Rapid Review
Pancreatic Cancer-Associated Thrombosis: Prevention and Treatment
By William B. Ershler, MD
Venothrombotic Events and Pancreatic Cancer
Deep vein thrombosis (DVT) and pulmonary embolus (PE) occur more frequently in patients with cancer, and the risk appears to vary by tumor type. The most common venothrombotic events (VTE)-associated cancers are breast, colorectal, and lung; yet, when adjusted for prevalence, cancers of the ovary, pancreas, and brain are most strongly associated with thrombotic complications. For example, in one study of 202 patients with pancreatic cancer, the incidence of a thrombotic event was 108.3 per 1000 patient years (10.8%) resulting in a 58.6-fold increase in relative risk as compared with an age- and sex-adjusted general population.1 Depending on the series, rates of occurrence in patients with pancreatic cancer vary from 5%-60%.2 The wide variance probably reflects the large number of factors that interact and influence thrombotic risk, and several of these factors have been identified including stage of disease, older age, obesity, comorbidities, and prior history.3 Furthermore, treatment with chemotherapy ups the risk approximately five-fold.4 Although it is difficult to determine the actual risk for a single patient, it is known that the occurrence of a VTE is of prognostic importance. Sorenson and colleagues found that 12% of cancer patients with VTE and 36% of cancer patients without VTE were alive after 1 year.5 Examining data from the California Cancer Registry including 235,149 cancer patients, Chew and colleagues found that the occurrence of VTE was highest among those with pancreatic cancer (20%), and that the occurrence correlated with stage of disease and was a significant predictor of death.6
Mechanisms Accounting for the High Rate of VTE in Pancreatic Cancer
Several factors contribute to the pathogenesis of VTE in cancer patients and most of these are commonly observed in pancreatic cancer patients. Such patients have been shown to have circulating procoagulants including tissue factor,7,8 thrombin,9,10 and fibrionogen,11-13 as well as decreased levels of coagulation inhibitors such as protein C, protein S, antithrombin III, and thrombomodulin.11,12 These occurring in mobility-impaired patients with invasive tumor in the retroperitoneal space no doubt contribute to the hypercoaguable state. Additionally, inflammatory factors known to be elevated in patients with pancreatic cancer, including transforming growth factor (TGF) and tumor necrosis factor (TNF), enhance coagulation pathways.14,15
Prevention of VTE
Primary anticoagulant prophylaxis is recommended for cancer patients admitted to the hospital for either surgical or medical reasons.16 In this regard, unfractionated heparin, low molecular weight heparin (LMWH), and warfarin each have been used, but most physicians currently recommend LMWH in this setting. Ambulatory patients receiving chemotherapy for pancreatic cancer also are at risk for VTE. Recent trials conducted in patients with advanced disease have shown positive results with LMWH prophylaxis. The CONKO-004 trial found an 87% risk reduction of VTE using enoxaparin at 1 mg/kg once daily for 3 months compared with no prophylaxis (9.9% vs. 1.3%, P < 0.01).17 Similarly, the UK FRAGEM study reported a 62% reduction in VTE with dalteparin (31% vs 12%; P = 0.02). These data are in conflict with the negative results from LMWH prophylaxis studies conducted in ambulatory cancer (primarily breast, gastrointestinal, and lung) patients. Thus, it seems LMWH is effective in reducing clinically important VTE in selected patients receiving chemotherapy, but the optimal dose, duration, and specific patient populations have to be further defined.
Treatment of Cancer-Associated VTE
The recommended treatment for cancer-associated VTE is LMWH, as it has proven effective both in the short- and long-term when compared with warfarin.16 The data for the newer oral anticoagulants, including dabigatran and rivaroxaban, are not yet available in the setting of cancer-associated VTE. Despite treatment for the initial VTE, recurrent VTE occurs in approximately 10%-20% of cancer-associated cases. Studies have suggested that in more advanced disease, a shorter interval between diagnosis and initial VTE (3 months or less) or young age are predictors of recurrent thrombosis despite anticoagulation. Data to guide the management of such patients are limited. For those being treated with LMWH, dose escalation (e.g., by 25%) has proven effective in the majority of patients. For those who were treated initially with warfarin, switching to LMWH would seem advisable rather than increasing warfarin to higher than therapeutic levels. The role for IVC filters remains to be established in cancer patients with VTE.
Summary
Pancreatic cancer is a hypercoaguable state with the occurrence of VTE ranging from 10%-60%. Notably, thromboembolic events are associated with poorer prognosis, and such events predict disease recurrence and shorter survival. LMWH has proven effective in both prophylaxis and VTE treatment in pancreatic cancer patients although much research is needed to determine the optimal dose, schedule, and duration of treatment. The new oral direct thrombin inhibitors (such as the recently approved dabigatran) are of great interest and need to be explored in the setting of VTE prophylaxis and treatment in cancer patients.
References
1. Blom JW, et al. High risk of venous thrombosis in patients with pancreatic cancer: A cohort study of 202 patients. Eur J Cancer 2006;42:410-414.
2. Khorana AA, Fine RL. Pancreatic cancer and thromboembolic disease. Lancet Oncol 2004;5:655-663.
3. Khorana AA, Connolly GC. Assessing risk of venous thromboembolism in the patient with cancer. J Clin Oncol 2009;27:4839-4847.
4. Otten HM, et al. Symptomatic venous thromboembolism in cancer patients treated with chemotherapy: An underestimated phenomenon. Arch Intern Med 2004;164:190-194.
5. Sorensen HT, et al. Prognosis of cancers associated with venous thromboembolism. N Engl J Med 2000;343:1846-1850.
6. Chew HK, et al. Incidence of venous thromboembolism and its effect on survival among patients with common cancers. Arch Intern Med 2006;166:458-464.
7. Haas SL, et al. Expression of tissue factor in pancreatic adenocarcinoma is associated with activation of coagulation. World J Gastroenterol 2006;12:4843-4849.
8. Khorana AA, et al. Tissue factor expression, angiogenesis, and thrombosis in pancreatic cancer. Clin Cancer Res 2007;13:2870-2875.
9. Rudroff C, et al. Expression of the thrombin receptor PAR-1 correlates with tumour cell differentiation of pancreatic adenocarcinoma in vitro. Clin Exp Metastasis 2002;19:181-189.
10. Wojtukiewicz MZ, et al. Expression of prothrombin fragment 1+2 in cancer tissue as an indicator of local activation of blood coagulation. Thromb Res 2000;97:335-342.
11. Lindahl AK, et al. Coagulation inhibition and activation in pancreatic cancer. Changes during progress of disease. Cancer 1992;70:2067-2072.
12. Wojtukiewicz MZ, et al. Immunohistochemical localization of tissue factor pathway inhibitor-2 in human tumor tissue. Thromb Haemost 2003;90:140-146.
13. Wojtukiewicz MZ, et al. Localization of blood coagulation factors in situ in pancreatic carcinoma. Thromb Haemost 2001;86:1416-1420.
14. Albo D, et al. Thrombospondin-1 and transforming growth factor beta-1 upregulate plasminogen activator inhibitor type 1 in pancreatic cancer. J Gastrointest Surg 1999;3:411-417.
15. Fareed D, et al. Blood levels of nitric oxide, C-reactive protein, and tumor necrosis factor-alpha are upregulated in patients with malignancy-associated hypercoagulable state: Pathophysiologic implications. Clin Appl Thromb Hemost 2004;10:357-364.
16. Lyman GH, et al. American Society of Clinical Oncology guideline: Recommendations for venous thromboembolism prophylaxis and treatment in patients with cancer. J Clin Oncol 2007;25:5490-5505.
17. Riess H, et al. A prospective, randomized trial of chemotherapy with or without the low molecular weight heparin (LMWH) enoxaparin in patients with advanced pancreatic cancer: Results of the CONKO-004 trial. J Clin Oncol 2009;27:LBA4506.
Financial Disclosure: Clinical Oncology Alert's Editor, William Ershler, MD, and peer reviewer, V.R. Veerapalli, MD, report no financial relationships to this field of study.
Deep vein thrombosis (DVT) and pulmonary embolus (PE) occur more frequently in patients with cancer, and the risk appears to vary by tumor type.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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