Cancer-associated thrombosis: rationale for an optimal strategy

Cancer-associated thrombosis: rationale for an optimal strategy Prof. Ismail Elalamy Hôpital Tenon. París (Francia) 2015 del autor. Este fichero en pdf y el material que contiene se proporciona para su estudio y se puede imprimir, descargar o enviar por correo electrónico para uso individual. Es necesaria la autorización del propietario del para la difusión pública en webs o mediante listas de distribución de correo electrónico.

CURRENT AND FUTURE ISSUES IN TREATMENT OF CANCER-ASSOCIATED THROMBOSIS I. ELALAMY Service d Hématologie Biologique HÔPITAL TENON INSERM U938 UPMC PARIS

Disclosures Conferences Clinical Studies Board Sanofi X X X Boehringer-Ingelheim X X Pfizer Bristol Myers Squibb X X X Bayer HealthCare X X X Leo-Pharma X X X

Agenda 1. Cancer: a natural prothrombotic disease with a multifactorial basis? 2. LMWH: the Best Anticoagulant Strategy? 3. Recommendations: a Consensual Need to Treat Unmet Needs? 4. Patients Preferences or Praticians Feelings? 5. Economical/Ethical Challenge: Primary Prevention

Cancer: prothrombotic state in 3D Inflammation Angiogenesis Extrinsic Factors Patient HYPERCOAGULABILITY Tumor Metastasis Procoagulant Factors Elalamy et al. Pathol Biol. 2008; 56: 184-194.

Thrombosis and cancer: stratified relation Factors related to Patient Age Comorbidity (heart, kidney ) Previous thrombosis Initial thrombocytosis Thrombophilia (FVL) Diabetes, infection Factors related to Tumor Hyperviscosity Diagnosis 3 months Acquired APCR Inflammation (IL6) Tumor Type (histology) Tumor Stage (mass) Metastasis TNM classification Factors related to Treatment Major Surgery Hospitalization (1 st line) Chemotherapiy (platins ) Anti-angiogenic (Thal, anti- VEGF) Growth Factor (EPO) Venous Central Catheter Radiotherapy Biological Factors (Markers) Haemoglobin, platelets, FVIII, scd62, Tissue Factor, Thrombin Generation, Ddimers, CRP Elalamy et al. Pathol Biol 2008.

Reciprocal relationship: procoagulant environment and oncogenetics D Asti et al. Semin Thromb Hemost. 2014; 40: 284-295.

Contribution of cells interaction to tumor progression investigation of platelets, their surface receptors, released products and their critical influence on coagulation pathways, will help to elucidate the mechanisms of tumour metastasis, as well as metastatic growth. Gay L et al, Nature Rev Cancer 2011; 11:123-134.

NETs (Neutrophils Extracellular Traps) and CAT Fuchs et al. Arterioscler Thromb Vasc Biol. 2012; 32(8): 1777-1783.

Agenda 1. Cancer: a natural prothrombotic disease with a multifactorial basis? 2. LMWH: the Best Anticoagulant Strategy? 3. Recommendations: a Consensual Need to Treat Unmet Needs? 4. Patients Preferences or Praticians Feelings? 5. Economical/Ethical Challenge: Primary Prevention

Lyman et al. J Clin Oncol. 2013; 31: 2189-2204.

LMWH: best antithrombotic option Recurrent VTE Major Bleeding Akl et al. Cochrane Database Syst Rev. 2014; 7: CD006650.

CATCH study: Comparison of Acute Treatment in Cancer Haemostasis Innohep 175 IU/kg anti-xa IU x 6 months N=449 Follow Up Screening Initial Innohep 175 IU/kg x 5-10 days + VKA x 6 months N=451 Follow Up Lee et al. ASH Meeting Dec 2014.

CATCH study: clinical efficacy Warfarin 10.5% TTR 47% Tinzaparin 7.2% Primary Analysis HR (innohep /warfarin) 95% CI P-value Recurrent VTE 0.65 0.41 1.03 0.068 Lee et al. ASH Meeting Dec 2014.

CATCH study: clinical efficacy Event Tinzaparin n/n Warfarin n/n HR HR [95% CI] Symptomatic DVT 12/449 24/451 0.48 [0.24, 0.96] Symptomatic PE 3/449 2/451 NA Fatal PE 17/449 17/451 0.96 [0.49, 1.88] Incidental VTE 0/449 2/451 NA Recurrent VTE (per protocol) 29/351 39/307 0.62 [0.38, 1.00] 0.0 0.5 1.0 1.5 2.0 Favors T Favors W HR, hazard ratio: tinzaparin /warfarin. Competing risk regression analyses adjusting for region, tumor stratum, and history of VTE. NA, not available Lee et al. ASH Meeting Dec 2014.

CATCH study: safety outcomes analysis Event Tinzaparin n/n Warfarin n/n HR HR [95% CI] Major bleeding 13/449 12/451 0.89 [0.40, 1.99] Clinically relevant 50/449 non-major bleeding 73/451 0.69 [0.49, 0.96] Overall mortality 150/449 138/451 1.08 [0.85, 1.36] 0.0 0.5 1.0 1.5 Favors T 2.0 Favors W HR, hazard ratio: tinzaparin /warfarin. Competing risk regression analyses adjusting for region, tumor stratum, and history of VTE Lee et al. ASH Meeting Dec 2014.

CATCH study: discussion CLOT CATCH Recurrent VTE risk reduction, % 52 35 Recurrent VTE in warfarin group, % 17 10 Asian and Middle East enrollment, % 0 44 Metastatic disease, % 67.3 52 ECOG status 2, % 35.5 17 Anticancer treatment, % 77.7 52.9 History of VTE, % 11.1 6.3 Cumulative 6-month mortality, % 39.3 33.2 Lee et al. ASH Meeting Dec 2014.

LMWH heterogeneity Heparin Mean MW (Da) Anti-Xa/ anti-iia Anti-Xa activity/mg UFH 15000 1 193 UI Tinzaparin 6500 1.8 90 IU Dalteparin 6000 2.5 160 IU Enoxaparin 4500 3.6 100 IU Nadroparin 4300 3.2 95-130 IU Reviparin 3800 3.25 106 IU Bemiparin 3600 9 80 IU European Pharmacopoeia 2010.

Non-anticoagulant effects of LMWH Prandoni P, et al. Lancet Oncol. 2005; 6: 401-410.

Clearance of polysaccharide chains UFH LMWH PentaS Reticulo-endothelial System Kidney Long chains Activity anti-xa and anti-iia Short chains Activity anti-xa Holbrook A, et al. Chest. 2012; 141(2 Suppl): e152s-e184s.

VTE, kidney and cancer 1684 patients with VTE and cancer (RIETE + Leiden) Curative Treatment 55% 19% 17% 9% Kooiman J, et al. JTH 2013.

VKA limits in cancer Narrow Therapeutic Window TTR < 50% => Inadequate INR Numerous Food and Drugs Interferences => Dangerous Fluctuations Genetic Polymorphisms => 60% of Instable INR Frequent Gastro-Intestinal Troubles => Pharmacodynamic variability Glossitis and Dysphagia or Mycosis => Complicated Treatment Management Cancer Procoagulant Factors are VKA resistant => Thrombosis extension or recurrence VKA Metabolites Accumulation if Renal Impairement => Increased Bleeding Risk in Cancer pts

VKA and renal impairment: bad association Deaths per 100 pts.year from Stroke: Warfarin users 1.3 vs. Non users 0.4 (n= 746) (n= 925) HR 4.31 (1.44-12.9)

VKA and renal impairment: bad association DELETERIOUS IMPACT ON KIDNEY: Interstitial nephritis Vascularitis Glomerular bleeding Hypoalbuminenia: INR more instable Limdi NA, et al. J Am Soc Nephrol 2009.

Tinzaparin and fragile patients N= 200 patients 175 UI/kg during # 1 month Mean Age 85,2 Mean Clearance Clcr 51,2 25% of pts with a 6,9 yo 22,9 ml/min Clcr 20 to 35 ml/min Mean Weight 58 14 kg No accumulation of tinzaparin (anti-xa activity) 1 fatal bleeding episode (co-morbidities+++) Pautas E et al. Drug Saf. 2002; 25: 725-733.

Enoxaparin and fragile patients MAJOR BLEEDING 6/105 pts (5.7%) with Clcr 80 vs. 13/59 pts (22.0%) with Clcr 30-50 OR 4.7 (95% CI, 1.7-13.0; p= 0.002) DeCarolis D, et al. Arch Intern Med. 2012; 172(22): 1713-1718.

Direct Oral Anticoagulants (DOA) Dabigatran 1 Rivaroxaban 1,2 Apixaban 1,3 Edoxaban 4-6 Target IIa Xa Xa Xa Cmax (h) 1.25-3 2-4 3-4 1-2 CYP metabolism No 2/3 (3A4-2J2) ½ (3A4) <4% Bioavailability 6.5% 80-100% 50% 62% Transporters P-gp P-gp/BCRP P-gp/BRCP P-gp Protein Binding 35% 93% 87% 50% Half-Live (h) 12-14 9-13 8-15 8-10 Renal Clairance 80% (active) 33% (active) 27% (active) 50% (active) Intake Mode BID BID/QD BID QD BCRP = breast cancer resistance protein CYP = cytochrome P450; P-gp = P-glycoprotein 1. Eriksson BI, et al. Clin Pharmacokinet. 2009; 48: 1-22. 2. Xarelto [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; 2011. 3. ELIQUIS Summary of Product Characteristics. Bristol Myers Squibb/Pfizer EEIG, UK. 4. Ruff CR, et al. Am Heart J. 2010; 160: 635-641. 5. Matsushima et al. Am Assoc Pharm Sci. 2011; abstract. 6. Ogata et al. J Clin Pharmacol. 2010; 50: 743-753.

Potential interactions Lee et al. Thromb Res. 2014; 133: S167-S171.

DOA LMWH/VKA RECOVER 1-2 6 months FU Total N= 4772 VTE Rec. Major Bleed. 2.4% 0.8% 2.1% 1.4% Dabigatran 150 mg x 2/d Cancer N= 334 (7%) VTE Rec. Major Bleed. MB + CRNMB* 5.8% 3.8% 14.5% 7.4% 4.6% 13.2% EINSTEIN 6 months FU Total N= 8862 VTE Rec. Major Bleed. 2.1% 1.0% 2.3% 1.7% Rivaroxaban 15 mg x 2/d and 20 mg/d Cancer N= 430 (4.8%) VTE Rec. Major Bleed. MB + CRNMB 2.5% 2.6% 13.5% 4.0% 4.1% 12.0% HOKUSAI VTE 12 months FU Total N= 8292 VTE Rec. CRB* 3.2% 8.5% 3.5% 10.3% Edoxaban 60 mg/d Cancer N= 771 (9,2%) VTE Rec. CRB MB + CRB 3.7% 12.4% 18.3% 7.1% 18.8% 25.3% CRNMB: Clinically Relevant Non Major Bleeding. CRB: Clinically Relevant Bleeding (Major and Non-Major). Van der Hulle. J Thromb Haemost. 2014; 12: 1116-1120. Vedovati et al. Chest. 2015 Feb 1;147(2):475-83

DOA and CAT? Patients with Cancer: co-morbidities and co-medications+++ (anti-fungal, chemotherapy, vomiting, nausea ). Frequent renal impairment: risk of accumulation. Intestinal Troubles: pharmacokinetics and bioavailability? Few patients with active cancer and few informations on patients characteristics (50% K <5 years, heterogeneous +++ ). Comparison with VKA and not LMWH. No documentation on potential drug interferences. Sub-groups analysis: no extrapolation to real life. Specific studies against LMWH: on-going. Lee & Carrier Thromb Res 2014; 33: S167-S171

DOA and CAT? Patients with Cancer: co-morbidities and co-medications+++ (anti-fungal, chemotherapy, vomiting, nausea ). Frequent renal impairment: risk of accumulation. Intestinal Troubles: pharmacokinetics and bioavailability? D Few patients with active cancer and few informations on patients characteristics (50% K <5 years, heterogeneous +++ ). Comparison with VKA and not LMWH. No documentation on potential drug interferences. Sub-groups analysis: no extrapolation to real life. Specific studies against LMWH: on-going. Lee & Carrier Thromb Res 2014; 33: S167-S171

Lyman et al. J Clin Oncol 2013.

Agenda 1. Cancer: a natural prothrombotic disease with a multifactorial basis? 2. LMWH: the Best Anticoagulant Strategy? 3. Recommendations: a Consensual Need to Treat Unmet Needs? 4. Patients Preferences or Praticians Feelings? 5. Economical/Ethical Challenge: Primary Prevention

Thrombosis and cancer: recommendations SOR 2008 CHEST 2012 ISTH 2013 SEOM 2014 ASCO 2013 & 2015 Initial Treatment: LMWH / UFH / pentasaccharide (<10 Days) Long Term Treatment: LMWH Minimal duration 3 months Optimal Duration 6 months Labelled LMWH in this indication: Dalteparin 200 UI/kg o.d. during 1 month then 150 UI/kg o.d. Enoxaparin 150 UI/kg o.d. Tinzaparin 175 UI/kg o.d. Guyatt,G, et al. Chest. 2012; 141; 48S. SOR InCA. Feb 2008. Farge et al. J Thromb Haemost. 2013; 11: 56. Lyman GH, et al. J Clin Oncol. 2013; 31: 2189. SEOM recommendations. Clin Transl Oncol. 2014; 16: 1079. Lyman et al. ASCO update. J Clin Oncol. 2015; 33.

How long is long enough: extended treatment Zwicker & Bauer. J Clin Oncol. 2014; 32: 3596-3599.

Asymptomatic «incidental thrombosis» >2/3 before 6 th month Risk x 3: Metastasis Leukocytes Cys-Platine Incidence Same risks as tic PE On going NCT01727427 (30 centres) Di Nisio et al. Thromb Haemost. 2010; 104: 1049-1054. Van ES, et al. Thromb Res. 2014; 133: S172-S178.

Lyman et al. J Clin Oncol. 2013; 31: 2189-2204.

In case of thrombocytopenia? Lee et al. Blood. 2013; 22(14): 2310-2317.

In case of recurrence? Lee et al. Blood. 2013; 22(14): 2310-2317.

Adherence to guidelines for the treatment of venous thromboembolism in cancer patients RIETE registry: 2945 CAT pts => 51% received LMWH at 3 months Monreal et al. J Thromb Haemost. 2006; 4: 1950-1956 Multicenter Advanced Study for a ThromboEmbolism Registry (MASTER) 424 CAT pts => 64% received VKA Imberti et al. Haematologica. 2008; 93: 273-278 CARMEN study 500 CAT pts => 58% adequate anticoagulation Sevestre et al. J Clin Oncol. 2012; 30(suppl): 1580 Use of LMWH in 600 cancer pts with PE => only 32% received LMWH and shorter period 5,8 months (3,1-8,8) Kleinjan et al. Neth J Med. 2014; 72: 467-472

Agenda 1. Cancer: a natural prothrombotic disease with a multifactorial basis? 2. LMWH is the Best Anticoagulant Strategy? 3. Recommendations: a Consensual Need to Treat Unmet Needs? 4. Patients Preferences or Praticians Feelings? 5. Economical/Ethical Challenge: Primary Prevention

Doctor perceptions on their patients view concerning anticoagulation and CAT 568 doctors and 825 patients of 5 countries Gap between patient view and physician perception of patient view Cimminiello et al. Thromb Res. 2012; 129: 139-145.

Cancer-associated thrombosis, low-molecular weight heparin and the patient experience: a qualitative study Seaman et al Patient Preferences and Adherence 2014; 8 : 453-461

Impact of VTE on quality of life? Major Impact on Daily Life: reduced autonomy basic activities more difficult! Other Disease Different From Cancer: worse context greater distress! Terrible Symptomatology of PE: frightening experience, sensation of imminent death! PE Diagnosis: greater shock than cancer diagnosis overshadowed the negative experienced attributed to cancer! Seaman et al Patient Preferences and Adherence 2014; 8 : 453-461

LMWH acceptability? Demonstrated benefit/risk ratio: acceptable inconvenience and accepted Protection with subcutaneous daily injection: compromise to avoid fear of recurrence Observance and persitence : ritual for systematic injection and routine Optimized tolerance : minimal bruising or fibrosis limited to injection sites multisites and cyclic regimen Confidence and pragmatism : System D to continue! Seaman et al Patient Preferences and Adherence 2014; 8 : 453-461

Agenda 1. Cancer: a natural prothrombotic disease with a multifactorial basis? 2. LMWH: the Best Anticoagulant Strategy? 3. Recommendations: a Consensual Need to Treat Unmet Needs? 4. Patients Preferences or Praticians Feelings? 5. Economical/Ethical Challenges: Primary Prevention

Cost of ThromboEmbolic Episodes (TEE) Retrospective studies (Medicare, Medicaid ) Study Follow-Up Mean Cost of a TEE Bullano et al 2005 Spyropoulos et al 2007 MacDougall et al 2006 Lefebvre et al 2012 21 months DVT : 7 712 $ PE : 9 566 $ DVT + PE : 12 200 $ 1 to 3 years TEE : 11 862 $ 1 year Overcosts of TEE: 16 832 $ > 1 year Overcost of TEE: 15 941 $ Conolly et al 2013 1 year Lung cancer pts: 84 187 $ pts TEE(+) vs 56 818 $ TEE (-) Borget et al. JEICT meeting Paris 2014

Cost of ThromboEmbolic Episodes (TEE) 80.000 74.959 Retrospective study K pts with CT Hospitalizations x 3 in pts with TEE Cout par patient par an ($) 70.000 60.000 50.000 40.000 30.000 20.000 21.299 47.091 29.901 41.691 10.000 0 7.490 6.569 4.331 Avec Evt TE Sans Evt TE Khorana et al., Clinico-econ Outcomes Res. 2013;5:101-8

Cost of recurrent episodes High rate of recurrences (25%) High rate of re-hospitalizations (70%) 14 975 $ / recurrence 2102 $ / year & pt with rec ce Spyropoulos et al 2007.

Thrombosis and cancer: consequences CAT Prevention and Treatment = Ethical and Economical Challenges Noble et al. Br J Cancer. 2010; 102(suppl 1): S2-S9.

Prophylaxis against venous thromboembolism in ambulatory patients with cancer Conors. N Engl J Med. 2014; 370: 2515-2519.

Parenteral anticoagulation in cancer ambulatory patients. Symptomatic VTE Akl et al. Cochrane Database of Systematic Reviews. 2014, Issue 12. Art. No.: CD006652.

Parenteral anticoagulation in cancer ambulatory patients. Symptomatic PE Akl et al. Cochrane Database of Systematic Reviews. 2014, Issue 12. Art. No.: CD006652.

Parenteral anticoagulation in cancer ambulatory patients. Mortality over duration of study Akl et al. Cochrane Database of Systematic Reviews. 2014, Issue 12. Art. No.: CD006652.

Parenteral anticoagulation in cancer ambulatory patients. Major bleeding Akl et al. Cochrane Database of Systematic Reviews. 2014, Issue 12. Art. No.: CD006652.

Parenteral anticoagulation in cancer ambulatory patients. Minor bleeding Akl et al. Cochrane Database of Systematic Reviews. 2014, Issue 12. Art. No.: CD006652.

The effect of LMWH on survival in cancer patients: an updated meta-analysis of randomized trials Sanford et al. J Thromb Haemost. 2014; 12: 1076-1085.

The effect of LMWH on survival in cancer patients: an updated meta-analysis of randomized trials The decision for a patient with cancer to start heparin therapy for survival benefit should balance the benefits and downsides, and should integrate the patient s values and preferences. Akl et al. Cochrane Database of Systematic Reviews. 2014, Issue 12. Art.No.: CD006652 Sanford et al. J Thromb Haemost. 2014; 12: 1076-1085.

Well-informed risk stratification adapted prophylaxis BALANCING THE RISKS PRESCRIBE TO THE HIGH PROSCRIBE TO THE LOW Bleeding risk Thrombotic risk

LMWH and cancer Double face «Janus-like» : Complex actions Multiple connexions Bio-active agent with anti-tumoral effects to notice and reinforce!

LMWH and cancer Double face «Janus-like» : Complex actions Multiple connexions Facing all Faces Bio-active agent with anti-tumoral effects to notice and reinforce!

Thrombosis and Cancer STAY AWARE!