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Anticoagulation and cancer
Not as straightforward as it
looks
ST CATHERINE’S
HOSPICE
How common is it?
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HOSPICE
Up to15% estimated
clinically apparent
>50% at post-mortem
in some tumour types
Huntershill hospice study
• 298 hospice in-patients with advanced
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ST CATHERINE’S
HOSPICE
cancer
Screened for lower limb venous
obstruction using a light reflection
rheograph
52% DVT
17% bilateral
9% symptomatic and confirmed (Doppler
and - or V/Q scan)
Case history – Mrs D
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42 year old, 2/52 vague abdominal discomfort
Presented with perforated sigmoid carcinoma
Liver metastases at laparotomy
Post-operative PE treated initially with
tinzaparin, 10/10/5 warfarin. Tinzaparin
stopped
INR 11, recurrent bouts of dyspneoa
Scared, breathless
ST CATHERINE’S
HOSPICE
Case history – Mrs P
• 72 year old, stomach cancer
• Wants to stay at home with daughters
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HOSPICE
popping in
Manages to potter about house
Overnight develops big, uncomfortable
right leg
Can’t get out of chair to get to toilet
unaided
Anticoagulation and cancer
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ST CATHERINE’S
HOSPICE
Pathophysiology
Management:
problems and
solutions
What about
prophylaxis?
Draw up a protocol?
pathophysiology
• 1865: Trousseau - “..a particular condition
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ST CATHERINE’S
HOSPICE
of the blood which predisposes it to
spontaneous coagulation”
Predicted his own death when he
developed a left arm thrombosis
Risk is in addition to that from other
contributory factors often found such as
surgery, immobility, infection, old age
Increased risk due to cancer
alone
• Incidence of VTE higher in cancer vs non-
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ST CATHERINE’S
HOSPICE
cancer patients in studies of:
- surgical patients
- non-surgical patients
- post-mortem studies
Occult malignancy is 7-8 times more
common in patients with VTE with no
apparent cause Prandoni P
Integral to cancer growth
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ST CATHERINE’S
HOSPICE
Patients with cancer and VTE have a 3 fold lower
1 year survival than cancer patients without VTE
(multi-factorial)
Evidence suggests activation of coagulation
enhances cancer growth and metastasis
Evidence suggests treatment with anticoagulation
improves survival (lung cancer)
Current FRAGMATIC trial to repeat these
smaller studies (5000U Fragmin vs placebo in
lung cancer patients) Simon Noble
Coagulation abnormalities
• Abnormalities of coagulation are found in
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ST CATHERINE’S
HOSPICE
over 90% of cancer patients if sensitive
indicators are sought
Low-grade activation of coagulation at
presentation of malignancy which worsens
with progressive disease
Evidence of chronic, low-grade
disseminated intravascular coagulation
(DIC).
Huntershill study (87 patients)
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ST CATHERINE’S
HOSPICE
Fibrinogen; 66% raised levels, 4.38g/dl
(NR 1.7-3.5)
Fragment 1+2; 71% raised levels, 1.9 nmol/l
(NR 0.57 – 1.31)
TAT; 89% raised levels, 10.3 microg/l
(NR 1 – 4.1)
Fibrinogen lower in patients with DVT (p = 0.04)
Mirrors disease activity
• Fibrinogen, platelet count, Fibrino-peptide-
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ST CATHERINE’S
HOSPICE
A, and D-dimer have all been suggested as
useful tumour growth markers but are
rather non-specific
Not useful predicting thrombotic events
i.e. don’t use D-dimer as a test for DVT in
a patient with active cancer (it’ll be raised)
Pathophysiology-summary
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ST CATHERINE’S
HOSPICE
Secretion of cancer procoagulant/tissue factor by
tumour/host cells
Consumption of clotting factors
Compensatory increase in production
Leads to disseminated intravascular coagulation
Platelet activation/thrombocytopenia
Reduced protein C, antithrombin III
Liver dysfunction
The upshot…
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ST CATHERINE’S
HOSPICE
Thus cancer patients
have an increased risk
of clotting and
bleeding
Standard VTE management
• Immediate treatment with heparin (usually
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ST CATHERINE’S
HOSPICE
LMWH)
Whilst commencing warfarin loading
(10mg/10mg/5mg)
Loading dose lower in elderly (3mg)
When INR is in therapeutic range stop
LMWH (5 days LMWH)
Treat for 3-6 months according to site of
VTE
Problems with cancer patients
• With warfarin: 3 x rate of recurrent VTE
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despite therapeutic INR
With warfarin: 6.2 x rate of major bleeding
Risks increase with extent of cancer
Risk of VTE persists as long as active cancer
persists
ST CATHERINE’S
HOSPICE
More problems
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ST CATHERINE’S
HOSPICE
Drug interactions
Malnutrition (particularly of Vitamin K)
Vomiting
Liver dysfunction
Poor venous access
Invasive procedures and chemo related
thrombocytopenia often require interruption of
anticoagulant
Lead to unpredictable and poor anticoagulant
control
Lesions liable to bleeding
Low molecular weight heparin
• renal excretion
• few drug interactions
• steady, predictable pharmacokinetics from
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ST CATHERINE’S
HOSPICE
weight adjusted dose
high subcutaneous bioavailability
long half life
no need for monitoring (except platelets
initially)
Secondary prevention with LMWH vs
warfarin Lee A et al. NEJM 2003; 349:146-153
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ST CATHERINE’S
HOSPICE
LMWH vs coumarin prospective rct
8% vs 15.7% recurrent VTE
No significant difference in bleeding
ECOG 3,4 excluded
Study conditions
Secondary prevention with
LMWH vs warfarin Meyer G et al Arch Int Med 2002;
162; 1729-1735
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ST CATHERINE’S
HOSPICE
LMWH vs coumarin prospective rct
Combined outcome event; major bleeding or
recurrent VTE in 3 months
10% vs 21%
6/71 warfarin; fatal bleed
0/67 LMWH; fatal bleed
17 warfarin all cause deaths vs 8 LMWH deaths
ECOG 3+4 included
A common sense approach – use
LMWH if…
• Advanced disease
• Liver metastasis (or other cause of liver
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ST CATHERINE’S
HOSPICE
dysfunction)
Malabsorption
Likely problem with changing medication
regimes
High bleeding risk
The first hint of a problem with warfarin
Patients won’t like the injections
• Some don’t
• Qualitative interviews; palliative care
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HOSPICE
patients on long term LMWH showed
minimal problems and some positive
feelings about “having the best treatment”
and “not being written off”Simon Noble
Many learn to self inject
Specific problems
• Brain tumour (primary or secondary)
• One smallish observational study showed
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ST CATHERINE’S
HOSPICE
no increase risk of bleeding with tight INR
control
Sensible to use LMWH to minimise risk of
over-anticoagulation
! Melanoma and renal tumours are very
vascular – reluctant to anticoagulate at all
if brain secondaries
Specific problems
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ST CATHERINE’S
HOSPICE
Actively bleeding lesions (or high risk)
Suggest bd LMWH to even out peaks and
troughs
IVC filter
Thrombocytopenia
Weigh up risk and benefits on individual patient
LMWH has least risk of over-anticoagulation
IVC filter
IVC filters
• Can be very useful if
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ST CATHERINE’S
HOSPICE
anticoagulation is
contraindicated
Long term risk of
bilateral leg oedema
Procedure involved
Expense, therefore
consider prognosis
Usual judgement is 3
months or more
expected prognosis
example
• 65 yr old nun with endometrial carcinoma
• Treated with progestagens
• Presented with 3 months h/o progressive
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ST CATHERINE’S
HOSPICE
breathlessness, can’t walk across room
V/Q multiple PEs
Continuous minor bleeding from tumour
(manageable, but increased bleed wouldn’t
be)
example
• Stopped progestagens
• Placed IVC filter
• Over next 3 months patient’s
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HOSPICE
breathlessness improved to the extent she
was now walking down to the shops and
back and going out for trips
14 months did well
Disease progression, leg oedema and died
about 18 months after I first saw her
summary
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ST CATHERINE’S
HOSPICE
Clinical decision making
with minimal evidence,
but there is some
Important to attempt
“decision making” rather
than knee jerk reaction
Discuss options with
patient if possible to
prevent “paternalistic
approach”
Often requires a
“bespoke regime”
Future options?
• Oral anti-thrombin agent Ximegalotran
• Looked promising, company withdrawn
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ST CATHERINE’S
HOSPICE
(deaths due to liver disease)
Pentasaccharides and heparinoids
Danaparoid = choice in heparin induced
thrombocytopenia
What about prophylaxis?
ST CATHERINE’S
HOSPICE
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Hickman lines?
Chemotherapy?
Orthopaedic surgery
Abdomino-pelvic surgery
Don’t forget for palliative procedures
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Spinal cord compression?
Acute reversible episodes – hypercalcemia?
- pneumonia?
Prophylaxis in the patients with
advanced disease
• Still little evidence
• Some qualitative data to suggest patient
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HOSPICE
want to be involved in the decision Simon Noble
However, what about the patient who is
not going to improve their performance
status? (i.e. in bed in hospital, in bed at
home) – nothing reversible
Currently we wouldn’t recommend
prophylaxis in that situation
Risks/benefits
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ST CATHERINE’S
HOSPICE
LMWH safer, effective
daily subcutaneous
injection but no
monitoring needed
Occasionally – IVC
filter
?how long to treat
still individual decision
Case histories – what would
you do?
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ST CATHERINE’S
HOSPICE
42 year old, 2/52 vague
abdominal discomfort
Presented with perforated
sigmoid carcinoma
Liver metastases at
laparotomy
Post-operative PE treated
initially with tinzaparin,
10/10/5 warfarin. Tinzaparin
stopped
INR 11, recurrent bouts of
dyspneoa
Scared, breathless
• 72 year old, stomach
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cancer
Wants to stay at home
with daughters popping in
Manages to potter about
house
Overnight develops big,
uncomfortable right leg
Can’t get out of chair to
get to toilet unaided
Protocol
• Literature review – currently underway for
secondary and primary prevention as part
of APM Science Committee Task Group Noble
and Johnson
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ST CATHERINE’S
HOSPICE
Prevalence and Pathophysiology
General considerations for cancer patients
Secondary prevention
Primary prevention