Coagulation biomarkers and prediction of venous thromboembolism and survival in small cell lung cancer: A sub-study of RASTEN - A randomized trial with low molecular weight heparin

Abstract

Coagulation activation and venous thromboembolism (VTE) are hallmarks of cancer; however, there is an unmet need of improved biomarkers for individualized anticoagulant treatment. The present sub-study of the RASTEN trial was designed to explore the role of coagulation biomarkers in predicting VTE risk and outcome in a homogenous cancer patient population. RASTEN is a multicenter, randomized phase-3 trial investigating the survival effect of low molecular weight heparin enoxaparin when added to standard treatment in newly diagnosed small cell lung cancer (SCLC) patients. Plasma collected at baseline, during treatment, and at follow-up was used in this ad hoc sub-study (N = 242). Systemic coagulation was assessed using four assays reflecting various facets of the coagulation system: Total tissue factor (TF); extracellular vesicle associated TF (EV-TF); procoagulant phospholipids (PPL); and thrombin generation (TG). We found small variations of biomarker levels between baseline, during treatment and at follow-up, and appeared independent on low molecular weight heparin treatment. Overall, none of the measured biomarkers at any time-point did significantly associate with VTE incidence, although increased total TF at baseline showed significant association in control patients not receiving low molecular weight heparin (P = 0.03). Increased TG-Peak was significantly associated with decreased overall survival (OS; P = 0.03), especially in patients with extensive disease. Low baseline EV-TF predicted a worse survival in the low molecular weight heparin as compared with the control group (HR 1.42; 95% CI 1.04–1.95; P = 0.03; P for interaction = 0.12). We conclude that the value of the analyzed coagulation biomarkers for the prediction of VTE risk was very limited in SCLC patients. The associations between TG-Peak and EV-TF with patient survival and response to low molecular weight heparin therapy, respectively, warrant further studies on the role of coagulation activation in SCLC aggressiveness.

Measurement of tissue factor activity in extracellular vesicles from human plasma samples

“…13 Importantly, increased levels of EV TF activity were associated with venous thromboembolism in patients with pancreatic cancer but not in other types of cancer including brain, colorectal, ovarian, and lung cancer. 13,16,22,23 Interestingly, patients with cirrhosis and acute liver injury have 17-fold and 38-fold increased levels of EV TF activity compared with healthy controls, respectively. 13 Increased levels of EV TF were detected in patients with endotoxemia (nine-fold) and urinary tract infection (six-fold).…”

“…Pancreatic cancer has the highest EV TF activity (16‐ to 26‐fold higher than healthy controls) among different types of cancer . Importantly, increased levels of EV TF activity were associated with venous thromboembolism in patients with pancreatic cancer but not in other types of cancer including brain, colorectal, ovarian, and lung cancer . Interestingly, patients with cirrhosis and acute liver injury have 17‐fold and 38‐fold increased levels of EV TF activity compared with healthy controls, respectively .…”

Role of Tissue Factor in Tumor Progression and Cancer-Associated Thrombosis

“…124 Moreover, a substudy of the RASTEN trial, including 242 small cell lung cancer patients, failed to show a correlation between EV TF activity and VTE. 125 In 648 advanced cancer patients (esophagus, lung, colorectal, pancreas, breast, gastric, ovarian, prostate and bladder cancer), van Es et al recently showed that EV TF activity was associated with a twofold increased risk of VTE. In agreement with observations described earlier in this paragraph, this association was demonstrated to be much stronger in pancreatic cancer (4.1-fold increased risk) than in other tumor types (1.5-fold increased risk).…”

Future Options of Molecular-Targeted Therapy in Small Cell Lung Cancer

“…As venous thrombosis and thromboembolism are risk factors for a dismal outcome, one study group focused on the additional use of low-molecular-weight heparin anticoagulants in SCLC treatment. Yet, the overall survival improved by the concomitant use of enoxaparin [60] nor was a biomarker established for predicting the risk of venous thrombosis and thromboembolism in SCLC patients [61]. Other than that, redox status and lipid metabolism were shown to be altered in lung cancer patients.…”