Venous Thromboembolism and Prognosis in Pancreatic Cancer

Abstract & Commentary

By William B. Ershler, MD, Editor

Synopsis: In a careful analysis of 227 patients with unresectable or metastatic pancreatic carcinoma treated on protocol with chemotherapy, the development of venous thromboembolism (VTE) was associated with shorter progression-free and overall survival.

Source: Mandala M, et al. Venous thromboembolism predicts poor prognosis in irresectable pancreatic cancer patients. Ann Oncology. 2007;18:1660-1665.

Whereas the occurrence of venous thromboembolism (VTE) is an acknowledged common development in patients with gastrointestinal malignancy, the relationship between the cancer itself, chemotherapy and thrombus formation has not been well established. The aim of the study by Mandala and colleagues was to determine the significance of VTE occurrence in patients with locally advanced (unresectable) or metastatic pancreatic carcinoma. For this, over an approximate 3 year period, 227 patients with Eastern Cooperative Oncology Group performance status (ECOG-PS) < 2 and non-resectable pancreatic cancer were identified from local registries and clinical trials. Of these 28 (12.3%) had VTE at the time of diagnosis, 15 (6.6%) developed VTE during chemotherapy and an additional 16 (7%) had VTE both prior to and during chemotherapy. All patients had received chemotherapy; 35% with PEFG (cisplatin, epirubicin, 5-fluorouracil, gemcitabine), and 65% with either gemcitabine alone or in combination with cisplatin. Of the total group, 1 patient had a complete response, 54 (24.8%) achieved partial response, 73 (33.5%) had stable disease and 90 (41.3%) had progressive disease. Analysis by univariate and multivariate logistic models examining the prognostic effect of synchronous VTE, the occurrence of VTE during chemotherapy, and the presence of VTE irrespective of the time of occurrence revealed that two factors seemed to be independently predictive of progressive disease; the use of chemotherapy other than PEFG (odds ration [OR] 6.38, 95% confidence interval [CI] 3.12-13.03, P = 0.0001) and synchronous VTE (ie, VTE that occurred prior to treatment; OR 2.90, 95% CI 1.40-6.84, P = 0.005). No statistically significant effect of occurrence of VTE during chemotherapy on response to treatment was observed. Over the three years, all but 5% of the patients had died. The median progression free survival (PFS) and overall survival (OS) were 5 and 9.6 months, respectively. With regard to PFS, by multivariate analysis, stage IV disease, and VTE occurring before or during chemotherapy were significant negative risk factors. Curiously, for each 5 year age increase, there was a lower risk of progression (hazard ratio [HR] 0.92, 95% CI 0.86-0.99, P = 0.044). Regarding overall survival, stage IV disease and VTE occurring before or during chemotherapy were significant by univariate analysis but only stage IV disease and VTE occurring during chemotherapy were statistically significant.

Commentary

Thus, in an analysis of a homogeneous cohort of advanced pancreatic caner patients there is now irrefutable evidence that VTE, whether present before, or developed during treatment, is a negative prognostic factor. Certainly, the concept is not new1, 2 but the current report offers an evaluation in the context of time of occurrence (prior to, or during chemotherapy), tumor stage and chemotherapy response. The analysis, which relied on a retrospective review for the presence of VTE, the actual number is likely to be an underestimate. Furthermore, all patients had been treated with chemotherapy and were ECOG PS < 2, and perhaps those with a greater number of comorbid conditions or functional impairments that would preclude clinical trial would have an even higher rate of VTE.

Given that VTE occur with increased frequency and indicate a more negative outcome in patients with locally advanced or metastatic pancreatic cancer, would there be any value in primary prophylaxis? Unfortunately, oral anticoagulation with vitamin K antagonists is problematic due to drug interactions, malnutrition and liver dysfunction. Furthermore, both recurrent VTE and hemorrhage are more common in cancer patients when treated with vitamin K inhibitors such as Coumadin. However, treatment with low molecular weight heparin (LMWH) has proven to be effective and relatively safe in this setting.3 Such might reduce the rate of new or recurrent VTE but its effect on tumor growth, spread and chemotherapy response remains to be fully clarified.

References

1. Chew HK, et al. Incidence of venous thromboembolism and its effect on survival among patients with common cancers. Arch Intern Med. 2006;166(4):458-464.

2. Sorensen HT, et al. N Engl J Med. 2000;343(25):1846-1850.

3. Lee AY, et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med. 2003;349(2):146-153.