1 is significantly overexpressed in the case of cardiotoxicity and has higher sensitivity compared with the classical TnI dosage (14). However, the ability of circulating miRNAs expression to predict FIC has not been explored.
In the present study, it was aimed to prospectively evaluate incidence, clinical manifestations, risk factors and predictive biomarkers of FIC in FP-treated patients with CRC.
Discussion
In this prospective observational study, incidence and clinical manifestations of FIC were evaluated in patients with CRC. The combination of female sex and high alcohol intake was identified as risk factor for FIC development.
The observed incidence of FIC, 15.5%, is in stark contrast with the general notion that this is an infrequent complication. The existing literature displays a moderate-high variability in the delineation of this value, to which different factors can contribute: retrospective nature, selection bias, differences in CV risk profiles of the analysed samples, and, importantly, the lack of a shared and widely accepted standard for a practical definition of FIC.
In the present study, a collection of PROs together with an objective assessment of the cardiac function was proposed. This led to the individuation and inclusion in our cohort of asymptomatic and mildly symptomatic patients with cardiovascular disease, potentially excluded from other prospective or retrospective analyses. Suspected FIC cases were subject to a cardiological verification.
In the present trial, 40% of patients with FIC reported chest pain, but only 15% presented an ECG alteration. Most of the patients with chest pain and normal ECG had also normal coronary enzymes, whereas severe events, such as acute myocardial infarction, were rare. This pattern is in accordance with other studies. Both the sudden onset of chest pain and the rarity of the occurrence of life-threatening complications support the pathogenetic hypothesis of a FP-induced transient vasospastic mechanism. In our experience, this was further corroborated by the subsequent angiographic finding of normal coronary arteries in the patient who had experienced FP-related acute myocardial infarction.
In line with this hypothesis, only a minority of patients displayed objective signs (e.g. ECG changes) of cardiotoxicity, and FIC was initially suspected on the clinical relevance of subjective symptoms. In this context, the physician's assessment of the patient's symptoms takes on a relevant role, passing from a passive registration of symptomatology to active discrimination of cardiac events.
Compared with other case series, the symptoms reported were prospectively and actively analyzed according to a global patient evaluation. This led to the discrimination between non-specific symptoms and clinically relevant cardiological events, showing the actual FIC incidence in the real-world CRC population. As an example, patient 13 was correctly identified at C2 as a CV event and a consequent cardiological assessment was performed. Nevertheless, due to the completely negative cardiological work-up, retreatment with FP was performed with strict monitoring and patient experienced an acute CV event at C6.
Except for this single event, retreatment with FP after the occurrence of cardiotoxicity was attempted in all other patients without any FIC recurrence. Overall, out of 18 patients experiencing FIC, 4 started a cardiological protective therapy without recurrence, whilst among 14 patients who were not prescribed any further cardiological therapy, only one experienced a FIC recurrence. The real value of cardiological therapy and FP dose reduction is questionable. A retrospective study on 668 patients and a prospective study on 644 patients treated with 5-FU or capecitabine reported a benefit from initiation of a prophylactic cardiological therapy that prevented symptoms at retreatment in 9 out of 12 patients and 12 out of 15 patients, respectively (19,20). By contrast, a small and non-randomised study could not demonstrate a prophylactic effect of calcium channel blockers on the occurrence of cardiotoxicity (21). With the limitation of the small numbers, the complex of these data suggested that resumption of FP-based chemotherapy is a generally feasible strategy with the following caveats: i) however carefully conducted, selection of patients to be subject to retreatment is rendered difficult by the proteiform manifestations of FIC; ii) rather than pharmacological secondary prevention, close cardiac monitoring is crucial; iii) retreatment requires considerable precaution given the unpredictable time-cardiotoxicity correlation. As more general considerations, the added value offered in this context by the collaboration between the oncologist and the cardiologist/cardioncologist should be noted, as well as the need for a frank discussion with the patient, in which duty of the oncologist is to carefully review the risk/benefit balance of resuming the treatment.
The multivariate logistic regression, applied to sex and alcohol consumption, revealed that both males and females are more protected from CV events if they do not consume alcohol; the subpopulation of females drinking more than 10 g of alcohol per day are the most at risk to FIC development and thus deserve particular attention.
Pursuing the objective of a real-world study, 44.6% of patients with high CV risk factors (such as myocardial infarction history) were included in the present cohort. Nevertheless, a predictive role for FIC was not demonstrated for pre-existing cardiac disease. High-risk subgroups cannot be identified on these bases, and, since FIC can be lethal in patients without a history of cardiac disease, attention must be paid in all FP-treated patients indiscriminately.
Although previous studies suggested that capecitabine is more likely to induce cardiotoxicity compared with 5-FU chemotherapy (20,22), results from the literature are contradictory (11,19). In our cohort, a comparable incidence of FIC between the oral pro-drug and the infusion regimens was observed.
Based on these results, careful monitoring of possible FIC throughout in all patients is recommended regardless of CV comorbidities, FP chemotherapy regimen, through all treatment cycles and, particularly, upon the occurrence of mildly symptomatic FIC. An effective work-up should be applied (e.g. ECG monitoring or use of cardiac therapy) but, in relation to its unpredictable nature, strict monitoring must be performed to avoid lethal events, particularly in the adjuvant setting, in which FP have a curative role and the risk-benefits should be carefully considered.
Albeit routinely used in the clinical management of cardiac disease, TnI and proBNP cannot be efficiently used for FIC prediction. Particularly, neither significantly changed their expression in CV-event patients at any cycle of treatment, except for patient 17 in which a TnI elevation was observed at the recurrence. No variation in proBNP expression between FIC and no FIC patients was found. A statistically significant increase of proBNP levels between D3 and D1 of all the first three cycles was observed only in patients treated with 5-FU; a potential explanation could be the cardiac parietal stress exerted by the transient mild hypervolemia due to the fluids infused during the 5-FU-based chemotherapy administration.
The exploratory analysis of miRNA profiling conducted on a small subset of patients who experienced FIC (n=8) and 16 control patients, at baseline, revealed no significant differences in terms of miRNA expression. A comparison between patients who experienced FIC and low risk controls revealed three differentially expressed microRNAs, two of which had been previously associated with cardiovascular diseases. Exploration of miRNA expression, either as a baseline regulators of enzymes activities or as modulators induced by treatment with chemotherapy and targeted therapy, is a promising field (23–25). Nevertheless, this was not pursued as the present study aimed to identify potential predictive biomarkers in FP-naïve patients; for this reason, plasma samples collected after the completion of FP treatment were not analyzed.
Certain limitations to the present study need to be discussed. Due to the early closure of accrual, a smaller sample size than planned was obtained, resulting in a low number of events (20 CV events) leading to wide CIs, low statistical power and increased risk of type II statistical errors. This, moreover, reduces the number of risk factors which could be could confidently examined in our multivariate model. The low number of events and multiple testing (increasing the risk of false-positive results) are weaknesses of most studies analysing risk factors and render the conclusions that can be drawn from these studies less valid and may conceal clinically significant differences between events and no event.
Lastly, the DPYD status was not available. While DPYD polymorphisms exert a well-known influence on enzymatic activity, FP catabolism and toxicity, the impact of the enzyme deficiency on cardiotoxicity remains unclear but appears to be limited.
In a large prospective study, 487 oncologic patients treated with a 5-FU-based chemotherapy regimen were characterized for single nucleotide polymorphisms (SNPs) of DPYD. Although 187 patients had SNPs, only 4 of these patients (2%) developed severe (grade 3 or 4) cardiotoxicity (26).
Nevertheless, DPYD polymorphisms are not the only factors that could affect DPDYD enzyme activities. The miR-27 level expression has been linked to the function of the DPD enzyme in the liver cells, and p53 status plays an important role in controlling pyrimidine catabolism through repression of DPYD expression (25,27). In addition, even abnormalities of thymidylate synthase, the main target of FP actions, appear to predict the risk of severe toxicity and the combination of DPYD and TYMS genotyping could identify ≥50% of patients at the greatest risk of adverse events (28).
However, differently from most other large studies on this topic, the present study is a monocentric, rigorous, prospective trial. This may result in a minor inter-variability in symptomatology assessment and cardiological evaluation, but it may not reflect the characteristics of the general population and practice patterns.
In conclusion, cardiotoxicity can be a life-threatening, unexpected complication of FP therapy that limits the appropriate treatment of a highly morbid and aggressive cancer. Despite females with an alcohol consumption habit being more prone to experience FIC at our institution, FIC was not clearly associated with classical CV comorbidities. Consequently, optimal information about the risk and close monitoring represent the best option to prevent serious events and lethal outcome in all patient subgroups, regardless of common risk factors.