Why is Pancreatic Cancer so Thrombogenic?

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

Total VTE Mortality per Year. (Extrapolated to 25 EU Countries)

DVT PE Mortality following VTE EU 25 684,019 434,723 543,454

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Deaths due to VTE : 543,454 1

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More than double the combined deaths due to:

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AIDS 5,860 2

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breast cancer prostate cancer 86,831 63,636 2 2

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transport accidents 53,599 2

1 Cohen AT. Presented at the 5th Annual Congress of the European Federation of Internal Medicine; 2005.

2 Eurostat statistics on health and safety 2001. Available from: http://epp.eurostat.cec.eu.int.

Adapted from Dr A.T. Cohen’s presentation at the ISTH July 7,2007

Risk of DVT in Hospitalized Patients

• No prophylaxis + routine objective screening for DVT Patient group Medical patients Major gyne/urol/gen surgery Neurosurgery Stroke Hip/knee surgery Major trauma Spinal cord injury Critical care patients DVT incidence 10 - 20 % 15 - 40 % 15 - 40 % 20 - 50 % 40 - 60 % 40 - 80 % 60 - 80 % 15 - 80 %

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

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

Thrombophilia Mutations

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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)

Relative Risk of VTE in Cancer Patients

Stein, Am J Med, 2006

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, p< 0.001, Nalluri) • ESA: RR 1.7

• RBC Transfusions vs none: 7.2 vs 3%

Risk factors for VTE in patients with cancer (2) G. Lyman, Cancer 2011, 117: 1334- 49

MM SHAH JOP, 2010,11:331

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Patient- disease- treatment related risk factors

Is there are Biomarker?

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?Biomarkers: Recent risk factors - Platelet count > 350.000

- WBC >11.000

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CRP

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TF expression

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D-dimers Khorana et al.: ASCO Ed. Book, 2008

L. Plawny, M. Dicato: Thrombosis in Cancer in Mellar & Davis, p275-283

Tumour cells

Physiopathology

TF, CP TNF-IL-1 TF monocytes endothelial cells Thrombin Platelet aggregation VIIA Xa VIIa 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.

Possible roles of TF activity in cancer

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

ASCO 2010: JCO 2010,28(suppl 15):4126

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…

Tumour cells

Physiopathology

TF, CP TNF-IL-1 TF monocytes endothelial cells Thrombin Platelet aggregation VIIA Xa VIIa 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.

Why is Pancreatic Cancer so Thrombogenic?

• Location: retroperitoneal, bedridden..

• Thrombophilic state:TF, Thrombin, GWAS… • Decrease in inhibitors: AT, Prot C&S, thrombomodulin..

• Platelet aggregation increase..

Mucin

• Inflammation: TGF, TNF,… • KRAS- mdm2/p53

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

Limitations of vitamin K antagonists (VKAs)

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

Warfarin thrombosis Warfarin bleeding Narrow therapeutic window Dose Ansell et al., Chest 2004; Hirsh et al., Chest 2004

What is New?

Clinic:

• Prevention of VTE: Semuloparin • Real life VTE

Research:

• Genome wide association studies

Oral Anticoagulants:

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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

Thank You

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Back- up slides

ASCO Guideline: Recommendations for Venous Thromboembolism Prophylaxis and Treatment in Patients with Cancer G.H. Lyman et al.: JCO 2007, 25:5490 - 5505

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

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

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

• All patients should be considered for prophylaxis • Laparotomy, laparoscopy or thoracotomy of >30’ 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

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

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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

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

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Anticoagulants are not recommended to improve survival in patients with cancer without VTE

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Patients with cancer should be encouraged to participate in clinical trials designed to evaluate anticoagulant therapy as an adjunct to standard anticancer therapy

G. Lyman, Cancer 2011, 117: 1334

Acquired APC Resistance (1/2) ASCO 2006:

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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.

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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.

Acquired APC Resistance (2/2)

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-62 patients with MM (Blood Coag. Fibrinolys.:2002,13: 187)

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23% APC resistance at baseline: 50% developed VTE. Increase of VTE with thalidomide, ++ Dexa & ADR

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-1178 patients (Br. J. Haem. 2006, 134: 399)

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109 patients APC resistance, 36 V Leiden 30/31 acquired APC resistance normalised after Rp

G. Lyman, Cancer 2011, 117: 1334