Thromboprophylaxis For The Lung Cancer PatientProf. Dr. Nil Molinas Mandel

Istanbul University

Cerrahpaşa Medical Faculty

Medical Oncology

Cancer and Thromboembolism

Armand Trousseau (1801-1867)

In cancer patients migrant thromboembolic events are

common.It was first recognized by Armand

Trousseau in 1865 as ‘’Phlegmacia alba dolens’’.

Dr. Trousseau died because of gastric cancer in 1867.

Thromboembolism in Lung Cancer

• The incidence of DVT in lung cancer is about 10-15%

• In the patients who developed DVT previously;– The possibility of recurrent DVT increases– The risk of death caused by acute thrombosis

increases 4-6 times.– The aspect of survival shortens as compared

to the cancer patients without DVT.

Concurrent VTE and cancer increases the risk of death

Probability of death within 183 days of initial hospital admission

Pro

bab

ilit

y o

f d

eath

1.00

0.80

0.60

0.40

0.20

0.00 0 40 80 120 180Number of days

Malignant disease alone

DVT/PE and malignant disease

Levitan et al. Medicine 1999; 78(5): 285-291

 

 

 

 

Effect of ‘’cancer and VTE’’on survival

201510500

10

20

30

40

50

60

70

80

90

100

Su

rviv

al (

% o

f p

atie

nts

)

Cancer at the time of VTE

Cancer without VTE

YearsSorensen et al. 2000Sorensen et al. NEJM 2000;343:1846-50

Patients with cancer assosiation

• 24% have pancreatic cancer

• 20% have lung cancer

• 13% have prostate cancer

• 12% have gastric cancer

• 5% have colon cancer

• Patients with stage IV disease are more likely to be hypercoagulable and develop clinically relevant thrombosis

Winoker S, NOCR Proceedings, 20000

Risk factors for VTE in cancer

Patient related•Increasing age•Obesity•Immobility•Inhereted thrombophilic abnormalities

Cancer related•Histological type•Stage•Anatomic location

Treatment related•Surgical intervention•Type of chemotherapy or biologic treatment•Central venous access devices

Under use of Prophylaxis

• 66 % of patients at risk DID NOT receive prophylaxis

• 60 % of patients at very high risk with multiple risk factors DID NOT receive prophylaxis

Geerts WH, et al. Chest 119; 132S, 2001Anderson FA, et al. Ann Intern Med 115; 591, 1991Bratzler DW, et al. Arch Intern Med 158; 1909, 1998Keene MG, et al. Chest 1994; 106: 13

Thromboprophylaxis for the lung cancer patients

• Primary prophylaxis

• Secondary prophylaxis

( recurrent VTE )

Common strategies considered for prophylaxis: do they work ?

• Ambulation

• Mechanical devices

• Unfractionated heparin

• Low molecular weight heparin

• Warfarin

aPTT measures anti-factor IIa activityanti-factor Xa assay measures anti-factor Xa activity

Heparin

LMWH

aPTT measures anti-factor IIa activityanti-factor Xa assay measures anti-factor Xa activity

Bioavailability (%)Plasma half-lifeEffect on plateletsEffect on haemostasisOsteoporosisThrombocytopenia

UFH

25–30Short

++++++++

LMWH

90–95Long+/–+/–+/–+

Advantages of LMWH over UFH

Weitz JI, N Engl J Med 1997;337:688-98; Hirsh J et al, Chest 1998;114:489S-510S

When to start?Which dosage?Optimal duration?

Prophylaxis for Cancer Surgery

Nu

mb

er

of p

atie

nts

with

fata

l PE

P<0.005

Prophylaxis against Fatal Post-operative PE with Low-dose UFH

16

2

02468

1012141618

Control UFH

Kakkar VV et al. Lancet 1975; 2:45–51

Overall mortality Fatal pulmonaryembolism

Thromboembolicmortality *

Nadroparin 0.3 ml

Placebo

Nadroparin 0.3 mL shown to reduce mortality in general surgery

0.36%(8/2247)

0.80%(18/2251)

0.09%(2/2247)

0.18%(4/2251)E

ven

ts (

%)

No fatal bleeding but postoperative bleeding less frequent (p<0.01) in the placebo group

0

1

0.50.09%

(2/2247)

0.36%(8/2251)

p<0.05

p<0.05

1/3 of patients in this trial were cancer patients

NS

Pezzuoli G et al. Int Surg 1989;74:205–10.

Clinical thromboembolism Cancer

0 1.0 2.0 3.0 4.0

Major hemorrhage

Asymptomatic DVT

Clinical PE

Death

Total hemorrhage

Wound hematoma

Transfusion

Non-cancer

Mismetti P et al. Br J Surg 2001;88:913–30.

Surgical Prophylaxis

LMWH better UFH better

7th ACCP Consensus Guidelines

Grade Recommendation for Cancer Patients

1APatients undergoing surgery should receive LDUH 5000 U tid or LMWH high risk dose once daily

2APatients undergoing surgery may receive post-hospital discharge prophylaxis with LMWH

Medical Patients

1APatients hospitalised with an acute medical illness should receive LDUH or LMWH

Geerts W, et al. Chest 2004; 126: 338S-400S.

Thromboprophylaxis for patients undergoing cancer surgery

• Give LDUH or LMWH 2 hours before surgery.• Optimal duration of thromboprophylaxis remains

the subject of debate. 7-10 days? 7-8 weeks?• The risk of spinal hematoma with neuroaxial

anesthesia may be acceptable.• When pharmacologic prophylaxis is used in

conjunction with mechanical prophylaxis the efficacy appears to increase.

Leonardii Mj, Ann Surg Oncol 2006Berqvist D, J Surg Oncol, 2007

Catheter-Related Thrombosis

• Low dose warfarin and LMWH prophylaxis have fared to show any reduction in symptomatic catheter-related thrombosis.

• Low dose warfarin is associated with an increase in bleeding.

• The risk of symptomatic catheter-related thrombosis in adults is low (about 5 %)

• Optimal prevention of CRT remains unclear.

Cu

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(%

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ent

thro

mb

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bo

lism

30

20

10

0

Hazard ratio 3.2

Cancer

No cancer

0181661

1160631

2 3129602

4 5 692

161

7 8 973

120

10 11 1264

115

Time (months)CancerNo cancer

Prandoni et al. Blood 2002;100:3484-8.

Recurrent VTE during anticoagulant therapy is increased in patients with cancer

Cu

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ve p

rop

ort

ion

(%

)m

ajo

r b

leed

ing

30

20

10

0

Hazard ratio 2.2

Cancer

No cancer

Time (months)CancerNo cancer

0181661

1170636

2 3141615

4 5 6102170

7 8 981

127

10 11 1268

124

Prandoni et al. Blood 2002;100:3484-8.

Bleeding during anticoagulant therapy is increased in patients with cancer

R

Which Anticoagulant?CLOT study design

Solid tumour malignancy and acute VTE

All patients received dalteparin 200 IU/kg od 5-7 days

Dalteparin1 month 200 IU/kg od 5 months 160 IU/kg od

Oral anticoagulant6 months

Lee et al. N Engl J Med 2003

CLOT study population

Inclusion criteria

– Objectively documented, symptomatic proximal DVT and/or PE

– Active cancer

• Cancer diagnosis within past 6 months

• Recurrent or metastatic malignancy

• Received cancer treatment within past 6 months

• 16 years or olderLee et al. N Engl J Med 2003

Days post-randomization

0

5

10

15

20

25

0 30 60 90 120 150 180 210

Pro

bab

ility

of

rec

urr

en

t V

TE

(%

)

Risk reduction = 52%

p=0.0017

Dalteparin

OAC

CLOT: dalteparin was more effective and as safe as OAC in long-term treatment of VTE

Lee et al. N Engl J Med 2003

7th ACCP Consensus Guidelines

Grade Recommendation for Cancer Patients

1AFor most patients with DVT and cancer, we recommend treatment with LMWH for at least the first 3 – 6 months of long-term treatment.

Buller et al. Chest 2004; 126: 401S-428S.

DVT Prophylaxis

• Physical methods:– Intermittent Pneumatic Leg Compression

(Venodynes)– Early ambulation– Compression stockings

• Pharmacological methods– Unfractionated heparin– LMWH– Warfarin

Prophylaxis Recommendations

Category Recommendation

Moderate RiskGeneral Abd, Thoracic, gyn, uro surg; medical pts

IPC, +/- heparin/LMWH based on other RF

Moderate to High RiskNeurosurgery IPC

High RiskHip/knee replacement IPC, LMWH, +/- warfarin

Hip fracture IPC, LMWH, warfarin

Spinal cord injury w/ paralysis LMWH, IPC

Long Term Anticoagulation

• 3-6 months:– First episode with

reversible or time limited RF (i.e. bed rest) –

• >= 6 months– Idiopathic first episode

• 12 months– First recurrent DVT

• Lifetime– First event with

• Cancer, until resolved• Anticardiolipin Ab• ATIII deficiency

– 2 or more recurrent DVTs

Conclusion

• Most pts who die from PE, die within 2 hours of onset, prior to implementation of treatment– THUS PREVENTION IS KEY