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

Summary

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.

Research support: Pfizer Inc

Keywords

Deep vein thrombosis - pulmonary embolism - clinical/epidemiological studies - angiogenesis and inhibitors

• References

• 1 Levitan N, Dowlati A, Remick SC. et al. Rates of initial and recurrent thromboembolic disease among patients with malignancy versus those without malignancy. Medicine (Baltimore) 1999; 78: 285-91.
• 2 Sallah S, Wan JY, Nguyen NP. Venous thrombosis in patients with solid tumors: determination of frequency and characteristics. Thromb Haemost 2002; 87: 575-9.
• 3 Levine MN, Gent M, Hirsh J. et al. The thrombogenic effect of anticancer drug therapy in women with stage II breast cancer. N Engl J Med 1988; 318: 404-7.
• 4 Goodnough LT, Hidehiko S, Manni A. et al. Increased incidence of thromboembolism in stage IV breast cancer treated with five-drug chemotherapy regimen. Cancer 1984; 54: 1264-8.
• 5 Pritchard KI, Paterson AH, Paul NA. et al. Increased thromboembolic complications with concurrent tamoxifen and chemotherapy in a randomized trial of adjuvant therapy for women with breast cancer. J Clin Oncol 1996; 14: 2731-7.
• 6 Recio FO, Piver MS, Hempling RE. et al. Lack of improved survival plus increase in thromboembolic complications in patients with clear cell carcinoma of the ovary treated with platinum versus nonplatinum-based chemotherapy. Cancer 1996; 78: 2157-63.
• 7 Kuenen BC, Rosen L, Smit EF. et al. Dose-finding and pharmacokinetic study of cispla-tin, gemcitabine, and SU5416 in patients with solid tumors. J Clin Oncol 2002; 20: 1657-67.
• 8 Kabbinabar F, Hurwitz HI, Fehrenbacher L. et al. Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol 2003; 21: 60-5.
• 9 Shalinsky DR, Brekken J, Zou H. et al. Broad antitumor and antiangiogenic activities of AG3340, a potent and selective MMP inhibitor undergoing advanced oncology clinical trials. Ann N Y Acad Sci 1999; 878: 236-70.
• 10 Chiarugi V, Ruggiero M, Magnelli L. Molecular polarity in endothelial cells and tumor-induced angiogenesis. Oncol Res 2000; 12: 1-4.
• 11 Smylie M, Mercier R, Aboulafia D. et al. Phase III study of the matrix metalloprotease (MMP) inhibitor prinomastat in patients having advanced non-small lung cancer (NSCLC). Proc Am Soc Clin Oncol 2001; 20: 307a
• 12 Bissett D, O’Byrne KJ, von Pawel J. et al. Phase III study of the matrix metalloprotease (MMP) inhibitor prinomastat (P) in combination with gemcitabine (G) and cisplatin (C) in non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 2002; 21: 296a
• 13 Research Triangle Institute. SUDAAN User’s Manual, Release 8.0. Research Triangle Park (NC): The Institute 2001
• 14 LaVange LM, Keyes LL, Koch GG. et al. Application of sample survey methods for modeling ratios to incidence densities. Stat Med 1994; 13: 343-55.
• 15 LaVange LM, Koch GG, Schwartz TA. Applying sample survey methods to clinical trials data. Stat Med 2001; 20: 2609-23.
• 16 Lawless JF. Statistical models and methods for lifetime data. New York: John Wiley and Sons; 1982
• 17 Heit JA, Silverstein MD, Mohr DN. et al. Risk factors for deep vein thrombosis and pulmonary embolism: a population-based case-control study. Arch Intern Med 2000; 160: 809-15.
• 18 Weijl NI, Rutten MFJ, Zwinderman AH. et al. Thromboembolic events during chemotherapy for germ cell cancer: a cohort study and review of the literature. J Clin Oncol 2000; 18: 2169-78.
• 19 Wermes C, von Depka Prondzinski M, Lichtinghagen R. et al. Clinical relevance of genetic risk factors for thrombosis in paediatric oncology patients with central venous catheters. Eur J Pediatr 1999; 158 Suppl 3 S143-6.
• 20 Nowak-Gottl U, Heinecke A, von Kries R. et al. Thrombotic events revisited in children with acute lymphoblastic leukemia: impact of concomitant Escherichia coli asparaginase/prednisone administration. Thromb Res 2001; 103: 165-72.
• 21 Kuenen BC, Levi M, Meijers JCM. et al. Analysis of coagulation cascade and endothelial cell activation during inhibition of vascular endothelial growth factor/vascular endothelial growth factor receptor pathway in cancer patients. Arterioscler Thromb Vasc Biol 2002; 22: 1500-5.