2008 Guidelines for the Treatment of Venous Thromboembolism in Cancer Patients: Report from the French Working Group.

Venous thromboembolism (VTE) is a major therapeutic issue in cancer. Advances in this field and heterogeneities in clinical practices prompted us to establish guidelines related to VTE treatment and to central venous catheter thrombosis (CVCT) management. in cancer patients according to the SOR Standards, Options: Recommendations (SOR) methodology for the development of evidence-based Clinical Practice Guidelines (CPG) as endorsed by the French National Cancer Institute.

Methods: After reviewing the published studies on the topics between 1999 and 2007, a first version of the guidelines was based on the levels of evidence derived from analysis of the 38 out of 418 selected studies for VTE treatment and the 40 out of 175 selected studies for the CVCT management. The recommendations were classified as Standards or Options and then peer-reviewed by 65 independent experts. Detailed methodology is available at www.sor-cancer.fr Standards in cancer patients: The treatment of VTE should be based on Low Molecular Weight Heparins (LMWH) at curative doses for at least 3 months. During the initial treatment (up to 10 days), there are no specific requirements and all drugs approved (including LMWH, Unfractionnated Heparin (UFH), fondaparinux and danaparoid) may be used. Beyond the first 10 days, VTE treatment should be based on LMWH at curative doses for at least 3 and optimally for 6 months, as validated with the following drugs and dosage regimens: dalteparin 200 IU/kg once daily for one month, then 150 IU/kg once daily; enoxaparin 150 IU/kg once daily; and tinzaparin 175 IU/kg once daily. In case of:

• severe renal impairment, UFH should be used rapidly followed by Vitamins K Antaogonist (VKA) for at least 3 months;

• severe Pulmonary Embolism (hemodynamic failure), the indications and usages of thrombolytic drugs are the same as in non-cancer patients;

• absolute contra-indication to anticoagulation or VTE recurrence despite optimal anticoagulation, vena cava filters (VCF) should be considered;

• intracranial malignancies, VTE treatment is the same as in cancer patients with non-intracranial tumors.

CVCT treatment relies on long term use of LMWH. In case of severe renal failure, UFH with early AVK must be used. Treatment is to be continued as long as the catheter is maintained. This can only be achieved if the catheter is functional, well positioned, not infected and if adapted anticoagulation has resumed the CVCT. If catheter withdrawal is necessary, there is no standard concerning the anticoagulation management. CVCT prophylaxis relies on positioning the catheter distal extremity at the “superior vena cava - right atrium” junction. Systematic CVCT anticoagulant prophylaxis is not recommended.

Options:Treatment of VTE: If LMWH administration for 3 months is impossible, short-term use of LWMH followed by VKA for at least 3 months may be proposed. It is recommended to administer LMWH for 3 to 6 months; LMWH should be used according to the same curative dosage regimen as during the first 3 months. Beyond the first 6 months, the anticoagulant treatment should be continued as long as the cancer is active or treated. In the event of a first VTE episode secondary to a transient risk factor and if the cancer is not active nor treated, anticoagulation may be discontinued after 6 months. The choice between LMWH and VKA depends on their benefit-risk ratio (influenced by drug interactions, chemotherapy, invasive procedures, and general health status) and acceptability. If a VCF is considered, a retrievable VCF may be discussed. CVCT treatment: If another catheter has to be inserted, prior evaluation of the venous circulation by scanner or ultrasound examination is recommended. If prolonged use of LMWH is impossible, VKA can be proposed. In case of severe superior vena cava syndrome, fibrinolytics can be used in the absence of contra-indications. Treatment by LMWH can be stopped 6 weeks after catheter withdrawal in non active cancer or after 3 to 6 months of LMWH followed by VKA in the other cases. CVCT prophylaxis: Right side catheter insertion and vein localisation by ultrasonography are preferred.

Conclusion: The French recommendations further support the 2006 Italian and the 2007 North American guidelines on VTE treatment in cancer patients and were extended to the use of VCF and treatment of patients with intracranial malignancies. In addition, we provide recommendations on CVCT treatment in cancer patients.