The document discusses the management of venous thromboembolism (VTE) in patients with cancer. It notes that cancers of the breast, colon, and lung are most commonly associated with VTE, though cancers of the pancreas, ovary, and brain have the strongest association when adjusted for prevalence. It recommends long-term anticoagulation with low molecular weight heparin over vitamin K antagonists or heparin for VTE in cancer patients. Extensive cancer screening in patients with idiopathic VTE is not routinely warranted, as it does not improve survival outcomes.

1. OCCULT CANCER AND VTE
MANAGEMENT OF VTE

2. BREAST, COLON & LUNG CANCERS
These are the most common malignancies associated with thrombosis that is reflecting the
prevalence of these malignancies in the general population, but when adjusted with
disease prevalence, the cancers most strongly associated with thrombotic complications
are those of the pancreas, ovary and brain.

3. • Idiopathic thrombosis can be the first manifestation of an occult malignancy. However
intensive screening for cancer in patients with VTE often does not improve the survival and
is not generally warranted.
• Independently of the timing of cancer diagnosis (before or after the VTE), the life
expectancy of cancer patients with VTE is relatively short, because of both death from
recurrent VTE and the cancer itself.
• A recent randomized trial, the Randomized comparison of the LMWH Vs oral
anticoagulant therapy for long term anticoagulation in cancer patients with VTE
showed that LMWH may be a better treatment option for this group of patients.

4. VTE IS A COMMON COMPLICATION OF MALIGNANT
DISEASE BUT THE PATHOPHYSIOLOGY REMAINS
POORLY UNDERSTOOD.
Patients under going surgery for cancer have a
higher risk of post operative DVT than
those having surgery for nonmalignant diseases.
Autopsy series have reported increased rates of pulmonary embolism in
cancer patients compared with patients without cancer.

5. FINALLY INDIVIDUALS PRESENTING WITH AN
UNPROVOKED EPISODE OF VTE ARE MORE
LIKELY
TO HAVE AN UNDERLYING CANCER THAN THOSE
WITH AN IDENTIFIABLE RISK FACTOR FOR
THROMBOSIS.

6. ACCORDING TO CLINICAL DATA PROSPECTIVELY
COLLECTED ON THE POPULATION OF OLMSTED COUNTY,
MINNESOTA SINCE 1966, THE ANNUAL INCIDENCE OF A
FIRST EPISODE OF VTE OR PE IN THE GENERAL POPULATION
IS 117 OUT OF 100,000. CANCER ALONE WAS ASSOCIATED
WITH A 4.1 FOLD RISK OF THROMBOSIS, WHEREAS
CHEMOTHERAPY INCREASED THE RISK 6.5 FOLD.
COMBINING THESE ESTIMATES YIELDS AN APPROXIMATE
ANNUAL INCIDENCE OF VTE OF 1 OF 200 IN A POPULATION
OF CANCER PATIENTS.

7. 10% OF WOMEN WITH ADVANCED OVARIAN CANCER RECEIVING
CHEMOTHERAPY AND UP TO 28% OF PATIENTS WITH MALIGNANT
GLIOMA HAVE BEEN REPORTED TO DEVELOP VTE. CLL HAVE 4% RISK OF
CEREBRAL VASCULAR THROMBOSIS DURING THERAPY WITH L-
ASPARGINASE WHEREAS 10% OF PATIENTS WITH HODGKIN’S OR
NONHODGKIN’S LYMPHOMA DEVELOP VTE.
Age, hormonal treatment and chemotherapy play synergistic roles in
thrombosis
development in patients with cancer. The extent of cancer also influences the
risk of thrombosis.

8. TUMOURS MOST STRONGLY
ASSOCIATED WITH THROMBOSIS
Very high rates of VTE have been
reported in patients treated with
combination therapy including an
antiangiogenic agent. For example
when thalidomide is combined with
cancer chemotherapy, VTE rates of
28% in patients with multiple
myeloma and 43% in patients with
RCC have been reported. The
pathophysiology of thrombosis in
these setting has not been
elucidate, but endothelial
dysfunction, alteration in pro- and
anticoagulant protein levels or
deregulation of cytokine activity
have been proposed as
mechanisms.
Cancers of pancreas, lung and
stomach and adenocarcinomas of
unknown primary are most strongly
associated with thrombosis.
In one study by Levitan et al found
the highest rates of VTE in cases of
ovarian cancer (1.2%), brain
tumours (1.2%) and cancer of the
pancreas (1.1%)
In summary although patients
with mucin-producing
adenocarcinomas seems most
likely to develop thrombosis, the
most frequent types of cancers
found in patients with thrombosis
are those most prevalent in the
population.
In every researches there is
different numbers of cancers with
different varieties and different
stages and grades so there is not a
unique result just we can find that
in every research which cancers
are highly associated with VTE.

9. “
”
THE ASSOCIATION BETWEEN VTE AND OCCULT
CANCER
A diagnosis of cancer is more likely to arise in patients without identified
risk factors for thrombosis who present with apparently spontaneous DVT
than in those in whom secondary DVT occurs postoperatively or in another
high risk situation or patients with signs and symptoms of DVT in whom
thrombosis is subsequently excluded.
On the basis of results from cohort studies and clinical trials 10% of persons
presenting with idiopathic VTE are subsequently diagnosed with cancer
over 5-10 years and the diagnosis is stablished within the first year of
presentation of DVT in more than 75% of cases.

10. In the study by Sorensen et al, 40% of patients diagnosed with cancer
within 1 year after VTE had distant metastasis by the time of cancer
diagnosis.
Given the association between idiopathic VTE and occult cancer, it has
been suggested that patients with unprovoked thrombosis routinely
undergo investigation for underlying malignancy. However, there is little
evidence to date that routine cancer screening would be worthwhile or
cost-effective in this situation.
The preliminary results of a small randomized trial evaluating extensive
screening versus no screening in patients presenting with idiopathic VTE
were reported recently.

11. Extensive screening means USS, CT scan of head, chest, abdomen
and pelvis, stool guaiac examination, gastroscopy, colonoscopy,
sputum cytology, mammography, manual pelvic or prostate
examination and measurement of tumour markers such as PSA, CEA,
AFP, ...
30 OF 99 PATIENTS ALLOCATED TO THE EXTENSIVE SCREENING GROUP
COMPARED WITH 0 OF 102 PATIENTS IN THE CONTROL GROUP WERE
INITIALLY FOUND TO HAVE CANCER BY THESE MEANS. DURING THE 2 YEAR
FOLLOWUP PERIOD, A DIAGNOSIS OF CANCER WAS ESTABLISHED IN 10
PATIENTS IN THE CONTROL GROUP AND 1 IN THE SCREENED GROUP. THERE
WAS NO SIGNIFICANT DIFFERENCE IN CANCER RELATED MORTALITY BETWEEN
THE 2 GROUPS (3.9% VERSUS 2%, RESPECTIVELY).
AS CONCLUSION EARLY DIAGNOSIS OF CANCER POST VTE DOESN’T
TRANSLATE INTO IMPROVED PROGNOSIS AND SURVIVAL.

12. “
”
IN PATIENTS WITH IDIOPATHIC VTE SUPPLEMENTATION OF A
COMPREHENSIVE MEDICAL HISTORY AND A PHYSICAL
EXAMINATION WITH BASIC BLOOD WORK, AND A CHEST XRAY
IN SMOKERS, CAN BE EXPECTED TO DETECT 90% OF OCCULT
CANCERS.
In summary acute VTE can be the first manifestation of an occult
malignancy, and patients presenting with idiopathic VTE are more
likely to have underlying cancer than those in whom a secondary
cause of thrombosis is apparent. Extensive screening for cancer in
patients with idiopathic VTE is not routinely warranted. However
further large-scale studies of the role of such screening in idiopathic
VTE are necessary.

13. WHAT IS THE TREATMENT OF VTE IN PATIENTS WITH
CANCER?
LMWH is superior to heparin plus warfarin
Long-term anticoagulation using vitamin K
antagonists is associated with high rates of
recurrent VTE and bleeding in patients with
cancer. This therapy is also difficult to
supervise in this group of patients, as it
requires frequent blood testing to maintain
dosage levels within the therapeutic range.

14. ANTICOAGULATION THERAPY AND CANCER
PROGRESSION
The potential for anticoagulant therapy to retard
tumour progression and improve survival was first
examined in a large clinical trial in 1984.
The first study designed to specifically examine the
influence of LMWH on overall survival in cancer
patients with advanced solid tumours was reported
recently.

15. In this randomized placebo controlled study, Kakkar et all found
no difference in survival at 1,2 and 3 years between 185 patients
treated with dalteparin and 181 patients who received placebo.
Patients with cancer who develop VTE have reduced life
expectancy. On the basis of long term follow-up data on patients
with thrombosis, those with cancer have a 4-8 fold higher risk of
dying after an acute thrombotic event than patients without
cancer.
Furthermore, patients with cancer and thrombosis have a lower
survival rate than those with cancer without thrombosis.

16. In a large population-based study, Sorensen and
colleagues examined the survival of patients
with cancer and VTE compared with those without
VTE matched for type of cancer, sex, age, and
the year of diagnosis.
The 1 year survival rate for patients with
thrombosis was 12% compared with 36% in control
patients (P<0.001). The mortality ratio
associated with VTE was 2.2 for the 1-year
follow-up period. This high mortality probably
reflects death due to both thromboembolism and a
more aggressive course of malignancies
associated with VTE.

17. CIRCULATION, AHA (AMERICAN HEART
ASSOCIATION)
TREATMENT OF VTEDrugs:
UFH: such as heparin
LMWH: enoxaparin, dalteparin, nadroparin, tinzaparin, certoparin,
reviparin, ardeparin, parnaparin and bemiparin
Indirect factor Xa inhibitor: Fondaparinux
Direct factor Xa inhibitor: rivaroxaban, apixaban, edoxaban
Direct thrombin inhibitor: dabigatran

18. Currently available anticoagulations have well-
known limitations. LMWH requires subcutaneous
administration. Vitamin K antagonists are orally
active but requires laboratory monitoring for dose
initiation and adjustment, have a narrow
therapeutic window, and are subject to drug and
food interactions. An orally active, safe, and effective
anticoagulant that requires no monitoring for dose
adjustment would have the potential to radically
simplify the management of thromboembolic
disorders (selective inhibitor of factor Xa).

19. Selective factor Xa inhibitor can be effective for the
prevention and treatment of VTE, as shown by clinical
experience with subcutaneous fondaparinux (an indirect
factor Xa inhibitor).
Rivaroxaban is an orally active, selective direct
factor Xa inhibitor and also inhibits prothrombinase
activity and clot-associated factor Xa activity.
Rivaroxaban has predictable pharmacokinetics and
pharmacodynamics in healthy subjects and those
undergoing orthopedic surgery. Its relative
bioavailability is high (80%) and has dual mode of
excretion.

20. WHAT IS VTE RISK FACTORS?
- Pregnancy
- Obesity
- Smoking
- Heart failure
- Previous DVT or PE
- Increased age
- Cancer
- Nephrotic syndrome
- Drugs such as OCP, thalidomide, HRT, tamoxifen and erythropoietin
- Surgery and immobility
- Acquired thrombophilia: PCV, essential thrombocytemia
- Antiphospholipid Ab, lupus anticoagulant and anti cardiolipin Ab
- Herediatry thrombophilia: anti thrombin, protein C and S deficiency and factor V
leiden

21. similar. In DVT, the main goal of treatment is to prevent a PE.
Other goals of treatment include preventing the clot from
becoming larger, preventing new blood clots from forming, and
preventing long-term complications of PE or DVT.
The primary treatment for venous thrombosis is anticoagulation.
Other available treatments, which may be used in specific
situations, include thrombolytic therapy or placing a filter in a
major blood vessel (the inferior vena cava).
●Low molecular weight heparin, which is given as an injection
under the skin – Options include enoxaparin (brand name:
Lovenox), dalteparin (brand name: Fragmin), and tinzaparin
(brand name: Innohep).
●Fondaparinux (brand name: Arixtra), also given by injection
●Unfractionated heparin, which is given into a vein
(intravenously) – This may be the preferred choice in certain
circumstances, such as if the patient has severe kidney failure or
unstable blood pressure.
●Direct oral anticoagulants – These are available in pill form;
they include rivaroxaban (brand name: Xarelto) and apixaban

22. Initial anticoagulation is continued for 5 to 10 days. After
that, long-term anticoagulation is continued for 3 to 12 months.
In most cases, the direct oral anticoagulants are the preferred
choice for long-term anticoagulation; these pills include
rivaroxaban (brand name: Xarelto), apixaban (brand name:
Eliquis), dabigatran (brand name: Pradaxa), and edoxaban (brand
name: Savaysa). In some situations, another oral medication
called warfarin (sample brand name: Coumadin) is given instead.
For patients taking warfarin, the clotting factors in the blood
need to be measured on a regular basis with a blood test called
the International Normalized Ratio (INR), whereas this is not
needed for patients on direct oral anticoagulations. Less
commonly, the patient does not take warfarin or any of the direct
oral anticoagulants but takes a daily injection of low molecular
weight heparin or fondaparinux for the entire treatment period.

23. Duration of treatment — Anticoagulation is recommended for a MINIMUM of three months in
a patient with DVT.
●In patients who had a reversible risk factor contributing to their DVT, such as
trauma, surgery, or being confined to bed for a prolonged period, the person is often
treated with anticoagulation for three months or until the risk factor is resolved.
●Expert groups suggest that people who develop a venous thrombosis and who do not have
a known risk factor for thrombosis may need treatment with an anticoagulant for an
indefinite period of time. However, this decision should be discussed with the person's
healthcare provider after three months of treatment, and then reassessed on a regular
basis. Some people prefer to continue the anticoagulant, which may carry an increased
risk of bleeding, while others prefer to stop the anticoagulant at some point, which
may carry an increased risk for repeat thrombosis.
●Most experts recommend continuing anticoagulation indefinitely for people with two or
more episodes of venous thrombosis or if a permanent risk factor for clotting is
present (eg, antiphospholipid syndrome, cancer).
Walking during DVT treatment — Once an anticoagulant has been started and symptoms (eg,
pain, swelling) are under control, the person is strongly encouraged to get up and walk
around. Studies show that there is no increased risk of complications (eg, pulmonary
embolus) in people who get up and walk, and walking may in fact help the person feel
better faster.

24. Thrombolytic therapy — In some cases, a healthcare provider will
recommend an intravenous medicine to dissolve blood clots. This
is called thrombolytic therapy. This therapy is reserved for
patients who have serious complications related to PE or DVT, and
who have a low risk of serious bleeding as a side effect of the
therapy. The response to thrombolytic therapy is best when there
is a short time between the diagnosis of DVT/PE and the start of
thrombolytic therapy.
Inferior vena cava filter — An inferior vena cava (IVC) filter is
a device that blocks the circulation of clots in the bloodstream.
It is placed in the inferior vena cava.The IVC filter typically
is inserted through a small incision in a leg vein with the use
of a local anesthetic and takes 20 to 30 minutes to perform. An
IVC filter is often recommended in patients with venous
thromboembolism who cannot use anticoagulants because of a very
high bleeding risk. However, in the long term, IVC filters can
increase the risk of developing blood clots.

25. Low molecular weight heparin (LMWH) is the parenteral treatment of
choice for most patients, although fondaparinux and unfractionated
heparin (UFH) are also options. Although effective, heparins and
fondaparinux require administration by injection, and UFH can also be
administered intravenously. Self-injection is an option with LMWH
and fondaparinux but may be unsuitable for patients who lack dexterity,
such as the elderly, or for those with self-injection anxiety. Heparin
induced thrombocytopenia (HIT) is an adverse event that should be
considered when using UFH, and to a lesser extent LMWH
and fondaparinux. Patients with a history of HIT should receive an
alternative anticoagulant, such as argatroban, lepirudin or danaparoid.
Limited evidence suggests that fondaparinux may be another alternative
treatment for patients with a history of HIT. Osteoporosis is another
potential adverse effect when heparin is administered for longer than 1
month.

26. The novel OACs apixaban, edoxaban, rivaroxaban,
(direct Factor Xa inhibitors) and dabigatran (direct
thrombin inhibitor), are approved in Europe and
North America for the treatment of DVT, PE and
prevention of recurrent DVT and PE in adult
patients. As with
VKAs, dabigatran and edoxaban are administered
as part of a dual-drug approach, following acute-
phase parenteral anticoagulation.
Rivaroxaban and apixaban can be administered
from the start of treatment in a ‘single-drug
approach’, thus overcoming the complications of
overlapping parenteral anticoagulant with VKA.

27. have recommended rivaroxaban,
dabigatran, apixaban and edoxaban as
alternatives to parenteral/VKA
anticoagulation for acute-phase treatment
and secondary prevention of patients at
an intermediate or low risk of early
mortality from PE. Rivaroxaban,
dabigatran and apixaban are also
recommended as alternatives to
conventional therapy for patients who
require extended anticoagulation (>3
months).

28. The novel OACs have been tested against conventional therapy in large studies for the
treatment of VTE: EINSTEIN DVT and EINSTEIN PE for rivaroxaban, RE-COVER and RE-
COVER II for dabigatran, AMPLIFY for apixaban and Hokusai-VTE for edoxaban Across
these studies, novel OACs (administered following initial heparin therapy in the case
of dabigatran and edoxaban) were shown to be at least as effective as VKAs for
preventing recurrent VTE and VTE-related death for all studies (primary efficacy endpoint
events), and demonstrated a similar or reduced incidence of the major, major-plus or
minor clinically relevant bleeding, compared with conventional treatment. The efficacy
and safety of novel OAC use for the extended secondary prevention of VTE following an
initial DVT/PE in patients who have received 6–12 months anticoagulation therapy has
been evaluated in placebo-controlled studies: EINSTEIN EXT for rivaroxaban, RE-SONATE
for dabigatran and AMPLIFY-EXT for apixaban. All three novel OACs demonstrated
superior efficacy compared with placebo for preventing recurrent VTE and VTE-related
death, with small but non-significant differences in the incidence of major
bleeding. Dabigatran was also compared with warfarin for extended VTE treatment in
the RE-MEDY study, and was associated with non-inferior efficacy and similar rates of
major bleeding. These studies are difficult to compare directly owing to variations in
study design; therefore, in the absence of head-to-head comparison trials, there is no
direct evidence to support the use of one novel OAC over another.

29. 2012 American College of Chest Physicians (ACCP) guidelines for the
treatment of DVT and PE with anticoagulants:
Acute DVT or PE: LMWH or fundaparinux following with VKA or
rivaroxaban
For long-term therapy of DVT or PE in patients without cancer:
VKA>LMWH and LMWH>dabigatran or rivaroxaban
In DVT or PE in patients with cancer: LMWH>VKA and VKA>dabigatran
or rivaroxaban
DURATION OF ANTICOAGULATION THERAPY:
Proximal DVT or PE: 3 month
First proximal DVT or PE provoked by surgery or nonsurgical transient
factor: 3 month
Unprovoked DVT or PE: extended therapy if risk of bleeding is low to
moderate, if risk of bleeding is high: 3 month
DVT or PE associated with active cancer: over 3 month therapy

30. 2014 updated European Society of Cardiology (ESC) guideline recommendations
for novel OACs for low- to intermediate-risk PE patients:
Novel OACs are recommended as alternatives to VKA/parenteral anticoagulation such
as: rivaroxaban (15 mg BID for 3 weeks, followed by 20 mg QD)
for patients ≥80 years of age or those under concomitant verapamil treatment following
acute-phase parenteral anticoagulation, then Dabigatran (150 mg bid, or 110 mg bid)
Edoxaban following acute-phase parenteral anticoagulation
Thrombolytic therapy (for patients who do not have high risk of bleeding)
All of the above mentioned doesn’t have superiority over each other.
In case of extended anticoagulation therapy for more than 3 month:
Novel OACs should be considered as alternatives to VKA anticoagulation if extended
anticoagulation treatment is necessary.
Rivaroxaban: 20 mg od
Dabigatran: 150 mg bid (or 110 mg bid for patients >80 years old /those taking
verapamil)
Apixaban: 2.5 mg bid

31. Approved anticoagulants for treatment of DVT and PE:
- UFH: Factor Xa and thrombin inhibitor (indirect via AntiThrombin)
- LMWH: Factor Xa and thrombin inhibitor (indirect via AntiThrombin)
- Fondaparinux: Factor Xa inhibitor (indirect via AntiThrombin)
- VKA: Vitamin K (inhibits synthesis of Factors II, VII, IX and X)
- Rivaroxaban: Factor Xa inhibitor(direct)
- Apaxiban: Factor Xa inhibitor (direct)
- Dabigatran: Thrombin inhibitor (direct)
- Edoxaban: Factor Xa inhibitor (direct)

32. IN PATIENTS WITH ATRIAL FIBRILLATION
IF THERE IS MECHANICAL
VALVULOPATHY VKA SHOULD BE
ADMINISTERED AND IN NON-
MECHANICAL CASES DABIGATRAN AS IN
CASES OF MECHANICAL VALVULOPATHY
DABIGATRAN INCREASE THE RISK OF
INTRA-ARTERIAL THROMBOSIS.
DABIGATRAN IS NOT PROVED BY FDA

33. THANK YOU