1. Venous Thrombosis and Long Term Use of Central Venous Catheter in Cancer Patients treated with Chemotherapy: Epidemiology and Risk Factors Giuseppe Curigliano Dipartimento di Medicina, Divisione di Oncologia Medica, Unità di Farmacologia Clinica e Nuovi Farmaci Istituto Europeo di Oncologia, Milano

2. M. Verso and G. Agnelli. Venous Thromboembolism Associated With Long-Term Use of Central Venous Catheters in Cancer Patients. J Clin Oncol 21:3665-3675, 2003. Epidemiology of catheter related Venous Thromboembolism (CVC-related VTE) in cancer patients  The reported incidence of symptomatic CVC-related VTE varies from 0.3 to 28.3%, with a rate of 12% in pediatric patients  The incidence of CVC-related VTE assessed by venography has been reported to vary from 27 to 66%. Most of the thrombi in these studies were asymptomatic.  There is no conclusive evidence that a particular type of CVC is more or less thrombogenic than others  Time course analysis of CVC-related VTE indicates the first 6 weeks after CVC insertion at higher risk of thromboembolic complication

3. AuthorsStudyNo. PatientsCVC-related VTE (%) Smith, 1983Retrospective Adults 28000.3 Soto-Velasco, 1984Retrospective Adults 16110.7 Cassidy, 1987Prospective Adults 4162.6 Gould, 1993Prospective Adults 25514.5 Eastridge, 1995Prospective Adults 32210 Kock, 1996Retrospective Adults 15002.5 Schwarz, 2000Prospective Adults 9233.1 Biffi, 2001 Kurtakose, 2002 Prospective Adults Prospective Adults 304 422 6.6 7.1 Incidence of clinically overt CVC-related VTE in cancer patients

4. AuthorsStudyNo. PatientsCVC-related VTE (%) Stoney, 1976Prospective Adults 20331 Ladefoged, 1978Retrospective Adults 4827.1 Brismar, 1982Prospective Adults 5335.8 Bern, 1990Retrospective Adults 4237.5 Monreal, 1996Retrospective Adults 2662 De Cicco, 1997Prospective Adults 12766 Martin, 1999Prospective Adults 6058.3 Glaser, 2001Prospecive Children 2450 Incidence of venographic CVC-related VTE in cancer patients

5. Risk factors for developement of CVC-related DVT in cancer patients CVC featuresPatients features Chemical structureHigh platelet counts Catheter diameterCancer related activation of coagulation Number of lumensCVC-related activation of coagulation Side of insertionChemotherapy-related activation of coagulation CVC-related infectionThrombofilic molecular abnormalities Insertion techniques

6. Venous thromboembolism (VTE) during chemotherapy Chemotherapy itself can increase the risk of thromboembolic disease:  Acute damage on vessel walls (bleomycin, carmustine, vinca alkaloids, adriamycin)  Decrease of natural coagulation inhibitors (reduced levels of protein C and S with cyclophosphamide, methotrexate and fluorouracil and reduced levels of antithrombin III with L-aspariginase)

7. Neil Goldenberg, Susan R. Kahn, and Susan Solymoss. Markers of Coagulation and Angiogenesis in Cancer-Associated Venous Thromboembolism. J Clin Oncol 21:4194-4199, 2003 Markers of coagulation and angiogenesis in cancer-associated venous thromboembolism  Peripheral blood was collected before anticoagulant therapy from cancer patients with acute deep venous thrombosis (DVP), those without DVP and patients with acute DVT and no cancer  Median levels of thrombin-antithrombin complex (p=0.0001), prothrombin fragments 1 2 (p=0.003), and von Willebrand factor antigen were significantly greater (p<0.001) in the DVT cancer group than in the cancer control and DVT control groups  Median levels of tissue-type plasminogen activator were also significantly higher (p=0.0005), while protein C activity was lower in the DVT cancer group than in the DVT control group (p=0.0008).

8. VTE in cancer patients: the role of chemotherapy Clahsen et al suggested a contributing role of perioperative chemotherapy to VTE especially in postmenopausal women and women who underwent mastectomy Incidence of deep venous thrombosis: 2.1% assigned to perioperative chemotherapy 0.8% assigned to no treatment Clahsen PC, et Al. Thromboembolic complication after perioperative chemotherapy in women with early breast cancer: an EORTC study. J Clin Oncol 1994: 12: 1266-71

9. VTE in cancer patients: the role of chemotherapy Prospective/Randomized trial: 12 weeks of chemo-hormone therapy (CMF-VP-A-T) 36 weeks of chemotherapy CMF-VP Incidence of VTE: 6.8% 4.9% chemo-hormone therapy arm (CMF-VP-A-T) 8.8% chemotherapy arm CMF-VP Levine et al. The thrombogenic effect of anticancer drug therapy in women with stage II breast cancer. New Engl J Med 1988, 318: 404-407

10. VTE in cancer patients: the role of chemotherapy 179 consecutive germ cell cancer patients Cisplatin containing regimens 15 patients (8.4%) developed 18 major VTE between the start of chemotherapy and 6 weeks after administration of the last cycle in first line treatment Of these 18 events, 3 (16.7%) were arterial events, including 2 cerebral ischemic strokes and 15 (83.3%) were VTE including 11 pulmonary embolism. One (5.6%) of the 18 events was fatal. Weijl 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

11. VTE in cancer patients: the role of hormone therapy and chemo- endocrine therapy Authors observed one or more thromboembolic events in 48 of 353 women (13.6%) randomized to receive tamoxifen plus CMF compared to 5 of 352 women (2.6%) randomized to receive tamoxifen alone (p=0.001). Significantly more women developed severe VTE in the T plus CMF arm than in the T arm (34 vs 5: p=0.0001). Most thromboembolic events occurred while women were actually receiving chemotherapy ( 39 of 54, p<0.0001). Pritchard K. 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: 2731-2737

12. AuthorsStudyRegimensVTE incidence (%) Clahsen et alProspective Randomized FAC perioperative No treatment 2.1 0.8 Levine et alProspective Randomized CMFVP + A + T CMFVP 36 weeks 4.9 8.8 IBCSG et alProspective Randomized CMF + AF periop No treatment 0.5 0 Weiss et alProspective Randomized CMF (2 years) CMFbCG (2 yrs) 3.5 6.3 5.4 Pritchard et alProspective Randomized CMF + T T 13.6 2.6 Fisher et alProspective Randomized Tamoxifen MTF CMF + T 1.2 4.2 4.5 Tormey et alProspective Randomized CMF CMF PT 0 3.8 Wils et alProspective Randomized E + T T 0.03 0.015

13. Kirwan et Al. Prophylaxis for venous thromboembolism during treatment for cancer: questionnaire survey. BMJ, 2003; 327: 597-598 Venous thrombosis in cancer patients: A questionnaire Survey 29% of medical oncologists respondents to questionnaire considered their patients not at risk of VTE More than a quarter of medical oncologists do not recognize the thrombogenic effects of cancer treatments

14. A.K. Kakkar, M. Levine et Al.. Venous thrombosis in cancer patients: Insights from the FRONTLINE survey. The Oncologist 2003; 8: 381-388 Venous thrombosis in cancer patients: Insights form the FRONTLINE (Fundamental Research in Oncology and Thrombosis) Survey 35% of respondents to questionnaire were medical oncologists 62% or respondents practice in Western Europe or North America 29 questions were reported for non surgical patients 10 questions were related to vascular access devices

15. A.K. Kakkar, M. Levine et Al.. Venous thrombosis in cancer patients: Insights from the FRONTLINE survey. The Oncologist 2003; 8: 381-388 Venous thrombosis in cancer patients: Insights form the FRONTLINE (Fundamental Research in Oncology and Thrombosis) Survey 80% of respondents to questionnaire considered the use of central venous lines to be associated with a high risk of VTE Western Europeans typically considered CVC to be associated with a 0-20% risk of VTE (74% perceived the risk to be in this range), while North American respondents considered the risk, without prophylaxis, between 11-30%.

16. Venous thrombosis in cancer patients In conclusion, the pathogenesis of UL-DVT in patients with CVC is probably multifactorial. Early thromboembolic events are essentially related to the loss of vessel integrity caused by CVC placement. Late thromboembolic events are probably related to CVC features, insertion technique, catheter tip position, and occurrence of catheter infection. The role of thrombophilic molecular abnormalities is less clear.

17. VTE in cancer patients European Institute of Oncology Policy Selection of patients at high risk Influence of Factor V Leiden and the G20210A prothrombin mutation on the development of deep vein thrombosis in cancer patients treated with chemotherapy

18. AIMS The major objective of the study is to evaluate retrospectively the influence of Factor V Leiden and the G20210A prothrombin mutation in the development of deep vein thrombosis in cancer patients treated with infusional chemotherapy.

19. Influence of Factor V Leiden and the G20210A prothrombin mutation on the development of deep vein thrombosis in cancer patients treated with chemotherapy EXCLUSION CRITERIA · Metastatic cancer patients with one or more of the following deficiency: antithombin III, protein C, or protein S. · Autoimmune desorders, including primary antiphospholipid-antibody syndrome. · Deep vein thrombosis not diagnosed by objective methods such as phlebography, unltrasonographic examination, or impedance plethysmography.

20. Patients and methods Between January 1999 and February 2001, we retrospectively analyzed the incidence of first deep vein thrombosis in 300 consecutive patients with locally advanced or metastatic breast cancer treated in a single institution with a combination of chemotherapy administered continuously through a totally implanted access port. We identified 25 women (study group) with catheter-related deep vein thrombosis. For each of the 25 patients we selected two women eligible for identical chemotherapy, with similar age, stage of disease and prognostic features as control. The prothrombotic factor V Leiden and prothrombin mutation G20210A genotype analyses were performed in all patients. Analyses were performed on blinded samples and all patients signed a specific informed consent.

21. Results A total of 25 cases (thrombosis) and 50 frequency-matched controls were evaluated for Factor V Leiden. Five cases and 2 controls were found with the mutation in the factor V Leiden for a frequency of 20% (95% CI= 9%-39%) and 4% (95% CI=1%-14%) respectively. Only one subject (case) was found with the G20210A mutation in the prothrombin gene. Time from start of infusion chemotherapy to thrombosis was not significantly different between those with (median=31 days) and without the mutation (median 43 days, p=0.6). Thus, the frequency of the mutation was significantly higher in the cases than in controls (p=0.04) and a logistic regression analysis, adjusted by age, yielded an odds ratio of 6.1 (95% CI=1.1-34.3; p=0.04).

22. Controls (n. 50) Cases (n. 25) p values Age5043-545146-550.4 Menopausal status Pre2449%1144%0.8 Post2551%1456% Tumor stage Locally advanced2959%1560%0.9 Metastatic2041%1040% Number of cycles64-632-50.9 Mutations Prothrombin00%14%0.3 Factor V Leiden24%520%0.04 Frequency1-14%9-39&

23. Conclusions The identification of a subgroup of patients at high risk for thrombosis could be a fair strategy to either avoid medical devices which increase the risk of thromboembolism, or to implement the compliance in prescribing anticoagulant prophylaxis in patients with cancer. We are not able to recommend thrombosis prophylaxis and immediate catheter removal after treatment, advising testing for the factor V Leiden in all patients receiving continuous infusion chemotherapy. It is however reasonable to offer testing for factor V Leiden in cases when there’s history of thromboembolism (even when not cancer related), to allow proper anticoagulation for those patients who were so identified.