DVT IN MALIGNANCYPRESENTER:DR.SATHISH,JR,RT

MODERATOR:DR.SHYAMA(ASSISTANT PROFESSOR OF RADIOTHERAPY)

INTRODUCTIONVTE(VENOUS

THROMBOEMBOLISM)=DVT+PEIn 1865-Armand Trousseau first described

venous thrombosisRisk of mortality doubles if cancer pts

develop DVT1

VTE is the second leading cause of death in hospitalized cancer patients1

1. J Thromb Haemost 2007;5(3):632.

Likelihood of Death After Hospitalization

0 20 40 60 80 100 120140 160 1800.00

0.20

0.40

1.00

0.80

0.60

DVT/PE and Malignant Disease

Malignant Disease

DVT/PE Only

Nonmalignant Disease

Number of Days

Pro

babi

lity

of D

eath

Levitan N, et al. Medicine 1999;78:285

PATHOPHYSIOLOGYVIRCHOW’S TRIAD

STASIS

HYPERCOAGULABILITY

VESSEL INJURY

OTHER AGENTS

•Cancer procoagulant----Xa Activation•PAI•TNF,1L-1 and 6•IFNs•Increased 8-vWF•Decreased protein C and S, Antithrombin

Patient related

• Age• Race• Obesity• Infection• Genetic

mutations• V leiden• Prothrombin

Disease related• Site of primary

• Brain,lung• Stomach,panc

reas• Kidney,ovary• Lymphomas,

melanoma• Metastatic

disease• h/o DVT• Renal disease• Pulmonary

disease

Treatment related• Surgery• Prechemo

platelet count>350000

• Hormonal therapy-tamoxifen,OCP

• Chemo- 6.5 fold risk of DVT-thalidomide, lenalidomide and bevacizumab

• Erythropoeitin• Central vein

catheter

Risk factors

VTE and Cancer: Epidemiology

Of all cases of VTE:● About 20% occur in cancer patients● Annual incidence of VTE in cancer

patients ≈ 1/250

Of all cancer patients:● 15% will have symptomatic VTE● As many as 50% have VTE at autopsy

Compared to patients without cancer:● Higher risk of first and recurrent VTE● Higher risk of bleeding on anticoagulants● Higher risk of dying

Lee AY, Levine MN. Circulation. 2003;107:23 Suppl 1:I17-I21

VTE Incidence In Various Tumors

Otten, et al. Haemostasis 2000;30:72. Lee & Levine. Circulation 2003;107:I17

Oncology Setting VTE Incidence

Breast cancer (Stage I & II) w/o further treatment 0.2%

Breast cancer (Stage I & II) w/ chemo 2%Breast cancer (Stage IV) w/ chemo 8%Non-Hodgkin’s lymphomas w/ chemo 3%Hodgkin’s disease w/ chemo 6%Advanced cancer (1-year survival=12%) 9%High-grade glioma 26%Multiple myeloma (thalidomide + chemo) 28%Renal cell carcinoma 43%Solid tumors (anti-VEGF + chemo) 47%Wilms tumor (cavoatrial extension) 4%

OCCULT CANCER AND VTESOMIT(Screening For Occult Malignancy In

Patients With Symptomatic Idiopathic VTE Trial) concluded that most cancers are diagnosed within four to six months of diagnosis of DVT and 40% will have metastasized

Greatest risk of DVT is within few months of diagnosis of cancer

No evidence of survival benefit due to screening and earlier detection

NCCN does not recommend screening VTE pts for cancer

DIAGNOSIS OF DVT/PEClinical assessment + D-

dimer assayFalse negative rates high

for D-dimer assayDuplex USG is the

investigation of choice for lower limb DVT

CT angiogram is the IOC for PE

CT/MRI is more sensitive for upper limb DVT

Deep vein thrombosis

Veins of the leg

Common femoral vein

Thrombus

KneeProximal

Distal

Symptoms of post-thrombotic syndrome – long “lag-phase” (years)

PainOedemaDiscolorationVaricesUlceration

Post-thrombotic syndrome

DVT – Wells Score

CancerParalysis or plaster

immobilizationBedrest > 3 d or

surgery in past 4 wks

Localized tenderness

Entire leg swollenCalf > 3cm larger

than unaffected legPitting edema

greater than unaffected leg

Collateral superficial veins

The following were assigned a point value of 1 if present:

• Probability High (≥ 3), Moderate (1-2) or Low (0 or less)• DVT risk: High – 75%, Moderate – 17%, Low – 3%

Wells PS, Andersen DR, Bormanis J et al. Lancet. 1997;350:1795-8

Symptoms of DVT and PE

.

DVT

Swelling Pain or tenderness -the

pain is usually in 1 leg and may only be present when standing or walking

Warm skin Red or discolored skin

PE

Unexplained shortness of breath

Chest pain and/or palpitations

Anxiety and/or sweating Coughing/coughing up

blood Fatigue and/or fainting

Not all people with DVT have signs or symptoms

16

Myths of the great masquerader!

Myth

– “Patients with pulmonary embolism are short of breath and have chest pain!”

Reality: You can forget about making the

diagnosis on clinical grounds, but wait…don’t plan on completely ruling it out either!

17

Clinical Features Symptoms in Patients with Angio Proven

PTE

Symptom Percent

Dyspnea 84Chest Pain, pleuritic 74Anxiety 59Cough 53Hemoptysis 30Sweating 27Chest Pain, nonpleuritic 14Syncope 13

18

Clinical Features Signs with Angiographically Proven PE

Sign Percent

Tachypnea > 20/min 92Rales 58Accentuated S2 53Tachycardia >100/min 44Fever > 37.8 43Diaphoresis 36S3 or S4 gallop 34

Thrombophebitis 32Lower extremity edema 24

19

Chest X-ray Eponyms of PE Westermark's sign

– A dilation of the pulmonary vessels proximal to the embolism along with collapse of distal vessels, sometimes with a sharp cutoff.

Hampton’s Hump

– A triangular or rounded pleural-based infiltrate with the apex toward the hilum, usually located adjacent to the hilum.

20

Radiographic Eponyms- Hampton’s Hump, Westermark’s Sign

Westermark’s Sign

Hampton’s Hump

21

Diagnostic Testing- CXR’s

Chest X-Ray Myth:

“You have to do a chest x-ray so you can find Hampton’s hump or a Westermark sign.”

Reality:

Most chest x-rays in patients with PE are nonspecific and insensitive

22

Diagnostic Testing - CXR’s

Chest radiograph findings in patient with pulmonary embolism

Result PercentCardiomegaly 27%Normal study 24%Atelectasis 23% Elevated Hemidiaphragm 20%Pulmonary Artery Enlargement 19%Pleural Effusion 18%Parenchymal Pulmonary Infiltrate 17%

23

Diagnostic Testing - Pulse Oximetry

The Pulse Oximetry Myth:

– “ You must do a pulse oximetry reading, since patients with pulmonary embolism are hypoxemic!”

Reality:

– Most patients with a PE have a normal pulse oximetry, and most patients with an abnormal pulse oximetry will not have a PE.

24

Diagnostic Testing - ABG’s

The ABG/ A-a Gradient myth:

– “You must do an arterial blood gas and calculate the alveolar-arterial gradient. Normal A-a gradient virtually rules out PE”.

Reality:

– The A-a gradient is a better measure of gas exchange than the pO2, but it is nonspecific and insensitive in ruling out PE.

25

So What Do We Do ???

Confusing for Emergency Physician

Do we under diagnose/over diagnose?

Why don’t we have a standardized method of work up after all these years?

26

Ventilation/Perfusion Scan- “V/Q Scan”

A common modality to image the lung.

Relatively noninvasive and sadly most often nondiagnostic!

In many centers it remains the initial test of choice

Preferred test in pregnant patients 50 mrem vs 800mrem (with spiral CT)

27

Spiral (Helical) Chest CT Advantages

– Noninvasive and Rapid– Alternative Diagnosis

Disadvantages

– Costly– Risk to patients with borderline renal

function– Hard to detect subsegmental pulmonary

emboli

CT revealing emboli in pulmonary artery.

29

Pulmonary Angiography

“Gold Standard”– Performed in an Interventional Cath Lab

Positive result is a “cutoff” of flow or intraluminal filling defect

“Court of Last Resort”

Pharmacologic(Prophylaxis & Treatment)

Nonpharmacologic(Prophylaxis)

Antithrombotic Therapy: Choices

IntermittentPneumaticCompression

Elastic Stockings

InferiorVena CavaFilter

OralAnticoagulants

UnfractionatedHeparin (UH)

Low Molecular Weight Heparin (LMWH)

New Agents: e.g. Fondaparinux,Direct anti-Xa inhibitors,Direct anti-IIa, etc.?

1. Should hospitalised cancer patients receive anticoagulation for VTE prophylaxis?

2. Should ambulatory cancer patients receive prophylactic anticoagulation during systemic chemotherapy for VTE?

3. Should patients with cancer undergoing surgery receive peri-op prophylaxis?

4. What is the best method to treat patients with cancer with VTE to prevent recurrence?

5. Should patients with cancer receive anticoagulation in the absence of established VTE to improve survival?

Lyman GH et al. J Clin Oncol (25) 2007; 34: 5490-5505.

ASCO Guidelines

VTE Prophylaxis Is Underused in Patients With Cancer

FRONTLINE Surgical

FRONTLINE: Medical

Stratton Bratzler Rahim DVT FREE0

10

20

30

40

50

60

70

80

90

100

52

5

89

3833

42

1.Kakkar AK et al. Oncologist. 2003;8:381-3882.Stratton MA et al. Arch Intern Med. 2000;160:334-3403.Bratzler DW et al. Arch Intern Med. 1998;158:1909-1912

Cancer:FRONTLINE Survey1— 3891 Clinician Respondents

Rate

of

Ap

pro

pri

ate

Pro

ph

ylaxi

s, %

Major Surgery2

Major ABDominothoracic Surgery (Elderly)3 Medical

Inpatients4

Confirmed DVT (Inpatients)5

Cancer: Surgical

Cancer: Medical

4.Rahim SA et al. Thromb Res. 2003;111:215-219

5.Goldhaber SZ et al. Am J Cardiol. 2004;93:259-262

PREVENTION OF DVT IN SURGICAL PATIENTS7 fold risk of post-op DVT and 54 fold in first three

months Risk of VTE as high as 50% without prophylaxisIf LMWH/UFH 7-10 days post-op VTE risk -15% and

bleeding risk is 4%UFH vs LMWH? No difference in efficacy15% develop DVT inspite of either S/c fondaparinux –equivalent efficacy and low incidence

of hitGraduated Compression Stockings(GCS) and Intermittent

Pneumatic Compression (IPC) devices can be used as an adjunct but not as a primary prophylaxis unless ACGs are contraindicated

Cancer patients have 2-fold risk of post-operative DVT/PE and >3-fold risk of fatal PE despite prophylaxis:

Kakkar AK, et al. Thromb Haemost 2001; 86 (suppl 1): OC1732

Incidence of VTE in Surgical Patients

No CancerN=16,954

CancerN=6124

P-value

Post-op VTE 0.61% 1.26% <0.0001

Non-fatal PE 0.27% 0.54% <0.0003

Autopsy PE 0.11% 0.41% <0.0001

Death 0.71% 3.14% <0.0001

ENOXACAN II STUDYENOXAPARIN 40MG/D SC OD FOR FIRST

10D POST-OP

12% DVT INCIDENCE

3.6% BLEEDING INCIDENCE

8th ACCP GUIDELINES RECOMMENDS EXTENDED LMWH IN CANCER SURGERY PTS

ENOXACAN Study Group. Br J Surg 1997;84:1099–103

-5%

0%

5%

10%

15%

placebo

enoxaparin 40 mg

VTE Prox Any Major DVT Bleeding Bleeding

P=0.02

5.1%

1.8%

Bergqvist D, et al. (for the ENOXACAN II investigators) N Engl J Med 2002;346:975-980

ENOXACAN II

In

cid

en

ce o

f O

utc

om

e E

ven

t

N=167

N=165

0% 0.4%

12.0%

4.8%

NNT = 140.6%

3.6%

Extended Prophylaxis inSurgical Patients

SOME SPECIAL SCENARIOSProphylaxis in laparascopic surgery-no

consensusCNS tumors and neurosurgery pts-both

thrombosis and bleeding risk highExtremely cautious use of ACGs and the

decision to start anticoagulation rests with the treating oncologist

Some consider it an absolute contraindication

PROPHYLAXIS IN CVCNone of the ACGs are beneficialThrombosis rates were similar with or

without ACG but risk of bleeding was high for pts on ACG

Placebo vs. anticoagulants?-No differenceSO 8TH ACCP CONSENSUS guidelines-no

routine prophylaxis to prevent thrombosis secondary to central venous catheters, including LMWH and fixed-dose warfarin

TREATMENT OF CVC THROMBOSISRemove the catheterFollow the same guidelines as for DVT in any

other site Decisions about duration, dose etc., of

therapy rests with treating oncologist

PROPHYLAXIS IN MEDICAL ONCOLOGYIn myeloma patients receiving

thalidomide+dexa and/or doxorubicinThe reason is not fully understoodNCCN recommends prophylaxis but no clear

cut regimens so farACCP –Assume that all inpatients on

chemo/chemoradiation/hormone therapy are at high risk for VTE and should be considered for ACGs

AMBULATORY PATIENTS ON CHEMOACG not routinely recommended(no studies

till now)special consideration for prophylaxis

Prechemo platelet>350000GIT,lung and lymphoid malignanciesAnemic pts on epoeitin

IVC FILTERSUsed if ACGs C/I or in recurrent VTE

Invasive procedure and requires expertiseParadoxically risk of thrombosis is highUsually considered as a last resort for

recurrent VTE

TREATMENT OF DVTINITIAL TREATMENT

LMWH vs. UFH ?- equivalent efficacyFondaparinux – equivalent to LMWH in efficacy

but no RCTs in cancer patients

1 mg/kg BD vs 1.5 mg/kg OD enox?Recurrence rate 6.4% in BD and 12.2% in OD

OD dosing is approved for inpatients and BD is preferred for outpatients

HOW TO INITIATE THERAPY?UFH/LMWH ONLY OR WITH

WARFARIN OVERLAP

OVERLAP HEPARIN AND WARFARIN TILL 2 PT INR

VALUES 24 HRS APART ARE IN THE RANGE OF 2-3 (usually first 5 days)

STOP HEPARIN AND CONTINUE WARFARIN OR CONTINUE LMWH FOR MINIMUM 6 MONTHS

REASSESS PERIODICALLY AND CONSIDER DISCONTINUATION

CLOT: Landmark Cancer/VTE Trial

CANCER PATIENTS WITH ACUTE DVT or PE Randomization

[N = 677]

► Primary Endpoints: Recurrent VTE and Bleeding► Secondary Endpoint: Survival

Lee, Levine, Kakkar, Rickles et.al. N Engl J Med, 2003;349:146

Dalteparin Dalteparin

Dalteparin Oral Anticoagulant

Landmark CLOT Cancer TrialReduction in Recurrent VTE

0

5

10

15

20

25

Days Post Randomization

0 30 60 90 120 150 180 210

Pro

babi

lity

of R

ecur

rent

VT

E,

%Risk reduction = 52%p-value = 0.0017

Dalteparin

OAC

Recurrent VTE

Lee, Levine, Kakkar, Rickles et.al. N Engl J Med, 2003;349:146

Dalteparin N=338

OACN=335

P-value*

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

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

* Fisher’s exact test

Bleeding Events in CLOT

Lee, Levine, Kakkar, Rickles et.al. N Engl J Med, 2003;349:146

THE LITE TRIAL(LONG TERM INNOVATIONS IN TREATMENT)

INITIAL UFH AND THEN WARFARIN

CONTINUE WARFARIN

16% RECURRENCEAFTER 1 YEAR

•N=200 CANCER PATIENTS•BLEEDING COMPLICATIONS COMPARABLE IN BOTH ARMS

DURATION OF TREATMENTUsually six months for responsive patients

without active cancer or metastatic diseaseFor patients with active malignancy and

metastatic disease duration is based on the treating physician’s opinion

If patients tolerate continue LMWH/warfarin

THROMBOLYSISUsed in PE with severe hemodynamic

instabilitySevere DVT leading to arterial insufficiencyClinically significant thrombus extensionTo maintain patency of occluded CVC

SIDE EFFECTS OF LONG TERM TREATMENT BleedingDecreased bone density –LMWHFetal warfarin syndromeDrug interactionsACCP recommends LMWH for long term

therapy

CONTRAINDICATIONS FOR ANTICOAGULATIONMajor active bleed- only absolute

contraindicationRecent CNS bleed;recent craniotomyBleeding diathesisParaspinal tumoursCNS tumors

RECURRENCE OF VTENo guidelines for optimal treatmentTrial evidence lacking for duration of therapy

1. Should hospitalised cancer patients receive anticoagulation for VTE prophylaxis? yes

2. Should ambulatory cancer patients receive prophylactic anticoagulation during systemic chemotherapy for VTE?no

3. Should patients with cancer undergoing surgery receive peri-op prophylaxis? yes

4. What is the best method to treat patients with cancer with VTE to prevent recurrence? LMWH

5. Should patients with cancer receive anticoagulation in the absence of established VTE to improve survival? no

Lyman GH et al. J Clin Oncol (25) 2007; 34: 5490-5505.

Cancer, clots and consensus

THE JIPMER CONSENSUSHISTORY/CLINICAL EXAM ---DVT

COMPRESSION USG

LMWH FOR 3D

WARFARIN FOR

3D WITH OVERLAP

STABILISE WITH

WARFARIN INR 2-3 (above

1.8)TWICE WEEKLY PT INR

IF WITHIN TARGET

RANGE(ABOVE 1.8)

PT INR EVERY

14D FOR A

MONTH OR TWO

PT INR MONTHL

Y FOR SIX

MONTHS

INFORM SOS IF MAJOR ACTIVE BLEED WARN

ABOUT DRUG

INTERACTIONS

CONSIDER

PROLONGED

THERAPY?

WHERE ALL CAN WE GO WRONG?PT INR monitoring and target rangeWarfarin drug interactionsWarfarin step up doseMissing a PEMissing occult bleed-e.g. melaenaRestarting Rx after major bleed-weigh the

risk vs. BenefitFollow up and patient educationLab limitations

THANK YOU