2/28/16. Cancer and Venous Thromboembolism. Outline. 1. Pathophysiology and Clinical Relevance. No Disclosures

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1 Cancer and Venous Thromboembolism No Disclosures Bob Richard, MD PhD VA Puget Sound Assoc Prof UW School of Medicine Outline 1. Pathophysiology and Clinical Relevance 2. Screening For Occult Malignancy in unprovoked thrombosis 3. Unsuspected/subsegmental PE 4. How Long to Treat and with What 5. Role for Target-specific Oral AnScoagulants 6. Primary Thrombosis Prophylaxis 1. Pathophysiology and Clinical Relevance 20% of cancer pasents develop VTE at some point during their illness. 20% of VTE occurs in cancer pasents. Heit, 2005; Prandoni et al, 2005; Hillen, Thrombosis (arterial and venous) is second leading cause of death in cancer. Khorana AA et al. JTH 5: , Thrombosis in cancer signifies aggressive disease, not simply manifestason of late stage. 3 1

2 Thrombosis and Cancer: A Bad CombinaSon Exposure Person-years Deaths (n) MR per 100 Person-years HR (95% CI) None 277,713 1, ( ) 1.0 (reference) VTE only 1, ( ) 2.6 ( ) Cancer only 5, ( ) 7.4 ( ) Cancer + VTE ( ) 31.2 ( ) Braekkan SK, et al. Am J Epidemiol. 2010;171(10): MetastaSc Disease = Higher Risk Alcalay et al. J Clin Oncol : MetastaSc Disease = Higher Risk Chew et al. Arch Intern Med. 2006;166(4):

3 Tumor Type and Thrombosis Risk Horsted F. PLoS Med. 2012;9(7):e average overall risk: 13 per 1,000 pt-yrs Virchow s Triad: Pathophysiology Of Thrombosis Altered blood vessel wall Altered blood flow/venous stasis Cancer Increase in blood coagulability Why is the Coagulant PotenSal of the Blood Increased in Cancer PaSents? 1. Tissue Factor: Tumor cells directly produce and release Tissue Factor. Tissue Factor circulates in microparscles and may result in systemic thrombosc risk. By promosng thrombin formason, TF leads to platelet acsvason. 2. Platelets: Early literature suggested role of platelets adhesion/metastasis of malignant cells. Elevated platelet count increases thrombosis rates in cancer. Khorana AA & Connolly GC. JCO. 27: , Mucin SecreSon (adenocarcinoma): May promote platelet acsvason. May explain why heparins are more effecsve than warfarin. 3

4 Why is the Pro-ThromboSc State Beneficial to the Cancer Cell? Fibrin deposison Stabilizes adhesion of metastasc cell to endothelium Platelet acsvason Protects tumor cell from anack by host immune system Palumbo et al. Blood 2004; 105: Ruf et al. Semin Thromb Hemost 2006; 32: Horowitz et al. Blood 2010; 116: TF Expression is Markedly Increased in PancreaSc Cancer, Compared With Normal PancreaSc Epithelium. Nitori N. et al. Clin. Canc. Res. 11, , Should we search for Occult Malignancy in unprovoked thrombosis? ~ 10% of pasents with unprovoked VTE will have cancer diagnosed within 12 months Time period Unprovoked Thrombosis Provoked Thrombosis Baseline To 6 mo. 8.6 % 2.4 % 6 12 mo. 1.4 % 0.5% Carrier et al. Ann Intern Med. 2008;149:

5 2. Screening For Occult Malignancy in Unprovoked VTE Extensive evaluason (e.g. CT abd/pelvis) increases the proporson of previously undetected cancers 49.5% (Limited screening) vs. 69.5% (Extensive screening)* At least 50% of pasents already have metastasc disease when their cancer becomes clinically evident Whether the earlier detecson of these cancers means that an Extensive Screening strategy will translate to bener survival is not known *Carrier et al. Ann Intern Med. 2008;149: Timp et al. Blood.2013;122: Extensive vs. Limited: Comparison of 2 centers Van Doormal et al. J Thromb Haemost. 2011;9(1): Unsuspected Pulmonary Embolism Pulmonary emboli idensfied on CT scans performed for other reasons Most insstusons now using highly sensisve CT machines for rousne oncology staging scans Incidence 3-6% depending on slice thickness, reader Higher in inpasents, older pasents 2 Smes more common in cancer pasents Farrell, et al. Clin Radiol 2010;65:1-5. Ritchie, et al. Thorax 2007;62: Dentali et al. Thromb Res Jun;125(6):

6 AsymptomaSc VTE (DVT or PE) associated with a poor prognosis All 62 pasents were ans-coagulated 92% LMWH, 8% warfarin 45% (28/62) died within 6 months of asymptomasc VTE diagnosis 27 % mortality in controls with similar age, tumor type/stage, chemo, epo use Dentali et al J Thromb Haemost May;9(5): Unsuspected PE = Decreased Survival Probability O Connell et al JTH 2011; 9: CumulaSve Recurrent VTE Common Whether Index Event is SymptomaSc or Not den Exter P L et al. JCO 2011;29:

7 CumulaSve Overall Survival is Poor Whether PE is SymptomaSc or Not den Exter P L et al. JCO 2011;29: Unsuspected PE: Where Do They Occur? Browne et al. J Thoracic Oncol 2010;5: Main 7 (10%) Lobar 26 (37%) Segmental 20 (29%) Subsegmental 17 (24%) O Connell CL et al. J Thromb Haemost Feb;9(2): O Connell et al JTH 2011; 9:

8 Sub-segmental Pulmonary Embolism More Common with Modern Scanners Single-detector CT MulS-detector CT (MDCT) MDCT 4 detectors MDCT 16 detectors MDCT 64 detectors N % SSPE Carrier M., et al. J Thromb Haemost 2010; 8: Older vs. Newer CT Scanners: No Difference in 3-month rate of VTE Single-detector CT MulS-detector CT (MDCT) MDCT 4 detectors MDCT 16 detectors MDCT 64 detectors N Rate of VTE in f/u Carrier M., et al. J Thromb Haemost 2010; 8: How Long Should we Treat a Cancer PaSent for VTE, and With What Drug? 8

9 Can We Predict Which Cancer PaSents Are Most Likely to Have Recurrent VTE? + 1 point for being a woman + 1 point for having lung cancer + 1 point for prior VTE. PaXents received - 1 point for breast cancer - 1 point for localized cancer (without metastasis) 1 High Risk 0 Intermediate Risk - 1 Low Risk Louzada et al. CirculaSon 2012; 126: CumulaSve Risk of Recurrent VTE den Exter et al. J Thromb Haemost 2013; 11: Daltecan: What are the consequences of extending dalteparin beyond 6 months? Assess consequences of extending dalteparin in cancer-associated VTE MulScenter cohort study dalteparin 200 IU/kg daily X 1month Then, dalteparin 150 IU/kg daily for up to 11 months 50 sites in the United States, Europe, and Canada Kakkar, A. et al. Abstract PresentaSon, ISTH Conference, Amsterdam

10 Daltecan Study Kakkar, A. et al. Abstract PresentaSon, ISTH Conference, Amsterdam Daltecan Study Kakkar, A. et al. Abstract PresentaSon, ISTH Conference, Amsterdam Role of New Direct Oral AnScoagulants: Should we use the new oral anscoagulants for VTE treatment in cancer? Dabigatran (Pradaxa ): Direct Thrombin Inhibitor Rivaroxaban (Xarelto ): FXa inhibitor Apixaban (Eliquis ): FXa inhibitor All 3 approved for non-valvular atrial fibrillason, All 3 appear to be at least as effecsve and safe as standard therapies for Acute VTE treatment Secondary VTE prevenson 10

11 New Oral AnScoagulants In Cancer PaSents VTE treatment studies with the new agents included few cancer pasents (< 10%). VTE treatment studies used warfarin as the control arm, but warfarin is not the preferred DVT/PE treatment strategy in cancer pasents. One More Time! If 1. LMWH > warfarin And 2. NOAC ~ warfarin Then you cannot conclude NOAC ~ LMWH! Other QuesSons For New Oral AnScoagulants In Cancer PaSents No reversal agent. Virtually no experience in pasents with thrombocytopenia. InteracSons with chemotherapy agents not tested. 11

12 6. Primary Thrombosis Prophylaxis Is there a role for thrombosis prophylaxis in outpasent, ambulatory cancer pasents prior to development of a thrombosis? Primary VTE PrevenSon in OutpaSents with Cancer Overall annual risk in unselected populason receiving chemotherapy: 10.9%* Highly variable (? 2 20%? Annual) Tumor type: Pancreas > lung >> breast, prostate Chemotherapy significantly increases risk Cis-plaSn, ans-angiogenic agents are notorious Difficult to define VTE risk Front-loaded events Different follow-up intervals High overall mortality * Onen, et al. Arch Intern Med 2004; 164: Meta-Analysis of VTE LMWH Prophylaxis Studies Statistics for each study MH risk ratio and 95% CI MH risk Lower Upper ratio limit limit p-value FAMOUS TOPIC TOPIC PRODIGE PROTECHT SIDERAS Other Cancers CONKO FRAGEM Pancreas < LMWH Control Kuderer et al ASH

13 Primary VTE PrevenSon in OutpaSents: Proof of Concept Study Tumor Comparison DuraSon N PROTECHT SAVE-ONCO Lung, colon, breast Mostly lung, GI, ovarian Low-dose LMWH vs. placebo (2.0% vs. 3.9%) Semuloparin vs. placebo (1.2% vs. 3.4%) 4 months 1150 Length of chemo + 1 month 3200 CONKO-004* Pancreas FULL-dose LMWH vs. No Rx (1.3% vs. 9.9%) UK FRAGEM Pancreas FULL-dose LMWH vs. No Rx (3.4% vs. 23%) Lethal VTE: (0% vs. 8.3%) 3 months months 123 * Presented as abstract only 12-months LMWH (vs. not) in Cancer PaSents Treated with Chemo Akl, E. NEJM Conclusions from primary prevenson studies to date Wide variason in VTE risk Treatment doses of anscoagulants may be preferable The hypothesis that VTE prevenson may result in survival benefit remains tantalizing but unproven Need to idensfy high-risk pasents; risk and cost of primary prevenson not jussfied in low-risk pasents 13

14 Conclusions Consider the cancer and consider the risk (easier said than done) Not ready to recommend the NOACs Clots need to be treated New guidelines will be coming! Many thanks to my expert David Garcia 14