Skip to main content
Download PDF

The association between systemic immune-inflammation index and cardiotoxicity related to 5-Fluorouracil in colorectal cancer

BMC Cancer volume 24, Article number: 782 (2024) Cite this article

Abstract

Background and aims

The cardiotoxicity related to 5-Fluorouracil (5-FU) in cancer patients has garnered widespread attention. The systemic immune-inflammation index (SII) has recently been identified as a novel predictive marker for the development of cardiovascular illnesses in individuals without pre-existing health conditions. However, it remains unclear whether the levels of SII are linked to cardiotoxicity related to 5-FU. This retrospective study aims to fill this knowledge gap by examining the correlation between SII and cardiotoxicity related to 5-FU in a colorectal cancer cohort.

Methods

The study comprised colorectal cancer patients who received 5-FU-based chemotherapy at the affiliated cancer hospital of Guizhou Medical University between January 1, 2018 and December 31, 2020. After adjustment for confounders and stratification by tertiles of the interactive factor, linear regression analyses, curve fitting and threshold effect analyses were conducted.

Results

Of the 754 patients included final analysis, approximately 21% (n = 156) of them ultimately experienced cardiotoxicity related to 5-FU. Monocytes (M) was found as an influential element in the interaction between SII and cardiotoxicity related to 5-FU. In the low tertile of M (T1: M ≤ 0.38 × 109/L), increasing log SII was positively correlated with cardiotoxicity related to 5-FU (Odds Ratio [OR], 8.04; 95% confidence interval [95%CI], 1.68 to 38.56). However, a curvilinear relationship between log SII and cardiotoxicity was observed in the middle tertile of M (T2: 0.38 < M ≤ 0.52 × 109/L). An increase in log SII above 1.37 was shown to be associated with a decreased risk of cardiotoxicity (OR, 0.14; 95%CI, 0.02 to 0.88), indicating a threshold effect. In the high tertile of M (T3: M > 0.52 × 109/L), there was a tendency towards a negative linear correlation between the log SII and cardiotoxicity was observed (OR, 0.85; 95%CI, 0.37 to 1.98).

Conclusion

Our findings suggest that SII may serve as a potential biomarker for predicting cardiotoxicity related to 5-FU in colorectal cancer patients. SII is an independent risk factor for cardiotoxicity related to 5-FU with low monocytes levels (T1). Conversely, in the middle monocytes levels (T2), SII is a protective factor for cardiotoxicity related to 5-FU but with a threshold effect.

Peer Review reports

Introduction

Colorectal cancer is the third most common cancer and a leading cause of cancer-related mortality globally, affecting both males and females [1]. 5-Fluorouracil (5-FU) is an essential component of chemotherapy for colorectal cancer. It has a critical role in reducing the risk of disease recurrence and mortality, ultimately improving quality of life [2]. However, the adverse effects of 5-FU have attracted widespread attention, particularly cardiotoxicity, which often manifests as chest pain similar to angina, arrhythmias, electrocardiogram ST segment alterations, myocardial infarction, cardiogenic shock, and sudden cardiac death [3]. Studies have indicated that cardiotoxicity related to 5-FU may affect 1.5–21% of patients [2, 4]. Drug-induced cardiac tissue injury might result from the over activation of several inflammatory signaling pathways [5, 6]. Both oncology and cardiovascular disorders have increasingly focused on the systemic immune-inflammation index (SII). This novel biomarker, based on neutrophils, lymphocytes, and platelets, reflects local immune responses and systemic inflammation, potentially serving as an additional diagnostic and prognostic biomarker for patients with colorectal cancer in cohort studies [7,8,9,10]. Moreover, cross-sectional studies have demonstrated a noteworthy correlation between the SII and mortality, as well as cancer-related mortality, in patients with cardiovascular diseases [11,12,13]. Studies have shown that cardiotoxicity related to 5-FU may be predicted through early indicators such as myocardial performance index and NT-proBNP [14, 15]. However, the correlation between SII and cardiotoxicity related to 5-FU remains unclear. This retrospective cohort study aims to investigate the correlation between SII and cardiotoxicity related to 5-FU in a colorectal cancer cohort to identify a potential predictive biomarker.

Patients and methods

Selection of patients

This study was a retrospective cohort study. The study received approval from the institutional ethics Committee of the Affiliated Cancer Hospital of Guizhou Medical University (FZ2021-11-298), with the requirement for informed consent waived by the committee due to the use of deidentified data. The study adhered to the reporting guidelines set forth by Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) [16].

The study included patients who were diagnosed with colorectal cancer at the Affiliated Cancer Hospital of Guizhou Medical University throughout the period from January 1, 2018, to December 31, 2020. The all data was obtained through reviewing electronic medical records system. The inclusion criteria for our study were as follows: (1) Pathologically confirmed colorectal adenocarcinoma; (2) Absence of severe internal medicine comorbidities before chemotherapy (such as uncontrolled serious hypertension, serious arrhythmia, unstable angina pectoris, acute stage of myocardial infarction, or uncorrected severe cardiac insufficiency); (3) Normal blood count, liver function, renal function, and electrocardiogram, with a left ventricular ejection fraction (LVEF) ≥ 50%; (4) Patients had received a 5-FU-based chemotherapy regimen [2, 17]. Standardized interviews, physical examinations, and laboratory tests were conducted on the participants to assess their baseline characteristics. Among the initial 4380 participants, 2770 were excluded due to missing fluorouracils or incomplete medical records, 694 were excluded due to uncontrolled internal medicine comorbidities before chemotherapy, and 162 were excluded for receiving capecitabine-based chemotherapy. A total of 754 people were eventually enrolled in the study (Fig. 1).

Fig. 1
figure 1

Flowchart of the participants selection

Full size image

Variables

The data we collected for our study primarily included information on demographic factors, personal history of smoking and alcohol, internal medical comorbidities before treatment, laboratory tests within three days prior to treatment, cancer stage according to the 8th edition of the AJCC/TNM system, details of the chemotherapy regimen, chemotherapy cycles and cardiotoxicity related to 5-FU. Internal medical comorbidities included history of cardiovascular diseases (acute myocardial infarction, ischemic heart disease, hypertension, heart failure or stroke) and endocrine diseases (diabetes, hyperlipidemia, hyperthyroidism, hypothyroidism). Laboratory tests contained blood count, liver function, renal function and electrolytes.

Exposure variable

The automated hematology analyzing devices (CoulterDxH 800 Analyzer) were used to measure the lymphocytes, neutrophils, and platelets. The SII level was determined based on prior research, which was documented as follows: SII index (×109/L) = neutrophils (×109/L) × platelets (×109/L)/lymphocytes (×109/L) [12, 18].

Outcome variable

All patients who did not experience cardiotoxicity related to 5-FU were followed up until four weeks following completion of treatment, while patients who experienced cardiotoxicity were followed up until outcome diagnosis.

Cardiotoxicity related to 5-FU is characterized by the appearance of new symptoms that are likely to cardiac-origin symptoms, such as chest pain, palpitations, dyspnea, or cardiogenic shock. It can also be identified by further abnormal findings on electrocardiograms, such as ST-T changes or arrhythmias, as well as abnormalities on echocardiograms or an obvious increase in myocardial enzymes. These symptoms and abnormalities were discovered during the period of 5-FU treatment or within four weeks following completion of treatment [19,20,21]. Moreover, the possibility that the new symptoms (chest pain, palpitations, dyspnea) are caused by other bodily systems, such as the respiratory or digestive system, has been eliminated. Cardiologists conducted additional evaluations and performed required auxiliary exams to confirm the diagnosis of cardiotoxicity related to 5-FU in cases that raised suspicion.

Covariates

The covariates used in this study are listed in detail. Variables that have been emphasized in prior research on factors linked to cardiotoxicity, as well as variables deemed significant based on our clinical knowledge, were included as potential confounders [22]. Finally, the confounding variables identified for our study included sex, age, cancer stage, history of cardiovascular diseases, history of endocrine diseases, history of smoking, use of targeted drug, dosage of 5-FU, chemotherapy cycles, alanine aminotransferase (ALT), and serum creatinine (SCR).

Statistical analysis

Summary statistics of baseline characteristics of all patients were expressed as frequency and percentage for categorical variables, mean ± SD or median (Q1- Q3) for continuous variables. To examine variances in characteristics between the presence or absence of cardiotoxicity associated with 5-FU, we utilized the independent samples t-test (for normal distribution), Mann-Whitney U test (for non-normal distribution), or chi-square test (for categorical variables).

The base 10 log-transformed SII (log SII) conforms to a normal distribution (P < 0.01), and in combination with clinical significance, log SII serves as the independent variable, while the dependent variable is cardiotoxicity related to 5-FU. In our study, after conducting an interaction test, we identified a statistically significant interaction (p < 0.05) between monocytes and log SII on cardiotoxicity related to 5-FU. After adjustment for confounders and stratification by tertiles of the interactive factor, linear regression analyses, curve fitting and threshold effect analyses were performed. Finally, a logarithmic likelihood ratio test (LRT test) was performed to determine the presence of a threshold effect.

Statistical analyses were conducted using R software version 4.2.0 (http://www.R-project.org), with all P values determined through two-tailed tests of statistical significance at a 5% type I error rate.

Results

At the last follow-up in January 2021, the study enrolled 754 patients. Of these, 156 patients (21%) developed cardiotoxicity related to 5-FU. The average time for outcome diagnosis in our study was the 3.14th cycle of 5-FU chemotherapy for the patients. Table 1 displays the baseline characteristics of the patients. Significant disparities in baseline characteristics were noted between the groups that experienced cardiotoxicity related to 5-FU and those that did not, including age, dosage of 5-FU, chemotherapy cycles, percentage of neutrophils (NE%), lymphocytes (LY), prognostic nutritional index (PNI), SCR, history of cardiovascular diseases, and use of targeted drug.

Table 1 aBaseline characteristics of participants
Full size table

Linear regression analyses were formulated both with and without adjustments for the confounding variables. To investigate an independent association between log SII and cardiotoxicity related to 5-FU, three models were utilized. As shown in Table 2, the results were presented by monocytes tertiles (T): T1: M ≤ 0.38 × 109/L; T2: 0.38 < M ≤ 0.52 × 109/L; T3: M > 0.52 × 109/L. In the unadjusted model, each increase in log SII was associated with a 3.92-fold increased risk of cardiotoxicity in T1 (OR, 3.92; 95%CI, 1.46 to 10.53). Meanwhile, in model I, an increase in log SII resulted in a 6.18-fold increase in the risk of cardiotoxicity in T1 (OR, 6.18, 95% CI: 1.87 to 20.46). In model II, the risk of cardiotoxicity increased by 8.04-fold (OR, 8.04; 95% CI, 1.68 to 38.56) with each additional log SII in T1. The ORs for T2 and T3 were not statistically significant in any of the three models.

Table 2 Risk association between log SII and cardiotoxicity related to 5-FU.
Full size table

Smooth curve fitting and threshold effect analysis were performed after the adjustment of all confounding variables, as illustrated in Fig. 2; Table 3. In the T1, a positive linear relationship (OR, 8.04; 95%CI, 1.68 to 38.56) existed between log SII and cardiotoxicity related to 5-FU. The LRT test P value was 0.021 in the T2, thus a non-linear relationship and a breakpoint was exhibited. The breakpoint (K) was identified as log SII = 1.37 (SII = 23.44), which is situated between the 25th and 50th percentile of SII in the T2. When the log SII was greater than 1.37, each increase in log SII was associated with an 86% decrease in the risk of cardiotoxicity related to 5-FU, with a threshold effect (OR, 0.14; 95% CI, 0.02 to 0.88). Whereas when log SII was below 1.37, a trend of positive correlation (OR, 10.13; 95%CI, 0.68 to 150.41) is observed between log SII and cardiotoxicity related to 5-FU. In the T3, the analysis showed a negative linear correlation trend (OR, 0.85; 95%CI, 0.37 to 1.98). The same results were obtained when SII values were transformed using the natural logarithm.

Fig. 2
figure 2

aIllustration of smooth curve fitting. aLow M tertile = T1 (M ≤ 0.38 × 109/L), Middle M tertile = T2 (0.38 < M ≤ 0.52 × 109/L), High M tertile = T3 (M > 0.52 × 109/L), SII Log = log SII

Full size image
Table 3 Threshold effect analysis after adjustment of the confounding factors
Full size table

Discussion

Inflammation is increasingly recognized as having an impact on the development and prognosis of cardiovascular diseases and cancer patients [23]. Research suggests that cancer can increase the risk of cardiovascular diseases, mostly due to inflammation, a prothrombotic state, and oxidative stress [24]. Therefore, it is imperative to examine the relationship between inflammation and cardiovascular adverse events related to chemotherapy in colorectal cancer patients, with the aim of providing more precise guidance for clinical management.

Our study has identified monocytes as an interactive factor, suggesting that the SII may be just one element in a pathway that causes damage to the heart [25]. The association between SII and cardiotoxicity related to 5-FU across different monocytes levels was observed. The stratification analysis revealed that elevating SII is an independent risk factor (OR, 8.04; 95%CI, 1.68 to 38.56) for cardiotoxicity related to 5-FU with low monocytes levels (T1). However, a protective role (OR, 0.14; 95%CI, 0.02 to 0.88) of SII was found in relation to middle monocytes levels (T2). Our results indicated that SII may aid in predicting the onset of cardiotoxicity related to 5-FU. The finding of curvilinear relationship and a breakpoint (log SII = 1.37) in the T2 is consistent with previous studies that indicate a non-linear relationship between SII and the development and prognosis of cardiovascular diseases [11, 26].

As a comprehensive indicator of systemic inflammation, the SII is commonly utilized in conjunction with monocytes to evaluate the immune status of the body comprehensively. Inflammatory tissues possess the capacity to attract monocytes from the circulatory system into injured tissues. Under the impact of several inflammatory stimuli, monocytes undergo a transformation into macrophages, which play an active role in regulating and carrying out immunological responses [27]. Studies have demonstrated that the heart contains both resident macrophages and monocyte-derived macrophages recruited to the area. Resident macrophages in the heart constitute an inherent population capable of self-maintenance and renewal, while monocyte-derived macrophages can replenish depleted tissue-resident macrophages resulting from heart injury or aging. Monocytes and macrophages play a pivotal role in cardiac injury and repair processes by acting as scavenger cells responsible for clearing cellular debris [28, 29]. Further research suggests that directing macrophage polarization effectively aids in cardiac healing in mouse models of myocardial infarction [30]. Studies targeting macrophage phagocytic receptors have revealed that low efficiency in clearing cellular debris can lead to impaired wound healing and decreased cardiac function [31, 32]. Diminished levels of monocytes indicate decreased clearance ability and relatively lower anti-inflammatory capacity within the body. Therefore, in the presence of myocardial inflammation, elevated SII levels increase the risk of cardiotoxicity related to 5-FU. However, when monocytes are relatively abundant (0.38 < M ≤ 0.52 × 109/L), the body possesses a certain level of anti-inflammatory capacity. In such cases, an increase in SII levels within a certain range is a normal response of the body. This inflammatory state has not reached a harmful level for the tissues, and a certain number of monocytes can enhance the phagocytosis of cellular debris through the interaction of inflammatory factors and other immune cells, thus promoting the repair of cell damage [28]. This may explain the curvilinear relationship in T2.

Our study found that the role of SII in cardiotoxicity related to 5-FU is related to the stratification of monocytes. Based on this study, we can explore the role of monocytes / inflammatory status in cardiotoxicity related to 5-FU. Furthermore, in the clinical practice of using 5-FU, it is necessary to closely monitor the inflammatory status of patients in order to enable early prevention, monitoring, and management of cardiotoxicity related to 5-FU, especially when monocyte levels are low (T1:M ≤ 0.38 × 109/L). A recent study has confirmed the close association between SII levels and the development of cardiovascular diseases, including hypertension, heart failure, and acute myocardial infarction [33,34,35]. In a meta-analysis conducted by Ye et al. in 2022, which encompassed 152,996 patients across 13 studies, it was observed that elevated SII levels were linked to an increased risk of cardiovascular diseases such as ischemic stroke, hemorrhagic stroke, and myocardial infarction [36]. Additionally, SII has the potential to predict the severity of coronary artery disease and acute ischemic stroke [37]. Therefore, SII not only serves as a significant clinical marker for cardiotoxicity related to 5-FU in colorectal cancer, but it may also be associated with adverse cardiovascular events in the general population.

Our study delved into and examined non-linearity and the threshold effect by stratifying the interactive factor into tertiles. This study is a retrospective cohort study, which inherently has limitations. However, we have taken measures to address these limitations by adjusting relevant variables to minimize any potential confounding effects. Despite these efforts, there are still some limitations to consider. Firstly, the patients for this study were selected from a single center, which may limit the generalizability of our conclusions to other hospitals or regions. Multiple similar studies in future trials will be required to validate our findings. Secondly, our study only examined baseline SII levels, and it would be beneficial for future studies to investigate changes in SII during the follow-up period. Third, capecitabine, a predrug form of 5-FU, is considered to have better safety, tolerability and intratumor drug concentration levels [38]. Thus, it would be valuable to explore whether the outcomes of our study can be applied to colorectal cancer patients undergoing capecitabine-based chemotherapy in future trials.

Conclusion

In conclusion, our study demonstrated that the association between SII and cardiotoxicity related to 5-FU in colorectal cancer has U-shape relationship and different impacts at various monocytes levels. SII is an independent risk factor for cardiotoxicity related to 5-FU with low monocytes levels (T1: M ≤ 0.38 × 109/L). Conversely, in the middle monocytes levels (T2: 0.38 < M ≤ 0.52 × 109/L), SII serves as a protective factor for cardiotoxicity related to 5-FU but with threshold effect. Our results raise the possibility that SII may be used as a biomarker for predicting the development of cardiotoxicity related to 5-FU in colorectal cancer patients.

Data availability

The datasets supporting the conclusions of this article are included within the article and its additional file. Further inquiries can be directed to the corresponding author.

Abbreviations

5-FU:

5-fluorouracil

SII:

systemic immune-inflammation index

M:

Monocytes

OR:

Odds Ratio

95%CI:

95% confidence interval

log SII:

log-transformed SII

LRT test:

logarithmic likelihood ratio test

BMI:

body mass index

SBP:

systolic blood pressure

DBP:

diastolic blood pressure

WBC:

white blood cells

NE:

neutrophils

NE%:

percentage of neutrophils

LY:

lymphocytes

LY%:

percentage of lymphocytes

EOS:

eosinophils

EOS%:

percentage of eosinophils

HGB:

hemoglobin

PLT:

platelets

NLR:

neutrophils to lymphocytes ratio (= NE/LY)

PLR:

platelets to lymphocytes ratio (= PLT/LY)

SII:

systemic immune-inflammation index (= (NE×PLT)/LY)

PIV:

Pan-Immune-Inflammation value (= (NE×PLT×M) /LY)

NAR:

neutrophil-to-albumin ratio (= NE/ALB)

MLR:

monocytes to lymphocytes ratio (= M/LY)

PNI:

prognostic nutritional index (= ALB + 5×PLT×LY)

AST:

glutamic oxaloacetic transaminase

ALT:

alanine aminotransferase

ALB:

albumin

LDH:

lactate dehydrogenase

GLU:

random blood glucose

UA:

uric acid

SCR:

serum creatinine

BUN:

urea nitrogen

K:

serum potassium

CA:

serum calcium

K:

breakpoint

References

  1. Spaander MCW, Zauber AG, Syngal S, Blaser MJ, Sung JJ, You YN, et al. Young-onset colorectal cancer. Nat Rev Dis Primers. 2023;9(1):21.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Wang Y, Wang W, Dong H, Wang G, Chen W, Chen J, et al. Risk factors for fluoropyrimidine-induced cardiotoxicity in colorectal cancer: a retrospective cohort study and establishment of a prediction nomogram for 5-FU induced cardiotoxicity. Front Oncol. 2023;13:1017237.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Polk A, Vaage-Nilsen M, Vistisen K, Nielsen DL. Cardiotoxicity in cancer patients treated with 5-fluorouracil or capecitabine: a systematic review of incidence, manifestations and predisposing factors. Cancer Treat Rev. 2013;39(8):974–84.

    Article  CAS  PubMed  Google Scholar 

  4. Kashyap MK, Mangrulkar SV, Kushwaha S, Ved A, Kale MB, Wankhede NL et al. Recent perspectives on Cardiovascular Toxicity Associated with Colorectal Cancer Drug Therapy. Pharmaceuticals (Basel). 2023;16(10).

  5. Gui Y, Famurewa AC, Olatunji OJ. Naringin ameliorates 5-fluorouracil induced cardiotoxicity: an insight into its modulatory impact on oxidative stress, inflammatory and apoptotic parameters. Tissue Cell. 2023;81:102035.

    Article  CAS  PubMed  Google Scholar 

  6. Tambe PK, Mathew AJ, Bharati S. Cardioprotective potential of mitochondria-targeted antioxidant, mito-TEMPO, in 5-fluorouracil-induced cardiotoxicity. Cancer Chemother Pharmacol. 2023;91(5):389–400.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Sato R, Oikawa M, Kakita T, Okada T, Abe T, Tsuchiya H, et al. A decreased preoperative platelet-to-lymphocyte ratio, systemic immune-inflammation index, and pan-immune-inflammation value are associated with the poorer survival of patients with a stent inserted as a bridge to curative surgery for obstructive colorectal cancer. Surg Today. 2023;53(4):409–19.

    Article  CAS  PubMed  Google Scholar 

  8. Feng Z, Lin H, Yang X, Cao S, Gu X, Zhang Z, et al. Diagnostic value of inflammation-related indicators in distinguishing early Colon cancer and adenomatous polyps. Cancer Control. 2023;30:10732748231180745.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Miyamoto Y, Akiyama T, Kato R, Sawayama H, Ogawa K, Yoshida N, et al. Prognostic significance of systemic inflammation indices by K-ras Status in patients with metastatic colorectal Cancer. Dis Colon Rectum. 2023;66(8):e809–17.

    Article  PubMed  Google Scholar 

  10. Hasirci I, Åžahin A. Importance of the neutrophil-lymphocyte ratio and systemic immune-inflammation index in predicting colorectal pathologies in fecal occult blood-positive patients. J Clin Lab Anal. 2023;37(7):e24878.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Xiao S, Wang X, Zhang G, Tong M, Chen J, Zhou Y, et al. Association of systemic Immune inflammation index with estimated pulse Wave Velocity, Atherogenic Index of plasma, triglyceride-glucose index, and Cardiovascular Disease: a large cross-sectional study. Mediators Inflamm. 2023;2023:1966680.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Xiao S, Wang Z, Zuo R, Zhou Y, Yang Y, Chen T, et al. Association of systemic Immune inflammation index with All-Cause, Cardiovascular Disease, and Cancer-related mortality in patients with Cardiovascular Disease: a cross-sectional study. J Inflamm Res. 2023;16:941–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Ye Z, Hu T, Wang J, Xiao R, Liao X, Liu M, et al. Systemic immune-inflammation index as a potential biomarker of cardiovascular diseases: a systematic review and meta-analysis. Front Cardiovasc Med. 2022;9:933913.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Schimmel KJ, Richel DJ, van den Brink RB, Guchelaar HJ. Cardiotoxicity of cytotoxic drugs. Cancer Treat Rev. 2004;30(2):181–91.

    Article  CAS  PubMed  Google Scholar 

  15. Jensen SA, Hasbak P, Mortensen J, Sørensen JB. Fluorouracil induces myocardial ischemia with increases of plasma brain natriuretic peptide and lactic acid but without dysfunction of left ventricle. J Clin Oncol. 2010;28(36):5280–6.

    Article  CAS  PubMed  Google Scholar 

  16. Cuschieri S. The STROBE guidelines. Saudi J Anaesth. 2019;13(Suppl 1):S31–4.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Meydan N, Kundak I, Yavuzsen T, Oztop I, Barutca S, Yilmaz U, et al. Cardiotoxicity of De Gramont’s regimen: incidence, clinical characteristics and long-term follow-up. Jpn J Clin Oncol. 2005;35(5):265–70.

    Article  PubMed  Google Scholar 

  18. He L, Xie X, Xue J, Xie H, Zhang Y. Association of the systemic immune-inflammation index with all-cause mortality in patients with arteriosclerotic cardiovascular disease. Front Cardiovasc Med. 2022;9:952953.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Peng J, Dong C, Wang C, Li W, Yu H, Zhang M, et al. Cardiotoxicity of 5-fluorouracil and capecitabine in Chinese patients: a prospective study. Cancer Commun (Lond). 2018;38(1):22.

    PubMed  Google Scholar 

  20. Dyhl-Polk A, Vaage-Nilsen M, Schou M, Vistisen KK, Lund CM, Kümler T, et al. Incidence and risk markers of 5-fluorouracil and capecitabine cardiotoxicity in patients with colorectal cancer. Acta Oncol. 2020;59(4):475–83.

    Article  CAS  PubMed  Google Scholar 

  21. de Forni M, Malet-Martino MC, Jaillais P, Shubinski RE, Bachaud JM, Lemaire L, et al. Cardiotoxicity of high-dose continuous infusion fluorouracil: a prospective clinical study. J Clin Oncol. 1992;10(11):1795–801.

    Article  PubMed  Google Scholar 

  22. Shiga T, Hiraide M. Cardiotoxicities of 5-Fluorouracil and other fluoropyrimidines. Curr Treat Options Oncol. 2020;21(4):27.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Huang YW, Yin XS, Li ZP. Association of the systemic immune-inflammation index (SII) and clinical outcomes in patients with stroke: a systematic review and meta-analysis. Front Immunol. 2022;13:1090305.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Velusamy R, Nolan M, Murphy A, Thavendiranathan P, Marwick TH. Screening for coronary artery disease in Cancer survivors: JACC: CardioOncology State-of-the-art review. JACC CardioOncol. 2023;5(1):22–38.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Zuo PY, Chen XL, Liu YW, Zhang R, He XX, Liu CY. Non-HDL-cholesterol to HDL-cholesterol ratio as an independent risk factor for the development of chronic kidney disease. Nutr Metab Cardiovasc Dis. 2015;25(6):582–7.

    Article  CAS  PubMed  Google Scholar 

  26. Cao Y, Li P, Zhang Y, Qiu M, Li J, Ma S, et al. Association of systemic immune inflammatory index with all-cause and cause-specific mortality in hypertensive individuals: results from NHANES. Front Immunol. 2023;14:1087345.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Rizzo G, Gropper J, Piollet M, Vafadarnejad E, Rizakou A, Bandi SR, et al. Dynamics of monocyte-derived macrophage diversity in experimental myocardial infarction. Cardiovasc Res. 2023;119(3):772–85.

    Article  CAS  PubMed  Google Scholar 

  28. Bhagat A, Shrestha P, Kleinerman ES. The Innate Immune System in Cardiovascular diseases and its role in Doxorubicin-Induced Cardiotoxicity. Int J Mol Sci. 2022;23(23).

  29. Zaman R, Hamidzada H, Epelman S. Exploring cardiac macrophage heterogeneity in the healthy and diseased myocardium. Curr Opin Immunol. 2021;68:54–63.

    Article  CAS  PubMed  Google Scholar 

  30. Yang M, Song L, Wang L, Yukht A, Ruther H, Li F, et al. Deficiency of GATA3-Positive macrophages improves cardiac function following myocardial infarction or pressure overload hypertrophy. J Am Coll Cardiol. 2018;72(8):885–904.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. DeBerge M, Yeap XY, Dehn S, Zhang S, Grigoryeva L, Misener S, et al. MerTK cleavage on Resident Cardiac macrophages compromises Repair after Myocardial Ischemia Reperfusion Injury. Circ Res. 2017;121(8):930–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Howangyin KY, Zlatanova I, Pinto C, Ngkelo A, Cochain C, Rouanet M, et al. Myeloid-Epithelial-Reproductive Receptor Tyrosine Kinase and Milk Fat Globule Epidermal Growth Factor 8 Coordinately improve Remodeling after myocardial infarction via local delivery of vascular endothelial growth factor. Circulation. 2016;133(9):826–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Zheng H, Yin Z, Luo X, Zhou Y, Zhang F, Guo Z. Associations between systemic immunity-inflammation index and heart failure: evidence from the NHANES 1999–2018. Int J Cardiol. 2024;395:131400.

    Article  PubMed  Google Scholar 

  34. Wei X, Zhang Z, Wei J, Luo C. Association of systemic immune inflammation index and system inflammation response index with clinical risk of acute myocardial infarction. Front Cardiovasc Med. 2023;10:1248655.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Shi Y, Zhou W. Threshold effect of systemic immune inflammatory index on hypertension in American adults (NHANES 2017–2020). J Hypertens. 2023;41(12):2107–12.

    Article  CAS  PubMed  Google Scholar 

  36. Islam MM, Satici MO, Eroglu SE. Unraveling the clinical significance and prognostic value of the neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, systemic immune-inflammation index, systemic inflammation response index, and delta neutrophil index: an extensive literature review. Turk J Emerg Med. 2024;24(1):8–19.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Weng Y, Zeng T, Huang H, Ren J, Wang J, Yang C, et al. Systemic Immune-inflammation index predicts 3-Month Functional Outcome in Acute ischemic stroke patients treated with intravenous thrombolysis. Clin Interv Aging. 2021;16:877–86.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Alzahrani SM, Al Doghaither HA, Al-Ghafari AB, Pushparaj PN. 5–Fluorouracil and capecitabine therapies for the treatment of colorectal cancer (review). Oncol Rep. 2023;50(4).

Download references

Acknowledgements

The authors thank the participants of the study, the editors and reviewers for providing editorial assistance and suggestions on revision, and all those who had contributed to the completion of this research.

Funding

This work was supported by Science and Technology Planning Project of Science and Technology Department of Guizhou Province ([2022]340), the Science and Technology Fund Project of the Guizhou Provincial Health Commission (gzwkj2021-052), and the Cultivation Project of Guizhou Medical University (20NSP040).

Author information

Authors and Affiliations

  1. Department of Oncology, Affiliated Hospital of Guizhou Medical University, Guiyang, China

    Xiaoqin Liu, Wenling Wang, Hongming Dong, Gang Wang, Wanghua Chen, Juan Chen & Weiwei Chen

  2. Department of Abdominal Oncology and Clinical Medicine, Affiliated Cancer Hospital of Guizhou Medical University, Guizhou Medical University, Guiyang, China

    Xiaoqin Liu, Yan Wang, Wenling Wang, Hongming Dong, Gang Wang, Wanghua Chen, Juan Chen & Weiwei Chen

Authors
  1. Xiaoqin Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wenling Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hongming Dong
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gang Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Wanghua Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Juan Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Weiwei Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

XQL and WWC designed the study. XQL, WWC, YW, WLW, HMD, and WHC contributed to the collection and analysis of the study data. XQL wrote the article. HMD, GW, JC and WLW revised the manuscript. All authors contributed to the article and approved the submitted version.

Corresponding author

Correspondence to Weiwei Chen.

Ethics declarations

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

The studies involving human participants were reviewed and approved by the Affiliated Cancer Hospital of Guizhou Medical University. The institutional ethics committee waived the requirement for informed consent given the deidentified data.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Material 1

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liu, X., Wang, Y., Wang, W. et al. The association between systemic immune-inflammation index and cardiotoxicity related to 5-Fluorouracil in colorectal cancer. BMC Cancer 24, 782 (2024). https://doi.org/10.1186/s12885-024-12568-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s12885-024-12568-0

Keywords

BMC Cancer

ISSN: 1471-2407

Contact us