Thromboprophylaxis For The Ambulant ‘Medical’ Cancer Patient FRCP, PhD

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
anthony.maraveyas@hey.nhs.uk