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) 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 1 Cohen AT. Presented at the 5 th Annual Congress of the European Federation of Internal Medicine; 2005. statistics on health and safety 2001. Available from: http: //epp. eurostat. cec. eu. int. 2 Eurostat 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 % 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 at ve Increased age ha ts TE Surgery ien r V at Trauma - major, local d p leg r fo lize facto paralysis Immobilization abedrest, stroke, it - isk Malignancy ande r treatment (CTX, hormonal. . ) osp its h t or respiratory failure os st on Heart M ea l Estrogen use, pregnancy, postpartum, SERMs Central venous lines Thrombophilic abnormalities
Thrombophilia Mutations l 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, S 1: 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
• Patient- disease- treatment related risk factors Is there are Biomarker? • - ? Biomarkers: Recent risk factors Platelet count > 350. 000 WBC >11. 000 CRP TF expression D-dimers Khorana et al. : ASCO Ed. Book, 2008
L. Plawny, M. Dicato: Thrombosis in Cancer in Mellar & Davis, p 275 -283
Physiopathology TF, CP Tumour cells TNF-IL-1 VIIA Xa TF VIIa monocytes endothelial cells Thrombin Platelet aggregation 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/) • a. PTT: decrease is risk of VTE: GWAS: Ile 582 Thr (in KNG 1 gene encoding HMWK) KNG 1 Knock out mice have an increase a. PTT and arterial thrombosis • PS: any SNP contributing to plasma variability, C’ and others; role of inflammation in VTE • v. WF 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…
Physiopathology TF, CP Tumour cells TNF-IL-1 VIIA Xa TF VIIa monocytes endothelial cells Thrombin Platelet aggregation 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- mdm 2/p 53
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) Ansell et al. , Chest 2004; Hirsh et al. , Chest 2004 Warfarin thrombosis Narrow therapeutic window Dose Bleeding Warfarin bleeding Thrombosis • 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
What is New? Clinic: • Prevention of VTE: Semuloparin • Real life VTE Research: • Genome wide association studies
Oral Anticoagulants: • Coumarinics: Pharmacogenetics: CYP 2 C 9 VKORC 1 • 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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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? • 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
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
G. Lyman, Cancer 2011, 117: 1334
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. u 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) u -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 u -1178 patients (Br. J. Haem. 2006, 134: 399) – 109 patients APC resistance, 36 V Leiden – 30/31 acquired APC resistance normalised after Rp
G. Lyman, Cancer 2011, 117: 1334
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