Incidence and Risk Factors for Central Venous Catheter-Related Venous Thromboembolism in Breast Cancer Patients Under Neoadjuvant Chemotherapy: the Caveccas (Catheter Veineux Central et Cancer du Sein) Study
Authors: Debourdeau Philippe , Espié Marc , Chevret Sylvie , Gligorov Joseph , Elias Antoine , Dupré Pierre Francois , Le Long Joel , Lavau-Denes Sandrine , Sevestre Marie-Antoinette , Bastit Laurent , Kalidi Issa , Frere Corinne , Farge Dominique 
Published: October 2019

Abstract
Background: Symptomatic Catheter Related Thrombosis (CRT) occurs in 3-5% of cancer patients with Central Venous Catheters (CVC) and, overall, the incidence of CRT could reach 30% when including asymptomatic cases (1). In women with Breast Cancer (BC), the most frequent cancer in females world-wide, the high risk of Venous Thromboembolism (VTE) during chemotherapy may be related in part to CRT (2). We therefore designed the CAVECCAS (Cathéter VEineux Central et CAncer du Sein) study to analyze CRT incidence and CRT risk factors in BC patients with CVC receiving (neo)adjuvant chemotherapy (NAC).
Methods: CAVECCAS is a prospective, multicenter cohort study of patients with non metastatic invasive BC undergoing insertion of a single lumen CVC for at least 3 months of NAC. All included patients with signed informed consent between September 2008 and December 2011 underwent repeated double-blind Doppler US evaluation before (D0) and at 7, 30 and 90 days (D) after CVC insertion. In case of VTE symptoms, diagnosis was confirmed by venography, ultrasonography and/or computed tomography. Venous blood samples were systematically drawn before and 2 days after CVC insertion to determine D-Dimers levels (VIDAS® D-Dimer Exclusion™), Platelet-derived MPs (Pd-MPs) and Pd-MPs expressing phosphatidyl serin (Pd-MP/PS+) levels (3), thrombin generation (Calibrated Automated Thrombogram assay®, Stago) and endogenous thrombin potential (ETP). After completing recruitment and follow-up (D90), a nested case-control study analyzed additional individual thrombophilic risk factors (Antithrombin, Protein C and Protein S levels, presence of Factor V and Factor II Leiden mutations, presence of antiphospholipid, anticardiolipin and antiβ2GP1 antibodies) using two controls without CRT from the CAVECCAS cohort matched for TNM status with each symptomatic or asymptomatic CRT patient.
Statistical analysis used Fisher or Wilcoxon tests for univariate analysis; step down selection procedure with p-values < 0.10 for multivariate models; conditional logistic model to study the occurrence of CRT based on thrombophilia testing (open-source software R Version 2.15.2 (2012-10-26).
Results(expressed as median and inter-quartile range [IQR] for quantitative data and numbers and percentages for categorical data). 524 patients with non metastatic BC (85% ductal carcinoma, 12.2% Lobular carcinoma, 2.8% other) with respective T0/T1/T2/T3/T4 staging (0.5%/47.6%/43.3%/8.0%/0.7%), SBR 1/2/3 grading (11.2%/53%/35.8%), 49.2 % having node involvement and 79.5% steroid hormone receptors, were analyzed. During follow-up, the overall CRT incidence rate was 2.18 cases/100 patient-months, with 14 symptomatic and 46 asymptomatic patients, 27, 10 and 9 of the asymptomatic CRT being respectively diagnosed on D8, 30 and day 90 US. In univariate analysis, increased age (>50 years) (OR, 1.80; 95% CI, 1.01-3.22; p=0.048), BMI> 30 kg/m² (OR, 2.64; 95% CI, 1.46-4.76; p=0.001) and comorbidities (OR, 2.05; 95% CI, 1.18-3.56; p=0.011) were associated with CRT. CRT was less frequent in ductal (OR, 0.55; 95% CI, 0.28-1.07; p=0.078) versus lobular carcinoma (OR, 2.53; 95% CI, 1.32-4.85; p= 0.005). In multivariate analysis, BMI>30 kg/m² (OR, 2.66: 99%CI, 1.46-4.84, p=0.001) and lobular carcinoma histology (OR, 2.56; 95%CI, .32-4.96, p=0.005) remained CRT risk factors. Pd-MPs (981.5 [518-2147] vs 758.5 [416.5-373] /mL; p<0.0001) and Pd-MP/PS+(778 [409-1851] vs 730 [380.5-412]/mL; p=0.021) levels decreased after CVC insertion versus baseline, while D-Dimers levels increased (454[294.2-757] vs 586 [366-842] ng/mL; p<0.0001), as did all thrombin generation parameters increased except ETP (1322 [1052-582] vs 1304 [1063-652] nM/min; p=0.023). None of these biomarkers appeared significant predictors for CRT.
Conclusion: In this large sample size study with serial measurements of clinical parameters and biomarkers for thrombosis, only obesity and lobular carcinoma histology appeared strong risk factors for CRT in non metastatic BC treated with NAC. Further studies will elucidate how individual stratification of BC patients may identify those who may benefit from CRT prophylaxis.
1) Debourdeau P and Farge D et al. J Thromb Haemost 2013; 11:71-80
2) Walker AJ et al. Blood 2016;127(7):849-57
3) Robert S et al J Thromb Haemost 2009;7:190-7

Disclosures
No relevant conflicts of interest to declare.