Venous thromboembolism among patients with advanced lung cancer randomized to prinomastat or placebo, plus chemotherapy

Abstract

Two clinical trials have suggested that the combination of vascular endothelial growth factor inhibitor with chemotherapy is associated with venous thromboembolism (VTE). This retrospective cohort study investigates whether a similar association exists when matrix metalloproteinase inhibitor (prinomastat) is combined with chemotherapy. Patients (n=1,023) with stage IIIB, IV, or recurrent non-small cell lung cancer (NSCLC) were followed during 2 randomized, double-blind trials of prinomastat versus placebo orally bid, plus gemcitabine/cisplatin (GC) or paclitaxel/carboplatin (PC). VTE included deep venous thrombosis (DVT) or pulmonary embolism (PE) confirmed by imaging or autopsy. Risks identified in univariate analysis (incidence densities compared by t test) were confirmed in multivariate analysis (proportional hazards model). During 7,500.3 patient-months, 58 VTE (31 PE, 27 isolated DVT) were confirmed in 54 patients. On univariate analysis, VTE was associated with central venous catheter placed within 3 months, 15 mg prinomastat plus GC, and to a lesser extent, 15 mg prinomastat plus PC, baseline performance status, and histologic type. VTE incidence was not increased by 15 mg prinomastat alone (post-discontinuation of chemotherapy), by chemotherapy plus placebo, or by 5 or 10 mg prinomastat plus chemotherapy. On multivariate analysis,VTE hazards (95% confidence interval) were 5.69 (2.61, 12.40) with recently placed central catheter, 2.78 (1.42, 5.43) with 15 mg prinomastat plus GC, and 2.06 (0.98, 4.31) with 15 mg prinomastat plus PC; performance status and histology were nonsignificant. We can conclude that combined treatment with 15 mg prinomastat plus chemotherapy approximately doubles the hazard of VTE among patients with advanced NSCLC.

Venous thromboembolism and nonsmall cell lung cancer

“…Although the patients randomized to BR.18, all of whom received chemotherapy and had advanced NSCLC, had the highest incidence of VTE, the addition of the metalloproteinase inhibitor BMS-275291 did not increase the risk. This result is in contrast to that observed by Behrendt and Ruiz, 13 who reported an increased risk of VTE when 15 mg of the metalloproteinase inhibitor prinomastat was added to platinum-based chemotherapy.…”

“…An increased risk of VTE also was reported with the use of the metalloproteinase inhibitor prinomastat in patients with advanced NSCLC. 13 However, the issues of whether there is a significant risk of VTE in early stage NSCLC, which factors predict for VTE occurrence, whether chemotherapy has an impact on the risk of VTE in NSCLC, and whether VTE is associated with worse clinical outcomes have been explored less thoroughly.…”

Prevention of venous thromboembolism in patients with advanced lung cancer receiving chemotherapy: a combined analysis of the PROTECHT and TOPIC‐2 studies

“…Among cancer patients, those with advanced lung cancer have been recently recognized as being at particularly high risk for VTE events [2]. In these patients, the incidence of VTE ranges from 40 to 100 events per 1000 patient-years, whereas it is estimated to be one to two events per 1000 person-years in the general population [3].…”

“…Two residues in the activation peptide domain contribute to the half-life of factor X in vivo In view of the promising therapeutic strategies based on factor X (FX) modified molecules to treat hemophilia, especially with inhibitors [1,2], a better knowledge of FX clearance mechanisms appears necessary. The persistence of FX in human blood is a plus compared with other established therapies (halflife of 40 h for FX [3] vs. 3 h for recombinant FVIIa [4]).…”

Cerebral Ischemic Events in Patients with Advanced Lung or Prostate Cancer

“…Prinomastat inhibits tumor angiogenesis through affi nity for gelatinases and collagenase, blocking proteolysis of the basement membrane which is necessary for the proliferation of endothelial cells [21] . Combined treatment with chemotherapy and prinomastat has been associated with doubling of the hazard of venous thromboembolism in patients with advanced lung cancer [22] .…”