Thromboprophylaxis For The Ambulant ‘Medical’ Cancer Patient Anthony Maraveyas FRCP, PhD Dpt. Academic Oncology (PGMI) Effect of Malignancy on Risk of Venous Thromboembolism (VTE) 53.5 40 30 • Population-based case-control (MEGA) study • N=3220 consecutive patients with 1st VTE vs. n=2131 control subjects • CA patients = 7x OR for VTE vs. non-CA patients 28 22.2 20.3 19.8 20 14.3 10 4.9 Type of cancer 1.1 > 15 years 2.6 5 to 10 years 1 to 3 years 3 to 12 months 0 to 3 months Distant metastases Breast Gastrointestinal 0 Lung 3.6 Hematological Adjusted odds ratio 50 Time since cancer diagnosis Silver In: The Hematologist - modified from Blom et. al. JAMA 2005;293:715 Thromboprevention in the Ambulant Cancer Patient : Warfarin • Double-blind, placebo-controlled RCT demonstrated the efficacy of low-intensity warfarin (*INR 1.3-1.9) in patients receiving chemotherapy for metastatic breast cancer • 311 women with metastatic breast cancer on 1st- or 2nd-line chemotherapy • Randomized to 1 mg warfarin for 6 weeks, then warfarin titrated to INR 1.3-1.9 or placebo • 1 VTE in warfarin group vs 7 in placebo arm • 85% risk reduction, P = .03, with no increased bleeding Levine M, et al. Lancet. 1994;343:886-889. *INR=international normalized ratio n=59 Twilley C. H. 2002 Capecitabine Tamoxifen Sorafenib Sunitinib n=59 Twilley C. H. 2002 Cumulative Incidence Of Major Bleeding On Warfarin % 20 Warfarin to maintain INR 2–3 Major bleeding 12.4% vs 4.9%; HR 2.2 P = 0.019 15 10 Cancer 5 Non-Cancer Months 2 Prandoni P, et al. Blood. 2002;100:3484-3488. 4 6 8 10 12 Recurrent thrombosis while on Warfarin Cumulative proportion recurrent VTE (%) 30 20.7% vs 6.8%; HR 3.2 at 1 year 20 Cancer 10 No cancer 0 0 Number of patients Cancer 181 No cancer 661 1 2 3 4 5 6 7 8 9 10 11 12 Time (months) 160 631 129 602 Prandoni P, et al. Blood. 2002;100:3484-3488. 92 161 73 120 64 115 LMWHs- Thromboprevention RCTs in Cancer RCTs Kakkar et al Sideras et al Altimbas et al Freund et al Gatzemeier et al Perry et al ACRONYM FAMOUS - - TOPIC-1 TOPIC-2 PRODIGE LMWH dose 5,000 U Continuous 5,000 U Continuous 5,000U for 18 /52 3,000 u For 6 /12 3,000 u For 6 /12 5,000 u For 6/12 (12 /12 option) Dalteparin Dalteparin Dalteparin Certoparin Certoparin Dalteparin Cancer Type All Cancers All Cancers SCLC Breast Cancer NSCLC Glioma Clinical VTE (C vs E) % 3 Vs 2 7 Vs 6 2.4 Vs 0 4 vs 3.9 8.3 vs 4.5 17 vs 11 Agent Strategy 1 : Treat ‘Cancer’ as a generic diagnosis ● Large trials but with little attention paid to – – – – – – – Anatomical site Time from diagnosis Accurate staging Grade of Histology Performance status Line of treatment Previous response ● 1PROTECHT – 1166 patients- 3800 units Nadroparine sc-od • The first significant difference • VTE incidence from 3.9% reduced to 2.0% • Risk reduction 49% 1Agnelli et al (2009) Lancet Oncol 2009; 10: 943-949. Thromboprophylaxis in ambulatory cancer patients receiving chemotherapyAgnelli PROTECHT study ● Patients with solid tumours receiving chemotherapy randomised (2:1) to nadroparin 3800 IU od or placebo for up to 4 months Overall VTE Nadroparin Placebo p value, RRR, NNT 2.0% (15/769) 3.9% (15/381) Single-sided p=0.024, RRR 49.6%, NNT 50.5 RRR 61.2%, NNT 18.9 VTE rates in cancer subgroups Lung 3.5% (7/199) 8.8% (7/80) Gastrointestinal 1.5% (4/272) 2.7% (4/148) – Pancreas 8.3% (3/36) 5.9% (1/17) – Other 0.4% (1/262) 2.2% (3/136) – 1. Agnelli G et al. Lancet Oncol 2009; 10: 943-949. 2. Agnelli G et al. Debate presentation at ICTHIC 2010. Thromboprophylaxis in ambulatory cancer patients receiving chemotherapy ● PROTECHT (lung cancer patients; nadroparin vs placebo)1 and TOPIC-2 (lung cancer patients; certoparin vs placebo)2 ad hoc combined analysis LMWH Placebo RR (95% CI), NNT/H Symptomatic thromboembolic events PROTECHT 3.5% (7/199) 8.8% (7/80) TOPIC-2 3.0% (8/268) 5.7% (15/264) Total 3.2% (15/467) 6.4% (22/344) PROTECHT 1.0% (2/199) 0 (0/80) TOPIC-2 3.7% (10/273) 2.2% (6/273) Total 2.5% (12/472) 1.7% (6/353) RR 0.50 (0.26–0.95) NNT 31 Major bleeding Agnelli G et al. Debate presentation at ICTHIC 2010. Adapted from 1. Agnelli G et al. Lancet Oncol 2009; 10: 943-949. And 2. Haas S et al. J Thromb Haemost 2005; 3 (suppl 1): OR059. RR 1.50 (0.57–3.95) NNH 125 Strategy 2 : ‘Cancer’ remains a generic diagnosis but select ‘High Risk’ groups Characteristic OR P value 3.88 1.86 1.5 0.03 0.0076 0.05 0.32 Pre-chemotherapy platelet count > 350,000/mm3 2.81 0.0002 Hgb < 10g/dL or use of red cell growth factor 1.83 0.03 Use of white cell growth factor in high-risk sites 2.09 0.008 Site of Cancer Upper GI Lung Lymphoma Khorana, Cancer, 2005 Predictive Model Patient Characteristic Score Site of Cancer Very high risk (stomach, pancreas) High risk (lung, lymphoma, gynecologic, GU excluding prostate) 2 1 Platelet count > 350,000/mm3 1 Hgb < 10g/dL or use of ESA 1 Leukocyte count > 11,000/mm3 1 BMI > 35 1 Khorana AA et al. JTH Suppl Abs O-T-002 Incidence of VTE Over 2.4 Months Predictive Model Actual Incidence Estimated Incidence 95 % Confidence Limits 18% 16% 14% 12% 10% 8% 6% 4% 2% 0% 0 1 2 3 4 Risk Score 0 1 2 3 4 N 1,352 974 476 160 33 VTE(%) /2.4 mo.s 0.8 1.8 2.7 6.3 13.2 Predicting VTE risk in cancer patients ● Biomarkers predictive of VTE have been identified, which could be added to the risk score: – Tissue factor: pancreatic cancer patients with high TF expression (in the tumour) had a venous thromboembolism rate of 26.3% compared with 4.5% in patients with low TF expression (p=0.04) 1 – Thrombin generation: patients with high peak thrombin generation (>75th percentile) had a significantly greater risk of VTE than other patients in the Vienna CATS study [HR 2.0 (95% CI 1.3–3.2), p=0.003) 2 – sP-selectin and d-dimer: adding these to the Khorana risk score allowed the identification of patients with a very high risk of VTE (30.3% for those with a score of >5) 3 1. Khorana AA et al. Clin Cancer Res 2007; 13: 2870-2875. 2. Ay C et al. Thromb Res 2010; 125: S166-S191 (abstract PO-32). 3. Ay C et al. J Thromb Haemost 2009; 7 (Suppl 2): OC-TU-016. Strategy 3: Study the anti-coagulant as an anti-cancer agent ● Imagine you are not studying a –rin but you are studying a –nib ● Single malignancy - Stage - Line - Identical ‘Cancer’ treatment - Accurately described (e.g dose intensity) - Performance Status - Survival risk modelling - E.g. Motzer, Childs Pugh etc - Previous surgery to primary - Histological parameters 16 Gemcitabine with or without prophylactic weight-adjusted dalteparin (WAD) in patients with advanced or metastatic pancreatic cancer (APC): a multicentre, randomised phase IIB trial. The UK FRAGEM study A. Maraveyas, J. Waters, R. Roy, D Fyfe, D. Propper, F. Lofts, E. Gardiner, J. Sgouros K.R. Wedgwood. The Queen’s Oncology & Hematology Centre, Hull. Kent Oncology Centre, Maidstone Diana Princess of Wales, Grimsby Lancaster Royal Infirmary, Lancaster St Bartholomew’s Hospital, London St George’s Hospital Medical School London Incidence of VTE Within 2 Years of Diagnosis of 5 Different Types of Cancer (235,149 cases) With regional-stage disease Adapted from Chew et al, Arch Intern Med 2006. With metastatic disease FRAGEM Study Design Eligibility Criteria: Inoperable Advanced Pancreatic Cancer Stratification factors PS (90-100 vs 60-80) Metastatic vs Locally Advanced Primary endpoint : Reduction of all-type VTE Secondary endpoints: Toxicity, effect on EDB, PFS,TTTF,OS. Dose-Schedule: Dalteparin 12 weeks sc od 200 IU/kg week 1-4 and 150 IU/kg week 5-12 (CLOT investigator’s WAD) Gemcitabine 1000 mg/m2 weekly (Burris schedule) Maraveyas A et al. Thromb Res 2010; 125: S166-S191 (abstract OC-02). R A N D O M I Z A T I O N Gemcitabine + Dalteparin 1:1 Gemcitabine Thromboprophylaxis in ambulatory cancer patients receiving chemotherapy FRAGEM study ● Patients with inoperable or metastatic advanced pancreatic cancer randomised to gemcitabine + weight-adjusted dalteparin (CLOT schedule) or gemcitabine alone for 12 weeks Gemcitabine (n=63) Gemcitabine + RR, (95% CI), p value dalteparin (n=60) ‘All-type’ VTE overall 31% 12% RR 0.380 (0.172, 0.840) p<0.02 Clinical VTE overall 24.2% 8.5% RR 0.350 (0.136, 0.903) p=0.038 ‘All-type’ VTE <100D 25% 3.5% RR 0.138 (0.033, 0.578) p<0.002 Clinical VTE <100D 17.7% 0% RR 0.046 (0.003, 0.758) p<0.001 9% 0% RR 0.083 (0.005, 1.447) p=0.028) Fatal VTE <100D Maraveyas A et al. Thromb Res 2010; 125: S166-S191 (abstract OC-02). Thromboprophylaxis in ambulatory cancer patients receiving chemotherapy FRAGEM study Secondary endpoints ● ● ● ● Low SAE (3% major bleed n.d) No difference in overall survival No difference in time to treatment failure No difference in response rate Conclusions ● WA-dalteparin in APC was well tolerated ● During the WA-dalteparin period there was almost total prevention of VTE and total prevention of the clinical impact of VTE – Maraveyas A et al. Thromb Res 2010; 125: S166-S191 (abstract OC-02). Prevention of fatal VTE ● Significant reduction in all-type VTE throughout the patients’ lifetime was also found ● WA-LMWH thromboprophylaxis with first-line gemcitabine in APC should now be considered a standard of care, with WAdalteparin for 3 months being an option Thromboprophylaxis in ambulatory cancer patients receiving chemotherapy Ongoing studies Study (agent) SAVE-ONCO (semuloparin up to 4 mos) Criteria for inclusion* Lung, bladder, GI, ovary N Endpoints 3200 DVT, PE, VTErelated death Metastatic or locally advanced PHACS (dalteparin x 12 weeks) Risk score >3 404 Asymptomatic and symptomatic VTE MicroTEC (enoxaparin x 6 mos) Lung, colon, pancreas 227 VTE Metastatic or unresectable Elevated TF-MPs *All studies enrol patients initiating a new chemotherapy regimen Connolly GC & Khorana AA. Thromb Res 2010; 125: S1-S7. BEST Strategy ● Combination of all three Strategies? – Cancer drug approach in Model Malignancy • Pancreatic Cancer – Biggest bang for buck? » If you can’t prove efficacy and cost effectiveness in this model what chances elsewhere? • Correct dose and duration of anticoagulant – Risk Modelling • Within the malignancy setting chosen – Previous DVT – Diabetes? – High platelets-WBC – Caucasians ( Western diet –lifestyle -risk factors) – Power • Power appropriately for SURVIVAL advantage Maraveyas WJGO 2009 FRAGMATIC ● Cancer drug approach – Lung Cancer – Cost effective? –Dose 5000 so will at least get data of quality on this dosing schedule ● Risk modelling? – Large trial allowing subgroup analyses (e.g SCLC) ● Power – 2200 patients! Griffiths GO et al. BMC Cancer 2009; 9: 355. LMWH therapy to prolong survival in cancer patients – FRAGMATIC study Ongoing open-label, randomised, multicentre study to assess the impact of long-term dalteparin on overall survival in patients with lung cancer 2200 (target enrolment) patients with histopathological or cytological diagnosis of primary bronchial carcinoma aged 18 years or over ● ● Primary outcome measure: overall survival Secondary outcome measures include: – – – – – – – – ● VTE-free survival Metastasis-free survival Quality of life Breathlessness Anxiety and depression Cost effectiveness Cost utility Serious adverse events/toxicity Expected primary completion date: August 2012 Griffiths GO et al. BMC Cancer 2009; 9: 355. Anticancer treatment according to local practice + dalteparin 5000 IU SC OD (n=1100) Primary outcome assessment R Anticancer treatment according to local practice + no dalteparin (n=1100) Day 1 24 weeks Thank you [email protected]