Venous Thromboembolism and Non-Small Cell Lung Cancer: A Pooled Analysis of National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) Trials.

Purpose: To determine the incidence of venous thromboembolism (VTE) in patients with early and advanced non-small cell lung cancer (NSCLC); to explore predictive factors for VTE occurrence during trials in these populations, and to investigate the effect of VTE on overall survival in patients with NSCLC.

Patients and Methods: Data from three National Cancer Institute of Canada Clinical Trials Group trials were included in the analyses (n=1987). JBR.10 was a randomized study of post-resection adjuvant vinorelbine/cisplatin versus observation in stage IB/II NSCLC. BR.18 was a randomized study of paclitaxel/carboplatin ± the metalloproteinase inhibitor BMS-275291 in advanced NSCLC (1^st line). BR.21 was a randomized study of erlotinib versus placebo in previously treated (2^nd or 3^rd line) NSCLC. The relationship between VTE, cancer treatment, concomitant medications, and baseline patient characteristics was explored with univariate and multivariate analysis. Cox regression analysis was performed to determine whether VTE was independently associated with survival. Each trial was analyzed separately; in addition a pooled analysis was performed with the advanced disease trials (BR.18 and BR.21).

Results: The incidence of VTE was 0% in the observation arm of JBR.10 and ranged from 3% in the adjuvant chemotherapy arm of JBR.10 to 8% in BR.18. In JBR.10, VTE was independently associated with the administration of adjuvant chemotherapy (p=0.015), baseline obesity (p=.001), and low platelet count (p=.007). For patients with advanced NSCLC, VTE was significantly more common in patients receiving chemotherapy (BR.18) compared to patients receiving erlotinib or placebo (BR.21) (8% vs 2%, p< 0.0001). In BR.18, but not BR.21, VTE was associated with a prior history of VTE (p=0.001). When BR.18 and BR.21 were pooled, prior VTE remained significant. In BR.18 and BR.21, VTE was associated with shorter survival in multivariate analysis (HR=1.69, 95%CI 1.32–2.17, p<.0001); further analyses, including JBR.10, are planned to explore this finding.

Conclusion: VTE is a frequent event in patients with advanced NSCLC and is associated with the administration of chemotherapy. Treatment with metalloproteinase or epidermal growth factor inhibitors does not appear to increase the risk of VTE. In early NSCLC, adjuvant chemotherapy, morbid obesity and a prior history of VTE are associated with increased risk. VTE is associated with shortened survival in patients with advanced NSCLC. Funding for this study was provided by the Canadian Cancer Society.