An Extended Time Frame for VTE Risk in Bladder Cancer

Cancer promotes the development of venous thromboembolism (VTE) by inducing a hypercoaguable state, through mechanisms that are complex and multifactorial.

It has been shown that tumor cells promote activation of blood coagulation by: (1) producing procoagulant factors; (2) releasing cytokines; and (3) initiating direct cell-to-cell interaction with the patient's endothelial cells, leucocytes, and platelets. Approximately 15% of all patients with cancer will develop VTE, which is the second leading cause of death in these patients. An advanced disease stage at diagnosis, treatment effects (from chemotherapy, hormonal therapy, surgery, and the presence of central venous catheters), lifestyle factors, and comorbidity are major determinants of the risk of VTE and could explain differences in the incidence of VTE by cancer site. For example, patients with metastatic cancer have at least a twofold to fourfold increased risk of VTE in the first 6 months after cancer diagnosis compared with patients who have limited-stage disease. Among patients with metastatic disease, the highest incidence of VTE is seen in those with cancer of the pancreas (20 incidents per 100 patient-years), stomach (10.7 per 100 patient-years), bladder (7.9 per 100 patient-years), uterus (6.4 per 100 patient-years), kidney (6.0 per 100 patient-years), and lung (5.0 per 100 patient-years).[1] Importantly, the true incidence of VTE according to tumor type is not known; this is because of the heterogeneity of the population and the lack of standardized screening protocols to detect VTEs. While more cases of VTE have been observed in patients with tumors of the breast, prostate, lung, and colon, these may be attributed to the higher prevalence of these malignancies and the longer survival time of patients with these diagnoses. The 2% rate of VTEs reported by Sandhu et al[2] likely severely underestimates the true incidence of VTEs among patients with bladder cancer in the 3 months following cystectomy. A recent retrospective review of 435 consecutive staging CT scans performed on patients with a variety of tumor types reported a prevalence of clinically silent VTE of 6.3%. These data suggest that the true incidence of VTE in cancer patients is likely much higher than indicated by any of the previous studies. A post–radical cystectomy series with closer follow-up demonstrated an 8% rate of VTE.[3] Patients undergoing similar pelvic surgeries, such as for colorectal cancer, have VTE rates of 4% to 5%, despite adherence to basic VTE prophylaxis protocols.[4] The concomitant and antecedent risk of VTE in patients with bladder cancer may be comparable to that seen with other cancers. The effect of bladder cancer on modulating biochemical factors involved in the coagulation cascade, such as tissue factor levels, is not unique and is seen in a number of malignancies. However, the older age of patients with bladder cancer, and the effects of extended pelvic surgery, intimal injury, and relative immobilization after surgery, may increase the risk of VTE following major pelvic surgery, such as radical cystectomy. These risk factors are similar to those seen in colorectal cancer.

There are several key take-home messages in the review by Drs. Fantony and Inman in this issue of
ONCOLOGY.[5] First and foremost, there needs to be heightened awareness of the VTE diathesis in patients with bladder cancer, as well as in those undergoing major pelvic surgery. Early institution of appropriate prophylactic interventions is critical to avoid VTE formation. Both unfractionated heparin and low-molecular-weight heparin (LMWH), administered subcutaneously in low doses, have been shown to be effective and safe for thromboprophylaxis in these settings in the general population. Guidelines from the American Society of Clinical Oncology (ASCO) recommend that VTE prophylaxis commence prior to surgery and that methods to prevent VTE continue to be applied for at least the duration of hospitalization after surgery.

Second, selected individuals at higher risk for VTE may need longer-term anticoagulation therapy, since the clotting diathesis remains elevated for a significant period of time following surgical intervention. Data from radical prostatectomy series indicate that the risk of VTE remains elevated for up to 6 weeks after surgery.

Third, it is important to be aware that along with the need for extended VTE prophylaxis, there is a need to reduce the risk of bleeding from anticoagulation, including bleeding from both malignant (unresected tumors) and non-malignant lesions (gastrointestinal bleeds). Patients with cancer and VTE have a twofold higher risk of major bleeding while receiving anticoagulant therapy than patients with VTE who do not have cancer.[6] Further challenges in administering VTE prophylaxis in these patients include their tendency to have chronic anemia, poor appetites, poor venous access, and need for multiple medications, which may lead to erratic international normalized ratios (INRs) and difficulties with warfarin monitoring and dosing.

Extended-duration LMWH has been clinically proven to reduce the risk of recurrent VTE without significantly increasing the risk of major bleeding in cancer patients with acute VTE. Additional benefits of LMWH over conventional anticoagulant therapy in this patient population include ease of administration at the time of invasive procedures and in patients with chemotherapy-induced thrombocytopenia; lack of interaction with other medications and effectiveness in patients with a poor diet; and lack of a need for laboratory monitoring. These recommendations need to be validated specifically for patients with bladder cancer. In addition, algorithms to determine the optimal length of VTE prophylaxis may help to minimize the burden of VTEs.

Importantly, as discussed by Drs. Fantony and Inman, patients with cancer and VTE who are treated with conventional anticoagulant therapy are more likely to develop recurrent VTE than patients with VTE who do not have cancer. It is not known whether patients with bladder cancer on VTE prophylaxis have a higher rate of VTEs than patients with other malignancies. Further studies of the specific biochemical changes in the clotting cascade in these patients are needed to help identify novel interventions that may decrease the risk of VTEs in the setting of bladder cancer.

Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1. Chew HK, Wun T, Harvey D, et al. Incidence of venous thromboembolism and its effect on survival among patients with common cancers. Arch Intern Med. 2006;166:458-64.

2. Sandhu R, Pan CX, Wun T, et al. The incidence of venous thromboembolism and its effect on survival among patients with primary bladder cancer. Cancer. 2010;116:2596-603.

3. Shabsigh A, Korets R, Vora KC, et al. Defining early morbidity of radical cystectomy for patients with bladder cancer using a standardized reporting methodology. Eur Urol. 2009;55:164-74.

4. Monn MF, Haut ER, Lau BD, et al. Is venous thromboembolism in colorectal surgery patients preventable or inevitable? One institution̢۪s experience. J Am Coll Surg. 2013;216:395-401.

5. Fantony JJ, Inman BA. Thromboembolism and bleeding in bladder cancer. Oncology (Williston Park). 2014;28:847-62.

6. Prandoni P. Cancer and thromboembolic disease: how important is the risk of thrombosis? Cancer Treat Rev. 2002;28:133-6. Review.