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Mark Levine MD Department of Oncology

McMaster University Hamilton Ontario Canada

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Prevention of Cancer-Associated Thrombosis: Where Are We Today?

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Risk of Thrombosis

•  Rates of thrombosis reported in literature vary because of case selection

•  Wide range - 1% to 20%

•  Rate is influenced by tumor burden, as reflected by tumor stage

•  Venous thrombosis is more common than arterial thrombosis

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Primary Prevention: Clinical States on Cancer Continuum

•  Hospitalized post surgery

•  Hospitalized medical

•  Ambulatory medical i.e. receiving anti-cancer treatment (chemotherapy, endocrine, molecular targeted, radiation)

•  Palliative

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Thromboembolism in Breast Cancer

Study Population Treatment Rate

NSABP 16 Node positive† T 1.6%

AC + T 3.1%

NCIC MA4 Node positive† T 1.4%

CMF + T 9.6%

† Postmenopausal patients  

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Thromboembolism in Breast Cancer

Study Population Treatment Rate

Weiss Node positive

CMFVP 6.3%

CMF 3.5%

CMFBCG 5.4%

Levine Node positive CMFVP 9 months 8.8%

CMFVP + AT 3m 4.9%

Goodnough Stage IV CMFVP 17.6%

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VTE in Solid Tumors: Hemapoetic Growth Factors

Study Agent(s) Tumor type

Number of Pts

VTE (%)

Wun cisplatin, rads, epo cervix 75 22.6

Wun cisplatin, rads cervix 72 2.7

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VEGFR-2 Pathway and Function

Endothelial Cell

Flk-1/KDR (VEGFR-2)

Growth, Migration, Permeability, Anti-apoptosis

VEGF

Kinase Activation Cascade

P PPLC

VEGF-C VEGF-D

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Incidence and Relative Risk (RR) of High-Grade Venous Thromboembolism With Bevacizumab Among Patients With Various Tumor Types

Nalluri, SR, et al. JAMA. 2008;300:2277-2285. Copyright restrictions may apply.

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Kaplan-Meier Analysis of Time-To-Arterial Thromboembolic Event for Patients in the Pooled Population

Scappaticci, FA, et al. J Natl Cancer Inst. 2007;99:1232-1239; doi:10.1093/jnci/djm086 Copyright restrictions may apply.

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Rajkumar: Myeloma, JCO 2008

Outcome Thalidomide + Dex

(n=234) Dexamethasone

(n=232)

DVT (3/4 AEs) 11.5% 1.7%

PE (3/4 AEs) 6.8% 1.7%

DVT (patients) 18.8% 5.6%

DVT=deep vein thrombosis; PE=pulmonary embolism.

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Incidental PE on Imaging for Staging

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Should I Give Prophylaxis?

Reduction in thrombosis

Increase in bleeding

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RCTs of Antithrombotic Prophylaxis in Ambulatory Cancer Patients

Study Cancer

Levine Stage IV breast

PRODIGE Advanced glioma

FAMOUS Solid tumors

TOPIC I Stage IV breast

TOPIC II NSCLC

PROTECHT Variety of solid tumors

RCTs=randomized controlled trials.

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Thromboprophylaxis Levine et al. Lancet 1994; 343, 886-9

•  311 women with metastatic breast cancer on 1st or 2nd line chemotherapy

•  Randomized to 1 mg warfarin for 6 weeks, then warfarin titrated to INR 1.3-1.9 or placebo

•  7 events vs.1 (85% risk reduction, P=0.03 with no increased bleeding)

INR=international normalized ratio.

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PRODIGE: Perry JR, et al.

•  Monthly follow-up

•  Clinically-suspected objectively-confirmed DVT/PE at 6m

•  Survival at 12m QOL, MMSE, AEs

Newly dx malignant

glioma R

Dalteparin 5000iu daily s.c.

Placebo daily s.c.

•  Stratified on KPS, weeks from surgery to randomization, tumor grade, center

•  Intended treatment for 6m, but as long as 12m

J Thromb Haemost. 2010;8:1959-1965. QOL=quality of life; AEs=adverse events.

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PRODIGE VTE During First 6 months

Placebo 87 84 79 74 65 61 56

Dalteparin 99 95 88 82 78 74 69 At Risk:

0.00

0.05

0.10

0.15

0.20

Days 0 30 60 90 120 150 180

Probability of VTE

p = 0.17

14 vs. 11

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Major Bleeding During First 12 Months

240

Placebo 87 82 71 62 52 47 38 27 21 19 17 14 8

Dalteparin 99 83 76 71 66 60 55 38 35 30 27 23 12

At Risk:

0.00

0.05

0.10

0.15

0.20

0 30 60 90 120 180 210 270 300 330 360

Probability of

Major Bleed

p = 0.17

5 vs. 1

150

Days

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Thromboprophylaxis

Trial Treatment VTE Bleeding

FAMOUS solid tumors (n=385)

dalteparin 2.4% 4.7%

placebo 3.3% 2.7%

TOPIC I Stage IV breast (n=353)

certoparin* 4% 1.7%

placebo 4% 0

TOPIC II Stage IV NSCLC (n=547)

certoparin* 4.5%† 3.7%

placebo 8.3% 2.2%

In FAMOUS, the primary outcome was survival. TOPIC not published

* 6 months † P=0.07

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PROTECHT: Agnelli et al.

•  Ambulatory patients with lung, GI, pancreas, breast, ovarian, head & neck cancer

•  Randomized in a 2:1 ratio to nadroparin (779) or placebo (387) for up to 4 months

•  Rate of VTE, 2% versus 3.9%, P= 0.02 1-tailed

•  5 (0.7%) major bleeds vs. 0, P=0.18 2-tailed

The Lancet Oncology, Volume 10, Issue 10, Pages 943 - 949, October 2009

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Myeloma

•  Many observational studies of prophylaxis

•  2 RCTs

–  659 on thalidomide randomized to ASA, Warfarin and LMWH (thrombosis = 6.4%, 8.2%, 5.0%, respectively)

–  342 patients treated with lenalidomide-based chemotherapy randomized to low-dose ASA (100 mg) or enoxaparin (VTE = 2.3% vs.1.2%)

Palumbo A, et al. J Clin Oncol. 2011;29:986-993. Larocca A, et al. Blood. 2012;119:933-939.

ASA=acetylsalicylic  acid  (aspirin);  LMWH=low  molecular  weight  heparin.  

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Direct Thrombin & Anti Factor Xa Inhibitors

*Direct thrombin inhibitor

a TF VII

IX

Xa X

IXa

II Va

IIa

VIIIa

Fibrinogen Fibrin

IIa

DTI*

Anti Xa

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ABLE Trial

•  A multi-center, randomized, double-blind, phase II 4-arm trial was conducted.

•  Patients with metastatic cancer on 1st or 2nd line chemotherapy received study drug once daily for 12 weeks

•  dose of 5, 10 or 20 mg of Apixaban or placebo.

Levine MN, et al. J Thromb Haemost. 2012;10:807-814.

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ABLE

•  The primary outcome measure was:

–  proportion of patients remaining free of major bleeding (MB), clinically relevant non-major bleeding (CRNMB), VTE, and grade >3 adverse events (AE) considered to be probably/definitely related to study drug.

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ABLE Trial

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SAVE ONCO: Study design

Randomization

Placebo o.d.

AVE5026 (20 mg o.d.)

End of treatment

Treatment duration variable: until change of chemotherapy regimen (initial if >3months or at

least 3 months and until change of ongoing regimen at M3)

•  Symptomatic DVT •  PE •  VTE-related deaths

End of study : 7 months after LPI

Stratification on: - Cancer location - Cancer stage - Geographical region

Double-blind, superiority study N = 3,200

DVT=deep vein thrombosis; EOT=end of treatment; FUP=follow up; PE=pulmonary embolism; RRR=relative risk reduction; VTE=venous thromboembolism. Agnelli G, Kakkar AK, et al. N Engl J Med. 2012;366:601-609.

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SAVE-ONCO – Results

Treatment Semuloparin Placebo

VTE 3.4% 1.2%

Major Bleeding 1.2% 1.1%

HR : 0.36 [0.21 – 0.60]

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Biomarkers to Predict Thrombosis

•  Elevated WBC

•  Elevated platelets

•  D-dimer

•  P-selectin

•  F1+2

•  TF micro particles

Pabinger I, et al. Blood. 2013;122:2011-2018. WBC=white blood cell count.

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Questions & Challenges

•  What is the baseline rate of thrombosis that would warrant prophylaxis? –  Don’t know

–  Very difficult to predict rate for an individual patient

–  Risk changes over time

–  Duration of prophylaxis could be many months

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Questions & Challenges

•  What is the magnitude of thrombosis reduction with prophylaxis?

•  Is there Level I evidence?

–  Levine 85% RR but baseline rate 4%

–  Agnelli 50% RR but baseline rate 3.9%

RR=relative risk.

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Questions & Challenges

•  What is the down-side (“hassle factor”) of prophylaxis?

–  Bleeding

–  Monitoring test of coagulation

–  Subcutaneous injections

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Questions & Challenges

•  What is the ideal prophylactic agent? –  Warfarin is inexpensive but requires laboratory

monitoring

–  LMWH requires daily subcutaneous injection and is expensive in North America

–  Both warfarin and LMWH may cause bleeding

–  Lack of data on new anti-thrombotics

–  No ideal agent

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Stick Factors

•  VTE Prophylaxis for the patient on chemotherapy:

– Safe

– Effective

– Hassle-free

– Cheap

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Prevention of Cancer-Associated Thrombosis: Where are we Today?

I Don’t Know

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Recommendation: ASCO 2013

•  Thromboprophylaxis is not routinely recommended for outpatients with cancer, but may be considered for selected high-risk patients.

•  Patients with multiple myeloma receiving thalidomide- or lenalidomide-based regimens with chemotherapy and/or dexamethasone should receive pharmacologic prophylaxis with either aspirin or LMWH for lower risk patients and LMWH for higher-risk patient

J Clin Oncol 2013: 31,2189-2204.

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What is Central Vein Catheter-Associated Thrombosis (CVCAT)?

•  No venous flow

•  Fibrin sheath

•  Ball valve clot

•  Venous thrombosis of large vein (subclavian, axillary vein)

•  We don’t even know what it is!

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Is it a Frequent Problem?

•  Lee et al. conducted a prospective study (JCO 2006;24,404)

•  444 cancer patients with CVCs were followed for 12 months (76,713 patient days)

•  19 (4.3%) developed symptomatic CVCT

•  0.3 per 1000 catheter days

CVCs=central venous catheters; CVCT=central venous catheter thrombosis.

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Is it Clinically Important?

•  Post phlebitic syndrome is not a problem in this population

•  If CVC is still working, then it is still used

•  Symptomatic pulmonary embolism is a rare occurrence

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What is the Most Appropriate Outcome of Prevention of CVCAT?

•  It must be a clinical outcome, e.g. painful swollen arm with or without CVC obstruction

•  It is not asymptomatic obstruction on screening venogram

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Is There Any Evidence to Support Thromboprophylaxis?

Study Rx Patient No. Outcome Clinical

Couban 2005 warfarin 1 mg

placebo 130 125

clinical 3.4 4.6

Young 2005 warfarin 1mg

control 408 403

clinical 5 6

Young 2005 warfarin (INR 1.5-2)

warfarin 1mg 473 471

clinical 3

7

Verso 2005 enoxaparin LMWH

placebo 155 155

clinical 3.1 1.0

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ASCO Catheter Guideline

•  Prophylactic use of warfarin or low–molecular weight heparin is not recommended

Schiffer CA, et al. J Clin Oncol. 2013:31;1357-1370.

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Recommendation: ASCO 2013

•  Most hospitalized patients with cancer require thromboprophylaxis throughout hospitalization

•  Patients undergoing major cancer surgery should receive prophylaxis, starting before surgery and continuing for at least 7 to 10 days.

•  Extending prophylaxis up to 4 weeks should be considered in those with high-risk features. LMWH

Lyman GH, et al. J Clin Oncol. 2013;31:2189-2204.