Cancer Associated Thrombosis

Guy MeyerUniversité Paris Descartes

Hopital Europeen Georges Pompidou, Paris, France

Disclosures G Meyer

• Investigator: Bayer, Daichi-Sankyo, Sanofi

Aventis, Leo Pharma

• Research Funding: Leo Pharma, Boehringer-

Ingelheim, Bayer

• Board membreship (uncompensated) : Sanofi

Aventis, Leo Pharma, Bayer, Boehringer-

Ingelheim, Pfizer

• Travel support: Leo Pharma, Boehringer-

Ingelheim, Bayer, Daichi-Sankyo

Incidence of venous thromboembolism in patients

with cancer

Study n Cancer VTE (% yrs)

Ay 20101 819 Unselected 7.7%

Khorana 20052 3003 New chemotherapy 4.4%

Kröger 20063 507 Unselected 18%

Prospective studies with various cancer types

1. Ay C et al. Blood 2010;116:5377–82

2. Khorana AA et al. Cancer 2005;104:2822–9

3. Kröger K et al. Ann Oncol 2006;17:297–303

115 US Centers ; 3,196 patients chemotherapy < 4 cycles

Characteristics Score

Site of cancerVery high risk (pancreas, stomach)

High risk (lymphoma, lung, gynecological, genito-urinary) 21

Platelet count > 350,000/mm3 1

Hemoglobin < 10g/dL 1

Leukocyte count > 11,000/mm3 1

BMI > 35 kg/m2 1

A predictive rule for Cancer Associated Thrombosis

Khorana AA et al. Blood 2008;111:4902–07

Ris

k of

VT

E o

ver

2.5

mon

ths

(%)

734 374 1627 842 340 149

n

Khorana AA et al. Blood 2008;111:4902–07

A predictive rule for Cancer Associated

Thrombosis

Prolonged prophylaxis: PROTECHT

Agnelli G. et al. Lancet Oncol 2009; 10: 943-49

Nadroparin 3800 IU (4 months) (n = 799) vs placebo (n = 387)

3.9% vs 2.0%; p = 0.02

SAVE-ONCO

Agnelli G. et al. N Engl J Med 2012; 366: 601-9

Metastatic or locally advanced cancer on chemotherapy Semuloparin, n = 1608 or placebo n = 1604; median FUP: 3.5 months

HR: 0,36 ; 0,21-0,60; p < 0,001

Pancreatic cancer

Gemcitabine

Gemcitabine +

Dalteparin

Maraveyas A. et al. Eur J cancer 2012 ;48:1283-92

Advanced Pancreatic cancer: gemcitabine +/-dalteparin: 200 IU/kg OD 4 weeks followed by 150 IU/kg 8 weeks.

All type VTE

17 (28%)

7 (12%) 0.42 (0.19–0.93)

ClinicalVTE

13 (22%)

5 (9%) 0.39 (0.15–1.0)

Major bleedings

2 (3%) 2 (3%)

Control(n = 60)

Dalteparin(n = 59)

RR (95% CI)

Enoxaparin in advanced pancreatic cancer

Pelzer U. et al. J Clin Oncol 2015; 33:2028-2034

Symptomatic VTE

Pelzer U. et al. J Clin Oncol 2015; 33:2028-2034

Major bleedings

Enoxaparin in advanced pancreatic cancer

Verso M. et al. J Thromb Haemost 2010; 8: 1649–51

LMWH

467

Placebo

344

RR

Symptomatic VTE 15 (3.2%) 19 (5.5%) 0.58 (95% CI 0.28–1.06)

All VTE 20 (4.3%) 27 (7.8%) 0.54 (95% CI 0.31–0.95)

Major bleeding 12 (2.5%) 6 (1.7%) 1.50 (95% CI 0.57–3.95)

•TOPIC 2 : NSCLC (n = 532); PROTECHT : Lung cancer (279)

• Certoparin 3000 U or placebo; 6 months

• Nadroparin 3800 IU or placebo 4 months

Long-term prophylaxis in lung cancer patients ?

• In patients receiving chemotherapy, prophylaxis is not

recommended routinely [Grade 1B].

• Primary pharmacological prophylaxis of VTE may be indicated

in patients with locally advanced or metastatic pancreatic

cancer treated with chemotherapy and having a low bleeding

risk [Grade 1B].

• Primary pharmacological prophylaxis of VTE may be indicated

in patients with locally advanced or metastatic lung cancer

treated with chemotherapy and having a low bleeding risk

[Grade 2B].

Farge D. et al. J Thromb Haemost 2013; 11: 56–70

Recommendations (ISTH)

Lee A. et al. N Engl J Med 2003; 349: 146-153

The CLOT Study

Recurrences* Major bleedings

Mortality

Dalteparin 8.8% 5.6% 39%

Warfarin 17.4% 3.6% 41%

*: p = 0.002

The CLOT Study

Lee A. et al. N Engl J Med 2003; 349: 146-153

CATCH. Recurrent VTE

0

2

4

6

10

12

Days post-randomization

0 30 60 90 120 150 180

Pro

ba

bil

ity

of

recu

rre

nt

VT

E (

%)

14

8

tinzaparin, n = 450: 7.2%

warfarin, n = 450: 10.5% (TTR 47%)

HR 0.65 (95% CI 0.41–1.03) p = 0.07

Lee A. et al. JAMA 2015; 314: 677-86

CATCH. Safety Outcomes

2.0

Major bleeding

Clinically relevant non-major bleeding

Overall mortality

13/449

50/449

150/449

12/451

73/451

138/451

0.89 [0.40, 1.99]

0.69 [0.49, 0.96]

1.08 [0.85, 1.36]

Favors T Favors W

0.0 0.5 1.0 1.5

Event Tinzaparinn/N

Warfarinn/N

HR [95% CI]HR

Lee A. et al. JAMA 2015; 314: 677-86

0.53 (0.36 – 0.76)

Louzada M. et al. Thromb Res 2009; 123: 837-844

Recurrences with LMWH and VKA in patients

with cancer-associated thrombosis

Louzada M. et al. Thromb Res 2009; 123: 837-844

0.98 (0.49 – 1.93)

Bleedings during LMWH and VKA in patients

with cancer-associated thrombosis

Limitations of prolonged LMWH

• Daily injections

• Platelet monitoring

• HIT

• Cost: 8.60 euros to 16.90 euros

• Nurse

• Bruising- hematomas

• Difficult to use over prolonged periods

• Recurrent VTE: 5% to 7% at 3 or 6 months

• Bleeding risk 5% to 7% not lower than VKA

Recurrent VTE: DOA vs VKA

Vedovati MC. et al. Chest. 2015; 147: 475-83

Major bleeding: DOA vs VKA

Vedovati MC. et al. Chest. 2015; 147: 475-83

Patients with cancer: EINSTEIN, CLOT and

CATCH

Einstein

(n = 655)

CLOT

(n = 672)

CATCH

(n = 900)

Recurrent or

metastatic cancer22% 67.3% 54.7%

Anticancer

treatment13%* 77.7%** 42.4%***

% INR 2-3 57%-59% 46% 47%

*: chemotherapy,

**: all anticancer treatments,

***: systemic treatment (chemo or targeted therapy or hormonal treatment)

Lee A. et al. N Engl J Med 2003; 349: 146-153

Prins M H. et al. Lancet Haematol. 2014; 1: e37–46

Lee A. et al. JAMA 2015; 314: 677-86

Conclusion

• Long-term prophylaxis: work in progress..

• LMWH remains the preferred therapeutic option for the

treatment of Cancer Associated Thrombosis.

• LMWH should be given for at least 3 to 6 months.

• These results are supported by the CATCH study.

• The optimal treatment option after 6 months of LMWH

treatment remains to be defined.

• Direct oral anticoagulants should not been used in

patients with CAT, yet