Cancer Associated Thrombosis: An Update Professor Anthony Maraveyas Hull University Teaching Hospitals NHS Trust &Hull-York Medical School.
Disclosures Honoraria: Bristol-Myers Squibb (BMS), Bayer, Daiichi Sankyo • Advisory Boards: BMS, Bayer Leo • Speaker's Bureau: Bayer, Pfizer • Grant: BMS, Leo •
The History of Cancer and Thrombosis Close interrelation between cancer and thrombosis: ‘two-way’ (clinical) association • Thrombosis can occur as a complication of cancer 1 • Thrombosis can be the first presenting sign of occult cancer 2 • Presence of cancer cells in thrombotic material 3 1. Trousseau A. Clin Med Hotel Dieu Paris 1865;3:654–712. 2. Bouillaud JB & Bouillaud S. Arch Gen Med 1823;1:188–204; 3. Billroth T. Lectures on surgical pathology and therapeutics: a handbook for students and practitioners, 1878;2:1829–1894.
Virchow’s Triad in Cancer Associated Thrombosis VASCULAR DAMAGE Damaged or dysfunctional endothelium Loss of anticoagulant nature and therefore acquisition of a procoagulant nature Endothelial layer permeability / Angiogenesis Virchow’s Triad in cancer 2 CIRCULATORY STASIS HYPERCOAGULABILTY Increased vascular compression/distortion Increased blood cell activation and aggregability, e.g., Increased stasis due to immobility (being bed-bound, in NETs ‘tumour educated’ platelets a wheelchair). Loss of haemostasis with increase in pro-coagulants, eg, increased fibrinogen, TF +MVs. Adapted from Blann AD and Dunmore S Cardiology Research and Practice Volume 2011
Possible mechanisms in cancer patients Chemotherapy Tumour TF+ Platelet Monocyte Neutrophil Endothelium cfDNA MVs TF NETs FXIIa NETs P-sel vWF Venous thrombus cfDNA, cell-free DNA; FXIIa, activated factor XII; NETs, neutrophil extracellular traps; P-sel, P-selectin; TF+ MVs, tissue factor-positive microvesicles; TF, tissue factor; vWF, von Willebrand factor. Adapted from Hisada Y et al. J Thromb Haemost 2015;13:1372–1382.
VTE in Patients with Cancer – Cancer-Associated Thrombosis Risk factors: 1 Patient-related A Tumour-related Treatment-related Biomarkers Prevalence and risk ratios: Approximately 20% of first venous thromboembolic events occur in patients with active cancer 2 VTE is a common cause of death in patients with cancer 3–5 VTE recurrence rate is twice as high in patients with VTE and cancer compared with those with VTE and no cancer 2,6,7 Common cancers contribute the greatest burden 2 1. Ay C et al , Thromb Haemost 2017;117:219–230; 2. Cohen AT et al , Thromb Haemost 2017;117:57–65; 3. Horsted F et al, PLoS Med 2012;9:e1001275; 4. Khorana AA et al, J Thromb Haemost 2007;5:632–634; 5. Chew HK et al, Arch Intern Med 2006;166:458–464; 6. Sallah S et al, Thromb Haemost 2002;87:575–579; 7. Stein PD et al , Am J Med 2006;119:60–68 6
Incidence and Prevalence of VTE After Cancer Diagnosis Incidence rate of first VTE Prevalence of first VTE Common cancer types (%) First VTE (N=6592) Pancreas Brain Prostate (men) 17.5 Ovary Breast (women) 15.1 Stomach Lung 13.9 Lung Colon 12.5 Uterus Haematological 10.1 Colon Ovarian (women) 9.5 Haematological Bladder 4.8 Prostate Uterus (women) 4.2 Breast Bladder Pancreas 3.9 0 5 10 15 Stomach 3.6 Incidence rate of first VTE per Brain 2.5 100 patient-years Cohen AT et al , Thromb Haemost 2017;117:57–65
How does the patient present? ‘Unprovoked’ VTE • 4% end up having an underlying cancer diagnosis within 12 months of presentation Hospital acquired • The most lethal – Frailty – Coexisting complications – First and last port of call (advanced presentation with complications) – Procedures (surgery) – Immobility (Bone metastases-Brain metastases) – Bleeding risks (not allowing thromboprophylaxis) – Difficult to diagnose from what else is going on Ambulant • Conventional presentation • Incidental
Effect of Malignancy on Risk of Venous Thromboembolism (VTE) 53.5 • Population-based case-control (MEGA) study 50 N=3220 consecutive patients with 1 st VTE vs. • Adjusted odds ratio n=2131 control subjects 40 • CA patients = 7x OR for VTE vs. non-CA patients 28 30 22.2 20.3 19.8 20 14.3 10 4.9 3.6 2.6 1.1 0 Gastrointestinal 3 to 12 months Lung Breast 0 to 3 months 5 to 10 years > 15 years Hematological 1 to 3 years metastases Distant Type of cancer Time since cancer diagnosis Silver In: The Hematologist - modified from Blom et. al. JAMA 2005;293:715
The Cancer Journey and VTE Risk Start chemo Metastasis + inpatient Diagnosis Relapse Risk of venous thromboembolism Chemo Cancer patient Remission General population Cancer journey Figure adapted from Lyman GH et al. Cancer 2011;117:1334–1349 .
Treatment of Cancer Associated Thrombosis LMWH Vs Warfarin
Warfarin failure in Cancer Patients 30 Warfarin to maintain INR 2–3 Cumulative proportion Major bleeding 12.4% vs 4.9%; HR 2.2 recurrent VTE (%) VTE and bleeding not predicted by INR 20 Cancer 10 20.7% vs 6.8%; HR 3.2 at 1 year No cancer 0 0 1 2 3 4 5 6 7 8 9 10 11 12 Time (months) Number of patients Cancer 181 160 129 92 73 64 No cancer 661 631 602 161 120 115 Prandoni P, et al. Blood. 2002;100:3484-3488.
Frequency of Potentially Interacting Drugs Carbamazepine Erythromycin 3% 3% APAP NSAID‘s 3% 3% Cimetidine Amiodarone 5% 26% Capecitabine Omeprazole 5% Tamoxifen Fluconazole Sorafenib 7% Metronidazole Ciprofloxacin Sunitinib 8% 22% Cotrimoxazole 15% n=59 Twilley C. H. 2002
CLOT Study: Reduction in Recurrent VTE Cancer patients with acute DVT or PE (n=677) 5 to 7 days Dalteparin 200 Control Group IU/kg OD Vitamin K antagonist (INR 2.0 to 3.0) x 6 mo Experimental Group Dalteparin 200 IU/kg OD x 1 mo then ~150 IU/kg OD x 5 mo 1 month 6 months Lee AY, et al. N Engl J Med. 2003;349:146-153.
CLOT Study: Reduction in Recurrent VTE Probability of Recurrent VTE, % Risk reduction = 52% 25 Recurrent VTE p -value = 0.0017 20 OAC 15 10 Dalteparin 5 0 0 30 60 90 120 150 180 210 Days Post Randomization Lee et.al. N Engl J Med, 2003;349:146
Efficacy and Safety Profile of LMWH Versus VKAs in the Treatment of CAT Recurrent VTE Major bleeding events Study RR (95% CI)* ,1 RR (95% CI)* ,1 ARR Study RR (95% CI)* ,1 RR (95% CI)* ,1 ARI CLOT 2 0.51 (0.33–0.79) 7.8% CLOT 2 1.57 (0.79–3.14) 2.0% Hull 3 1.00 (0.38–2.64) 2.1% Hull 3 0.44 (0.19–0.99) 9.0% Deitcher 4 0.66 (0.18–2.52) 3.4% Deitcher 4 3.04 (0.52–18.99) 6.1% Romera 5 0.26 (0.06–1.02) 15.7% CATCH 6 1.09 (0.51–2.32) 0.3% 0.1 0.2 0.5 1 2 5 10 100 CATCH 6 0.69 (0.45–1.07) 3.1% Favours LMWH Favours VKA 0.01 0.1 0.2 0.5 1 2 3 Favours VKA Favours LMWH LMWH is associated with a significant reduction in the risk of recurrent VTE without a significant increase in major bleeding events versus VKA *Random effects model 1. Carrier M, Prandoni P, Expert Rev Hematol 2017;10:15–22; 2. Lee AYY et al, N Engl J Med 2003;349:146–153; 3. Hull RD et al, Am J Med 2006;119:1062–1072; 4. Deitcher SR et al, Clin Appl Thromb Hemost 2006;12:389–396; 5. Romera A et al , Eur J Vasc Endovasc Surg 2009;37:349–356; 6. Lee AYY et al, JAMA 2015;314:677–686
LMWH: Effective and Safe – Residual Burden of Disease LMWH monotherapy LMWH overlapping HR (95% CI) with VKA n/N (%) n/N (%) Recurrent VTE CLOT study* 1 27/336 8.0 53/336 15.8 CATCH study #2 31/449 6.9 45/451 10.0 Meta-analysis ‡3 42/591 7.1 82/571 14.4 Major bleeding CLOT study* 1 19/338 5.6 12/335 3.6 Not reported CATCH study #2 12/449 2.9 11/451 2.4 Meta-analysis §3 37/556 6.7 32/536 6.0 0.1 1 10 Favours LMWH Favours VKA CAT, cancer-associated thrombosis; CI, confidence interval; HR, hazard ratio; LMWH, low molecular weight heparin; VKA, vitamin K antagonist; VTE, venous thromboembolism *Dalteparin versus VKA; in the VKA arm the estimated time in therapeutic range was 46% (30% below and 24% above); # tinzaparin versus warfarin; in the warfarin arm the time in therapeutic range was 47% (26% below and 27% above); ‡ meta-analysis included four other small studies in addition to the CLOT study; § meta-analysis included three other small studies in addition to the CLOT study 1. Lee AYY et al , New Engl J Med 2003;349:146–153; 2. Lee AYY et al, JAMA 2015;314:677–686; 3. Akl EA et al , Cochrane Database Rev 2014;7:CD006650
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