1. C ANCER -A SSOCIATED T HROMBOSIS : W HAT YOU NEED TO KNOW Anne McLeod

2. O BJECTIVES To discuss the risk of thrombosis in cancer patients To discuss signs and symptoms of thrombosis To discuss treatment of thrombosis in cancer pts

3. W HY SHOULD YOU CARE ABOUT CAT? Cancer increases the risk of VTE ~4-7x Diagnosis of venous thromboembolism (VTE) is associated with worsened mortality and morbidity in patients with cancer Active cancer accounts for 20% of new VTEs

4. VTE IN C ANCER PATIENTS  VTE is a major complication of cancer affecting 5-20% of pts  Second leading cause of death  Autopsy rates of VTE in cancer patients~ 50%

5. National Hospital Discharge Survey Stein AJM 2006 119,60-68 827,000 of 40, 787,000 cancer pts also had a diagnostic code for VTE

6. C ONSEQUENCES OF VTE IN CANCER PTS Hospitalized cancer pts with VTE have greater inpatient mortality and longer admissions Risk of fatal PE in cancer surgery is 3X greater than similar noncancer surgery Khorana JCO 24:484, 2006 Gallus Thromb Haemost 78:126, 1997

7. C ONSEQUENCES OF VTE IN CANCER PTS Cancer patients with VTE have increased risk of recurrent VTE, bleeding complications, morbidity and utilization of health care resources Newer anticancer drugs particularly antiangiogenic drugs more thrombogenic Khorana JCO 27: 4919 2009

8. Fatal PE, Deaths and Bleeding after Cancer Surgery Haas – Thromb Haemost 2005;94:814 Non-cancer Cancer Outcome (N=16,954) (N=6,124)RR P Fatal PE* 0.09 % 0.33 %3.7 0.0001 Death 0.7 % 3.1 %4.5 0.0001 Abn bleeding 0.04 % 0.29% 7.3 0.0001 double-blind RCT of LDH TID vs certoparin QD * autopsy-proven

9. 0 5 10 15 20 100 80 60 40 20 Years after Diagnosis Survival, % of patients VTE, C ANCER AND S URVIVAL Sorensen - NEJM 2000;343:1846 1- yr survival Cancer at time of VTE 12% Cancer without VTE 36% p<.001

10. R ISK F ACTORS FOR VTE IN C ANCER P TS  Patient-related factors Older Age Race (> African Americans) Comorbid conditions (obesity, medical illness) Prior VTE Elevated prechemotherapy plt count Inherited thrombophilia

11. R ISK F ACTORS FOR VTE IN C ANCER P TS  Cancer-related factors- tumours can produce procoagulants Type of cancer Initial 3-6 mons after diagnosis Metastatic disease

12. C ANCER AND VTE M ETASTATIC D ISEASE AND VTE Metastatic Disease increases VTE risk 4-13X Incidence of VTE / 100 pt- yr Pancreas 20.0 Stomach 10.7 Bladder7.9 Renal 6.0 Lung5.0 Chew et al. Arch Int Med. 2006;166: 458-64

13. Levitan Medicine 1999 78:295

14. R ISK F ACTORS FOR VTE IN C ANCER P TS  Treatment-related factors Current hospitalization- lines procedures immobility Active chemotherapy Active hormonal therapy Antiangiogenic therapy (thalidomide, lenolidomide, becacizumab) Erythropoietin stimulating agents

15. Volume 25 Number 34 December 1 2007

16. ASCO R ECOMMENDATIONS #1 Should hospitalized pts with cancer receive anticoagulation for VTE prophylaxis? YES 3 large RCTs in “acute medical pts” ~15% cancer pts Bleeding complication rate was low

17. A RE GUIDELINES BEING USED ? ACCP guidelines recommend prophylaxis for acutely ill hospitalized medical and surgical cancer pts FRONTLINE Survey in Oncologist 2003 found >50% of oncology surgeons but only 5% of medical oncologists reported use of primary prophylaxis for high risk pts

18. Kakkar, A. K. et al. Oncologist 2003;8:381-388 Medical Inpatients

19. ServiceTotal no. of patients (2009) (2010) No. of pts excluded 1 (2009) (2010) Prophylaxis indicated (2009) (2010) Appropriate Prophylaxis (2009) Appropriate Prophylaxis (2010) Cardiac Surgery19216813 12 (92%) Cardiology37172810973 (33%)5 (71%) Endocrinology02NA0 2 2 (100%) General Medicine13014635319511591 (96%)90 (78%) General Surgery403977333233 (100%)30 (94%) Gastroenterology200NA2 0 (0%)NA Gynecology31121761469 (64%)6 (100%) Gyne. Oncology11700 710 (91%)7 (100%) Neurology10NA01 1 (100%)NA Nephrology101164470 (0%)3 (43%) Neurosurgery192077121310 (83%)9 (69%) Med. Oncology36381015262314 (54%)12 (52%) Rad. Oncology11171210157 (70%)8 (53%) Ophthalmology10NA01 0 (0%)NA Orthopedics75901820577055 (96%)69 (99%) Otolaryngology41117343 (100%)3 (75%) Plastics – Burn810107 7 (100%)10 (100%) Plastic Surgery4211313 (100%)1 (100%) Respirology201NA1 0 (0%)NA Trauma252161192017 (89%)19 (95%) Urology12931985 (56%)5 (63%) Vascular Surgery81314797 (100%)9 (100%) Combined486 149124337362287 (85%)300 (83%) Table 3: Appropriate Thromboprophylaxis by Clinical Service 1 = includes patients on therapeutic anticoagulants and those for whom thromboprophylaxis was not indicated

20. W HERE IS THE LESION ? Under recognition of risk factors? Because many pts are elderly? Because of the risk of bleeding? Because of the risk of HIT?

22. ASCO R ECOMMENDATIONS #2 Should ambulatory pts with cancer receive anticoagulation for VTE prophylaxis during systemic chemotherapy? NO

23. P REVENTION OF T HROMBOEMBOLISM IN C ANCER M EDICAL O NCOLOGY P TS  Levine 1994 Stage IV Breast – RRR 85%  Hass 2005 TOPIC Breast/Lung -NS  Perry 2007 PRODIGE – Gliomas - NS  Agnelli 2008 PROTECHT Metastatic Ca- RRR 47%

24. Prevention of Thromboembolism in Cancer  Stage IV breast cancer patients receiving CTX  Double-blind RCT  Very low-dose warfarin: 1 mg x 6 wks  INR 1.3-1.9 Placebo Warfarin No.159152 Thromboembolism 4.4 % 0.6 % p = 0.03 Major bleeding 1.3 % 0.6 % NS All bleeding 3.1 % 5.3 % NS Levine - Lancet (1994)

25. P REVENTION OF T HROMBOEMBOLISM IN C ANCER TOPIC STUDIES Advanced Cancer on ChemoRx LMWH vs. placebo x 6 months Dopplers q 4 weeks TOPIC 1- Breast Ca Placebo LMWH p VTE 3.9% 4% Bleeding 0% 1.7% TOPIC 2 - Lung Ca Overall VTE 8.3% 4.5%.07 Stage IV VTE 10.1% 3.5%.03 Bleeding 2.2% 3.7% Haas et al J Throm Haemos 2005; 3 (suppl) OR 059

26. P REVENTION OF T HROMBOEMBOLISM IN C ANCER PROTECHT STUDY 2009 O CT ;10(10):943-9  Metastatic or locally advanced Ca (lung, gastrointestinal, pancreatic, breast, ovarian, or head and neck) on ChemoRx  RCT double-blind clinical outcome  LMWH vs placebo 2:1 randomization while on ChemoRx  maximum 4 months 1,150 pts LMWH 769: Placebo 381  Primary Efficacy Endpoint: Composite of Venous/Arterial Thromboembolic events- 2% treated vs 3.9% untreated  Safety: Major Bleeding –NS difference Lancet Oncol.Lancet Oncol. 2009 Oct;10(10):943-9

27. ASCO R ECOMMENDATIONS #2 Except pts receiving thalidomide or lenolidamide with chemo or dexamethasone should Studies to identify better markers of increased risk ambulatory pts needed

28. ASCO R ECOMMENDATIONS #3 Should pts with cancer undergoing surgery receive perioperative VTE prophylaxis? YES 1) All pts undergoing major surgical intervention for malignant disease should be considered for prophylaxis 2) Patients undergoing laporotomy, laparoscopy or thoracotomy lasting greater the 30 mins

29. ASCO R ECOMMENDATIONS #3 3) Prophylaxis should be commenced preoperatively, or as early as possible in the postoperative period 4) Mechanical methods may be added to pharmacologic methods, but should not be used as monotherapy for VTE prevention unless contraindicated because of active bleeding

30. ASCO R ECOMMENDATIONS #3 5) A combined regimen of pharmacologic and mechanical prophylaxis may improve efficacy 6) Prophylaxis should be continued for at least 7-10 days postop. Consider up to 4 wks in major abdo or pelvic surgery in pts with high-risk features such as residual disease, obese or previous VTE

31. ASCO RECOMMENDATION # 4 What is the best treatment for patinets with cancer and with established VTE to prevent recurrent VTE? In general LMWH

32. ASCO R ECOMMENDATION #5 Should patients with cancer receive anticoagulants in the absence of established VTE to improve survival?

33. C OCHRANE D ATABASE S YSTEMATIC R EVIEW J ULY 2007 Five RCTs (UFH or LMWH) Heparin associated with a statistically and clinically significant survival benefit (HR=0.77 CI 0.65 to 0.91) Subgroup analyses: limited small cell lung CA had a clear survival benefit (HR=0.56 CI 0.65 to 0.83)

34. ASCO R ECOMMENDATION #5 Should patients with cancer receive anticoagulants in the absence of established VTE to improve survival? Recommendations: 1) NO 2) Pts should be encouraged to participate in trials

35. W HY TREAT ? To prevent fatal PE To prevent recurrence To prevent post-thrombotic syndrome

36. T REATING PATIENTS WITH VTE Does the patient need treatment? Small subsegmental PE? PICC line clots? Is it real? VOMIT Is patient symptomatic- then treat Lovenox 1.5 mg/kg od or 1 mg/kg bid Check plt count and creatinine clearance may need dose adjustment in renal dysfunction Weight based dosing even in obese pts If can’t anticoagulate use TEDS stockings and TE service should assess role of IVC filter

37. I NCIDENCE OF CVC-R ELATED DVT Rate of thrombosis requiring PICC removal – 3.4% 1.1/1,000 catheter days - no prophylaxis (n=351) Walshe – J Clin Onc 2002; 20:3276 Symptomatic thrombosis - 4% 0.3 /1,000 device days PICCs, Porta- caths, Hickman catheters – 444 pts A. Lee - J Clin Onc 2006; 24:1404 Clinically Important CVC-related DVT 2 - 4%

38. Preventing Central Venous Catheter Thrombosis in Cancer (RCTs) Warfarin 1 mg/day DVT sympt DVT Study Endpoint No. control warf control warf Bern, 1990 venogram D90 82 38 % * 10 % 25 % 10 % Couban, 2002 sympt. DVT 255 NR NR 4 % 5 % Heaton, 2002 sympt. thromb 88 NR NR 12 % 18 %

39. Preventing Central Venous Catheter Thrombosis in Cancer (RCTs) LMWH DVT Study Endpoint No. control LMWH P Monreal, 1996 venogram Day 90 29 62 % * 6 % 0.002 Reichardt, 2002 clinical 425 3.4 % 3.7 % 0.9

40. CVC-related Thrombosis in Cancer Pts Rate of clinically-important symptomatic DVT appears to have decreased ~ 4% Rate of thrombosis requiring PICC removal – 3.4% Primary prophylaxis with Minidose warfarin or LMWH appear to NOT be effective nor necessary in general

41. Apixaban Idraparinux Rivaroxaban Dabigatran

42. Questions?