Why is Pancreatic Cancer so Thrombogenic?

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Why is Pancreatic Cancer so Thrombogenic?

• M. DICATO M.D., FRCP
• Hematology- Oncology
• Centre Hospitalier
• L- 1210 Luxembourg

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Total VTE Mortality per Year. (Extrapolated to 25
EU Countries)
EU 25
DVT 684,019
PE 434,723
Mortality following VTE 543,454

• Deaths due to VTE 543,4541
• More than double the combined deaths due to
• AIDS 5,8602
• breast cancer 86,8312
• prostate cancer 63,6362
• transport accidents 53,5992

1Cohen AT. Presented at the 5th Annual Congress
of the European Federation of Internal Medicine
2005. 2Eurostat statistics on health and safety
2001. Available from http//epp.eurostat.cec.eu.i
nt.
Adapted from Dr A.T. Cohens presentation at the
ISTH July 7,2007
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Risk of DVT in Hospitalized Patients

• No prophylaxis routine objective screening for
  DVT

Patient group DVT incidence
Medical patients 10 -
20 Major gyne/urol/gen surgery 15 - 40
Neurosurgery 15
- 40 Stroke
20 - 50 Hip/knee surgery
40 - 60 Major trauma
40 - 80 Spinal cord injury
60 - 80 Critical care
patients 15 - 80
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Risk Factors for VTE

• Previous venous thromboembolism
• Increased age
• Surgery
• Trauma - major, local leg
• Immobilization - bedrest, stroke, paralysis
• Malignancy and its treatment (CTX, hormonal..)
• Heart or respiratory failure
• Estrogen use, pregnancy, postpartum, SERMs
• Central venous lines
• Thrombophilic abnormalities

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Risk Factors for VTE

• Previous venous thromboembolism
• Increased age
• Surgery
• Trauma - major, local leg
• Immobilization - bedrest, stroke, paralysis
• Malignancy and its treatment (CTX, hormonal..)
• Heart or respiratory failure
• Estrogen use, pregnancy, postpartum, SERMs
• Central venous lines
• Thrombophilic abnormalities

Most hospitalized patients have at least one risk
factor for VTE
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Thrombophilia Mutations

• In cancer patients with VTE, testing for
  mutations VLeiden, PT, (MTHFR ) is only
  useful if there is a previous personal or family
  history of VTE

(M. Dicato et al. Blood 2001,S1 3984)
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Relative Risk of VTE in Cancer Patients
Stein, Am J Med, 2006
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VTE Risk and Cancer

• Rate of growth and spread
• Sites pancreas (rate 8.1), kidneys ovaries
  (5.6), stomach (4.9)..
• Therapy thalidomide, lenalidomide (?),
  bevacizumab (2 fold arterial thrombosis p 0.031,
  VTE none, posthoc analysis, Scapatacci
  meta-analysis VTE RR 1.33, plt 0.001, Nalluri)
• ESA RR 1.7
• RBC Transfusions vs none 7.2 vs 3

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Risk factors for VTE in patients with cancer
(2) G. Lyman, Cancer 2011, 117 1334- 49
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MM SHAH JOP, 2010,11331
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• Patient- disease- treatment related risk factors
• Is there are Biomarker?
• ?Biomarkers Recent risk factors
• - Platelet count gt 350.000
• - WBC gt11.000
• CRP
• TF expression
• D-dimers

Khorana et al. ASCO Ed. Book, 2008
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L. Plawny, M. Dicato Thrombosis in Cancer in
Mellar Davis, p275-283
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Physiopathology
Pathways of activation of coagulation in cancer
TF (tissue factor) and CP (cancer procoagulant)
activate factors VIIa and Xa. TNF (tumour
necrosis factor), IL-1 (interleukin-1) induce TF
expression on monocytes and on endothelial cells.
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Possible roles of TF activity in cancer

• initiation of a hypercoagulable state and
  thrombosis
• primary tumor growth angiogenesis
• secondary tumor spread - metastasis

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ASCO 2010 JCO 2010,28(suppl 15)4126
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RISK FACTORS FOR VTE IN CANCER PATIENTS

• Patient related
• Age
• Comorbidity
• Prior history of VTE
• High platelet count
• Cancer related
• Primary (GI, brain,)
• Initial 3-6 mo of diagnosis
• Current metastatic disease
• Treatment related
• Major surgery (factor 3)
• Hospitalisation
• Chemo-or hormonal therapy (factor 6,5)
• Anti-angiogenic Rp (thalidomide, lenalidomide,
  ?bevacizumab?)
• ESAs
• Central venous catheter

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GWAS in VTE (www.genome.gov/gwastudies/)

• aPTT decrease is risk of VTE GWAS Ile582Thr
  (in KNG1gene encoding HMWK)
• KNG1 Knock out mice have an increase aPTT and
  arterial thrombosis
• PS any SNP contributing to plasma variability,
  C and others role of inflammation in VTE
• vWF increase
• Other GWAS data
• Prot C level interference
• Plasminogen activator inhibitor-1 (PAI-1), MPV
  SNPs variability on ABO VTE, lipids,
  inflammatory markers, DM type 2 and CHD.
• Overall these risk are 1- 1.5. Multiple SNPs with
  modest effect and rare variants with stronger
  impact add DNA methylation modif, histone
  modifications

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Physiopathology
Pathways of activation of coagulation in cancer
TF (tissue factor) and CP (cancer procoagulant)
activate factors VIIa and Xa. TNF (tumour
necrosis factor), IL-1 (interleukin-1) induce TF
expression on monocytes and on endothelial cells.
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Why is Pancreatic Cancer so Thrombogenic?

• Location retroperitoneal, bedridden..
• Thrombophilic stateTF, Thrombin, GWAS
• Decrease in inhibitors AT, Prot CS,
  thrombomodulin..
• Platelet aggregation increase..Mucin
• Inflammation TGF, TNF,
• KRAS- mdm2/p53

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ASCO 2010, Riess H. et al. Prospective
randomised trial of simultaneous pancreatic
cancer treatment with enoxaparin and
chemotherapy Final results of the CONKO-004
trial, JCO 2010, 28( Suppl.15) 4033
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Limitations of vitamin K antagonists (VKAs)

• Unpredictable pharmacology
• Narrow therapeutic window
• Difficult to keep within therapeutic range
• Multiple drugdrug and fooddrug interactions
• Dosing problems in the initial phase of therapy
• Increased risk of major and minor bleeding

Warfarin thrombosis
Warfarin bleeding
Narrow therapeutic window
Thrombosis
Bleeding
Dose
Ansell et al., Chest 2004 Hirsh et al., Chest
2004
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What is New?

• Clinic
• Prevention of VTE Semuloparin
• Real life VTE
• Research
• Genome wide association studies

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Oral Anticoagulants

• Coumarinics
• Pharmacogenetics CYP2C9
• VKORC1
• Antithrombins
• Ximelagatran hepatotoxicity, off market EMEA
  2008
• Dabigatran
• Anti Xa
• Rivaroxaban (Xarelto) marketed 2008/2009 VTE
  med. 2011
• Dabigatran (Pradaxa)
• Apixaban

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Thank You
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Back- up slides
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ASCO Guideline Recommendations for Venous
Thromboembolism Prophylaxis and Treatment in
Patients with CancerG.H. Lyman et al. JCO
2007, 255490 - 5505
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1. Should hospitalized patients with cancer
receive anticoagulation for VTE prophylaxis?

• Recommendation hospitalized patients with cancer
  should be considered candidates for VTE
  prophylaxis in the absence of bleeding or other
  anticoagulant contraindications

JCO 2007
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2. Should ambulatory patients with cancer
receive anticoagulation for VTE
prophylaxis during systemic chemotherapy?

• Routine prophylaxis not recommended
• Thalidomide or lenalidomide with chemotherpy or
  dexamethasone is a high risk and warrants
  prophylaxis
• Randomised controlled studies needed
• Research identifying better risk markers needed

JCO 2007
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3. Should patients with cancer undergoing
surgery receive perioperative VTE prophylaxis?

• All patients should be considered for prophylaxis
• Laparotomy, laparoscopy or thoracotomy of gt30
  should receive prophylaxis unless contraindicated
• Prophylaxis should be started preoperatively or
  as soon as possible postoperatively
• Mechanical methods may be added
• Prophylaxis to be continued for at least 7-10
  days, up to 4 weeks to be considered in major
  abdominal or pelvic surgery for cancer with
  high-risk (residual malignant disease, obesity)
  and with a history of previous VTE

JCO 2007
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4.What is the best treatment for patients with
cancer with established VTE to prevent recurrent
VTE?

• LMWH for initial 5-10 days
• LMWH for at least 6 months is preferred. VKA with
  a target INR of 2-3 is acceptable, when LMWH not
  available
• After 6 months consider indefinite
  anticoagulation for selected patients with active
  cancer
• Vena cava filter is only indicated for patients
  with contraindications to anticoagulant therapy
  and recurrence needing long term treatment
• For patients with CNS malignancies
  anticoagulation is recommended as for other
  cancer patients. To be avoided in active
  intracranial bleeding, recent surgery, bleeding
  diathesis
• For elderly patients as for other patients with
  close monitoring

JCO 2007
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5. Should patients with cancer receive
anticoagulants in the absence of established VTE
to improve survival

• Anticoagulants are not recommended to improve
  survival in patients with cancer without VTE
• Patients with cancer should be encouraged to
  participate in clinical trials designed to
  evaluate anticoagulant therapy as an adjunct to
  standard anticancer therapy

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G. Lyman, Cancer 2011, 117 1334
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Acquired APC Resistance (1/2)

• ASCO 2006 ? 8563 adriamycin and epirubicin
  downregulate endothelial Protein C receptor and
  impair the APC (activated protein C) pathway. The
  conversion of Protein C to APC is hampered.
• After the treatment with these anthracyclins 25
  of patients had a low APC.
• Conclusion This might be one of the
  contributing factors of chemotherapy induced
  thrombophilia.

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Acquired APC Resistance (2/2)

• -62 patients with MM (Blood Coag.
  Fibrinolys.2002,13 187)
• 23 APC resistance at baseline 50 developed
  VTE. Increase of VTE with thalidomide, Dexa
  ADR
• -1178 patients (Br. J. Haem. 2006, 134 399)
• 109 patients APC resistance, 36 V Leiden
• 30/31 acquired APC resistance normalised after Rp

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G. Lyman, Cancer 2011, 117 1334