-
UvA-DARE is a service provided by the library of the University
of Amsterdam (https://dare.uva.nl)
UvA-DARE (Digital Academic Repository)
Cancer, thrombosis and low-molecular-weight heparins
Piccioli, A.
Publication date2015Document VersionFinal published version
Link to publication
Citation for published version (APA):Piccioli, A. (2015).
Cancer, thrombosis and low-molecular-weight heparins.
General rightsIt is not permitted to download or to
forward/distribute the text or part of it without the consent of
the author(s)and/or copyright holder(s), other than for strictly
personal, individual use, unless the work is under an opencontent
license (like Creative Commons).
Disclaimer/Complaints regulationsIf you believe that digital
publication of certain material infringes any of your rights or
(privacy) interests, pleaselet the Library know, stating your
reasons. In case of a legitimate complaint, the Library will make
the materialinaccessible and/or remove it from the website. Please
Ask the Library: https://uba.uva.nl/en/contact, or a letterto:
Library of the University of Amsterdam, Secretariat, Singel 425,
1012 WP Amsterdam, The Netherlands. Youwill be contacted as soon as
possible.
Download date:14 Jun 2021
https://dare.uva.nl/personal/pure/en/publications/cancer-thrombosis-and-lowmolecularweight-heparins(1860fc0b-cb7d-46ab-9c9e-0e2327b181b7).html
-
CANCER, THROMBOSIS AND
LOW-MOLECULAR-WEIGHT HEPARINS
ANDREA PICCIOLI
AN
DR
EA P
ICC
IOLI
C
AN
CER
, TH
RO
MBO
SIS
AN
D L
OW
-MO
LEC
ULA
R-W
EIG
HT
HEP
AR
INS
-
CANCER,THROMBOSIS AND LOW-MOLECULAR-WEIGHT HEPARINS
Andrea Piccioli
-
Cover: watercolor of Vicenza, Italy. Reproduced with permission
of Gilberto Padovan Editore
-
CANCER, THROMBOSIS AND LOW-MOLECULAR-WEIGHT HEPARINS
ACADEMISCH PROEFSCHRIFT
ter verkrijging van de graad van doctor
aan de Universiteit van Amsterdam op gezag van de Rector
Magnificus
prof.dr. D.C. van den Boom
ten overstaan van een door het college voor promoties
ingestelde
commissie, in het openbaar te verdedigen in de Agnietenkapel
op vrijdag 20 maart 2015, te 10.00 uur
door
Andrea Piccioli
geboren te Vicenza, Italië
-
Promotiecommissie:
Promotor: Prof. dr. H.R. Büller Co-promotor: Prof. dr. P.
Prandoni Overige leden: Prof. dr. D.P.M. Brandjes Dr. S.C.
Cannegieter Prof. dr. M.M. Levi Prof. dr. S. Middeldorp Dr. H.M.
Otten Prof. dr. M.H. Prins
Faculteit der Geneeskunde
-
Labor omnia vicit /
Improbus et duris urgens in rebus egestas
Verg., Georg. I, 145-146
-
CONTENTS
Chapter 1. Piccioli A.
Introduction and outline of the
thesis...................................................................................Page
01
Part A. Venous thromboembolism in cancer patient
Chapter 2. Cancer and venous thromboembolism.
Published in past in: Amer Heart J 1996;132:1010-4, Lancet Oncol
2005; 6:401, Expert Opin
Pharmacother. 2014 Apr; 15 (6): 799-807
..........................................................................Page
11
Chapter 3. Recurrent venous thromboembolism and bleeding
complications during anticoagulant
treatment in patients with cancer and venous thrombosis.
Blood 2002;100:3484 -8 ……..…………………………………………………………………..Page
31
Chapter 4. Predicting recurrences or major bleeding in cancer
patients with venous
thromboembolism. Findings from the RIETE Registry.
Thromb Haemost 2008;100:435-9.
....................................................................................Page
41
Chapter 5. Approach to venous thromboembolism in the cancer
patient.
Curr Treat Options Cardiovasc Med 2011;13 (2):
159-68...................................................Page
49
Part B. Venous thromboembolism and the risk of cancer
Chapter 6. Venous thromboembolism as first manifestation of
cancer.
Acta Haematol 2001;106:13-7.
...........................................................................................Page
61
Chapter 7. Screening for occult cancer in patients with
idiopathic venous thromboembolism: Yes.
J Thromb Haemost 2003;1:
2271-2....................................................................................Page
69
Chapter 8. Extensive screening for occult malignant disease in
idiopathic venous
thromboembolism: a prospective randomized clinical trial.
J Thromb Haemost
2004;2:884-9........................................................................................Page
75
Chapter 9. Decision analysis for cancer screening in idiopathic
venous thromboembolism.
J Thromb Haemost
2005;3:2391-6......................................................................................Page
85
Chapter 10. The value of CT scanning for detection of occult
cancer in patients with idiopathic
VTE. D’Acquapendente Study. Submitted
2014.................................................................Page
95
-
Chapter 11. The long-term risk of cancer in patients with a
first episode of venous
thromboembolism. J Thromb Haemost 2009;7:546-51.
………………………………..…..Page 107
Chapter 12. The risk of cancer in patients with venous
thromboembolism does not exceed
that expected in the general population after the first 6
months.
J Thromb Haemost 2010; 8 (5): 1126-7.
............................................................................Page
117
Part C. Effect of low-molecular-weight heparins on survival in
cancer patients
Chapter 13. Anticoagulants and cancer survival.
Semin Thromb Haemost 2006;32:810-3.
...........................................................................Page
123
Chapter 14. The effect of low-molecular-weight heparin on
survival in patients with advanced
malignancy. J Clin Oncol
2005;23:2130-5.........................................................................Page
129
Summary.
...........................................................................................................................Page
139
Samenvatting.
....................................................................................................................Page
143
-
CHAPTER 1
INTRODUCTION
Andrea Piccioli
University Hospital of Padua, Italy
-
2
BACKGROUND
Since Trousseau’s time, the clinical association between cancer
and venous thromboembolism
(VTE) has been observed and documented (1).
The relationship between cancer and VTE insist on a two way
clinical correlation. In fact it has
been clearly established that cancer patients exhibit a higher
risk of developing a thrombotic
event when compared to non-cancer patients, especially in the
presence of the well-known risk
factors for thrombosis, such as prolonged immobilization,
surgery and chemo-radio-hormonal
therapy. It has also been clearly noticed that a first episode
of idiopathic VTE may represent the
first manifestation of a yet undisclosed cancer, offering
chances for an earlier diagnosis of the
pathology (2,3,4).
A substantial number of cancer patients receive anticoagulants
either for prophylaxis, due to the
high risk of developing thrombosis, or for treatment of an
already established thrombotic event.
The initial treatment of VTE in cancer patients should not
differ from that of non cancer patients.
In fact they will receive UFH or LMWH at therapeutic dosages.
They begin also with warfarin.
Once the INR has reached the therapeutic target, heparin or LMWH
can be stopped and
warfarin is continued for the remainder of the treatment period
(4).
Cancer patients are at high risk of recurrent VTE when
anticoagulation is stopped: studies
conducted during the past decade, assessing the clinical course
of patients with thrombosis,
have documented that the risk of recurrence increases
progressively in the course of time,
being as high as 30% after 10 years from the thrombotic event.
If risk factors for recurrence are
considered, malignancy is the most common, being more frequent
than thrombophilia. For
these reasons, in patients with cancer and thrombosis,
anticoagulation is recommended for as
long as cancer is active (2,5).
Moreover cancer patients are at higher risk of both recurrence
and major bleeding
complications during anticoagulation, even if they are within
the therapeutic range. Several
published clinical trial have examined the administration of
long-term LMWH as an alternative to
warfarin therapy in cancer patients with VTE. There is strong
evidence that LMWH is more
efficacious than warfarin for preventing symptomatic recurrent
VTE in cancer patients (4,6).
A complex relation exists between the coagulation system and
cancer. Hemostasisand
malignancy share linking mechanisms so that it has been noticed
that the inhibition of
hemostasis activation may impact on outcomes from malignancy. In
particular LMWH may have
potential antitumor effects. Further evaluations is warranted to
assess if anticoagulation has the
potential to prolong survival in cancer patients (7,8).
The incidence of newly diagnosed cancer during the follow-up of
patients with VTE is higher
than in the general population. VTE, especially in its
idiopathic presentation, may represent the
first manifestation of a yet undisclosed cancer, offering a
possible chance for early diagnosis
and treatment. Newly diagnosed malignancies are not confined to
certain subtypes, but involve
virtually all body systems. Some of these malignancies can be
identified by routine assessment
at the time of the diagnosis of the thrombotic event. Moreover,
in patients with idiopathic VTE,
who are apparently cancer free at baseline, there remains an
approximate 7-10% incidence of
clinically overt malignant disease during the follow-up period
after the thrombotic event (1,2,9).
-
3
OUTLINE OF THE THESIS
Part A “Venous thromboembolism in cancer patients”
In chapter 2 we have analysedthe two way clinical correlation
between cancer and venous
thromboembolism presenting data from three review articles which
have
examinedepidemiology, risk factors, prophylaxis and treatment of
VTE in cancer patients
(1,2,3).
The risk of recurrent VTE and bleeding complications during
anticoagulant treatment in cancer
patients is presented in chapter 3. In this prospective
follow-up study we sought to determine
whether in patients with established thrombosis those with
cancer are at higher risk for recurrent
venous thromboembolism or bleeding complications during
anticoagulant treatment than those
without cancer. It has been demonstrated that cancer patients
with venous thrombosis are more
likely to develop recurrent thromboembolic complications and
major bleeding during
anticoagulant treatment than those without malignancy. These
risks correlate with the extent of
cancer (5).
Chapter 4 deals with the predictors of recurrent VTE or major
bleedings in cancer patients with
VTE, examining some variables available at entry among patients
from the RIETE International
Registry. We tried to identify which cancer patients are at a
higher risk for recurrent pulmonary
embolism (PE), deep vein thrombosis (DVT) or major bleeding. On
multivariate analysis,
patients aged
-
4
In chapter 7 evidence has been provided in favourof extensive
screening procedures for cancer identification to be performed
among patients with a first episode of idiopathic VTE in whom a
routine initial screening for cancer identification is negative.
Arguments originate from available literature on this topic (10).
In chapter 8 we presented the SOMIT study, a prospective evaluation
in which apparently
cancer-free patients with acute idiopathic venous
thromboembolism were randomized to either
the strategy of extensive screening for occult cancer or to no
further testing. Patients had a 2-
year follow-up period. Although early detection of occult
cancers may be associated with
improved treatment possibilities, it is uncertain whether this
improves the prognosis (12).
In chapter 9, a decision analysis from the data of the
SOMIT-trial is presented. The screening
tests were divided in several possible strategies. The number of
detected cancers and the
number of patients who underwent further investigations
eventually ending in a benign
condition, were calculated for each strategy and the total costs
were determined. Based on
tumor type, stage, age and gender of the individual cancer
patient, the difference in life-years
gained (LYG) was calculated between the two study groups. It has
been found that the
screening for cancer including adbomino/pelvic CT with or
without mammography and/or
sputum cytology appears potentially cost effective in patients
with idiopathic VTE (13).
Chapter 10 presents the D’Acquapendente Study, a randomized open
label trial among
patients with a first episode of idiopathic VTE and a normal
baseline routine screening, which
compared an extensive compound strategy based of CT scan of
thorax, abdomen and pelvis
plus haemoccult to a common clinical practice strategy based on
the attending physician
preference (but excluding CT as a first line test) for the
identification of hidden cance r(14).
Chapter 11 and chapter 12 deals with the long-term risk of
cancer in patients with VTE. In
patients with VTE, 15-20% will have overt cancer when VTE is
diagnosed but little is known
about such patients' long-term risk, time course and predictors
of new cancer. In patients with a
first VTE and without clinically evident cancer, the risk for
new cancer is about 1-2% per year,
appears to be uniform over time, and is higher in patients with
unprovoked VTE and those with
advanced age. Moreover the risk of cancer in patients with VTE
does not exceed that expected
in the general population after the first 6 months (15,16).
Part C. Effect of low-molecular-weight heparins on survival
in cancer patients
The association between cancer and activation of blood
coagulation has been described since
Trousseau's time (1). The hypercoagulable state often
encountered in cancer patients not only
acts as an important risk factor for thrombosis, but also may
play a role in tumour progression
and metastatization. An anti-neoplastic effect of anticoagulants
in this setting has often been
hypothesized. The results of recently conducted clinical trials
suggest that cancer patients could
benefit from the administration of low molecular weight
heparins, particularly those with
-
5
nonadvanced disease. Additional clinical trials are needed to
provide further insight into this
challenging setting. Studies in cancer patients with venous
thromboembolism suggested that
low molecular weight heparin may prolong survival. Chapter 13 is
an overview of the current
knowledge in this field (17) and chapter 14 presents the results
of a trial among patients with
metastasized or locally advanced solid tumours, who were
randomly assigned to receive a 6-
week course of subcutaneous nadroparin or placebo. The primary
efficacy analysis was based
on time from random assignment to death. The primary safety
outcome was major bleeding
(18).
-
6
References
1. Trousseau A Phlegmasia alba dolens. Lectures on clinical
medicine. The New Sydenham Society, London 1868; 5:281-331
2. Piccioli A, Prandoni P, Goldhaber SZ. Epidemiologic
characteristics, management, and outcome of deep venous thrombosis
in a tertiary care hospital: The Brigham and Women's Hospital DVT
Registry. Amer Heart J 1996;132:1010-4
3. Prandoni P, Falanga A, Piccioli A. Cancer and venous
thromboembolism. Lancet Oncol 2005;6:401- 410
4. Prandoni P, Piovella C, Filippi L, Vedovetto V, Dalla Valle F
& Piccioli A. What are the pharmacotherapy options for treating
venous thromboembolism in cancer patients? Expert Opin Pharmacother
2014 Apr;15(6):799-807
5. Prandoni P, Lensing AWA, Piccioli A, Bernardi E, Simioni P,
Girolami B, Marchiori A, Sabbion P, Prins MH, Noventa F, Girolami
A. Recurrent venous thromboembolism and bleeding complications
during anticoagulant treatment in patients with cancer and venous
thrombosis. Blood 2002;100:3484-8
6. Piccioli A, Prandoni P. Approach to venous thromboembolism in
the cancer patient. Curr Treat Options Cardiovasc Med 2011; 13 (2):
159-68
7. Piccioli A,Falanga A, Prandoni P. Anticoagulants and cancer
survival. SeminThromb Haemost 2006;32:810-3
8. Klerk CP, Smorenburg SM, Otten HM, Lensing AW, Prins MH,
Piovella F, Prandoni P, Bos MM, Richel DJ, van Tienhoven G, Buller
HR, for the MALT Investigators (including Piccioli A). The Effect
of Low Molecular Weight Heparin on Survival in Patients With
Advanced Malignancy. J ClinOncol 2005;23:2130-5
9. Piccioli A, Prandoni P. Venous thromboembolism as first
manifestation of cancer. Acta Haematol 2001;106:13-7
10. Piccioli A.Prandoni P. Screening for occult cancer in
patients with idiopathic venous thromboembolism: Yes. J
ThrombHaemost 2003;1: 2271-2
11. Tryjillo-Santos J, Nieto JA, Tiberio G, Piccioli A, Di Micco
P, Prandoni P, Monreal M; RIETE Registry.Predicting recurrences or
major bleeding in cancer patients with venous thromboembolism.
Findings from the RIETE Registry. Thromb Haemost 2008;100:435-9
12. Piccioli A, Lensing AW, Prins MH, Falanga A, Scannapieco GL,
Ieran M, Cigolini M, Ambrosio GB, Monreal M, Girolami A, Prandoni
P, for the SOMIT Investigators Group. Extensive screening for
occult malignant disease in idiopathic venous thromboembolism: a
prospective randomized clinical trial. J Thromb Haemost
2004;2:884-9
13. Di Nisio M, Otten HM, Piccioli A, Lensing AWA, Prandoni P,
Büller HR, Prins MH. Decision analysis for cancer screening in
idiopathic venous thromboembolism. J Thromb Haemost
2005;3:2391-6
-
7
14. Piccioli A, Bernardi E, Dalla Valle F, Visonà A, Tropeano
PF, BovaC,Bucherini E , Barbar S, Falanga A, Prandoni P. The value
of CT scanning for detection of occult cancer in patients with
idiopathic VTE: D’Acquapendente Study. Submitted 2014
15. Douketis JD, Gu C, Piccioli A, Ghirarduzzi A, Pengo V,
Prandoni P.The long-term risk of cancer in patients with a first
episode of venous thromboembolism. J Thromb Haemost
2009;7:546-51
16. Prandoni P, Casiglia A., Piccioli A,Ghirarduzzi A, Pengo V,
Gu C, and Douketis JD. The risk of cancer in patients with venous
thromboembolism does not exceed that expected in the general
population after the first 6 months. J Thromb Haemost 2010;8 (5):
1126-7
17. Piccioli A, Falanga A, Prandoni P. Anticoagulants and cancer
survival. Semin Thromb Haemost 2006;32:810-3
18. Klerk CP, Smorenburg SM, Otten HM, Lensing AW, Prins MH,
Piovella F, Prandoni P, Bos MM, Richel DJ, van Tienhoven G, Buller
HR, for the MALT Investigators (including Piccioli A). The Effect
of Low Molecular Weight Heparin on Survival in Patients With
Advanced Malignancy. J ClinOncol 2005;23:2130-5
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=
-
8
-
9
A. VENOUS THROMBOEMBOLISM IN CANCER PATIENTS
-
10
-
11
CHAPTER 2
Cancer and venous thromboembolism
Piccioli A, Prandoni P
Published in part in: Andrea Piccioli MD, Paolo Prandoni, MD,
Bruce M Ewenstein MD, and Samuel Z. Goldhaber MD. Padua, Italy and
Boston, Mass. Cancer and venous thromboembolism, Amer Heart J
1996;132:1010-4. Paolo Prandoni, Anna Falanga, Andrea Piccioli.
Cancer and venous thromboembolism. Lancet Oncol 2005;6:401-410.
Piccioli A, Falanga A, Baccaglini U, Marchetti M, Prandoni P Cancer
and venous Thromboembolism. Semin Thromb Hemost 2006; 32(7);694-9.
Paolo Prandoni, Chiara Piovella, Lucia Filippi, Valentina
Vedovetto, Fabio Dalla Valle & Andrea Piccioli What are the
pharmacotherapy options for treating venous thromboembolism in
cancer patients? Expert Opin Pharmacother 2014
Apr;15(6):799-80.7
-
12
Abstract
Venous thromboembolism occurs commonly in patients with cancer.
The pathogenetic mechanisms of thrombosis involve a complex
interaction between tumour cells, the haemostatic system, and
characteristics of the patient. Among risk factors for
thromboembolism the most important are long-term immobilisation,
especially in hospital, surgery, and chemotherapy with or without
adjuvant hormone therapy. Although prophylaxis and treatment of
thromboembolism in patients with cancer draw on the agents that are
commonly used in those without cancer, there are many special
features of patients with cancer that make use of these drugs more
challenging. Low-molecular weight heparins are the cornerstone of
prophylaxis and treatment of venous thromboembolism in patients
with cancer. These drugs have the potential to increase survival,
at least in patients with more favourable outlook. Introduction
Thromboembolism is a well-recognised complication of malignant
disease. Clinical manifestations vary from venous thromboembolism
to disseminated intravascular coagulation and arterial embolism.
Disseminated intravascular coagulation is most commonly observed in
patients with haematological malignant disorders and those with
widespread metastatic cancer, whereas arterial embolism is most
commonly observed in patients undergoing chemotherapy and in those
with non-bacterial thrombotic endocarditis. This review focuses on
the relation between cancer and venous thromboembolism.
Pathogenesis of thrombosis in cancer Cancer growth is associated
with the development of a hypercoaguable state. Patients with
malignant disorders but no thrombosis commonly present with
abnormalities in laboratory coagulation tests, which suggest a
continuous process of fibrin formation and removal at different
rates in these patients (1). Fibrin and other clot components have
roles not only in thrombogenesis but also in tumour
adhesion,spread,and metastasis (2). Many histopathological studies
have shown the presence of fibrin or platelet plugs in and around
many types of tumours (3) which suggests local activation of blood
coagulation and an involvement of clotting mechanisms in the growth
of malignant tissues. Prothrombotic mechanisms The activation of
blood coagulation in patients with cancer is complex and
multifactorial (4). General prothromboticmechanisms are related to
the host response to cancer and include the acute-phase reaction,
paraprotein production, inflammation,necrosis, and hemodynamic
disorders. Procoagulant effects are also exerted by anticancer
chemotherapy and radiotherapy. However, a prominent part is played
by tumour-specific clot-promoting mechanisms resulting from the
prothrombotic properties expressed by tumour cells themselves.
These properties are unique to the malignant state. Malignant cells
can activate blood coagulation in several ways: by producing
procoagulant, fibrinolytic, and proaggregating activities; by
releasing pro-inflammatory and proangiogenic cytokines; and by
interacting directly with host vascular and blood cells, such as
endothelial cells, leucocytes, and platelets, by means of adhesion
molecules. Procoagulant,fibrinolytic, and proaggregating activities
Tumour cells produce procoagulant factors, among which the most
studied are tissue factor and cancer procoagulant (5). Tissue
factor, the primary activator of healthy blood coagulation, forms a
complex with factor VII to activate factors X and IX by
proteolysis. In healthy vascular cells, expression of tissue factor
is tightly controlled; the factor is normally not expressed but is
induced by inflammatory stimuli such as the cytokines interleukin 1
and tumour necrosis factor
-
13
(TNF) as well as bacterial lipopolysaccharides. In malignant
cells, however, tissue factor is constitutively expressed. By
contrast, cancer procoagulant is a cysteine proteinase that
directly activates factor X independently of factor VII; it has
been found in tumour cells and in tissues of the amnion and chorion
but not in normal differentiated cells. Tissue factor and cancer
procoagulant have been identified in several human and animal
tumour tissues (6). The finding that severe coagulopathy in acute
promyelocytic leukaemia resolves in parallel with the loss of
blast-cell procoagulant activities from the patient’s bone marrow
strongly supports the role of tumour procoagulants in promoting
clotting complications in malignant disorders (7). Tumour cells can
express all proteins that regulate the fibrinolytic system,
including the urokinase-type and tissue-type plasminogen
activators, plasminogen-activator inhibitors 1 and 2, and
plasminogen-activator receptor (8). The increase in plasma
concentrations of plasminogen-activator inhibitors and impairment
in plasma fibrinolytic activity in patients with solid tumours
indicate another tumour-associated prothrombotic mechanism. Tumour
cells induce platelet activation and aggregation by direct
cell–cell contact or by releasing soluble factors, such as ADP,
thrombin, and other proteases (9). Circulating activated platelets
expose on their surface the activation-dependent antigens
P-selectin and CD 63. On aggregation they release their granule
contents. Activation of platelets increases their capacity to
interact by specific adhesive mechanisms with endothelial cells,
leucocytes, and tumour cells. Tumour-cell-derived cytokines Tumour
cells produce and release various cytokines, including TNF,
interleukin 1, and vascular endothelial growth factor (VEGF), which
can be involved in the development of thrombotic disorders in
patients with cancer (10). The major targets of tumour-derived
cytokines are the vascular endothelium and leucocytes. TNFa and
interleukin 1 induce the expression of endothelial procoagulant
activity (tissue factor) and simultaneously down regulate the
expression of thrombomodulin, the endothelial surface high affinity
receptor for thrombin, which complexes thrombin to activate the
potent anticoagulant protein-C system. Together, up-regulation of
tissue factor and down-regulation of thrombomodulin lead to a
prothrombotic condition in the vascular wall. The same cytokines
strongly stimulate the production of the fibrinolysis inhibitor
plasminogen-activator inhibitor 1, thus impairing the endothelial
antithrombotic response. Tumour-derived VEGF also induces
expression of tissue factor by endothelial cells, which implies
involvement of tissue factor in tumour neovascularisation (11).
Finally, cytokines induce changes in expression of endothelial-cell
adhesion molecule, increasing the capacity of the vessel wall to
attract leucocytes and platelets and promoting localised clotting
activation and fibrin formation. In a similar way to endothelial
cells, monocytes are activated by tumour cells, their products, or
both to express tissue factor on their surfaces (12).
Tumour-associated macrophages obtained from experimental and human
tumours express substantially more tissue factor than do control
cells, and circulating monocytes from patients with various types
of cancer show increased tissue-factor activity. Tumour cytokines
also attract and activate polymorphonuclear leucocytes, which
release reactive oxygen species and intracellular proteases that
have several activities on endothelial cells and platelets,
modifying the haemostatic balance towards a prothrombotic state
(13). Cell–cell interactions The presence of cell-adhesion
molecules on the surface of tumour cells allows the possibility of
direct interaction with healthy cells. During haematogenous spread,
this interaction occurs with endothelial cells, platelets, and
leucocytes. The capacity of tumour cells to adhere to both resting
and cytokine-stimulated endothelium is well known, and
adhesion-molecule pathways specific to different tumour-cell types
have been identified (2,4). Malignant cells attached to the vessel
wall promote localised clotting activation and thrombus formation
and promote the adhesion and arrest of leucocytes and platelets by
releasing cytokines. Cancer cells also directly activate platelets,
adhere and migrate through the vessel wall, and are assisted by
polymorphonuclear leucocytes in their interaction with endothelial
cells.
-
14
Prothrombotic mechanisms and tumour progression Tumour-specific
prothrombotic properties contribute to the process of tumour growth
and dissemination. The formation of thrombin, the final effector
enzyme of the clotting cascade, and production of fibrin, the final
product of the activation of blood coagulation, are
coagulation-dependent mechanisms of tumour progression. In
addition, tumour prothrombotic properties can interfere with the
malignant process by coagulation-independent mechanisms . Relevant
in this setting is the emerging role of the non-coagulant
activities of tissue factor (2), particularly its capacity to
modulate VEGF expression by malignant cells and normal vascular
cells. This property regulates tumour neovascularisation and
provides an important link in patients with cancer between
activation of coagulation, inflammation, thrombosis, and cancer
growth and metastasis (14). Epidemiology and risk factors for
thromboembolism in patients with cancer Since the initial
observation by Trousseau in 1865, many studies have addressed the
relation between cancer and venous thromboembolism. This disorder
is a common complication in patients with cancer. In some cases it
is the first manifestation of cancer, so offering opportunities for
diagnosis and treatment (15). In patients with malignant disorders,
venous thromboembolism is an important cause of morbidity and
mortality. Of every seven patients with cancer who die in hospital,
one dies of pulmonary embolism (16). Of these patients, 60% have
localised cancer or limited metastatic disease, and they would have
survived for longer in the absence of pulmonary embolism. According
to the Medicare Provider Analysis and Review Record database that
records the primary discharge diagnosis and an additional four
discharge diagnoses in the USA, initial or recurrent
thromboembolism in patients with cancer exceeds by far that
recorded in those without malignant disorders; thromboembolism
complicates the course of cancers of virtually all body systems
with similar frequency (17). The true frequency of venous
thromboembolism in patients with cancer is not known, because of
the surprising lack of information in almost all studies dealing
with the natural course of malignant diseases. Most thrombotic
episodes occur spontaneously, in the absence of triggering factors
commonly accounting for thromboembolic complications in people
without cancer (18,19). Patients with cancer have a highly
increased risk of venous thromboembolism in the first few months
after diagnosis and in the presence of distant metastases (19). The
risk is further increased in the presence of inherited
thrombophilic abnormalities (19). The most common situations that
increase the risk of venous thromboembolism in patients with cancer
include immobilisation, surgery, chemotherapy with or without
hormone therapy, and the insertion of central venous catheters
(20). Immobilisation One of the most important triggering factors
for venous thromboembolism is long-term immobilisation, especially
during a hospital stay. This pattern was clearly confirmed by
Shenand Pollack, (16) who reported that up to 14% of patients with
cancer admitted to hospital died of autopsy-confirmed pulmonary
embolism, compared with 8% of those without cancer (16). Surgery In
the absence of adequate prophylaxis, patients with active cancer
face a very high risk of developing venous thromboembolism
postoperatively. In the absence of thromboprophylaxis, the overall
incidence of postoperative deep-vein thrombosis is about two times
higher in patients with cancer than in patients without malignant
disease (15). Many factors contribute to this high frequency,
including advanced age, long and complicated surgical procedures,
and late mobilisation with long postoperative course owing to the
patient’s poor condition. If
-
15
thromboprophylaxis is not extended beyond the hospital stay,
patients with cancer remain at risk of developing late venous
thromboembolism (21, 22). Chemotherapy, radiotherapy, and adjuvant
hormone therapy Patients with cancer are also at high risk of
developing both venous and arterial thrombosis when they receive
chemotherapy (23). In patients with high-grade glioma undergoing
chemotherapy, the frequency of thromboembolic complications was as
high as 16% (24). In a retrospective study in patients who had been
given chemotherapy, the rate of thromboembolic complications
arising within the first (3) months was unexpectedly high, giving
an annual rate of 11% (25). The most reliable estimate of
thromboembolic complications in patients undergoing chemotherapy
comes from those with breast cancer. The frequency of
chemotherapy-induced thromboembolic complications in women with
stage II breast cancer undergoing chemotherapy was on average 7% in
available studies assessing this risk (23). Among patients with
stage IV breast cancer the risk was even higher (26). Hormone
therapy combined with chemotherapy further increases the risk of
thromboembolic complications in women with breast cancer (27). Even
when given alone, tamoxifen to prevent recurrence or for prevention
of breast cancer in women at high risk, slightly increases the rate
of venous thromboembolism (28,29). By comparison with tamoxifen,
third-generation oral aromatase inhibitors, such as the
irreversible steroid inactivator exemestane, have the potential to
be associated with a lower rate of thromboembolic events (30).
Although radiotherapy is widely believed to be a risk factor for
venous thromboembolism in patients with cancer, no study has as yet
adequately investigated its role. Central venous catheters
Long-dwelling central venous catheters have greatly improved the
management of patients with cancer. However, their use has been
associated with the occurrence of deep-vein thrombosis in the arms,
especially in patients undergoing chemotherapy (31). The true
frequency of deep-vein thrombosis in patients with central venous
lines is difficult to estimate, because published data are somewhat
conflicting. In the absence of thromboprophylaxis, Bern and
colleagues (32) found that the rate of deep-vein thrombosis, as
shown by phlebography, was 37%. Monreal and co-workers (33) found
an even higher rate. By contrast, in case series in which
ultrasonography or other non-invasive methods were used to detect
arm deep-vein thromboses, a much lower rate has been reported
(31,34). Along with the lower sensitivity of objective non-invasive
methods in comparison with phlebography, the availability of new
textures and coating of catheters, and the introduction of new
procedures to reduce their invasiveness is likely to account for
discrepancies between older and more recent studies.
Thromboprophylaxis Although many patients with active cancer
develop thrombotic complications spontaneously, in the absence of
other risk factors, there is probably little point in providing
thromboprophylaxis to all patients with cancer who are not
undergoing surgical or medical therapy. However, a history of
thromboembolism puts patients with cancer at such a high risk of
recurrence that the systematic use of mechanical or pharmacological
prophylaxis should be considered even in the absence of the common
risk factors for thrombosis. Prevention of venous thromboembolism
in cancer is an important challenge, because patients experiencing
a thrombotic episode have a poor outcome with greater probability
of death. Surgical interventions According to widely accepted
guidelines, low-molecular-weight heparin (LMWH) in low doses,
low-dose unfractionated heparin, or physical measures should be
used in patients with cancer who face long-term immobilisation or
low-risk surgical procedures (35). Patients with cancer
-
16
undergoing extensive surgery are at extremely high risk of
postoperative venous thromboembolism. Accordingly, more intensive
prophylactic regimens are needed, such as doses of LMWH about twice
as high as suggested for low riskprocedures, adjusted-dose heparin,
or oral anticoagulants (35). Once-daily injections of LMWH are at
least as effective and safe as several injections of unfractionated
heparin for prevention of postoperative venous thromboembolism in
patients with cancer (36–38). In this setting, fondaparinux (a
short-acting pentasaccharide) shows promise. In a trial to address
the value of fondaparinux (2,5 mg once daily) for prevention of
postoperative venous thromboembolism in patients undergoing major
abdominal surgery, fondaparinux was more effective than enoxaparin
in the subgroup of patients with cancer without increasing the risk
of haemorrhage (39). Recent trials (22,40) have suggested that use
of LMWH until 4 weeks after surgical intervention provides an
additional thromboprophylactic effect without increasing the risk
of haemorrhage.In patients who have had bleeding episodes or who
are at high risk of bleeding, physical measures such as graduated
compression stockings or external pneumatic compression should be
used instead of pharmacological prophylaxis (41). According to the
results of two randomised trials (42,43) in patients with cancer
undergoing elective neurosurgery, the combination of LMWH (starting
within 24 h of surgery) and graduated compression stockings is more
effective than, and as safe as, elastic stockings alone for
prevention of postoperative venous thromboembolism. Chemotherapy
and radiotherapy In the only available study,(44) fixed low-dose
warfarin (1 mg/day) for 6 weeks, followed by doses that maintained
the international normalised ratio (INR) at 1·3–1·9was effective
and safe for prevention of chemotherapy-induced thromboembolism in
women with metastatic breast cancer. Whether this strategy or
approaches that involve LMWH are effective and safe in other
oncological settings remains to be shown.No adequate study has yet
assessed the preventive value of antithrombotic strategies in
patients undergoing radiotherapy. Central venous catheters Two
randomised controlled studies (32,45) documented the benefit of
fixed low-dose warfarin (1 mg once daily) in decreasingthe
frequency of arm venous thrombosis related to indwelling central
venous catheters. Subcutaneous dalteparin (2500 IU once daily for
90days) was also highly beneficial for prevention of arm thrombosis
in patients with cancer who had venous access devices (33).
However, three other clinical trials found no benefit from 1 mg
warfarin daily (46,47) or 40 mg enoxaparin once daily (48) compared
with no prophylaxis. Thus, neither low-dose warfarin nor
prophylactic LMWH can be recommended as routine prophylaxis
forpatients with cancer who have indwelling central venouslines
(35). Treatment of venous thromboembolism Initial treatment Those
patients who present with clinically unstable life threatening
PEand who do not have contraindications tothrombolysis(such as
ongoing or recent bleeding and brain metastasis) should promptly be
administered drugs that have the potential to rapidly restore the
patency of obstructed pulmonaryarteries (49-51). Among the drugs
that have been shownto achieve a rapid and substantial lysis of
fresh pulmonary emboli are urokinase, streptokinase and tissue-type
plasminogenactivator (t-PA). The use of the last should been
encouraged, because the administration of a loading dose of10 mg
followed by the intravenous infusion of 90 mg produces in only 2 h
the result that can be obtained by 12 - 24 h of infusion of
urokinase or streptokinase (52,53). As compared to heparin alone,
the administration of t-PA relieves patients’symptoms and improves
prognosis to a greater extent (54-56). During the administration of
t-PA or soon after its discontinuation heparin treatment should be
implemented
-
17
(1). As far as the role of thrombolytic agents for acute
deep-vein thrombosis (DVT) in cancer patients is concerned,
available evidence is against their use except for very selected
patients with massive ilio-femoral thrombosis who are at risk of
limb gangrene and for whom a rapid venous decompression and flow
restoration may be desirable (49-51). In patients with
contraindications to catheter-directed thrombolysis, surgical
thrombectomy can be considered (49-51). Anticoagulant therapy
Except for selected patients requiring aggressive treatments, the
large majority of cancer patients should be treated with
therapeutic doses of low-molecular-weight heparin (LMWH),
unfractionated heparin or fondaparinux (UFH) (49-51). Except for
patients with severe renal failure, in whom UFH still represents
the treatment of choice, in all other patients the VTE episode
should be managed with LMWHs, as they represent the standard of
long-term treatment (49-51). In the absenceof contraindications,
LMWHs should be administered as soon as there is a high probability
that venous thrombosis exists, even before the diagnostic algorithm
is completed. LMWHs present a number of potential advantages
overUFH, including a longer plasma half-life, an improved
subcutaneous bioavailabilityand less variability in response to
fixed doses (49). As a result of these pharmacokinetic properties,
a stable and sustained anticoagulant effect is achieved when these
drugs are administered subcutaneously in doses adjusted to
bodyweight, once or twice daily, without laboratory
monitoring(49).These compounds have the potential to greatly
simplify the initial treatment of DVT and of selected low-risk
patients with PE (9), making the treatment of suitable patients
feasible in an outpatient setting (58-60). Treatment on home basis
appears feasible and safe, which is particularly attractive for
cancer patients, in whom prevention or reduction of hospital stay
haste potential to improve the quality of life (61-62). According
to the results of worldwide surveys, LMWHs are by far the most
commonly used drugs for the initial treatment of VTE in cancer
patients(63,64). Based on the results of many comparativetrials
between UFH and LMWH for the initial treatment of patients with DVT
that were conducted in the 1990s, LMWHs appear to be at least as
effective and safe as UFH both in patients with and in those
without cancer (65,66). It should be noted, however, that in these
clinical trials cancer patients represented only 10 - 15% of the
total population, as the majority of them were excluded because of
their poor performance status. Of interest, the use of LMWH was
associated with a significantly lower mortality, which was
essentially dependent on the reduction of cancer-related mortality
(65,66). It should not be forgotten that patients undergoing LMWH
treatment require close monitoringof platelet count, as the risk of
heparin-induced thrombocytopeniain medical patients treated with
LMWHmay not be negligible (67). Although in clinical practice UFH
has virtually been replaced by LMWHs, we think that several
indications still remain for UFH, especially in cancer patients.
The short half-life of intravenous UFH indeed allows for rapid
reversal of anticoagulation in patients who begin to bleed or will
require an invasive procedure. Also, the presence of severe renal
insufficiency (i.e., creatinine clearance lower than 30
ml/min)makes it attractive to use as a short-acting drug that in
addition can be timely monitored and possesses a specific antidote
(the protamine sulfate). UFH is generally administered
intravenously, whereas the use of nomograms assures that most
patients will achieve the therapeutic range for the activated
partial thromboplastin time (APTT), the most commonly recommended
test for its monitoring (68).Subcutaneous heparin treatment has
been suggested as an alternative to intravenous standard heparin,
provided that the APTT is performed in order to achieve a full
therapeutic effect(69). This modality of heparin administration,
which is particularly desirable in those cancer patients who have
difficult vein access, has been shown to be as effective and safe
as LMWH for treatment of patients with acute VTE, including >
20% of cancer patients (70). In addition, fixed-dose unmonitored
UFH isreasonableoption for out-of-hospital management in patients
with severe renal impairment (71). Fondaparinux is the first drug
of a new class of synthetic antithrombotic agents designed
specifically for a single physiological target in the coagulation
cascade and acts by indirect inhibition of factor Xa. This compound
does not bind to platelet factor-4, which makes the development of
immunethrombocytopenia extremely unlikely. In two large Phase III
multicenter
-
18
clinical trials, involving the treatment of almost 4500 patients
with clinically symptomatic DVT or PE (~10% with cancer), the
once-daily subcutaneous administration of 7.5 mg of fondaparinux (5
mg in individuals weighing < 50 kg, 10 mg in those weighing >
100 kg) overlapped with and followed by vitamin K antagonists (VKA)
was found to be at least as effective and safe as UFH or LMWH for
the treatment of DVT or PE (72,73). However, when the analysis is
confined to the only cancer patients randomized to the Matisse DVT
study, recurrent VTE was found to be significantly more frequent in
patients who had received an initial treatment with fondaparinux
than in those allocated to the enoxaparin arm (74). In any case,
fondaparinux is rarely employed for the initial treatment of VTE in
cancer patients, because unlike LMWHs it is not (yet) registered
for the long-termtreatment of thromboembolic disorders nor can it
be followed by VKAs, whose efficacy is definitely lower than that
of LMWHs (75). Alternative options: intracaval filters On average,
patients with cancer present with major-often
permanent-contraindications to anticoagulant treatment much more
frequently than patients free from malignancy. In these patients,
the only therapeutic option is the insertion of a (either
retrievable or permanent) vena caval filter (49-51), which should
be done without hesitation, as it has the potential to prevent
(recurrent) PE events in patients with acute VTE. Indeed,
prolonging life and/or improving its quality are invaluable goals
to be achieved even in patients with poor condition. Our view is
supported by findings from a Spanish registry. In a large number of
patients with acute VTE who were managed without the insertion of a
vena caval filter after a recent episode of major bleeding, the
incidence of fatal bleeding and that of fatal PE in patients with
cancer was 10 times as high as that observed in those without
malignancy (76). As soon as the bleeding resolves, anticoagulation
should be resumed; accordingly, the filter should be removed (77).
Long-term anticoagulation While on VKA treatment, cancer patients
with venous thrombosis have a risk of recurrent VTE and major
bleeding that is higher than that reported in patients free from
malignancies. The best evidence comes from a retrospective analysis
of data from two large randomized clinical trials and two
prospective cohort studies (78-80). Hutten et al. extractedthe
rates of recurrent VTE and major bleedings in more than1300
patients receiving at least 3 months of oral anticoagulant therapy
for an acute episode of DVT (78). The overall incidence of
recurrent thrombosis in patients with cancer was 27.1/100
patient-years, versus 9.0/100 patient-years in those without
cancer. The risk of major bleeding was 13.3/100 patient-years and
2.1/100 patients-years, respectively.Palaretiet al. comparedthe
outcome of anticoagulation courses in 95 cancer patients and 733
patients without malignancy (79). Based on 744 patient-years of
treatment and follow up, there was a trend toward a higher rate of
thrombotic complications in cancer patients (6.8 vs 2.5%; relative
risk = 2.5). The rate of major bleeding was significantly higher in
cancer patients (5.4%) than in those without malignancy (0.9%;
relative risk = 6.0). We conducted a prospective cohort study in
842 consecutive patients with DVT who were administered
conventional anticoagulation, of whom 181 had cancer(80). The
12-month cumulative incidence of recurrent thromboembolism in
cancer patients was 20.7 versus 6.8% in patients without cancer,
for an age-adjustedhazard ratio of 3.2 (95% CI: 1.9 - 5.4). The
12-month cumulative incidence of major bleeding was 12.4% in
patients with cancer and 4.9% in patients without cancer, for an
age-adjusted hazard ratio of 2.2 (95% CI:1.2 - 4.1). In summary,
cancer patients have a three- to four-fold higher risk of recurrent
VTE during anticoagulant therapy than cancer-free patients, very
likely as a consequence of the release of cancer procoagulants that
are not inhibited by conventional anticoagulation. This risk
correlates with the extent and the type of cancer (80). Recently, a
stratification score has been developed and validated that has the
potential to help clinicians predict the VTE recurrence risk and
thus tailor treatment, improving clinical outcomes while minimizing
costs (81). According to the results of three randomized clinical
trials, LMWHs in full doses for the first month followed by a dose
ranging from 50 to
-
19
100% of the initial regimen have the potential to provide a more
effective antithrombotic regimen in cancer patients with venous
thrombosis than the conventional treatment and are not associated
with an increasedhemorrhagic risk (75,82,83), even in patients with
disseminated cancer such as those with liver or brain
metastases(84). In addition, LMWHs provide an anticoagulation that
is easier to administer, more convenient and flexible and not
influenced by nutrition problems or liver impairment (1). Thus, the
long-term administration of LMWH should now be considered the
treatment of choice in patients with metastatic disease and in
those with conditions limiting the use of oral anticoagulants
(49-51). On average, after discontinuation of antithrombotic
treatment cancer patients with venous thrombosis present a risk for
recurrences that is almost twice as high as that observed in
patients free from malignancies (85-87). However, the risk of
recurrence after stopping anticoagulation depends on the setting.
For example, a patient who develops VTE after surgery for cancer
has a low risk of recurrence if the cancer was completely resected.
Like wise, a patient who develops VTE while receiving neo-adjuvant
chemotherapy for potential micrometastatic cancer has a
considerably lower risk of recurrence if anticoagulation is stopped
after the chemotherapy is completed than a patient with metastatic
disease who continues to receive combination chemotherapy. In
principle, prolongation of anticoagulation should be considered for
as long as the malignant disorder is active provided that it is not
contraindicated. This decision should be frequently reassessed
during patients’ follow up. Treatment of challenging situations The
treatment of challenging situations has recently been addressed by
the Subcommittee of the International Society of Thrombosis and
Haemostasis (77). Management of recurrent VTE despite
anticoagulation Recurrent VTE despite appropriate anticoagulation
is common among cancer patients (88,89). Cancer patients with
symptomatic recurrent VTE despite therapeutic anticoagulation with
VKA should be switched to therapeutic weight adjusted doses of
LMWH. Cancer patients with symptomatic recurrent VTE despite
anticoagulation with LMWH should continue with LMWH at a higher
dose, starting at an increase of ~ 25% of the current dose or
increasing it back up to the therapeutic weight-adjusted dose if
they have been receiving on-therapeutic dosing. All cancer patients
with recurrent VTE despite anticoagulation should be reassessed 5-7
days after a dose escalation of their anticoagulant therapy.
Patients with symptomatic improvement should continue the same dose
of LMWH and resume their usual follow up. In patients without
symptomatic improvement, the peak anti-Xa level can be used to
estimate the dose of further escalation (77). Management of
cancer-associated VTE in patients with thrombocytopenia Thrombosis
is commonly diagnosed in patients with malignancy and
thrombocytopenia. Full therapeutic doses of anticoagulation without
platelet transfusion should be given in patients with platelet
count ≥ 50 109/l. In patients with platelet count < 50 109/l,
the recommended strategy diverges in patients with acute (< 1
month) from those withsubacute (1-3 months) or chronic (> 3
months) VTE. In the former group, full therapeutic doses of
anticoagulation with platelet transfusion should be given to
maintain a platelet count ≥ 50 109/l. If platelet transfusion is
not possible or contraindicated, the insertion of a retrievable
filter is suggested, as well as its removal when platelet count
recovers and anticoagulation can be resumed. In the remaining
groups, subtherapeutic orprophylactic doses of LMWH should be used
in patients with platelet count of 25 - 50 109/l, whereas
anticoagulation should be discontinued in patients with platelet
count< 25 109/l (77).
-
20
Management of cancer-associated VTE patients who are bleeding A
careful and thorough assessment of each bleeding episode, including
identification of the source, its severity or impact, and
reversibility should be done, as well as the usual supportive care
with transfusion and surgical intervention to correct the bleeding
source, whenever indicated and possible. Withholding
anticoagulation in patients having a major or
life-threateningbleeding episode is mandatory. Insertion of a caval
filter is suggested for patients with acute or subacute VTE who are
having a major or life-threatening bleeding episode, whereas it is
discouraged in patients with chronic VTE. Once the bleeding
resolves, anticoagulation should be initiated or resumed, and the
retrievable caval filter (if inserted)should be removed (77).
Potential of the novel direct oral anticoagulants As new categories
of drugs have emerged that have the potential to replace
conventional treatment for the initial and long-term treatment of
VTE, major improvements are expected for the management of cancer
patients with venous thrombosis. They include direct inhibitors of
factor Xa (such as rivaroxaban, apixaban and edoxaban) and direct
inhibitors of factorIIa (such as dabigatran etexilate). They
possess several advantages over conventional drugs, including the
inhibition of fibrin-bound Xa or thrombin, respectively, a
dose-response that is more predictable because there is no binding
to plasma proteins, and a lack of potential to produce immune
thrombocytopenia. As a consequence of their pharmacokinetic and
pharmacodynamic properties, they can be administered orally, in
fixed doses, without laboratory monitoring. Based on available
information coming from well-designed and conducted Phase III
randomized clinical trials, they possess a morefavourable
benefit-to-risk profile than the old compounds, make it possible to
implement the treatment from the beginning and cover the whole
spectrum of clinical presentations, including severe PE (90-95).
However, for the time being their use in patients with cancer
requires caution. Indeed, only a small minority of patients with
cancer (consistently around 5%) were included in theabovementioned
studies. More importantly, in these studies the comparator was
warfarin, and not a LMWH, which represents the standard of
treatment in cancer patients with thrombosis (49). Severe liver and
renal dysfunctions, which contraindicate the use of all new oral
compounds, are quite common in patients with cancer. There is
uncertainty about the proper management of patients requiring
emergency procedures and in those with thrombocytopenia. Finally,
for the time being these drugs still lack proper antidotes. The
novel anticoagulants should be investigated more carefully before
routine usage in cancer patients. There are lessons to be learned
from the studies conducted long time ago withfondaparinux, a
parenteral potent inhibitor of factor Xa.Indeed, when the analysis
of the Matisse DVT study, addressing the treatment of patients with
DVT, was confined to theonlysubgroup of cancer patients, recurrent
VTE was found to be significantly more frequent inpatients who had
received an initial treatment with fondaparinux than in those
allocated toenoxaparin (74). Management of incidentally detected
isolated VTE Asymptomatic PE is a common finding in medical
oncology dueto the routine use of modern computed tomography (CT)
scanners for cancer staging. Although the clinical relevance of
these incidental findings is unknown, based on the results of a few
investigations conducted in recent years, they are likely to impact
on both the incidence of recurrent VTE and on the overall prognosis
to the same degree as the symptomatic findings (96-102).
Accordingly, the most recent international guidelines recommend the
same initial and long-term anticoagulation as for comparable
patients with symptomatic PE (49). However, there is still
uncertainty about the optimal management of patients with the
incidental detection of isolated(i.e., not associated with DVT)
sub-segmental PE. Indeed, whether the outcome of these patients is
comparable to that of patients with symptomatic involvement of
sub-segmental arterial vessels (103) is unknown, as is the accuracy
of detecting on CT scans that were not specifically ordered to
diagnose PE.
-
21
Higher risk of false positive diagnosis compared to patients
with suspected PE cannot be excluded. In a series of70 patients
diagnosed with subsegmental PE, this diagnosis was confirmed in
only 51% by a reviewing radiologist (104). PE may not be acute but
chronic. In a series of 65 cases of untreatedsubsegmental PE
reported so far, none of these patients developed recurrent VTE
(105). Finally, there is uncertainty about the outcome of patients
with incidental PE who receive anticoagulants. In a cohort study of
51 patients with incidental PE, 5 (9.8%) patients developed major
bleeding of which 2 cases were fatal (100). Thus, a careful
evaluation should be individually done rather than giving full-dose
anticoagulation to all cancer patients with the occasional
detection of isolated subsegmental PE. An exception can be made for
patients with the involvement of multiple sub-segmental vessels, as
these patients are unlikely to differ from those with the
involvement of more proximal arteries. While patients with
incidentally detected proximal DVTshould be managed not differently
from those with clinical symptoms, in patients with incidentally
detected below-knee DVT, as well as in those with incidental
thrombosis in other sites, such as portal, splenic or mesenteric
veins, there is no evidencefavouring anticoagulation (49).
Treatment of catheter-related thrombosis Central venous catheters
are extensively used in patients with cancer to secure delivery of
chemotherapy and to facilitate phlebotomy. Unfortunately,
considerable morbidity can result from early complications or late
sequelae, ranging from arterial puncture, pneumothorax and
bloodstream infections to catheter-related thrombosis. Contemporary
studies have shown that the incidence of symptomatic
catheter-related thrombosis is ~ 5%, whereas the incidence of the
asymptomatic one is higher, at 14 -- 18% (106). The significance
and mechanisms of catheter design, material, insertion location and
technique, position of the catheter tip and other risk factors in
contributing to the development of catheter-related thrombosis are
not well understood. Efforts to reduce thrombotic complications,
involving flushing the catheter with heparinized solutions, the use
of heparin-bonded catheters and systemic anticoagulant prophylaxis,
have been largely ineffective (106). As published data and clinical
experience suggest that catheter-related thrombosis is associated
with a low risk of thrombosis recurrence and post-thrombotic
syndrome (107), conservative treatment is recommended. A sensible
approach is to remove the catheter only if central venous access is
no longer required, the device is non-functional or defective or
line-related sepsis is suspected or documented. Unless
contraindicated, therapeutic anticoagulation should be given using
either LMWH alone or LMWH followed by warfarin therapy. A short
period of anticoagulation (3 - 5 days of LMWH) may even salvage
some thrombosed catheters and obviate the need to remove and
replace the line. Anticoagulation is recommended for a minimum of 3
months and while the catheter remains in place (49). Impact of
antithrombotic drugs on cancer evolution Anticoagulant treatment of
cancer patients, particularly those with lung cancer, has been
reported to improve survival (108). Since then, studies conducted
in animal tumour models have demonstrated that both UFH and LMWH
interfere with various processes involved in tumour growth and
metastasis (109). These processes might include fibrin formation,
binding of heparin to angiogenic growth factors such as basic
fibroblast growthfactor and vascular endothelial growth factor,
modulation of tissue factor and other mechanisms (109). The
evidence of lowered cancer mortality in patients on LMWH in
comparison with those treated with UFH (65,66) has stimulated
renewed interest in these agents as antineoplastic drugs. Five
randomized studies have compared the long-term survival of cancer
patients receiving conventional treatment with that of patients
receiving a supplementary dose of LMWH in therapeutic or
prophylactic doses (110-114). Two of these studies showed a
favourable impact of the tested heparin on patients’ survival, this
result being particularly evident in those with better prognosis
(112,113). In the other two studies, post-hoc analysis showed a
better survival in subgroups of patients with less
-
22
advanced disease (110,111). The fifth virtually excluded any
appreciable advantages (114). Although a meta-analysis gave some
support to this hypothesis (115), current evidence that LMWH
reduces mortality is weak.
-
23
References
1. Falanga A, Barbui T, Rickles FR, Levine MN. Guidelines for
clotting studies in cancer patients. Thromb Haemost 1993;70:343–50
2. Rickles FR, Falanga A. Molecular basis for the relationship
between thrombosis and cancer. Thromb Res 2001;102:V215–24 3.
Costantini V, Zacharski LR. Fibrin and cancer. Thromb Haemost
1993;69:406–14 4. Falanga A, Donati MB. Pathogenesis of thrombosis
in patients with malignancy. Int J Hematol 2001;73:137–44 5. Gale
AJ, Gordon SG. Update on tumor cell procoagulant factors. Acta
Haematol 2001;106: 25–32 6. Falanga A, Marchetti M, Vignoli A,
Balducci D. Clotting mechanism and cancer: implications in thrombus
formation and tumor progression. Clin Adv Hematol Oncol
2003;1:673–78 7. Falanga A, Iacoviello L, Evangelista V, et al.
Loss of blast cell procoagulant activity and improvement of
hemostatic variables in patients with acute promyelocytic leukemia
given all-trans-retinoic acid. Blood 1995;86:1072–84 8. Kwaan HC,
Keer HN. Fibrinolysis and cancer. Semin Thromb Haemost
1990;16:230–35 9. Varon D, Brill A. Platelets cross-talk with tumor
cells. Haemostasis 2001;31(suppl 1):64–66 10. Grignani G, Maiolo A.
Cytokines and hemostasis. Haematologica 2000;85:967–72 11. Contrino
J, Hair G, Kreutzer DL, Rickles FR. In situ detection of tissue
factor in vascular endothelial cells: correlation with the
malignant phenotype of human breast disease. Nat Med 1996;2:209–15
12. Semeraro N, Colucci M. Tissue factor in health and disease.
Thromb Haemost 1997;78: 759–64 13. Falanga A, Marchetti M,
Evangelista V, et al. Polymorphonuclear leukocyte activation and
hemostasis in patients with essential thrombocythemia and
polycythemia vera. Blood 2000;96: 4261–66 14. Shoji M, Hancock WW,
Abe K, et al. Activation of coagulation and angiogenesis in cancer.
Immunohistochemical localization in situ of clotting proteins and
VEGF in human cancers. Am J Pathol 1998;152: 399–411 15. Prandoni
P, Piccioli A, Girolami A. Cancer and venous thromboembolism: an
overview. Haematologica 1999;84:437–45 16. Shen VS, Pollak EW.
Fatal pulmonary embolism in cancer patients: is heparin prophylaxis
justified? South Med J 1980;73:841–43 17. Levitan N, Dowlati A,
Remick SC, et al. Rates of initial and recurrent thromboembolic
disease among patients with malignancy versus those without
malignancy: risk analysis using Medicare claims data. Medicine
(Baltimore) 1999;78:285–91
-
24
18. Otten HM, Prins MH. Venous thromboembolism and occult
malignancy. Thromb Res 2001; 102:V187–94 19. Blom JW, Doggen CJ,
Osanto S, Rosendaal FR. Malignancies, prothrombotic mutations, and
the risk of venous thrombosis. JAMA 2005;293:715–22 20. Piccioli A,
Prandoni P, Ewenstein BM, Goldhaber SZ. Cancer and venous
thromboembolism. Am Heart J 1996;132:850–55 21. Huber O, Bounameaux
H, Borst F, Rohner A. Postoperative pulmonary embolism after
hospital discharge: an underestimated risk. Arch Surg
1992;127:310–13 22. Bergqvist D, Agnelli G, Cohen AT, et al.
Duration of prophylaxis against venous thromboembolism with
enoxaparin after surgery for cancer. N Engl J Med 2002;346:975–80.
23. Levine MN. Prevention of thrombotic disorders in cancer
patients undergoing chemotherapy. Thromb Haemost 1997;78:133–36.
24. Cheruku R, Tapazoglou E, Ensley J, et al. The incidence and
significance of thromboembolic complications in patients with
high-grade gliomas. Cancer 1991;68:2621–24 25. Otten HMMB,
Mathijssen J, ten Cate H, et al. Symptomatic venous thromboembolism
in cancer patients treated with chemotherapy: an underestimated
phenomenon. Arch Intern Med 2004;164:190–94 26. Goodnough LT, Saito
A, Manni A, et al. Increased incidence of thromboembolism in stage
IV breast cancer patients treated with a five-drug chemotherapy
regimen: a study of 159 patients. Cancer 1984;54:1264–68 27.
Prichard KI, Paterson AHG, Paul NA, et al. Increased thromboembolic
complication with concurrent tamoxifen and chemotherapy in a
randomized trial of adjuvant therapy for women with breast cancer.
J Clin Oncol 1996;14:2731–37 28. Deitcher SR, Gomes MPV. The risk
of venous thromboembolic disease associated with adjuvant hormone
therapy for breast carcinoma. Cancer 2004;101:439–49 29. Goldhaber
SZ. Tamoxifen: preventing breast cancer and placing the risk of
deep vein thrombosis in perspective. Circulation 2005;111:539–41
30. Coombes RC, Hall E, Gibson LJ, et al. A randomized trial of
exemestane after two to three years of tamoxifen therapy in
postmenopausal women with primary breast cancer. N Engl J Med
2004;350:1081–92 31. Verso M, Agnelli G. Venous thromboembolism
associated with long-term use of central venous catheters in cancer
patients. J Clin Oncol 2003;21:3665–75 32. Bern MM, Lokich JJ,
Wallach SR, et al. Very low dose of warfarin can prevent thrombosis
in central venous catheters: a prospective trial. Ann Intern Med
1990;112:423–28 33. Monreal M, Alastrue A, Rull M, et al. Upper
extremity deep venous thrombosis in cancer patients with venous
access devicesprophylaxis with a low molecular weight heparin
(fragmin). Thromb Haemost 1996;75:251–53 34. Levine MN, Lee AY,
Kakkar AK. From Trousseau to targeted therapy: new insights and
innovations in thrombosis and cancer. J Thromb Haemost
2003;1:1456–63
-
25
35. Geerts WH, Pineo GF, Heit JA, et al. Prevention of venous
thromboembolism: the seventh ACCP Conference on Antithrombotic and
Thrombolytic Therapy. Chest 2004;126:338–400S 36. Bergqvist D,
Burmark US, Flordal PA, et al. Low molecular weight heparin started
before surgery as prophylaxis against deep vein thrombosis: 2500
versus 5000 XaI units in 2070 patients. Br J Surg 1995;82:496–501
37. Enoxacan Study group. Efficacy and safety of enoxaparin versus
unfractionated heparin for prevention of deep vein thrombosis in
elective cancer surgery: a double-blind randomized multicentre
trial with venographic assessment. Br J Surg 1997;84:1099–103 38.
McLeod RS, Geerts WH, Sniderman KW, et al. Subcutaneous heparin
versus low-molecular-weight heparin as thromboprophylaxis in
patients undergoing colorectal DVT prophylaxis trial: a randomized,
double-blind trial. Ann Surg 2001;233:438–44 39. Agnelli G,
Bergqvist D, Cohen A, et al. A randomized doubleblind study to
compare the efficacy and safety of fondaparinux with dalteparin in
the prevention of venous thromboembolism after high-risk abdominal
surgery: the Pegasus study. In: Programs and abstracts of the XIX
Congress of the International Society on Thrombosis and
Haemostasis, Birmingham, UK; July 12–18, 2003. Malden: Blackwell
Publishing, 2003 (abstr) 40. Rasmussen MS, Jorgensen LN,
Wille-Jorgensen JP, et al. Prolonged prophylaxis with low molecular
weight heparin (dalteparin) after major abdominal surgery: the Fame
study. In: Programs and abstracts of the XIX Congress of the
International Society on Thrombosis and Haemostasis, Birmingham,
UK; July 12–18, 2003. Malden: Blackwell Publishing, 2003 (abstr)
41. Wells PS, Lensing AWA, Hirsh J. Graduated compression stockings
in the prevention of postoperative venous thromboembolism: a
meta-analysis. Arch Intern Med 1994;154:67–72 42. Nurmohamed MT,
van Riel AM, Henkens CM, et al. Low molecular weight heparin and
compression stockings in the prevention of venous thromboembolism
in neurosurgery. Thromb Haemost 1996;75:233–38 43. Agnelli G,
Piovella F, Buoncristiani P, et al. Enoxaparin plus compression
stockings compared with compression stockings alone in the
prevention of venous thromboembolism after elective neurosurgery. N
Engl J Med 1998;339:80–85 44. Levine MN, Hirsh J, Gent M, et al.
Double-blind randomised trial of very-low-dose warfarin for
prevention of thromboembolism in stage IV breast cancer. Lancet
1994;343:886–89. 45. Bern MM, Bothe A Jr, Bistrian B, et al.
Prophylaxis against central vein thrombosis with low-dose warfarin.
Surgery 1986;99:216–21 46. Couban S, Goodyear M, Burnell M, et al.
Randomized, placebo-controlled study of low-dose warfarin for the
prevention of central venous catheter-associated thrombosis in
patients with cancer. J Clin Oncol 2005 (in press) 47. Heaton DC,
Han DY, Inder A. Minidose warfarin as prophylaxis for central vein
catheter thrombosis. Intern Med 2002;32:84–88 48. Verso M, Agnelli
G, Bertoglio S, et al. Enoxaparin for the prevention of venous
thromboembolism associated with central vein catheter: a double
-blind, placebo-controlled, randomized study in cancer patients J
Clin Oncol 2005 (in press)
-
26
49. Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy
for VTE disease: antithrombotic Therapy and Prevention of
Thrombosis, 9th ed: American College of Chest Physicians
Evidence-Based Clinical Practice Guidelines. Chest2012;141(2
Suppl):e419-94S 50. Lyman GH, Khorana AA, Kuderer NM, et al. Venous
thromboembolism prophylaxis and treatment in patients with cancer:
American Society of Clinical Oncology Clinical Practice
GuidelineUpdate. J Clin Oncol 2013;31:2189-204 51. Farge D,
Debourdeau P, Beckers M,et al. International clinical practice
guidelines for the treatment and prophylaxis of venous
thromboembolism in patients with cancer.J Thromb Haemost
2013;11:56-70 52. Goldhaber SZ, Kessler CM, Heit J, et
al.Randomised controlled trial of recombinant tissue plasminogen
activator versus urokinase in the treatment of acute pulmonary
embolism. Lancet1988;2:293-8 53. Meyer G, Sors H, Charbonnier B, et
al.Effects of intravenous urokinase versus alteplase on total
pulmonary resistance in acute massive pulmonary embolism: a
European multicenter double-blind trial. J Am Coll Cardiol
1992;19:239-45 54. Dalla Volta S, Palla A, Santolicandro A, et al.
Alteplase combined with heparin versus heparin in the treatment of
acutepulmonary embolism. J Am Coll Cardiol 1992;20:520-6 55.
Goldhaber SZ, Haire WD,Feldstein ML, et al. Alteplase versus
heparin in acute pulmonary embolism:randomised trial assessing
right ventricular function and pulmonary perfusion. Lancet
1993;341:507-11 56. Konstantinides S, Gebel A, Heusel G,et al.
Heparin plus alteplase compared with heparin alone in patients with
submassive pulmonary embolism. N Engl J Med 2002;347:1143-50 57.
Hirsh J, Raschke R. Heparin and low-molecular-weight heparin. Chest
2004;126:188-203S 58. Aujesky D, Roy PM, Verschuren F, et
al.Outpatient versus inpatient treatment for patients with acute
pulmonary embolism:an international, open-label, randomised,
non-inferiority trial. Lancet 2011;378:41-8 59. Zondag W, Kooiman
J, Klok F, et al. Outpatient versus inpatient treatment in patients
with pulmonary embolism: a meta-analysis. Eur Respir J
2012;42:134-44 60. Wells PS, Kovacs MJ, Bormanis J, et al.Expanding
eligibility for outpatient treatment of deep venous thrombosis and
pulmonary embolism with low-molecular-weight heparin:a comparison
of patient self-injection with homecare injection. Arch Intern Med
1998;158:1809-12 61. Ageno W, Grimwood R, Limbiati S,et al.
Home-treatment of deep vein thrombosis in patients with cancer.
Haematologica 2005;90:220-4 62. Siragusa S, Arcara C, Malato A, et
al. Home therapy for deep vein thrombosis and pulmonary embolism in
cancer patients. Ann Oncol 2005;16:136-9S 63. Kakkar AK, Levine M,
Pinedo HM,et al. Venous thrombosis in cancer patients: insights
from the Front-line survey. Oncologist 2003;8:381-8
-
27
64. Kleinjan A, van Doormaal FF, Prins MH, et al. Limitations of
screening for occult cancer in patients with idiopathic venous
thromboembolism. Neth J Med 2012;70:311-17 65. Gould MK, Dembitzer
AD, Doyle RL,et al. Low-molecular-weight heparins compared with
unfractionated heparin for treatment of acute deep venous
thrombosis. A meta-analysis of randomized, controlled trials. Ann
Intern Med 1999;130:800-9 66. Dolovich LR, Ginsberg JS, Douketis
JD,et al. A meta-analysis comparing low-molecular-weight heparins
with unfractionated heparin in the treatment of venous
thromboembolism. Arch Intern Med 2000;160:181-8 67. Prandoni P,
Siragusa S, Girolami B,Fabris F. The incidence of heparin-induced
thrombocytopenia in medical patients treated with
low-molecular-weight heparin. Blood 2005;106:3049-54 68.
Cruickshank MK, Levine MN, Hirsh J,et al. A standard heparin
nomogram for the management of heparin therapy. Arch Intern Med
1991;151:333-7 69. Hommes DW, Bura A, Mazzolai L, et al.
Subcutaneous heparin compared with continuous intravenous heparin
administration in the initial treatment ofdeep vein thrombosis. A
meta-analysis. Ann Intern Med 1992;116:279-84 70. Prandoni P,
Carnovali M, Marchiori A. Subcutaneous adjusted-dose unfractionated
heparin vs fixed-dose low-molecular-weight heparin in the initial
treatment of venous thromboembolism. Arch Intern Med
2004;164:1077-83 71. Kearon C, Ginsberg JS, Julian JA, et
al.Comparison of fixed-dose weight-adjusted unfractionated heparin
and low-molecular-weight heparin for acute treatment of venous
thromboembolism. JAMA 2006;296:935-42 72. Buller HR, Davidson BL,
Decousus H,et al. Fondaparinux or enoxaparin for the initial
treatment of symptomatic deep venous thrombosis. Ann Intern
Med2004;140:867-73 73. The Matisse Investigators. Subcutaneous
fondaparinux versus intravenous unfractionated heparin in the
initial treatment of pulmonary embolism. N Engl J Med
2003;349:1695-702 74. van Doormaal FF, Raskob GE,Davidson BL, et
al. Treatment of venous thromboembolism in patients with cancer:
subgroup analysis of the Matisse clinical trials. Thromb Haemost
2009;101:762-9 75. Lee AY, Levine MN, Baker RI, et
al.Low-molecular-weight heparin versus a coumarin for the
prevention of recurrent venous thromboembolism in patients with
cancer. N Engl J Med 2003;349:146-53 76. Nieto JA, De Tuesta AD,
Marchena PJ, et al. Clinical outcome of patients with venous
thromboembolism and recent major bleeding: findings from a
prospective registry (RIETE). J Thromb Haemost 2005;3:703-9 77.
Carrier M, Khorana A, Zwicker J, et al.Management of challenging
cases of patients with cancer-associated thrombosis including
recurrent thrombosis and bleeding: guidance from the SSC of the
ISTH. J Thromb Haemost 2013;11:1760-5 78. Hutten B, Prins M, Gent
M, et al.Incidence of recurrent thromboembolic and bleeding
complications among patients with venous thromboembolism in
relation to both malignancy and achieved international normalized
ratio: a retrospective analysis. J Clin Oncol 2000;18:3078-83
-
28
79. Palareti G, Legnani C, Agnes L, et al. A comparison of the
safety and efficacy of oral anticoagulation for the treatment of
venous thromboembolic disease in patients with or without
malignancy.Thromb Haemost 2000;84:805-10 80. Prandoni P, Lensing
AWA, Piccioli A, et al. Recurrent venous thromboembolism and
bleeding complications during anticoagulant treatment in patients
with cancer and venous thrombosis. Blood 2002;100:3484-8 81.
Louzada ML, Carrier M,Lazo-Langner A, et al. Development of a
clinical prediction rule for risk stratification of recurrent
venous thromboembolism in patients with cancer-associated venous
thromboembolism. Circulation 2012;126:448-54 82. Meyer G,
Marjanovic Z, Valcke J, et al.Comparison of low-molecular-weight
heparin and warfarin for the secondary prevention of venous
thromboembolism in patients with cancer. Arch Intern Med
2002;162:1729-35 83. Hull RD, Pineo GF, Brant RF, et al.Long-term
low-molecular-weight heparin versus usual care in proximal-vein
thrombosis patients with cancer. Am J Med 2006;119:1062-72 84.
Monreal M, Zacharski L, Jimenez JA, et al. Fixed-dose
low-molecular-weight heparin for secondary prevention of venous
thromboembolism in patients with disseminated cancer: a prospective
cohort study. J Thromb Haemost 2004;2:1311-15 85. Prandoni P,
Lensing AWA, Cogo A,et al. The long-term clinical course of acute
deep venous thrombosis. Ann Intern Med 1996;125:1-7 86. Hansson PO,
Sorbo J, Eriksson H. Recurrent venous thromboembolism after deep
vein thrombosis. Incidence and risk factors. Arch Intern Med
2000;1260:769-74 87. Heit JA, Mohr DN, Silverstein MD,et al.
Predictors of recurrence after deep vein thrombosis and pulmonary
embolism. A population-based cohort study. Arch Intern Med
2000;160:761-8 88. Carrier M, Le Gal G, Cho R, et al.
Doseescalation of low molecular weight heparin to manage recurrent
venous thromboemblic events despite systemic anticoagulation in
cancer patients.J Thromb Haemost 2009;7:760-5 89. Luk C, Wells PS,
Anderson D, kovacs MJ. Extended outpatient therapy with low
molecular weight heparin for the treatment of recurrent venous
thromboembolism despite warfarin therapy. Am J Med 2001;111:270-3
90. Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus
warfarin in the treatment of acute venous thromboembolism. N Engl J
Med2009;361:2342-52 91. Schulman S, Kakkar AK, Goldhaber SZ, et al.
Treatment of acute venous thromboembolism with dabigatran or
warfarin and pooled analysis. Circulation 2013,
doi:10.1161/CIRCULATIONAHA.113.004450 92. The Einstein
Investigators. Oral rivaroxaban for symptomatic venous
thromboembolism. N Engl J Med 2010;363:2499-510 93. The Einstein
Investigators. Oral rivaroxaban for the treatment of symptomatic
pulmonary embolism.N Engl J Med 2012;366:1287-97
-
29
94. Agnelli G, Buller HR, Cohen A, et al. Oral apixaban for the
treatment of acute venous thromboembolism. N Engl J Med
2013;368:699-708 95. The Hokusai-VTE Investigators. Edoxaban versus
warfarin for the treatment of symptomatic venous thromboembolism. N
Engl J Med 2013;369:1406-15 96. Menapace LA, Peterson DR, Berry
A,et al. Symptomatic and incidental thromboembolism are both
associated with mortality in pancreatic cancer.Thromb Haemost
2011;106:371-8 97. Sahut D’Izarn M, Caumont Prim A,Planquette B, et
al. Risk factors and clinical outcome of unsuspected pulmonary
embolism in cancer patients: a case-control study. J Thromb Haemost
2012;10:2032-8 98. Agnelli G, Verso M, Mandala` M, et al. A
prospective study on survival in cancer patients with and without
venous thromboembolism. Intern Emerg Med 2013;doi:
10.1007/s11739-013-0985-z 99. Connolly GC, Menapace L, Safadjou
S,et al. Prevalence and clinical significance of incidental and
clinically suspected venous thromboembolism in lung cancer
patients.Clin Lung Cancer 2013;14:713-18 100. den Exter PL, Hooijer
J, Dekkers OM,Huisman MV. Risk of recurrent venous thromboembolism
and mortality in patients with cancer incidentally diagnosed with
pulmonary embolism: a comparison with symptomatic patients. J Clin
Oncol 2011;29:2405-9 101. Heidrich H, Konau E, Hesse P.
Asymptomatic venous thrombosis in cancer patients. A problem often
overlooked. Results of a retrospective and prospective study. Vasa
2009;38:160-6 102. O’Connell C, Razavi P, Ghalichi M, et al.
Unsuspected pulmonary emboli adversely impact survival in patients
with cancer undergoing routine staging MDCTscanning. J Thromb
Haemost 2010;9:305-11. 103. den Exter PL, van Es J, Klok FA, et
al.Risk profile and clinical outcome of symptomatic subsegmental
acute pulmonary embolism. Blood 2013;122:1144-9 104. Pena E,
Kimpton M, Dennie C, et al.Difference in interpretation of
computedtomography pulmonary angiography diagnosis of subsegmental
thrombosis in patients with suspected pulmonaryembolism. J Thromb
Haemost2012;10:496-8 105. Donato AA, Khoche S, Santora J,Wagner B.
Clinical outcomes in patients with isolated subsegmental pulmonary
emboli diagnosed by multidetector CTpulmonary angiography. Thromb
Res 2010;126:e266-70 106. Lee AY, Kamphuisen PW. Epidemiologyand
prevention of catheter-related thrombosis in patients with cancer.J
Thromb Haemost 2012;10:1491-9 107. Frank DA, Meuse J, Hirsch D, et
al.The treatment and outcome of cancer patients with thrombosis on
central venous catheters. J Thromb Thrombolysis 2000;10:271-5 108.
Zacharski LR, Henderson WG, Rickles FR, et al. Effect of warfarin
anticoagulation on survival in carcinoma of the lung, colon, head
and neck, and prostate. Cancer 1984;53:2046-52109
-
30
109.Mousa SA. Anticoagulants in thrombosis and cancer: the
missing link. Expert Rev Anticancer Ther 2002;2:227-33 110. Klerk
CP, Smorenburg SM, Otten HM,et al. The effect of low molecular
weight heparin on survival in patients with advanced malignancy. J
Clin Oncol 2005;23:2130-5 111. Kakkar AK, Levine MN, Kadziola Z,et
al. Low molecular weight heparin therapy with dalteparin, and
survival in advanced cancer: the Fragmin Advanced Malignancy
Outcome Study. J Clin Oncol 2004;22:1944-8 112. Lee AY, Rickles FR,
Julian JA, et al. Randomized comparison of low molecular weight
heparin and coumarin derivatives on the survival of patients with
cancer and venous thromboembolism. J Clin Oncol 2005;23:2123-9 113.
Altinbas M, Coskun HS, Er O, et al.A randomized clinical trial of
combination chemotherapy with andwithout low-molecular-weight
heparin in small cell lung cancer.J Thromb Haemost 2004;2:1266-71
114. van Doormaal FF, Di Nisio M,Otten HM, et al. Randomized trial
of theeffect of the low molecular weight heparin nadroparin on
survival in patients with cancer. J Clin Oncol 2011;29:2071-6 115.
Lazo-Langner A, Goss GD, Spaans JN, Rodger MA. The effect of
low-molecular-weight heparin on cancer survival. A systematic
review and meta-analysis of randomized trials. J Thromb Haemost
2007;5:729-37
-
31
CHAPTER 3
Recurrent venous thromboembolism and bleeding
complications during anticoagulant treatment in
patients with cancer and venous thrombosis.
●Prandoni P, ■Lensing AWA, ●Piccioli A, ●Bernardi E, ●Simioni
P
●From the Department of Medical and Surgical Sciences, Second
Chair ofInternal Medicine, and the Department of Clinical and
Experimental Medicine,Clinical Epidemiology Group, Fifth Chair of
Internal Medicine, University Hospital of Padua, Italy; ■Center for
Vascular Medicine and the Department of Clinical Epidemiology,
Academic Medical Center, University of Amsterdam, The
Netherlands.
Published in:
-
32
Blood 2002;100:3484-8
Abstract
A small proportion of patients with deep-vein thrombosis develop
recurrent complications orbleeding during anticoagulant treatment.
These complications may occur more frequently if these patients
have concomitantcancer. This prospective follow-up study sought to
determine whether in thrombosis patients those with cancer have a
higher risk for recurrent venousthromboembolism or bleeding during
anticoagulant treatment than those without cancer. Of the 842
included patients, 181 had known cancer at entry. The 12-month
cumulative incidence of recurrent thromboembolism cancer patients
was 20.7%(95% CI, 15.6%-25.8%) versus 6.8% (95%CI, 3.9%- 9.7%) in
patients without cancer, for a hazard ratio of 3.2 (95% CI,
1.9-5.4)The 12-month cumulative incidence of major bleeding was
12.4% (95% CI, 6.5%-18.2%) in patients with cancer and 4.9% (95%
CI, 2.5%-7.4%) in patients without cancer, for a hazard ratio of
2.2 (95% CI,1.2-4.1). Recurrence and bleeding were bothrelated to
cancer severity and occurred predominantly during the first month
of anticoagulant therapy but could not be explained by sub- or
overanticoagulation.Cancer patients with venous thrombosis are more
likely to develop recurrent thromboembolic complications and major
bleeding during anticoagulant treatment than those without
malignancy. These risks correlate with the extent of cancer.
Possibilities for improvement using the current paradigms of
anticoagulation seem limited and new treatment strategies should be
developed. (Blood. 2002;100:3484-3488).
Introduction
Based on studies performed in the 1970s, it was established that
patients with deep vein thrombosis (DVT) should receive
anticoagulants for period of 3 months to prevent recurrent venous
thromboembolism (VTE) (1). Further studies demonstrated that the
presence of active canceror thrombophilic conditions were
persisting risk factors for recurrent DVT (2-5). Subsequently,
longer durations of anticoagulation became gradually adopted in
these patient groups (6,7). Despite effective treatment, still
approximately 5% to 7% of patients with DVT have
recurrentvenousthromboembolic complications during heparinization
or the subsequent 3-month period of oral anticoagulant therapy
(6,7). Patients with DVT who also have cancer seem to be at a
higher risk for recurrent venous thromboembolic complications
during anticoagulation (8-10).This risk may be related to release
of procoagulants by tumor cells that could make patients with
cancer resistant to the usual intensities of anticoagulant drugs
(11-13). Also the risk of anticoagulant-induced bleeding seems to
be enhanced in patients with cancer, (9,14-16) although this is not
consistently found (17,18). Little is known about whether the
perceived higher risks for recurrent VTE and bleeding during
anticoagulation apply to all patients with cancer or to specific
groups. We analyzed the data of our cohort of consecutive patients
with first episode of symptomatic DVT with specific attention to
the period of anticoagulation. The aim of this analysis was to
assess the relative risk for recurrent VTE and major bl
