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the primary discharge diagnosis and an additional four discharge diagnoses in the United
States, the rate of initial or recurrent thromboembolism in patients with cancer exceeds by
far that recorded in those without malignancy, and affects with similar frequency virtually
all body systems (17).
Although the true rate of VTE in cancer patients is virtually unknown, because of
the surprising lack of information in almost all studies dealing with the natural history of
malignant diseases, the majority of thrombotic episodes occur spontaneously, i.e., in the
absence of triggering factors commonly accounting for thromboembolic complications in
subjects without cancer. This is confirmed by the high frequency of patients with known
malignancy referred to clinicians for the development of VTE (18). The most common
situations that make cancer patients at higher risk of VTE include immobilization, surgery,
chemotherapy with or without adjuvant therapy, and the insertion of central venous
catheters (19).
Immobilization
One of the most important triggering factors for VTE is prolonged immobilization,
especially during hospital stay. This pattern was clearly confirmed by Shen and Pollack,
who reported that as many as 14% of cancer patients admitted to the hospital died of
autopsy-confirmed PE, compared with 8% of those who were free from cancer (20).
Surgery
In the absence of adequate prophylaxis, patients with active malignancy face a markedly
high risk of developing postoperative VTE. In the absence of thromboprophylaxis, the
overall incidence of postoperative deep vein thrombosis (DVT) in patients with cancer is
about twice as high as that in patients free from malignancy (Table 1) (15,21).
Many factors can account for this high frequency, including advanced age, long and
complicated surgical procedures, and late mobilization with long postoperative course due
to patient’s poor condition. If thromboprophylaxis is not prolonged beyond the hospital
stay, cancer patients remain at risk of developing late VTE complications (29,30).
Chemotherapy, Radiotherapy, and Adjuvant Hormone Therapy
Cancer patients also face a particularly high risk of developing both venous and arterial
thrombosis when they receive chemotherapy (31). In patients with high-grade glioma
Table 1 Postoperative DVT in Patients With and Without Cancer
Authors Patients with cancer Patients without cancer
Kakkar et al. (1970) (22) 24/59 (41%) 38/144 (26%)
Walsh et al. (1974) (23) 16/45 (35%) 22/217 (10%)
Rosenberg et al. (1975) (24) 28/66 (42%) 29/128 (23%)
Sue-Ling et al. (1986) (25) 12/23 (52%) 16/62 (26%)
Allan et al. (1983) (26) 31/100 (31%) 21/100 (21%)
Multicentre Trial et al. (1984) (27) 9/37 (22%) 13/53 (24%)
Hills et al. (1972) (28) 8/16 (50%) 7/34 (21%)
Overall 128/346 (37%) 146/738 (20%)
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undergoing chemotherapy, the incidence of thromboembolic complications may be as
high as 12%–16% (32–34). In a small series of patients with nonresectable or metastatic
colonic tumor, the incidence of chemotherapy-induced thromboembolic complications has
been reported as high as 17% (35). In a recent retrospective study conducted in a wide
series of cancer patients who had been administered chemotherapy, the rate of thrombo-
embolic complications arising within the first three months was unexpectedly high,
yielding to an annual incidence of 11% (36).
The most reliable estimate of thromboembolic complications in patients undergoing
chemotherapy comes from breast cancer patients. The incidence of chemotherapy-induced
thromboembolic complications in women with stage II breast cancer undergoing chemo-
therapy was found to be on average 7% in a wide series of studies dealing with this risk
(Table 2) (37). Among patients with stage IV breast cancer this risk was found to be even
higher (49). Adjuvant hormone therapy, alone or in combination with chemotherapy,
cancer stage, and postmenopausal state further increases the incidence of thromboembo-
lism in women with breast cancer (50,51).
Although radiotherapy is often advocated as a risk factor of VTE in cancer patients,
no study has as yet properly evaluated its role.
Central Venous Catheters
Long-term central venous catheters have considerably improved the management of
cancer patients. However, their use has been associated with the occurrence of upper limb
DVT, especially in those patients who require the administration of chemotherapy (52).
The true incidence ofDVT in patients with central venous lines isdifficult to estimate,
since data fromliterature are somehow conflicting. Inabsence of thromboprophylaxis, Bern
et al. found an incidence of DVT, as shown by phlebography, of 37% (53). Monreal et al.
found an even higher incidence (54). Conversely, in recent case series that adopted
ultrasonography or other non-invasive methods to detect upper limb DVT, a much lower
rate of this thrombotic disorder has been reported (52,55). Along with the lower sensitivity
of objective non invasive methods in comparison with phlebography, the introduction
of new texture and coating of catheters, as well as of new procedures to reduce their
invasiveness, is likely to account for discrepancies between older and more recent studies.
Table 2 Thromboembolism in Breast Cancer Patients Undergoing Chemotherapy
Authors Patients Stage Thrombosis Type
Weiss et al. (1981) (38) 433 II 5% V
Goodnough et al. (1984) (39) 159 IV 17.6% VCA
Levine et al. (1988) (40) 205 II 7% VCA
Wall et al. (1989) (41) 1014 Variable 1.3% A
Fisher et al. (1989) (42) 383 II 3% V
Saphner et al. (1991) (43) 2352 Variable 5% VCA
Clahsen et al. (1994) (44) 1292 Variable 2% V
Rifkin et al. (1994) (45) 603 II 2.5% VCA
Pritchard et al. (1996) (46) 353 II 9.6% VCA
Tempelhoff et al. (1996) (47) 50 II 10% V
Orlando et al. (2000) (48) 182 Variable 7.7% V
Abbreviations: V, venous; A, arterial.
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THROMBOPROPHYLAXIS
The principal objective of thromboprophylaxis in the cancer patients is to reduce the
incidence of fatal PE. Indeed, most of these patients do not live long enough to develop
postthrombotic sequelae.
Although patients with active cancer often develop thrombotic complications
spontaneously, i.e., in the absence of additional risk factors, there is probably little
rationale behind providing thromboprophylaxis to all cancer patients who are not receiving
surgical or medical therapy. However, a history of thromboembolism places cancer
patients at such a high risk of recurrences that the systematic use of either mechanical or
pharmacological prophylaxis may be considered even outside the common risk factors
of thrombosis.
Prevention of VTE in cancer patients represents an important challenge since cancer
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 adopted in cancer
patients who require prolonged immobilization or undergo low-risk surgical procedures
(56). Extensive surgery places cancer patients at a remarkably high risk of post-operative
VTE. Accordingly, these patients require more intensive prophylactic regimens such as
higher doses of LMWHs (on average, twice as high as those suggested for low-risk
procedures), adjusted-dose heparin, or oral anticoagulants (56).
Once daily injections of LMWH are at least as effective and safe as multiple
injections of unfractionated heparin for prevention of postoperative VTE in cancer patients
(57–59). In this setting, fondaparinux (a short-acting pentasaccharide) shows promise.
In a recent trial addressing the value of fondaparinux, 2.5 mg o.i.d., for prevention of
postoperative VTE in patients requiring major abdominal surgery, in the subgroup
of patients with cancer fondaparinux was shown to be significantly more effective than
dalteparin without increasing the hemorrhagic risk (60).
Of interest, recent trials suggest that prolonging the administration of LMWH until
the completion of the first four weeks after surgical intervention provides an additional
thromboprophylactic effect without increasing the hemorrhagic risk (30,61).
In patients with ongoing bleeding or those who are at high risk for it, physical
measures such as graduated compression stockings or external pneumatic compression
should be used in the substitution for pharmacological prophylaxis (62).
According to theresults of two recent randomized trials in cancer patients undergoing
elective neurosurgery, the combination of LMWH (starting within 24 hr after surgery) with
graduated compression stockings is more effective than, and as safe as, elastic stockings
alone for prevention of postoperative VTE (63,64).
Chemotherapy and Radiotherapy
In the only available study, fixed low-dose warfarin (1 mg/day) for six weeks, followed by
doses that maintained the INR at 1.3 to 1.9, was an effective and safe method for
prevention of chemotherapy-induced thromboembolism in women with metastatic breast
cancer (65). Whether this strategy or strategies that involve LMWHs are effective and safe,
as well in other oncologic patterns, remains to be demonstrated.
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Unfortunately, no proper study has been performed as yet to assess the preventive
value of antithrombotic strategies in patients undergoing radiotherapy.
Central Venous Catheters
Two randomized, controlled studies documented the benefit of fixed low-dose warfarin
(1 mg o.i.d.) in decreasing the incidence ofarm veinthrombosis relatedto indwelling central
venous catheters (53,66). The subcutaneous administration of dalteparin (2500 IU o.i.d.)
for 90 days was also shown to be highly beneficial for prevention of upper extremity
thrombosis in cancer patients with venous access devices (54). However, three recent
clinical trials failed to show any benefit from a 1 mg daily dose of warfarin (67,68) or 5000
daily units of dalteparin (69), respectively, compared to no prophylaxis. Thus, neither
mini-dose warfarin nor prophylactic LMWH can be recommended on a routine basis
as prophylaxis for cancer patients with indwelling central venous lines (56). Either
thromboprophylactic regimen, however, is likely to be effective whenever central venous
catheters are used for administration of chemotherapy (70).
TREATMENT OF ESTABLISHED VENOUS THROMBOEMBOLISM
Initial Treatment
In general, the same therapeutic approaches that are used in non cancer patients are also
used in patients with malignant diseases. Except for selected patients requiring aggressive
treatments, the large majority of cancer patients should receive the subcutaneous injection
of therapeutic doses (adjusted to body weight) of a LMWH in once or twice daily
administrations. Alternatively, a proper course of full-dose unfractionated heparin, i.e.,
a heparin regimen that prolongs the APTT up to 1.5 to 3.0 times the control value, can be
employed (56). Whenever possible, (LMW) heparin should be administered as soon as
there is a reasonable possibility that venous thrombosis exists, and should be overlapped
and followed by oral anticoagulant therapy (56). Thrombolytic drugs are rarely indicated.
The limited cases in which thrombolysis may be considered include massive pulmonary
embolism, extension of venous thrombosis despite extensive anticoagulation, and upper-
extremity thrombosis in patients who have an indwelling central venous catheter, which
must be kept patent (56). Finally, the insertion of an inferior vena cava filter should be
considered whenever a full-dose anticoagulation is contraindicated or unsuccessful.
There are many unique issues in cancer patients that often make treatment more
difficult. Chemotherapy, hormonal agents, invasive procedures and the presence of long-
term venous catheters not only increase the risk of thrombosis but also create complex
clinical situations that make anticoagulation particularly problematic. For example,
temporary cessation of anticoagulant therapy may be needed to accommodate
chemotherapy-induced thrombocytopenia and invasive procedures, while poor nutrition,
infection, concomitant medication and impaired liver function can cause unpredictable
changes in the dose response of oral anticoagulants.
Long-Term Anticoagulation
What are the main questions clinicians confront when facing cancer patients with an
episode of venous thrombosis? The main controversies deal with the most appropriate
duration and intensity of anticoagulation; the risk of extension and/or recurrence of VTE
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during anticoagulation; and the potential for an increased risk of bleeding during the
course of proper anticoagulant therapy.
According to the results of recent prospective cohort and population-based studies
(71–73), after discontinuation of warfarin cancer patients with venous thrombosis present
a risk for recurrences that is almost twice as high as that observed in patients free from
malignancies. In view of the persistently high risk of recurrent thrombotic events and the
acceptable risk of bleeding, prolongation of warfarin should be considered for as long as
the malignant disorder is active. The suggested policy is to administer warfarin to maintain
the INR between 2.0 and 3.0.
Of interest, cancer patients have a three- to four-fold higher risk of recurrent VTE
while on anticoagulation (74–76). This risk correlates with the extent of cancer.
Accordingly, more aggressive initial or long-term treatment has the potential to reduce the
risk of recurrent thrombosis. However, a complicating factor in improving anticoagulant
therapy in cancer patients is the occurrence of excess bleeding in combination with excess
recurrent thromboembolism. Although some improvements can be expected from
optimizing laboratory monitoring of anticoagulant therapy, most bleeding and thrombotic
complications occur in patients with anticoagulant parameters within the therapeutic
range. Possibilities for improvement using the current paradigms of anticoagulation seem,
therefore, limited.
According to the results of recent randomized clinical trials, LMWH in full doses for
the first month followed by three-fourth of the initial regimen has the potential to provide
a more effective antithrombotic regimen in cancer patients with venous thrombosis than
the conventional treatment, and is not associated with an increased hemorrhagic risk
(77,78). Although LMWHs are more expensive than oral anticoagulants, they provide an
anticoagulation that is easier to administer, more convenient and flexible, and not
influenced by nutrition problems or liver impairment.
The anticoagulation strategy in the treatment of patients with recurrent VTE during
oral anticoagulation is not rigidly standardized. A patient who develops a recurrent VTE
while the INR is subtherapeutic can be retreated with unfractionated or LMWH for a few
days, and oral anticoagulanttherapy can be continued with theINR kept between 2.0 and3.0.
For those who experience warfarin failure and develop a recurrence while the INR is
therapeutic, the long-term management is less clear. Three options are acceptable after
initial re-treatment with unfractionated or LMWH: continue with oral anticoagulant therapy
aiming for a highertarget INR of 3.0 to 3.5,switch to adjusted-dose twice dailysubcutaneous
standard heparin to maintain a therapeutic APTT, or use once daily weight-dose LMWH.
For patients with a high risk of pulmonary embolism,or whoare hemodynamicallyunstable,
an inferior vena cava filter can be inserted in addition to any one of the above options.
IMPACT OF ANTITHROMBOTIC DRUGS ON CANCER EVOLUTION
AND DEVELOPMENT
Anticoagulant treatment of cancer patients, particularly those with lung cancer, has been
reported to improve survival (79). These interesting, albeit preliminary, results of
controlled trials lent some support to the argument that activation of blood coagulation
plays a role in the natural history of tumor growth.
Numerous studies have been performed in recent years that have addressed the value
of LMWH in comparison with standard heparin in the treatment of VTE, and an updated
meta-analysis of the most adequate reports has been published in 2000 (80). In eight of the
nine studies reporting on the long-term follow-up of enrolled patients, the analysis of total
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mortality exhibited a surprising trend in favour of LMWH. In the five studies that provided
subgroups analysis, this effect was entirely attributable to the differences in the subgroup
of patients with cancer.
Which is the rationale for the antitumor effect of anticoagulant drugs? In the last
decades, strategies to impair the hemostatic system of the host in order to affect the growth
and the dissemination of malignant tumors have been explored (81). The biological
mechanisms of coumarins mainly rely on the inhibition of blood coagulation (coagulation-
dependent mechanisms). Instead the biological mechanisms of heparins, particularly
LMWH, in addition to clotting inhibition, involve coagulation-independent activities able
to affect: (1) tumor cell growth by binding to growth factors, (2) tumor cell invasion by
heparin-inhibitable enzyme systems, (3) tumor cell metastasis by binding to cell surface
selectins (presumably by competing with these ligands), (4) tumor-induced angiogenesis
by interacting with angiogenic growth factor, (5) tumor matrix formation related to
deposition of fibrinogen/fibrin, and (6) tumor cell invasion of the vascular basement
membrane by inhibiting tumor cell heparanase (82).
The evidence of lowered cancer mortality in patients on LMWH has stimulated
renewed interest in these agents as antineoplastic drugs. Three small randomized studies
have recently 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 (83–85). All three studies showed a favorable impact of the tested
heparin on patients’ survival. This result was particularly evident in patients with better
prognosis. Further studies on wider samples of patients are needed before LMWH can be
implemented in the routine treatment of patients with cancer.
Of interest, in a recent trial addressing the value of different durations of warfarin for
prevention of recurrent thromboembolism in patients with the first episode of VTE, the
development of late malignancies was recorded much more frequently in patients
allocated to six weeks than in those allocated to six months of anticoagulation (86).
Although these results have not been confirmed by those of a subsequent similar study
(87), they prospect the distinct possibility that cancer and thrombosis share common
mechanisms, and that antithrombotic drugs may interfere with cancer development.
RISK OF CANCER IN PATIENTS WITH VENOUS THROMBOEMBOLISM
The strong association between cancer and VTE is further emphasized by the high rate
of cancer detection or development in patients with VTE.
In patients presenting with VTE, the prevalence of concomitant cancer, defined as
cancer not known before VTE and discovered by routine investigation (history taking,
physical examination, urinanalysis, routine blood tests, and chest X-ray) varies
considerably between the studies, this variation being related to the depth of the routine
examinations and to the characteristics of the included patients (18). The risk of
concomitant cancer was increased among patients with idiopathic VTE by a factor of
3–19, while the prevalence of concomitant cancer disease in patients with secondary VTE
from detectable risk factors was low and, in general, comparable with the 2%–3%
prevalence expected in the general population after middle age (88). According to the
results of a recent retrospective study, the values of D-dimer at presentation can help
predict the presence of concomitant cancer disease (88). Using a quantitative latex test,
these authors were able to detect cancer much more frequently in patients with values
exceeding 1000 ng/ml than in those with lower values. These findings require
confirmation from prospective studies.
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As far as the risk of developing subsequent overt malignancy, this risk was found
across prospective studies to be consistently higher (4 to 5 times) in patients with
idiopathic VTE than in those with secondary thrombosis (Table 3) (15). Newly discovered
malignancies, whose incidence in idiopathic VTE is consistently around 10%, involve
virtually all body systems. The risk of cancer is even higher in patients with recurrent
thromboembolism (90) and in those with bilateral VTE (95).
These findings have been confirmed by those of three large, population-based
studies conducted in Denmark, Sweden and Scotland, respectively (96–98). By examining
data from both cancer and thromboembolic disease national registries, in all three studies
the authors found a significantly increased risk for developing cancer in patients
discharged with thromboembolism, particularly in the first year following VTE diagnosis.
Of interest, in two of these studies a significant effect persisted for up to 10 years,
suggesting that either a malignant disorder can induce hypercoagulability many years prior
to its overt clinical development, or, more likely, cancer and thrombosis may share
common pathogenetic mechanisms (96,97).
Despite the conclusive evidence of a strong relationship between idiopathic VTE
and the risk for hidden cancer, whether extensive screening for occult malignancy in
patients with idiopathic VTE is appropriate is still controversial. Since extensive screening
procedures are associated with high costs and themselves carry some morbidity, they are
only acceptable if they prove to be cost-effective and have an impact on cancer
related mortality.
A recent publication has raised some concern about the utility of screening for occult
malignancy all patients with idiopathic thromboembolism (99). By assessing the survival
rate in patients with cancer diagnosed in the first year following the thrombotic episode in
comparison with that of matched cancer patients without thrombosis, Sorensen and
co-workers found increased mortality in the former group.
The same was true of cancers diagnosed at the time of hospitalisation for VTE.
Results seem discouraging, as it appears that whenever a cancer disease is preceded by
a clinical manifestation of thrombosis, its prognosis is far worse. However, due to the
retrospective nature of the study design, we suppose that the large majority of identified
cancers were already symptomatic at the time of detection. The early detection of occult
cancers at the time they are totally asymptomatic might still lead to a more favorable
clinical outcome. Two adequate studies have recently addressed this issue (100,101).
Monreal and colleagues published the results of a prospective cohort follow-up study
in consecutive patients with acute VTE (100). All patients underwent a routine clinical
Table 3 Incidence of Occult Cancer After VTE Diagnosis
Cancer
Authors All VTE Secondary VTE Idiopathic VTE
Aderka et al. (1986) (89) 11/83 (13.3%) 2/48 (4.2%) 9/35 (25.7%)
Prandoni et al. (1992) (90) 13/250 (5.2%) 2/105 (1.9%) 11/145 (7.6%)
Ahmed and Mohuddin (1996)
(91)
3/196 (1.5%) 0/83 (0%) 3/113 (2.7%)
Monreal et al. (1997) (92) 8/659 (1.2%) 4/563 (0.7%) 4/96 (4.2%)
Hettiarachchi et al. (1998) (93) 13/326 (4.0%) 3/171 (1.8%) 10/155 (6.5%)
Rajan et al. (1998) (94) 21/264 (8.0%) 8/112 (7.1%) 13/152 (8.6%)
Schulman (2000) (95) 111/854 (13.0%) 18/320 (5.6%) 93/534 (17.4%)
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evaluation for malignancy, if negative followed by a limited diagnostic work-up consisting
of abdominal and pelvic ultrasound and laboratory markers for malignancy. The routine
clinical evaluation was performed in 864 patients and revealed malignancy in 34 (3.9%) of
them. Among the remaining 830 patients the limited diagnostic work-up revealed 13
further malignancies. During follow-up, cancer became symptomatic in 14 patients who
were negative for cancer at screening (sensitivity of limited diagnostic work-up,
48%). Malignancies that were identified by the limited diagnostic work-up were early
stage in 61% of cases versus 14% in cases occurring during follow-up. Most patients with
occult cancer had idiopathic VTE and were older than 70 years. According to these study
results, a limited diagnostic work-up for occult cancer in patients with VTE has the
capacity to identify approximately one-half of the malignancies, predominantly in an
early stage.
We have recently conducted a multicenter randomized clinical trial (the SOMIT
study) in apparently cancer-free patients with acute idiopathic venous thrombosis or
pulmonary embolism (101). Of 201 patients with a first episode of idiopathic VTE, after
initial negative routine battery tests, 99 were randomized to undergo either extensive
screening (Table 4), and 102 no further testing for malignancy. All patients were
followed until the completion of two years of follow-up. Of the 14 malignancies that
occurred in the extensive screening group, the screening was able to detect 13 (mostly
detected by CT scanning), resulting in sensitivity higher than 90%. The risk for occult
cancer was higher among elderly patients and in those without thrombophilic
abnormalities. Ten malignancies developed in the follow-up of patients allocated to
the control group. Overall, malignancies identified in the extensive screening group were
at an earlier stage and the mean delay to diagnosis was reduced from 11 months to
one month. The earlier discovery and subsequent treatment resulted in a slightly
improved cancer related mortality (2.0% vs. 3.9%) and cancer-free survival (5.1 vs. 7.9)
of the patients in the extensive screening group. Although these differences were not
statistically significant, the reductions observed are in line with the hypothesis and would
translate into a number needed to screen of only 50 patients to prevent one cancer-related
death at two years.
Although data from either study do not conclusively demonstrate that early
diagnosis ultimately prolongs life, the collective observations make such a beneficial
effect likely. The earlier discovery of cancer, which might mean identification of the
disease at an attackable state, may be crucial in an unpredictable rate of patients, especially
nowadays when continuous protocol innovations are providing growing chances of
success and eradication of malignancies.
Table 4 Extensive Screening Procedure According to the SOMT Study
Procedures
Ultrasound of abdomen/pelvis
CT scanning of abdomen and pelvis
Gastroscopy or double contrast barium swallowing
Flexible sigmoidoscopy or rectoscopy followed by barium enema or colonoscopy
Hemoccult, sputum citology, tumor markers (CEA, aFP, CA125)
Mammography and Pap-smear in women
Transadbominal ultrasound of the prostate and PSA in men
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KEY POINTS
† Malignancy produces a prothrombotic state.
† Venous thromboembolism (VTE) is a well-recognizedcomplication of malignant
disease.
† VTE may the first sign of an occult malignancy.
† Screening for occult malignancy in VTE patients remains controversial.
† Thromboprophylaxis should be used in immobile cancer patients or those
undergoing surgery.
† Caval filters may be used in those with recurrent disease or if anticoagulation is
contraindicated.
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