Cancer and Thrombosis:Cancer and Thrombosis:Prevention and Treatment of VTE in
Cancer Patients
Development Committee:
Christine Cripps, MD, FRCCP
Kelly Savage, RN
Bonnie Kuehl, PhD
Cancer and Thrombosis
Tumour infiltration into vessels Vessel obstruction Immobility Central venous catheters Post-surgery Medications (tamoxifen, thalidomide) Chemotherapy
Why do patients with cancer get blood clots?
Why should we care?
CVC: central venous catheter | DVT: deep vein thrombosis | PE: pulmonary embolismHeit JA,et al. Arch Intern Med. 2002;162:1245-1248.
Cancer patients represent about 18% of all DVT and PE cases
Why should we care?
Khorana AA, et al. Cancer 2007.
The Increasing Frequency of VTE
The incidence of VTE increases with cancer therapy
Why should we care?
• 47-fold increased risk of mortality from VTE • 2nd leading cause of death in cancer patients
• VTE associated with early mortality during chemotherapy (HR=6.98)
Cancer progression 71%
Unknown 4%Other 6%
Thromboembolism9%
Infection 9%
RespiratoryFailure 4%
Bleeding 1%
Aspiration 1%
Khorana AA. Thromb Res. 2010;125(6):490-3.
Causes of Death in Patients with Cancer
VTE in Cancer Patients: Greater risk, Significant Burden
• Among patients with malignancy, VTE is one of the leading causes of mortality
• Cancer increases VTE risk several-fold; inpatients and those receiving active therapy are at greatest risk
• Incidence of VTE ranges from 4-20%; cancer patients have a 3-fold increased risk for recurrence over non-cancer patients
• Clinical rates may underrepresent burden; at autopsy, VTE rates in cancer patients as high as 50%
• VTE 2nd most common cause of death in ambulatory cancer patients (tied with infection)
Agnelli & Verso, J Thromb Haemost 2011; 9 Suppl1: 316-324; Heit et al Arch Int Med 2000;160:809-815 and 2002;162:1245-1248; Prandoni et al Blood 2002;100:3484-3488; White et al Thromb Haemost 2003;90:446-455; Sorensen et al New Engl J Med 2000;343:1846-1850); Levitan et al Medicine 1999;78:285-291; Khorana et al J Thromb Haemost 2007;5:632-4; Lyman GH, et al. ASCO Update. J Clin Oncol. 2013; accessed online ahead of Print.
Cancer VTE
Cancer increases VTE risk several-fold; Greatest risk during first 3-6 months
1. Alcalay A, et al. J Clin Oncol. 2006;24:1112-1118.2. Chew HK, et al. J Clin Oncol. 2007;25:70-76.
Colorectal CancerN=68 1421
Breast CancerN=108 2552
Incid
en
ce o
f V
TE (
%)
8%
6%
4%
2%
0%
50 100 150 200 250 300 350 400In
cid
en
ce o
f V
TE (
%)
0%
1%
2%
3%
4%
5%
6%
7%
Days after Cancer Diagnosis Days after Cancer Diagnosis
100 200 300 400 500 600 700 800
Effect of VTE on Long-Term Prognosis is Signficant
Levitan N, et al. Medicine 1999;78:285-291.Sorensen HT, et al. N Engl J Med. 2000; 343:1846-50..
100%
CancerDVT/PE
No Cancer+ No DVT/PE
Cancer at time of VTE 12%
Cancer without VTE 36%
1-year survival
Pro
babili
ty o
f D
eath
(%
)
Pro
babili
ty o
f Surv
ival
(%)
80%
60%
40%
20%
0%0 40 120
Number of Days after Admission
Years after Diagnosis
P<0.001P=0.001
18080
DVT/PE + Cancer
Recurrence Rate of DVT/PE is Higher in Cancer Patients
Prandoni P, et al. Blood 2002;100:3484-3488.
Cum
ula
tive P
roport
ion
of
Recu
rrent
DV
T/P
E (
%)
25%
20%
15%
10%
5%
0%0 1 2 3 4 5 6 7 8 9 10 11 12
N=82, Prospective follow-up study
Cancer
No Cancer
20.7%
HR 3.2%
Months
6.8%
How does cancer lead to blood clots?
Shelke AR, Khorana AA. Drug Discovery Today: Disease Mechanisms. 2011;8:e39-e45.
Incidental and symptomatic VTE are both associated with worsened 3-month
mortality in pancreatic cancer
0 200 400 600 800 1000 1200
100%
75%
50%
25%
0%
Menapace LA, et al. Thromb Haemost. 2011;106:371-8.
No prior event
≥ 1 Asymptomatic VTE (but no symptomatic events)
≥ 1 Symptomatic VTE (DVT/PE/ VVT)
VTE Prevention/ Prophylaxis is Low
ENDORSE study Findings• Multinational cross-sectional survey in 358 acute care
hospitals across 32 countries
• 68 183 adult screened charts (medical & surgical)
51.8% of all medical and surgical patients are at risk of VTE
VTE prophylaxis is underused 58.5% of surgical patients received it
39.5% of medical patients received it
37% of medical patients with active malignancy received VTE prophylaxis
Cohen AT, et al. Lancet. 2008;371:387-94.
ENDORSE (Epidemiologic International Day for the Evaluation of Patients at Risk for Venous Thromboembolism in the Acute Hospital Care Setting)
Multiple Myeloma & VTE
16%Lenalidomide/dex
3%Dexamethasone
10-20%Thal/dex
3%Thalidomide
17% vs. 2%MPT vs. MP
10-58%Thal/anthracyclines
12% vs. 4% vs. 8%MPT vs. MP vs. iv Melphalan
5-10%Background incidence in MM
Zonder JA. Hematology. (Am Soc Hematol Educ Program) 2006:348–355Rodeghiero F, Elice F. Thromb Res. 2012;129:360-6.Niesvizky R, et al. Blood. 2008;111:1101-9.
23%Lenalidomide/dex + ESA
Incidence of Thromboembolic Events
VTE Treatment in Cancer Patients - GAP
Recovery Study• Canadian outpatient prospective study, 12 Canadian
centres• 868 outpatients with acute symptomatic VTE
• ~60% of patients with cancer received LMWH monotherapy for > 3 months
Kahn SR, et al. Thromb Haemost. 2012;108:493-8.
Can we predict VTE risk in our cancer patients?
Can we identify which patients may benefit most from
prophylaxis?
Risk Factors for Cancer-Associated VTE
Patient-related factors•Increased age•Ethnicity (risk increased in African Americans)•Co-morbidities (infection, renal and pulmonary disease, arterial thromboembolism, VTE history, inherited prothrombotic mutations)•Obesity•Performance status
Treatment-related factors•Chemotherapy, antiangiogenesis agents, hormonal therapy•Radiation therapy•Surgery ≥60 mins•ESAs, transfusions•Indwelling venous access
Cancer-related factors•Primary site of cancer•Stage (risk increases with higher stage)•Histology•Time since diagnosis (risk increases during first 3-6 months)
Biomarkers•Platelet count ≥ 350 x 109/L•Leukocyte count >11 x 109/L •Hemoglobin < 100g/L
Lyman GH, et al. ASCO Update. J Clin Oncol. 2013; accessed online ahead of Print.
% P
ati
ents
P>0.0001 for allComparisons vs. controls
Lung Colorectal
Bladder Ovarian Pancreatic Stomach Control0
10.6
8.2
11
19.2
15.8
1.4
Rates of VTE by Cancer TypeN=17,284
Khorana AA et al, ISTH 2011
5
10
15
20
13.9
VTE Risk Score for Cancer PatientsKhorana Risk Score•Simple, validated score to identify patients at highest risk of VTE
•Developed using prospective observational study of 2 700 ambulatory cancer patients receiving at least 4 cycles of chemotherapy
•Validated in >10 000 patients in multiple countries
Patient Characteristic Score
Site of CancerVery high risk (stomach, pancreas)
High risk (lung, lymphoma, gynecologic, GU excluding prostate)
2
1
Platelet Count ≥ 350 x 109/L
1
Hb <100 g/L or use of ESA 1
Leukocyte count >11 x 109/L
1
BMI ≥ 35 kg/m2 1
Total
Khorana AA, et al. Blood. 2008;111:4902-7.
RISK OF VTE:•Score 0 = 0.5%•Score 1 – 2 = 2%•Score ≥ 3 = 7%
Rates of VTE according to scores from the risk model in the derivation
and validation cohorts.
©2008 by American Society of Hematology
Khorana AA, et al. Blood. 2008;111:4902-7.
VTE Prevention can make a difference!
Placebo Enoxaparin Placebo Dalteparin Placebo Fondaparinux
Francis CW. N Engl J Med. 2007:356;1438-1444.
Prophylaxis in Hospitalized Medical Patients: Risk Reduction
0
5
10
15
20
PREVENT ARTEMIS
14.9
5.5 5.0
10.5
2.8
5.6
RR 63%
RR 44%
RR 47%
Rate
of
VTE
(%)
MEDENOX
RR: Relative Risk Reduction
Prophylaxis in Out-Patients: Risk Reduction
Rates of VTE in the various arms of four recent RCTs of prophylaxis including: PROTECHT (various locally advanced or metastatic solid tumors), GIMEMA (myeloma only), CONKO-004 and FRAGEM (both pancreatic cancers only). The control arm in PROTECHT was placebo and in CONKO and FRAGEM was observation.
Adapted from Menapace LA, Khorana AA. Curr Opin Hematol. 2010;17: 450–456.
All trials found a benefit from thromboprophylaxis with a significant decrease in VTE incidence with no increase in major bleeding
Risk Score Validation– Putting it all to the test
SAVE ONCO applying the risk scoreRisk Score % with Risk Score
0 19%
1-2 63%
≥3 17.4%
No. of risk factors
Semuloparin(N=1608)
PlaceboN=1604
Hazard Ratio(95% CI)
0 9/923 (1.0%) 23/932 (2.5%) 0.39 (0.18-0.84)
1-2 9/652 (1.4%) 27/632 (4.3%) 0.32 (0.15-0.68)
≥3 2/33 (6.1%) 5/40 (12.5%) 0.56 (0.11-2.93)
Agnelli G, SAVE-ONCO Investigators, et al. N Engl J Med. 2012;366:601-9.
Risk reduction with VTE thromboprophylaxis
Prophylaxis in Cancer Out-Patients
• No difference in major bleeding observed between groups.
Agnelli G, SAVE-ONCO Investigators, et al. N Engl J Med. 2012;366:601-9.
VTE occured in 1.2% receiving semuloparin vs. 3.4% receiving placebo (HR 0.36; 95% CI, 0.21 to 0.60; P<0.001).
Thromboprophylaxis in Cancer Patients Reduces Incidence of VTE
• Primary thromboprophylaxis with LMWH significantly reduced the incidence of symptomatic VTE in ambulatory cancer patients treated with chemotherapy
Di Nisio M, et al., Cochrane Database Syst Rev. 2012 Feb 15;2:CD008500.
Outcomes
Illustrative comparative risk (95% CI)
Relative effect (95% CI)No. of participants
(studies)Assumed riskCorresponding
risk
Placebo or no anticoagulant
LMWH
Symptomatic VTE
44 per 1000 27 per 1000 RR 0.62 [0.41, 0.93] 2464 (6)
Major bleeding
11 per 1000 18 per 1000 RR 1.57 [0.69, 3.60] 2394 (5)
Symptomatic PE
8 per 1000 5 per 1000 RR 0.63 [0.21, 1.91] 1710 (3)
1-year mortality
503 per 1000 523 per 1000 RR 1.04 [0.92, 1.16] 1848 (4)
Current Thromboprophylaxis Guidelines for Cancer Patients
Inpatient Thromboprophylaxis Guidelines
• Risk of VTE is 7 times higher in hospitalized cancer patients1
ASCO 2013/NCCN 2012 – Anticoagulate all hospitalized patients without bleeding risk
ESMO 2011– Anticoagulate all bedridden patients with acute medical
complication
ACCP 2012– Anticoagulate all hospitalized patients at high risk for
thrombosis without bleeding risk1. Heit JA, Archives Intern Med. 2000; 860:809.; ASCO 2013; NCCN2.2013; AACP 2012; ESMO 2011
Contraindications to Thromboprophylaxis
Cancer Increases Risk of Clotting as well as Risk of Bleeding
ACCP 2012 reports multinational study of 10,866 medical inpatients with overall risk (OR) factors for bleeding
Risk Factors for Bleeding Overall Risk (OR)
Active gastroduodenal ulcer
Bleeding in 3 mo pre admission
Platelet count < 50
Age 85 y (vs. 40 y)
Hepatic failure (INR 1.5)
Renal failure (eGFR <30 mL/min)
ICU/CCU admission
Central venous catheter
Rheumatic disease
Current cancer
Male sex
4.15
3.64
3.37
2.96
2.18
2.14
2.10
1.85
1.78
1.78
1.48
Outpatient Thromboprophylaxis Guidelines
• Outpatient definition is not consistent • Risk of VTE remains high even when ambulatory
• ASCO 2013/ESMO 2011– No evidence to support routine prophylaxis in ambulatory cancer
patients excluding patient receiving lenalidomide/thalidomide & chemo/dexamethasone
– Clinicians may consider LMWH prophylaxis on a case-by-case basis in highly selected outpatients with solid tumors receiving chemotherapy.
• ESMO 2011– Consider prophylaxis in high risk ambulatory cancer patients (not
defined)
ASCO 2013; NCCN2.2013; AACP 2012; ESMO 2011
Outpatient Thromboprophylaxis Guidelines
ACCP 2012• No routine anticoagulation UNLESS
i. Solid tumor *ii. Presence of risk factors including: previous VTE, hormone
therapy*, immobilization, angiogenesis inhibitors, lenalidomide, thalidomide
If above then LMWH or unfractionated heparin
NCCN 2012• Thalidomide/lenalidomide patients, otherwise no routine
prophylaxis outside of clinical setting• Utilizing Khorana predictive risk model: patients with high
risk (>3) COULD BE considered for prophylaxis on an individual basis evaluating risk/benefit ratio
ASCO 2013; NCCN2.2013; AACP 2012; ESMO 2011
Current Antithrombotic Treatment Guidelines
for Cancer Patients
Why treat?
• To prevent fatal PE
• To prevent recurrence
• To prevent post-thrombotic syndrome
Cochrane review demonstrated a significant 29% mortality reduction in cancer patients receiving LMWH for initial treatment of VTE vs. those receiving UFH.3
LMWH Provides a Survival Benefit in Cancer Patients1-3
1. Green D, et al. Lancet. 1992;339:1476. 2. Lazo-Langner A. et al. J Thromb Haemost. 2007;5:729-37.3. Akl E, et al. Cochrane Database Syst Rev. 2008;1:CD006649.
Recommended Anticoagulant Treatment & Secondary ProphylaxisASCO 2013/NCCN 2013/ ACCP 2012/ ESMO 2011LMWH:•Preferred over UFH for initial 5-10 days in pts with newly diagnosed VTE•Preferred for at least 6 months as monotherapy due to improved efficacy over warfarin Warfarin:•2.5-5 mg every day initially, subsequent dosing based on INR value; target INR 2-3•Concomitant therapy and frequent INR monitoring required during transition from LMWH to warfarin
Duration of Anticoagulation•Minimum 3-6 mo for DVT and 6-12 mo for PE•Recommend indefinite anticoagulation if active cancer or persistent risk factors
ASCO 2013/ NCCN 2.2013 Update/ ACCP 2012 / ESMO 2011
CLOT Trial: Reduction in Recurrent VTE Dalteparin vs. Warfarin
Lee AYY et al. N Engl J Med. 2003. 349: 146–153.
LMWHN=338
OACN=335
P
Major Bleed 19 (6%) 12 (4%) 0.27
Any Bleed 46 (14%) 62 (19%) 0.093
*P Fishers exact test
Pro
bab
ility
of
Rec
urr
ent
VT
E (
%)
Recurrent VTE (%)
Risk reduction=52%p=.0017
OAC
Dalteparin
0
25
20
15
10
5
0 30 60 90 120 150 180 210Days Post Randomization
LITE Trial: Reduction in Recurrent VTE Tinzaparin vs. Warfarin
Hull RE, et al. Am J Med. 2006;119(12):1062-72.
At 12 months: 7 of 100 patients (7 percent) in the low-molecular-weight heparin group and 16 of 100 patients (16 percent) in the heparin-warfarin group had new episodes of symptomatic venous thromboembulism (p=0.044; risk ratio=0.44; absolute difference, -9.0, 95 percent confidence interval -2.17 to -0.7 percent).
# at risk 100 78 65 56 51 46 44IV Hep/War 100 80 68 65 57 54 47
Cumulative incidence of recurrent venous thromboembolism in the cancer groups
Cum
ulat
ive
inci
denc
e %
0
5
10
15
20
0 100 200 300
IV Heparin/Warfarin
LMWH
Risk of Bleeding on Warfarin in the Cancer Patient
Increased warfarin effect can occur if:• Poor nutrition and low vitamin K intake• Frequent use of antibiotics• Diarrheal disease and toxicity from antacids• Chemotherapy• Liver disease from cancer involvement• Decreased clotting factor synthesis• Poor clearance of activated clotting factors (DIC)• Malabsorption of vitamin K• High fever/infection
Streiff MB, et al. NCCN Clinical Practice Guidelines in Oncology, Venous Thromboembolic Disease. JNCCN 2011; 9: 714-777.
Dosing
• LMWH:– Tinzaparin: 175 units/kg subcutaneous OD– Dalteparin: 200 units/kg subcutaneous daily– Enoxaparin: 1 mg/kg subcutaneous BID- no completed
phase III trials in cancer patients• Unfractionated heparin (IV): 80 units/kg loading dose,
target a PTT of 2-2.5 x control• Fondaparinux: 7.5 mg (50-100 kg) subcutaneous daily
Recommended Anticoagulant Treatment for VTE
Streiff MB, et al. NCCN Clinical Practice Guidelines in Oncology, Venous Thromboembolic Disease. JNCCN 2011; 9: 714-777.
Where do we go from here?
1.Healthcare Professional awareness
2.Patient awareness and education of VTE risk and role of therapy (prevention or treatment)
Survey of 500 adults with cancer within 12 months of Sampling
Patient and Provider Awareness(or Lack Thereof)
Rickles FR, et al. J Clin Oncol. 29: 2011 (suppl; abstr 9101)
Were informed by Doctor or Healthcare Professional about DVT Risk Due to Cancer
27%
44%
14%
All Respondents (n=500) Inpatients (n=206)
Outpatients (n=294)
Why don’t we use LMWH for prophylaxis in the outpatient setting?
• Why give it to everyone when less than 5% will get a clot
– Risk assess to determine patients at highest risk of clot• Cost
– All LMWHs covered by provincial formulary, patient compassionate programs
• Inconvenience to the patient
– Clot far more inconvenient• Bleeding
– Monitor, educate patients about symptoms and procedure (bleeding card)
• Therapy challenges with chemo-induced side effects such as low platelets and increased sCr
– PE management and VTE treatment long-term challenges impacting QoL
GOALS in Treatment and Prevention of VTE in Cancer Patients
• Increase awareness amongst healthcare professionals
• Increase awareness and educate patients about risks and symptoms of VTE
• Identify patients at high risk of VTE – prophylax and educate
• Detect VTE early
1. Appropriate treatment and treatment duration
2. Patient education: adherence and awareness of bleeding symptoms