The CTOX-Score, a clinical risk prediction tool for cardiovascular toxicity secondary to cancer therapies
Authors: Lopez Trigo N , Martinez-Gomez A , Mazon P , Martinez-Monzonis A , Pedreira M , Palacios P , Zamora P , Buno A , Lopez Sendon J L , Brion M , Gonzalez Juanatey J R 
Published: October 2024

Abstract

Introduction
Cardiovascular toxicity (cardiotoxicity) is recognized as a major side-effect of cancer therapies. As early diagnosis and management is crucial in clinical practice1,2, knowledge about risk factors and risk scores is scarce3,4.

Purpose
The aim of this study is to develop a clinical prediction score to identify patients at high/very high risk of cardiotoxicity.

Methods
The CARDIOTOX registry5,6 included patients receiving cancer therapies related to moderate/high risk for cardiotoxicity (2012-2017). Clinical, laboratory and echo parameters were collected at baseline and at 3 weeks, 3 and 6 months, 1, 1.5 and 2 years after initiation of cancer therapy. Patients were classified according to current cardioncology guidelines2 and divided in two groups: no or mild cardiotoxicity vs moderate or high cardiotoxicity. Difference between groups were tested with t-student or U Mann-Withney for continuous variables and Fisher’s exact test for categorical data. Variables with p&lt;0.05 were included in a multivariate binary logistic regression model to find independent predictors of cardiotoxicity and construct a clinical risk score, CTOX-Score. The calibration was evaluated by Hosmer-Lemeshow goodness-of-fit test and discrimination using ROC curves.

Results
From the 1324 individuals included in the registry we discarded all those with pre-existing symptomatic heart failure or LVEF&lt;40% at baseline and those with incomplete baseline data. We considered 998 patients, aged 54.62±14.15 years, 176 men (17.6%), of which 53 (5.3%) developed moderate or severe cardiotoxicity. These patients had lower baseline LVEF (59.91±7.50% vs 64.20±5.88%), higher creatinine levels (0.90 (0.76, 1.10) mg/dl vs 0.74 (0.62, 0.90) mg/dl) and higher NT-ProBNP (177 (58, 476) pg/ml vs 66 (38, 133) pg/ml) compared with patients with no or mild cardiotoxicity (p&lt;0.001). We found previous radiotherapy (OR=4.66, CI:1.24-17.52), acute myeloid leukemia (OR=6.85; CI:1.16-40.50), monoclonal antibodies (OR=3.27; CI:1.35-7.89), LVEF (OR=0.96; CI:0.84-0.98) and serum creatinine (OR=5.43; CI:1.63-18.14) as independent predictors of cardiotoxicity (p&lt;0.05). A clinical risk score was developed based in beta coefficient of variables (Table 1). The model has good calibration according to Hosmer-Lemeshow goodness-of-fit (χ2=2.800, p=0.424) and good discrimination power (AUC:0.780, CI:0.69-0.87; p&lt;0.001). The best cut-off value of CTOX-Score is ≥3 points (Sensitivity:70.00%, Specificity:72.25%, NPV:98.11%). Patients were classified in four risk categories: low (0-1 points); moderate (2); high (3-4); very high (≥5) (Figure 1). The model has good accuracy to identify very high-risk patients (Specificity 98.80%).

Conclusion
The CTOX-Score is a clinical risk prediction model to identify patients at high/very high-risk of cardiotoxicity and could allow for more personalized monitoring of patients. Additional studies are needed to externally validate the model prior to implementation in clinical practice.Multivariate binary logistic regressionCTOX-Score values among population