Pankaj Handa

Department of General Medicine

Tan Tock Seng Hospital

CANCER ASSOCIATED THROMBOSIS

My Talk Today

1.Introduction

2. Are All Cancer Patients at Risk of VTE ?

3. Should All VTE Patients Be Screened For Cancer ?

4. Are there any Biomarkers for VTE in Cancer Patients ?

5. Risk Stratification of VTE in Cancer Patients.

6. CAT at Tan Tock Seng Hospital .

7. Treatment Options/ ACCP Guidelines

TROUSSEAU’S SYNDROME 1865

“Spontaneous venous thromboembolism in association

with clinically occult malignant disease”

“when you are undecided about

the nature of the disease of the

stomach, when you hesitate

among chronic gastritis, simple

ulcer, and a carcinoma, a

phlegmatia alba dolens

occuring in the leg or arm will

enable you to assert positively

that a cancer is present”

-Armand Trousseau 1865 lecture in Paris

Introduction

Thrombosis – Cancer : A Double-Edged Sword.

Malignancy increases the risk of VTE by a factor of 7

15-20% cancer patients may develop with VTE

Development of VTE in a patient with known cancer is

the most common presentation, but VTE may precede

the diagnosis of malignancy by many months.

Introduction

Critical oncogenic events

Activation of the coagulation cascade

Prothrombotic environment

VTE Growth and Progression of

the Malignancy

Introduction

CAT is the 2nd leading cause of death in cancer patients

1-year survival

With VTE : Without VTE (12% vs. 36%)

In- hospital Mortailty

Double in the patients who develop VTE in hospital

Significant proportion of cancer patients with VTE have

limited cancer disease that in the absence of fatal PE

would have been associated with considerably longer

survival

Introduction

Cancer patients are also prone to adverse effects and failure of anticoagulant therapy.

Annual risk : recurrent VTE is 21%–27%

major bleeding is 12%–13%

On warfarin : 2 to 6 times more major bleeding episodes 2 to 3 times more VTE recurrences.

2. Are All Cancer Patients At Risk of VTE ?

Risk Factors for VTE in Cancer Patients

Risk Factors for VTE in Cancer Patients

Metastatic disease at the time of diagnosis is the strongest predictor of thromboembolism (1.4–21.5 fold higher risk of VTE than patients with localised disease)

VTE : chemotherapy three times radiotherapy two times distant metastases six times

Annual VTE Risk in Cancer Patient

(Solid Tumours)

Type of Cancer Localised Metastatic

Pancreas 4.2% 20%

Stomach 2.5% 10.7%

Uterus 0.8% 6.4%

Kidney 1.2% 6%

Lung 1.1% 5%

VTE and Type of Malignancy

Type Adjusted Odds Ratio

(95%CI)

Haematological 28 (4-199.7)

Lung 22.2 (3.6-136.1)

Gastrointestinal 20-3 (4.9-83)

Risk of VTE in Acutely ILL Ca Patients

In hospitalised medical patients with acute illness, cancer is independently associated with a 1.6-fold increase in the risk of VTE

In-hospital mortality rate is significantly greater

- VTE vs No VTE (OR 2.01; 95% CI 1.83–2.22)

- localised cancer as well as advanced disease

International guidelines recommend the use of prophylaxis with UFH or LMWH for patients with active cancer who are confined to bed in hospital

3. Should We Screen All VTE Patients for

Cancer ?

Screening for Occult Malignancy

The most appropriate strategy in patients with

unprovoked VTE is a thorough history and physical

examination, followed by patient-specific laboratory

testing and imaging.

Routine screening for cancer using extensive

investigations in these patients does not appear to

provide a survival advantage

4. Are There Any Biomarkers For Diagnosis

of VTE in Cancer Patients ?

Candidate Biomarkers

Blood Counts:

- Platelet count

- Leukocyte count

- Haemoglobin

Tissue Factor

Soluble P - selectin

D - dimer

C – reactive protein

Candidate Biomarkers

Tissue Factor

- physiologic initiator of the coagulation cascade,

but it appears to play multiple roles in cancer

pathogenesis and may be important for

angiogenesis in tumors as well.

- high levels have been identified in blood of

patients to be associated with the risk for VTE

Two-Way Biological Relationship

Activation of coagulation

Growth and Metastatic potential of

tumor cells

inhibition of the clotting cascade activation or

thrombin activity may have antineoplastic effects

(LMWH)

5.

Risk Stratification of VTE in Cancer Patients

6.

Cancer Associated Thrombosis At

Tan Tock Seng Hospital

CAT at Tan Tock Seng Hospital

Total 93

Age 68.9 years

Sex Male(47.31%) Female(52.68%)

Race Chinese (79.56 %)

Malay (13.97 %)

Indian (06.45 %)

Retrospective 5 year study (Jan 2006-December 2010)

Patients discharged with diagnosis of Cancer and

Thrombosis

VTE Association with Type of Cancer

Lung

Haematological Colon

Pancreas Stomach Breast Gall Bladder

0

5

10

15

20

25

VTE : Prevalence

DVT

67%

BOTH

16%

PE

17%

DVT

PE

BOTH

0

5

10

15

20

25

30

35

40

Proximal Distal Both UL DVT Others No DVT

40%

10% 11%

8%

14%

17%

Pe

rce

nta

ge

VTE - Deep Vein Thrombosis

Onset of VTE

0

5

10

15

20

25

30

35

Only VKA Only LMWH Only IVC VKA + LMWH VKA + IVC LMWH + IVC Nil

1

26

14 16

3

9

31

Axis

Tit

le

Axis Title

Treatment

7.

Treatment Options for VTE in Cancer

Patients

Treatment of VTE in Patients with Cancer

(A) Initial Treatment

LMWHs have become preferred mode of treatment for

the initial treatment of VTE in cancer

Hettiarachchi RJ, Curr Opin Pul Med, 1998

- A meta-analysis of studies: UFH vs LMWH.

LMWH : at least as safe and effective as UFH

: reduced mortality risk in these patients.

Treatment of VTE in Patients with Cancer

(B) Long-Term Treatment

Difficulties with (OAC) Warfarin :

Prandoni P; Blood,2002.

- OAC in patients with cancer( vs without cancer)

- two to three-fold increase in recurrent VTE

- two to six fold increase in major bleeding

Other problems :

potential for drug interactions( chemotherapy)

poor intestinal absorption

altered hepatic function

Treatment of VTE in Patients with Cancer

Difficulties with (OAC) Warfarin :

In patients with cancer receiving warfarin for VTE, the risk of bleeding and recurrent VTE remains high, even when the INR is within the target range.

Palareti G; Throb Haemost 2000.

Bleeding rate is consistently high and is independent of the INR value in patients with cancer.

Prandoni P; Blood,2002.

At the time of recurrence, the INR value is within or above the target range in a higher proportion of cancer

Treatment of VTE in Patients with Cancer

Meta-analysis of 4 studies:

- Prolonged treatment with LMWH

statistically significant and clinically important 50% reduction in the rate of recurrent VTE (6.5 vs12.6%,RR 0.52, 95% CI 0.35–0.76; p=0.001)

No significant difference between warfarin and LMWH for the risk of bleeding

LMWH :Treatment of VTE in Ca Patients

American College of Chest Physicians (ACCP) American Society of Clinical Oncology (ASCO)

National Comprehensive Cancer Network (NCCN)

The Italian Medical Oncology Society (AIOM)

Long-term anticoagulant therapy for patients with DVT and cancer should involve LMWH rather than VKAs.

Duration: at least three to six months

8.

Anticoagulant Treatment and Survival in

Cancer Patients

Effects of Anticoagulant treatment on

Survival in Patients with Cancer

Several studies have suggested a link between

anticoagulant therapy and improved survival in patients

with malignancy.

Zacharaski LR;Cancer,1984

a prospective, randomised clinical trial

warfarin was associated with significant prolongation of

progression-free and overall survival in patients with

small-cell lung cancer

However, in patients with other types of tumour, warfarin

had no effect on survival.

Effects of Anticoagulant treatment on

Survival in Patients with Cancer

Furthermore, subsequent trials of VKAs in patients with cancer have provided conflicting results.

Smorenburg SM;Thromb Haemost,2001

- a systematic review concluded that there was insufficient evidence that long-term VKA administration provided a survival benefit in patients with cancer

Smorenburg SM;Thromb Haemost, 1999

Similar uncertainty surrounds the effect of UFH on survival

LMWHs on Survival in Patients with

Cancer

Hettiarachchi RI. Curr Opin Pulm Med,1998.

- Ca patients who receive LMWH (vs UFH) for the initial treatment of acute DVT may have prolonged survival

Altinbas M. J Thromb Haemost,2004.

- small-cell lung cancer.

- overall survival - significantly prolonged (LMWH + Chemotherapy)

- both in patients with extensive / limited disease.

LMWHs on Survival in Patients with

Cancer

Improvement in survival associated with LMWHs may be independent of their anticoagulant effects.

Antitumour effects of LMWH:

- inhibition of neoangiogenesis

- inhibition of tumour-cell-derived heparanase activity,

- induction of apoptosis

- inhibition of tumour cell adhesion to endothelial cells

LMWHs on Survival in Patients with

Cancer

Clinical studies conducted so far have produced conflicting results, and evidence for prolonged survival in cancer patients with LMWH comes mainly from post hoc analyses

Additional studies conducted in patients with specific cancer types are needed to confirm these preliminary findings

Such studies are currently under way in several cancer types including lung, prostate, pancreas, ovary and stomach

ACCP Guidelines on VTE in

Cancer Patients A. P R O P H Y L A X I S

1. Ambulatory patients receiving chemotherapy.

Routine prophylaxis NOT recommended.(1C)

2. Patients with Central Venous Catheters.

Routine prophylaxis NOT recommended. (1A)

3. Hospitalised patients with Acute Medical Illness.

Routine Thrombo - prophylaxis recommended. (1A)

ACCP Guidelines on VTE in

Cancer Patients 4. Prophylaxis during Surgery

- Routine thrombo-prophylaxis that is appropriate for the type of surgery is recommended………………(1A)

5. Prophylaxis after discharge

- High risk GS patients, including those who have undergone major Ca surgery/ past DVT

: Continue LMWH thrombo- prophylaxis x 28/7…. (2A)

-Similar Gynaecology patients.

: Continue LMWH thrombo- prophylaxis x 28/7…..(2C)

ACCP Guidelines on VTE in

Cancer Patients

6. Suggested Regimen for Prophylaxis of VTE

- ACCP: No specific recommendation

- ASOC: UFH 5000 U TID

LMWH: Dalteparin 5000 U OD

Enoxaparin 40 mg OD

Fondaparinux 2.5 mg OD

- NCCN Tinzaparin 4500 U or 75 U/kg OD

ACCP Guidelines on VTE in

Cancer Patients

7. Mechanical Devices where anticoagulant treatment (ACT) is contraindicated

- graduated compression stockings

- intermittent pneumatic compression (1A)

When the bleeding risk decreases, pharmacological thrombo-prophylaxis be substituted for or added to the mechanical one (1C)

Recommendation against the use of IVC filter in trauma patients with acute spinal injury (1C)

ACCP Guidelines on VTE in

Cancer Patients

B. T R E A T M E N T

1. Acute DVT

- LMWH : first 3 – 6 months (1A)

- Subsequent LMWH/ VKA therapy indefinitely or until the cancer is resolved

2. Mechanical Devices where ACT is contraindicated

- IVC filter (1C)

- when the bleeding risk decreases, conventional course of ACT should be given.

ACCP Guidelines on VTE in

Cancer Patients

3. Treatment similar to that for DVT of the leg is also recommended for DVT of the upper extremity

4. Patients with lower- and upper-extremity DVT may be considered for thrombus removal using catheter-based thrombolytic techniques.

5. Prophylactic or four weeks of intermediate doses of LMWH or UFH should be used in patients with extensive Superficial Vein Thrombosis

Take Home Message

Patients with cancer are at high risk of thrombosis, and this is an important cause of avoidable mortality in these patients.

CAT is associated with : Higher - Mortality

- Recurrence of VTE

- Bleeding complications

These patients present unique challenges that affect the safety and efficacy of antithrombotic therapies.

Take Home Message

Current data indicate that LMWHs offer several practical

advantages for cancer patients, in addition to superior

efficacy to OAC without increasing the risk of bleeding.

Preliminary data suggest that LMWH administration may

be associated with an increase in patient survival

THANKS VERY MUCH

Treatment of VTE in Patients with Cancer

Other important issues of LMWH therapy:

- Heparin Induced Thrombocytopaenia (HIT)

- Drug Accumulation: Short term

Long term

LMWH :Treatment of VTE in Ca Patients

Heparin Induced Thrombocytopaenia (HIT)

Eight studies: Prospective cohorts; 900 patients

Not a single episode of HIT.

Thrombocytopenia is a common complication in cancer patients receiving chemotherapy

Lee; NEJM,2003

For the use of Dalteparin

Platelet >100,000/mm3 Standard Dose

50,000-100,000 Reduce dose to 3000 IU

< 50,000 Stop treatment

LMWH :Treatment of VTE in Ca Patients

Risk of Drug Accumulation

(A) Short Term

CLOT trial:

- 24 patients receiving dalteparin 200IU/kg once daily - anti-Xa measurement at weeks one and four.

- at week four, the mean anti-Xa level was 1.03 anti-Xa units/ml (95% CI 0.5–1.7) and did not differ significantly from the value obtained during week one.

LMWH :Treatment of VTE in Ca Patients

(B) Long Term:

Renal impairment is a frequent co-morbid condition in

patients having cancer.

Renal function may be further impaired as a result of

chemotherapy-related nephrotoxicity.

Measurement of creatinine clearance is recommended

before starting prolonged LMWH

LMWH :Treatment of VTE in Ca Patients

Tinzaparin may be the most suitable option for patients

with moderately impaired renal function.

Siguret; Thromb Haemost 2000.

The results of a study completed in a group of patients

with a wide distribution of creatinine clearance indicate

that the anti-Xa effect of tinzaparin does not increase

over 10 days of administration