Cancer and Thrombosis:Cancer and Thrombosis:Prevention and Treatment of VTE in

Cancer Patients

Development Committee:

Christine Cripps, MD, FRCCP

Kelly Savage, RN

Bonnie Kuehl, PhD

Cancer and Thrombosis

Tumour infiltration into vessels Vessel obstruction Immobility Central venous catheters Post-surgery Medications (tamoxifen, thalidomide) Chemotherapy

Why do patients with cancer get blood clots?

Why should we care?

CVC: central venous catheter | DVT: deep vein thrombosis | PE: pulmonary embolismHeit JA,et al. Arch Intern Med. 2002;162:1245-1248.

Cancer patients represent about 18% of all DVT and PE cases

Why should we care?

Khorana AA, et al. Cancer 2007.

The Increasing Frequency of VTE

The incidence of VTE increases with cancer therapy

Why should we care?

• 47-fold increased risk of mortality from VTE • 2nd leading cause of death in cancer patients

• VTE associated with early mortality during chemotherapy (HR=6.98)

Cancer progression 71%

Unknown 4%Other 6%

Thromboembolism9%

Infection 9%

RespiratoryFailure 4%

Bleeding 1%

Aspiration 1%

Khorana AA. Thromb Res. 2010;125(6):490-3.

Causes of Death in Patients with Cancer

VTE in Cancer Patients: Greater risk, Significant Burden

• Among patients with malignancy, VTE is one of the leading causes of mortality

• Cancer increases VTE risk several-fold; inpatients and those receiving active therapy are at greatest risk

• Incidence of VTE ranges from 4-20%; cancer patients have a 3-fold increased risk for recurrence over non-cancer patients

• Clinical rates may underrepresent burden; at autopsy, VTE rates in cancer patients as high as 50%

• VTE 2nd most common cause of death in ambulatory cancer patients (tied with infection)

Agnelli & Verso, J Thromb Haemost 2011; 9 Suppl1: 316-324; Heit et al Arch Int Med 2000;160:809-815 and 2002;162:1245-1248; Prandoni et al Blood 2002;100:3484-3488; White et al Thromb Haemost 2003;90:446-455; Sorensen et al New Engl J Med 2000;343:1846-1850); Levitan et al Medicine 1999;78:285-291; Khorana et al J Thromb Haemost 2007;5:632-4; Lyman GH, et al. ASCO Update. J Clin Oncol. 2013; accessed online ahead of Print.

Cancer VTE

Cancer increases VTE risk several-fold; Greatest risk during first 3-6 months

1. Alcalay A, et al. J Clin Oncol. 2006;24:1112-1118.2. Chew HK, et al. J Clin Oncol. 2007;25:70-76.

Colorectal CancerN=68 1421

Breast CancerN=108 2552

Incid

en

ce o

f V

TE (

%)

8%

6%

4%

2%

0%

50 100 150 200 250 300 350 400In

cid

en

ce o

f V

TE (

%)

0%

1%

2%

3%

4%

5%

6%

7%

Days after Cancer Diagnosis Days after Cancer Diagnosis

100 200 300 400 500 600 700 800

Effect of VTE on Long-Term Prognosis is Signficant

Levitan N, et al. Medicine 1999;78:285-291.Sorensen HT, et al. N Engl J Med. 2000; 343:1846-50..

100%

CancerDVT/PE

No Cancer+ No DVT/PE

Cancer at time of VTE 12%

Cancer without VTE 36%

1-year survival

Pro

babili

ty o

f D

eath

(%

)

Pro

babili

ty o

f Surv

ival

(%)

80%

60%

40%

20%

0%0 40 120

Number of Days after Admission

Years after Diagnosis

P<0.001P=0.001

18080

DVT/PE + Cancer

Recurrence Rate of DVT/PE is Higher in Cancer Patients

Prandoni P, et al. Blood 2002;100:3484-3488.

Cum

ula

tive P

roport

ion

of

Recu

rrent

DV

T/P

E (

%)

25%

20%

15%

10%

5%

0%0 1 2 3 4 5 6 7 8 9 10 11 12

N=82, Prospective follow-up study

Cancer

No Cancer

20.7%

HR 3.2%

Months

6.8%

How does cancer lead to blood clots?

Shelke AR, Khorana AA. Drug Discovery Today: Disease Mechanisms. 2011;8:e39-e45.

Incidental and symptomatic VTE are both associated with worsened 3-month

mortality in pancreatic cancer

0 200 400 600 800 1000 1200

100%

75%

50%

25%

0%

Menapace LA, et al. Thromb Haemost. 2011;106:371-8.

No prior event

≥ 1 Asymptomatic VTE (but no symptomatic events)

≥ 1 Symptomatic VTE (DVT/PE/ VVT)

VTE Prevention/ Prophylaxis is Low

ENDORSE study Findings• Multinational cross-sectional survey in 358 acute care

hospitals across 32 countries

• 68 183 adult screened charts (medical & surgical)

51.8% of all medical and surgical patients are at risk of VTE

VTE prophylaxis is underused 58.5% of surgical patients received it

39.5% of medical patients received it

37% of medical patients with active malignancy received VTE prophylaxis

Cohen AT, et al. Lancet. 2008;371:387-94.

ENDORSE (Epidemiologic International Day for the Evaluation of Patients at Risk for Venous Thromboembolism in the Acute Hospital Care Setting)

Multiple Myeloma & VTE

16%Lenalidomide/dex

3%Dexamethasone

10-20%Thal/dex

3%Thalidomide

17% vs. 2%MPT vs. MP

10-58%Thal/anthracyclines

12% vs. 4% vs. 8%MPT vs. MP vs. iv Melphalan

5-10%Background incidence in MM

Zonder JA. Hematology. (Am Soc Hematol Educ Program) 2006:348–355Rodeghiero F, Elice F. Thromb Res. 2012;129:360-6.Niesvizky R, et al. Blood. 2008;111:1101-9.

23%Lenalidomide/dex + ESA

Incidence of Thromboembolic Events

VTE Treatment in Cancer Patients - GAP

Recovery Study• Canadian outpatient prospective study, 12 Canadian

centres• 868 outpatients with acute symptomatic VTE

• ~60% of patients with cancer received LMWH monotherapy for > 3 months

Kahn SR, et al. Thromb Haemost. 2012;108:493-8.

Can we predict VTE risk in our cancer patients?

Can we identify which patients may benefit most from

prophylaxis?

Risk Factors for Cancer-Associated VTE

Patient-related factors•Increased age•Ethnicity (risk increased in African Americans)•Co-morbidities (infection, renal and pulmonary disease, arterial thromboembolism, VTE history, inherited prothrombotic mutations)•Obesity•Performance status

Treatment-related factors•Chemotherapy, antiangiogenesis agents, hormonal therapy•Radiation therapy•Surgery ≥60 mins•ESAs, transfusions•Indwelling venous access

Cancer-related factors•Primary site of cancer•Stage (risk increases with higher stage)•Histology•Time since diagnosis (risk increases during first 3-6 months)

Biomarkers•Platelet count ≥ 350 x 109/L•Leukocyte count >11 x 109/L •Hemoglobin < 100g/L

Lyman GH, et al. ASCO Update. J Clin Oncol. 2013; accessed online ahead of Print.

% P

ati

ents

P>0.0001 for allComparisons vs. controls

Lung Colorectal

Bladder Ovarian Pancreatic Stomach Control0

10.6

8.2

11

19.2

15.8

1.4

Rates of VTE by Cancer TypeN=17,284

Khorana AA et al, ISTH 2011

5

10

15

20

13.9

VTE Risk Score for Cancer PatientsKhorana Risk Score•Simple, validated score to identify patients at highest risk of VTE

•Developed using prospective observational study of 2 700 ambulatory cancer patients receiving at least 4 cycles of chemotherapy

•Validated in >10 000 patients in multiple countries

Patient Characteristic Score

Site of CancerVery high risk (stomach, pancreas)

High risk (lung, lymphoma, gynecologic, GU excluding prostate)

2

1

Platelet Count ≥ 350 x 109/L

1

Hb <100 g/L or use of ESA 1

Leukocyte count >11 x 109/L

1

BMI ≥ 35 kg/m2 1

Total

Khorana AA, et al. Blood. 2008;111:4902-7.

RISK OF VTE:•Score 0 = 0.5%•Score 1 – 2 = 2%•Score ≥ 3 = 7%

Rates of VTE according to scores from the risk model in the derivation

and validation cohorts.

©2008 by American Society of Hematology

Khorana AA, et al. Blood. 2008;111:4902-7.

VTE Prevention can make a difference!

Placebo Enoxaparin Placebo Dalteparin Placebo Fondaparinux

Francis CW. N Engl J Med. 2007:356;1438-1444.

Prophylaxis in Hospitalized Medical Patients: Risk Reduction

0

5

10

15

20

PREVENT ARTEMIS

14.9

5.5 5.0

10.5

2.8

5.6

RR 63%

RR 44%

RR 47%

Rate

of

VTE

(%)

MEDENOX

RR: Relative Risk Reduction

Prophylaxis in Out-Patients: Risk Reduction

Rates of VTE in the various arms of four recent RCTs of prophylaxis including: PROTECHT (various locally advanced or metastatic solid tumors), GIMEMA (myeloma only), CONKO-004 and FRAGEM (both pancreatic cancers only). The control arm in PROTECHT was placebo and in CONKO and FRAGEM was observation.

Adapted from Menapace LA, Khorana AA. Curr Opin Hematol. 2010;17: 450–456.

All trials found a benefit from thromboprophylaxis with a significant decrease in VTE incidence with no increase in major bleeding

Risk Score Validation– Putting it all to the test

SAVE ONCO applying the risk scoreRisk Score % with Risk Score

0 19%

1-2 63%

≥3 17.4%

No. of risk factors

Semuloparin(N=1608)

PlaceboN=1604

Hazard Ratio(95% CI)

0 9/923 (1.0%) 23/932 (2.5%) 0.39 (0.18-0.84)

1-2 9/652 (1.4%) 27/632 (4.3%) 0.32 (0.15-0.68)

≥3 2/33 (6.1%) 5/40 (12.5%) 0.56 (0.11-2.93)

Agnelli G, SAVE-ONCO Investigators, et al. N Engl J Med. 2012;366:601-9.

Risk reduction with VTE thromboprophylaxis

Prophylaxis in Cancer Out-Patients

• No difference in major bleeding observed between groups.

Agnelli G, SAVE-ONCO Investigators, et al. N Engl J Med. 2012;366:601-9.

VTE occured in 1.2% receiving semuloparin vs. 3.4% receiving placebo (HR 0.36; 95% CI, 0.21 to 0.60; P<0.001).

Thromboprophylaxis in Cancer Patients Reduces Incidence of VTE

• Primary thromboprophylaxis with LMWH significantly reduced the incidence of symptomatic VTE in ambulatory cancer patients treated with chemotherapy

Di Nisio M, et al., Cochrane Database Syst Rev. 2012 Feb 15;2:CD008500.

Outcomes

Illustrative comparative risk (95% CI)

Relative effect (95% CI)No. of participants

(studies)Assumed riskCorresponding

risk

Placebo or no anticoagulant

LMWH

Symptomatic VTE

44 per 1000 27 per 1000 RR 0.62 [0.41, 0.93] 2464 (6)

Major bleeding

11 per 1000 18 per 1000 RR 1.57 [0.69, 3.60] 2394 (5)

Symptomatic PE

8 per 1000 5 per 1000 RR 0.63 [0.21, 1.91] 1710 (3)

1-year mortality

503 per 1000 523 per 1000 RR 1.04 [0.92, 1.16] 1848 (4)

Current Thromboprophylaxis Guidelines for Cancer Patients

Inpatient Thromboprophylaxis Guidelines

• Risk of VTE is 7 times higher in hospitalized cancer patients1

ASCO 2013/NCCN 2012 – Anticoagulate all hospitalized patients without bleeding risk

ESMO 2011– Anticoagulate all bedridden patients with acute medical

complication

ACCP 2012– Anticoagulate all hospitalized patients at high risk for

thrombosis without bleeding risk1. Heit JA, Archives Intern Med. 2000; 860:809.; ASCO 2013; NCCN2.2013; AACP 2012; ESMO 2011

Contraindications to Thromboprophylaxis

Cancer Increases Risk of Clotting as well as Risk of Bleeding

ACCP 2012 reports multinational study of 10,866 medical inpatients with overall risk (OR) factors for bleeding

Risk Factors for Bleeding Overall Risk (OR)

Active gastroduodenal ulcer

Bleeding in 3 mo pre admission

Platelet count < 50

Age 85 y (vs. 40 y)

Hepatic failure (INR 1.5)

Renal failure (eGFR <30 mL/min)

ICU/CCU admission

Central venous catheter

Rheumatic disease

Current cancer

Male sex

4.15

3.64

3.37

2.96

2.18

2.14

2.10

1.85

1.78

1.78

1.48

Outpatient Thromboprophylaxis Guidelines

• Outpatient definition is not consistent • Risk of VTE remains high even when ambulatory

• ASCO 2013/ESMO 2011– No evidence to support routine prophylaxis in ambulatory cancer

patients excluding patient receiving lenalidomide/thalidomide & chemo/dexamethasone

– Clinicians may consider LMWH prophylaxis on a case-by-case basis in highly selected outpatients with solid tumors receiving chemotherapy.

• ESMO 2011– Consider prophylaxis in high risk ambulatory cancer patients (not

defined)

ASCO 2013; NCCN2.2013; AACP 2012; ESMO 2011

Outpatient Thromboprophylaxis Guidelines

ACCP 2012• No routine anticoagulation UNLESS

i. Solid tumor *ii. Presence of risk factors including: previous VTE, hormone

therapy*, immobilization, angiogenesis inhibitors, lenalidomide, thalidomide

If above then LMWH or unfractionated heparin

NCCN 2012• Thalidomide/lenalidomide patients, otherwise no routine

prophylaxis outside of clinical setting• Utilizing Khorana predictive risk model: patients with high

risk (>3) COULD BE considered for prophylaxis on an individual basis evaluating risk/benefit ratio

ASCO 2013; NCCN2.2013; AACP 2012; ESMO 2011

Current Antithrombotic Treatment Guidelines

for Cancer Patients

Why treat?

• To prevent fatal PE

• To prevent recurrence

• To prevent post-thrombotic syndrome

Cochrane review demonstrated a significant 29% mortality reduction in cancer patients receiving LMWH for initial treatment of VTE vs. those receiving UFH.3

LMWH Provides a Survival Benefit in Cancer Patients1-3

1. Green D, et al. Lancet. 1992;339:1476. 2. Lazo-Langner A. et al. J Thromb Haemost. 2007;5:729-37.3. Akl E, et al. Cochrane Database Syst Rev. 2008;1:CD006649.

Recommended Anticoagulant Treatment & Secondary ProphylaxisASCO 2013/NCCN 2013/ ACCP 2012/ ESMO 2011LMWH:•Preferred over UFH for initial 5-10 days in pts with newly diagnosed VTE•Preferred for at least 6 months as monotherapy due to improved efficacy over warfarin Warfarin:•2.5-5 mg every day initially, subsequent dosing based on INR value; target INR 2-3•Concomitant therapy and frequent INR monitoring required during transition from LMWH to warfarin

Duration of Anticoagulation•Minimum 3-6 mo for DVT and 6-12 mo for PE•Recommend indefinite anticoagulation if active cancer or persistent risk factors

ASCO 2013/ NCCN 2.2013 Update/ ACCP 2012 / ESMO 2011

CLOT Trial: Reduction in Recurrent VTE Dalteparin vs. Warfarin

Lee AYY et al. N Engl J Med. 2003. 349: 146–153.

LMWHN=338

OACN=335

P

Major Bleed 19 (6%) 12 (4%) 0.27

Any Bleed 46 (14%) 62 (19%) 0.093

*P Fishers exact test

Pro

bab

ility

of

Rec

urr

ent

VT

E (

%)

Recurrent VTE (%)

Risk reduction=52%p=.0017

OAC

Dalteparin

0

25

20

15

10

5

0 30 60 90 120 150 180 210Days Post Randomization

LITE Trial: Reduction in Recurrent VTE Tinzaparin vs. Warfarin

Hull RE, et al. Am J Med. 2006;119(12):1062-72.

At 12 months: 7 of 100 patients (7 percent) in the low-molecular-weight heparin group and 16 of 100 patients (16 percent) in the heparin-warfarin group had new episodes of symptomatic venous thromboembulism (p=0.044; risk ratio=0.44; absolute difference, -9.0, 95 percent confidence interval -2.17 to -0.7 percent).

# at risk 100 78 65 56 51 46 44IV Hep/War 100 80 68 65 57 54 47

Cumulative incidence of recurrent venous thromboembolism in the cancer groups

Cum

ulat

ive

inci

denc

e %

0

5

10

15

20

0 100 200 300

IV Heparin/Warfarin

LMWH

Risk of Bleeding on Warfarin in the Cancer Patient

Increased warfarin effect can occur if:• Poor nutrition and low vitamin K intake• Frequent use of antibiotics• Diarrheal disease and toxicity from antacids• Chemotherapy• Liver disease from cancer involvement• Decreased clotting factor synthesis• Poor clearance of activated clotting factors (DIC)• Malabsorption of vitamin K• High fever/infection

Streiff MB, et al. NCCN Clinical Practice Guidelines in Oncology, Venous Thromboembolic Disease. JNCCN 2011; 9: 714-777.

Dosing

• LMWH:– Tinzaparin: 175 units/kg subcutaneous OD– Dalteparin: 200 units/kg subcutaneous daily– Enoxaparin: 1 mg/kg subcutaneous BID- no completed

phase III trials in cancer patients• Unfractionated heparin (IV): 80 units/kg loading dose,

target a PTT of 2-2.5 x control• Fondaparinux: 7.5 mg (50-100 kg) subcutaneous daily

Recommended Anticoagulant Treatment for VTE

Streiff MB, et al. NCCN Clinical Practice Guidelines in Oncology, Venous Thromboembolic Disease. JNCCN 2011; 9: 714-777.

Where do we go from here?

1.Healthcare Professional awareness

2.Patient awareness and education of VTE risk and role of therapy (prevention or treatment)

Survey of 500 adults with cancer within 12 months of Sampling

Patient and Provider Awareness(or Lack Thereof)

Rickles FR, et al. J Clin Oncol. 29: 2011 (suppl; abstr 9101)

Were informed by Doctor or Healthcare Professional about DVT Risk Due to Cancer

27%

44%

14%

All Respondents (n=500) Inpatients (n=206)

Outpatients (n=294)

Why don’t we use LMWH for prophylaxis in the outpatient setting?

• Why give it to everyone when less than 5% will get a clot

– Risk assess to determine patients at highest risk of clot• Cost

– All LMWHs covered by provincial formulary, patient compassionate programs

• Inconvenience to the patient

– Clot far more inconvenient• Bleeding

– Monitor, educate patients about symptoms and procedure (bleeding card)

• Therapy challenges with chemo-induced side effects such as low platelets and increased sCr

– PE management and VTE treatment long-term challenges impacting QoL

GOALS in Treatment and Prevention of VTE in Cancer Patients

• Increase awareness amongst healthcare professionals

• Increase awareness and educate patients about risks and symptoms of VTE

• Identify patients at high risk of VTE – prophylax and educate

• Detect VTE early

1. Appropriate treatment and treatment duration

2. Patient education: adherence and awareness of bleeding symptoms