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Cancer-Associated Thrombosis. Professor Mark Levine, MD, MSc McMaster University Juravinski Cancer Centre Hamilton, Ontario, Canada. Guidelines for Treatment. Why do we treat proximal DVT? To improve symptoms To prevent progression and recurrence To prevent pulmonary embolism

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Cancer associated thrombosis

Cancer-Associated Thrombosis

Professor Mark Levine, MD, MSc

McMaster University

Juravinski Cancer Centre

Hamilton, Ontario, Canada

Guidelines for Treatment


Why do we treat proximal DVT?

  • To improve symptoms

  • To prevent progression and recurrence

  • To prevent pulmonary embolism

  • To prevent post-phlebitic syndrome


Why do we treat pulmonary embolism?

  • To improve symptoms

  • To prevent pulmonary hypertension

  • To prevent death


Adapted from barritt and jordan lancet 1960
Adapted from Barritt and Jordan Lancet 1960.

  • Patients with pulmonary embolism diagnosed clinically.

  • Randomized to heparin 10,000 units Q6H x 6 doses plus concurrent nicoumalone for 14 days (target PT 2-3x control) or no treatment.


Adapted from barritt and jordan lancet 19601
Adapted from Barritt and Jordan Lancet 1960.

  • In the 1st 35 patients, 0 of 16 anticoagulant patients died compared to 5 of 19 control patients, P=0.036 and 5 additional control patients had recurrent PE based on clinical diagnosis.

  • 3 minor bleeds on anticoagulant therapy.

  • Randomization was discontinued and then 38 additional patients were treated with anticoagulants with no adverse outcomes.


Initial therapy unfractionated or low molecular weight heparin

Initial Therapy: Unfractionated or Low Molecular Weight Heparin?


Depolymerisation of ufh
Depolymerisation of UFH

UFH

Molecular weight =

16,000 Da

DEPOLYMERISATION

LMWH

Molecular weight =

4,500-5,000 Da

High affinity for AT III


Advantages of lmwh over ufh

Binds less avidly to plasma proteins, platelets, and cells

Dose-independentrenal clearance

Good bioavailabilityafter sc injection

Experimentally less bleeding

Once-daily sc injection

Weight-adjusted dosing

No laboratory monitoring

Less HIT

Outpatient therapy

Advantages of LMWH over UFH

HIT = heparin-induced thrombocytopenia; sc = subcutaneous


Initial treatment of vte lmwh vs ufh
Initial treatment of VTE LMWH vs UFH

Major bleeding(n=3,674)

Recurrent thromboembolism(n=3,566)

Primary studies

Duroux (1991)

Hull (1992)

Prandoni (1992)

Lopaciuk (1992)

Simonneau (1993)

Lindmarker (1994)

Levine (1996)

Koopman (1996)

Fiessinger (1996)

Luomanmaki (1996)

Columbus (1997)

All studies (FEM)

OR 0.57 (P=0.047)

OR 0.85 (P=0.28)

OR 0.87 (P=0.40)

OR 0.71 (P=0.25)

All studies (REM)

100

0.01

0.1

1

10

0.01

0.1

1

10

100

FavoursLMWH

Oddsratio

FavoursUFH

FavoursLMWH

Oddsratio

FavoursUFH

Adapted from Gould et al., Ann Intern Med 1999;130:800-9.


Initial treatment of vte outpatient lmwh vs inpatient ufh
Initial treatment of VTEOutpatient LMWH vs inpatient UFH

Adapted from: 1. Levine et al., N Engl J Med 1996;334:677-81. 2. The Columbus Investigators.

N Engl J Med 1997;337:657-62. 3. Koopman et al., N Engl J Med 1996;334:682-87.


Initial treatment of vte outpatient lmwh vs inpatient ufh cont d
Initial treatment of VTE Outpatient LMWH vs inpatient UFH (cont’d)

† Significantly fewer hospital days in LMWH group.

Adapted from 1. Levine et al., N Engl J Med 1996;334:677-81. 2. The Columbus Investigators.

N Engl J Med 1997;337:657-62. 3. Koopman et al. N Engl J Med 1996;334:682-87.


Cumulative incidence of recurrent vte during anticoagulant therapy

30

Hazard ratio 3.2

20

Cancer

Cumulative proportionrecurrent thromboembolism (%)

10

No cancer

0

0

181

661

1

160

631

2

3

129

602

4

5

6

92

161

7

8

9

73

120

10

11

12

64

115

Time (months)

Cancer

No cancer

Cumulative Incidence of Recurrent VTE During Anticoagulant Therapy

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


Cumulative incidence of clinically important bleeding during anticoagulant therapy

30

Hazard ratio 2.2

20

Cumulative proportionmajor bleeding (%)

Cancer

10

No cancer

0

0

181

661

1

170

636

2

3

141

615

4

5

6

102

170

7

8

9

81

127

10

11

12

68

124

Time (months)

Cancer

No cancer

Cumulative Incidence of Clinically Important Bleeding During Anticoagulant Therapy

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


Oral anticoagulant therapy in cancer patients
Oral Anticoagulant Therapy in Cancer Patients

  • Warfarin therapy is complicated:

    • difficult to maintain tight therapeutic control(anorexia, vomiting, drug interactions).

    • frequent interruptions for thrombocytopenia and procedures.

    • venous access difficult.

    • increased risk of recurrence and bleeding.


Long term anticoagulant therapy with lmwh
Long-term Anticoagulant Therapy with LMWH

  • Does not require laboratory monitoring

  • Once- or twice-daily subcutaneous injection

  • Effective in warfarin resistance

  • Potentially less bleeding


Canthanox trial
CANTHANOX Trial

  • Cancer patients with proximal DVT and/ or PE received initial enoxaparin 1.5 mg/kg subcu daily for at least four days.

  • Randomized to continue enoxaparin at same dose or warfarin.

  • Duration of therapy was three months.

Adapted from Meyer et al., Arch Intern Med 2002;162,1729.


Canthanox
CANTHANOX

P=0.09

5 bleeds in LMWH and 12 in Warfarin


Clot trial

Dalteparin

Dalteparin

Cancer patients with

acute DVT and/or PE

R

Dalteparin

CLOT Trial

Oral anticoagulant

DVT, deep vein thrombosis; PE, pulmonary embolism.

Adapted from Lee et al., NEJM 2003;349:146-53.


Adapted from lee et al clot trial 2003

CLOT Trial

Adapted from Lee et al. CLOT Trial 2003

Group Initial treatment Long-term therapy (5–7 days) (6 months)

OAC Dalteparin 200 IU/kg Warfarin or acenocoumarol sc once daily (target INR 2.5)

LMWH Dalteparin 200 IU/kg Month 1: dalteparin 200 IU/kg sc once daily Month 2–6: 75–80% of full dose

OAC, oral anticoagulant.


Baseline characteristics
Baseline Characteristics

LMWH OAC N = 338 N = 338

Female gender 179 169

Age, mean (years) 62 63

Outpatient 169 156

Qualifying VTE

DVT only 235 230

PE ± DVT 103 108

ECOG score

0 80 63

1 135 150

2 118 122


Baseline characteristics1
Baseline Characteristics

LMWH OAC N = 338 N = 338

Extent of solid tumour 298 308

no evidence 36 33

localised 39 43

metastatic 223 232

Haematological malignancy 40 30

Cancer treatment 266 259

Central venous catheter 46 40

Previous VTE 39 36


Recurrent vte

Risk reduction = 52%P=0.0017

25

20

OAC

15

Probability of recurrent VTE (%)

Dalteparin

10

5

0

0

30

60

90

120

150

180

210

Days post-randomization

Recurrent VTE

Adapted from Lee et al., NEJM 2003;349:146-53.


Bleeding events
Bleeding Events

LMWH OAC P* N = 336 N = 336

Major bleed 19 (5.6%) 12 (3.6%) 0.27

Any bleed 46 (13.6%) 62 (18.5%) 0.093

* Fisher’s exact test


Treatment of vte long term
Treatment of VTE: Long-term

  • Long-term LMWH “simplifies” treatment.

  • In the CLOT trial each patient who received oral anticoagulants had on average 23 INRs performed (maximum 83).


American society of clinical oncology guidelines treatment of vte

What is the best treatment for patients with cancer with established VTE to prevent recurrent VTE

LMWH is the preferred choice for the initial treatment.

LMWH given for at least six months is preferred for long term.

Vitamin K antagonist INR (2-3) when LMWH not available.

American Society of Clinical Oncology Guidelines: Treatment of VTE

Adapted from JCO 2007;25,5490-505.


Treatment asco

What is the best treatment for patients with cancer with established VTE to prevent recurrent VTE.

After six months, indefinite anticoagulant therapy for selected patients with active cancer e.g. metastases.

IVC Filter only in patients with contraindications to anticoagulant therapy and in those with recurrent VTE despite LMWH therapy.

Treatment: ASCO

Adapted from JCO 2007;25,5490-505.


Treatment asco 2007

What is the best treatment for patients with cancer with established VTE to prevent recurrent VTE.

For CNS malignancy, same therapy as for other cancers. However avoid anticoagulants if active intracranial bleeding, low platelets, etc.

For elderly patient with cancer and VTE same approach as for other age groups.

Treatment: ASCO 2007

Adapted from JCO 2007;25,5490-505.


Esmo guidelines
ESMO Guidelines established VTE to prevent recurrent VTE.

Initial Therapy

Adapted from Ann Oncol 2008.


Esmo guidelines1
ESMO Guidelines established VTE to prevent recurrent VTE.

Long Term

Adapted from Ann Oncol 2008.


Consensus statement international union of angiology and union internationale de phlebologie
Consensus Statement: International Union of established VTE to prevent recurrent VTE.Angiology and Union Internationale de Phlebologie

Adapted from Int Angiol 2006;25,101-61.


So where are we in 2008

So Where are We in 2008? established VTE to prevent recurrent VTE.

Has there been much research progress since 2003 in terms of treatment of VTE in Cancer?


Recurrent vte1

Risk reduction = 52% established VTE to prevent recurrent VTE.P = 0.0017

25

20

OAC

15

Probability of recurrent VTE (%)

Dalteparin

10

5

0

0

30

60

90

120

150

180

210

Days post-randomization

Recurrent VTE

Adapted from Lee et al., NEJM 2003;349:146-53.


Progress in Treatment? established VTE to prevent recurrent VTE.

  • Can we do better than 8% recurrence at six months?

  • Has long term LMWH been adopted?

  • What is the duration of long term treatment?

  • How should a patient who develops recurrent VTE on LMWH be treated?


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