CANCER-ASSOCIATED THROMBOSIS: WHAT YOU NEED TO KNOW

Anne McLeod

OBJECTIVES To discuss the risk of thrombosis in

cancer patients

To discuss signs and symptoms of thrombosis

To discuss treatment of thrombosis in cancer pts

WHY 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

VTE IN CANCER 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%

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

CONSEQUENCES 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

CONSEQUENCES 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

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

0 5 10 15 20

100

80

60

40

20

Years after Diagnosis

Surv

ival

, % o

f pat

ient

s

VTE, CANCER AND SURVIVAL

Sorensen - NEJM 2000;343:1846

1- yr survivalCancer at time of VTE 12%Cancer without VTE 36% p< .001

RISK FACTORS FOR VTE IN CANCER PTS

Patient-related factors• Older Age• Race (> African Americans)• Comorbid conditions (obesity, medical illness)• Prior VTE• Elevated prechemotherapy plt count• Inherited thrombophilia

RISK FACTORS FOR VTE IN CANCER PTS

Cancer-related factors- tumours can produce procoagulants• Type of cancer

• Initial 3-6 mons after diagnosis

• Metastatic disease

CANCER AND VTEMETASTATIC DISEASE AND VTEMetastatic Disease increases VTE risk 4-

13X

Incidence of VTE / 100 pt-yr

Pancreas 20.0Stomach 10.7Bladder 7.9Renal 6.0Lung 5.0

Chew et al. Arch Int Med. 2006;166: 458-64

Levitan Medicine 1999 78:295

RISK FACTORS FOR VTE IN CANCER PTS

Treatment-related factors• Current hospitalization- lines procedures

immobility

• Active chemotherapy

• Active hormonal therapy

• Antiangiogenic therapy (thalidomide, lenolidomide, becacizumab)

• Erythropoietin stimulating agents

Volume 25 Number 34 December 1 2007

ASCO RECOMMENDATIONS #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

ARE 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

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

Medical Inpatients

Service Total no. of patients

(2009) (2010)

No. of pts excluded1

(2009) (2010)

Prophylaxis indicated

(2009) (2010)

AppropriateProphylaxis

(2009)

AppropriateProphylaxis

(2010)

Cardiac Surgery 19 21 6 8 13 13 12 (92%) 12 (92%)Cardiology 37 17 28 10 9 7 3 (33%) 5 (71%)Endocrinology 0 2 NA 0 NA 2 NA 2 (100%)General Medicine 130 146 35 31 95 115 91 (96%) 90 (78%)General Surgery 40 39 7 7 33 32 33 (100%) 30 (94%)Gastroenterology 2 0 0 NA 2 NA 0 (0%) NAGynecology 31 12 17 6 14 6 9 (64%) 6 (100%)Gyne. Oncology 11 7 0 0 11 7 10 (91%) 7 (100%)Neurology 1 0 NA 0 1 NA 1 (100%) NANephrology 10 11 6 4 4 7 0 (0%) 3 (43%)Neurosurgery 19 20 7 7 12 13 10 (83%) 9 (69%)Med. Oncology 36 38 10 15 26 23 14 (54%) 12 (52%)Rad. Oncology 11 17 1 2 10 15 7 (70%) 8 (53%)Ophthalmology 1 0 NA 0 1 NA 0 (0%) NAOrthopedics 75 90 18 20 57 70 55 (96%) 69 (99%)Otolaryngology 4 11 1 7 3 4 3 (100%) 3 (75%)Plastics – Burn 8 10 1 0 7 10 7 (100%) 10 (100%)Plastic Surgery 4 2 1 1 3 1 3 (100%) 1 (100%)Respirology 2 0 1 NA 1 NA 0 (0%) NATrauma 25 21 6 1 19 20 17 (89%) 19 (95%)Urology 12 9 3 1 9 8 5 (56%) 5 (63%)Vascular Surgery 8 13 1 4 7 9 7 (100%) 9 (100%)Combined 486 486 149 124 337 362 287 (85%) 300 (83%)

Table 3: Appropriate Thromboprophylaxis by Clinical Service 1 = includes patients on therapeutic anticoagulants and those for whom thromboprophylaxis was not indicated

WHERE 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?

ASCO RECOMMENDATIONS #2 Should ambulatory pts with cancer receive

anticoagulation for VTE prophylaxis during systemic chemotherapy?

NO

PREVENTION OF THROMBOEMBOLISM IN CANCERMEDICAL ONCOLOGY PTS

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%

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 WarfarinNo. 159 152Thromboembolism 4.4 % 0.6 % p = 0.03 Major bleeding 1.3 % 0.6 % NSAll bleeding 3.1 % 5.3 % NS

Levine - Lancet (1994)

PREVENTION OF THROMBOEMBOLISM IN CANCERTOPIC STUDIESAdvanced Cancer on ChemoRxLMWH vs. placebo x 6 months Dopplers q 4

weeks

TOPIC 1- Breast Ca Placebo LMWH pVTE 3.9% 4%Bleeding 0% 1.7%TOPIC 2 - Lung Ca Overall VTE 8.3%

4.5% .07Stage IV VTE 10.1%

3.5% .03Bleeding 2.2% 3.7%

Haas et al J Throm Haemos 2005; 3 (suppl) OR 059

PREVENTION OF THROMBOEMBOLISM IN CANCERPROTECHT STUDY 2009 OCT;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. 2009 Oct;10(10):943-9

ASCO RECOMMENDATIONS #2

Except pts receiving thalidomide or lenolidamide with chemo or dexamethasone should

Studies to identify better markers of increased risk ambulatory pts needed

ASCO RECOMMENDATIONS #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

ASCO RECOMMENDATIONS #33) 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

ASCO RECOMMENDATIONS #35) 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

ASCO RECOMMENDATION # 4 What is the best treatment for patinets with

cancer and with established VTE to prevent recurrent VTE?

In general LMWH

ASCO RECOMMENDATION #5

Should patients with cancer receive anticoagulants in the absence of established VTE to improve survival?

COCHRANE DATABASE SYSTEMATIC REVIEW JULY 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)

ASCO RECOMMENDATION #5 Should patients with cancer receive

anticoagulants in the absence of established VTE to improve survival?

Recommendations:1) NO2) Pts should be encouraged to

participate in trials

WHY TREAT? To prevent fatal PE

To prevent recurrence

To prevent post-thrombotic syndrome

TREATING 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

INCIDENCE OF CVC-RELATED 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 ptsA. Lee - J Clin Onc 2006; 24:1404

Clinically Important CVC-related DVT 2 - 4%

Preventing Central Venous Catheter Thrombosis in Cancer (RCTs)

Warfarin 1 mg/day

DVT sympt DVT Study Endpoint No. control warf control warfBern, 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 %

Preventing Central Venous Catheter Thrombosis in Cancer (RCTs)LMWH

DVT Study Endpoint No. control LMWH PMonreal, 1996 venogram Day 90 29 62 % * 6 % 0.002Reichardt, 2002 clinical 425 3.4 % 3.7 % 0.9

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

ApixabanIdraparinuxRivaroxaban

Dabigatran

Questions?