Download Does antithrombotic therapy improve survival in cancer patients?

Blood Reviews 23 (2009) 129–135
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Blood Reviews
journal homepage: www.elsevier.com/locate/blre
REVIEW
Does antithrombotic therapy improve survival in cancer patients?
Moya S. Cunningham a, Roger J.S. Preston b, James S. O’Donnell b,c,*
a
b
c
Academic Unit of Clinical and Molecular Oncology, Institute of Molecular Medicine, Trinity College Dublin, Ireland
Haemostasis Research Group, Institute of Molecular Medicine, Trinity Health Centre, St. James’s Hospital, Trinity College Dublin, Ireland
National Centre for Hereditary Coagulation Disorders, St. James’s Hospital, James’s Street, Dublin, Ireland
a r t i c l e
i n f o
Keywords:
Warfarin
Heparin
Cancer
Venous thromboembolism
s u m m a r y
Venous thromboembolism (VTE) is a common complication of malignancy, and is associated with significant morbidity and mortality. Anticoagulant therapy, in the form of heparin and warfarin, plays an
important role in the prevention of recurrent VTE. Recent studies have demonstrated that long-term therapy with low molecular weight heparin (LMWH) is more effective than warfarin in patients with cancer.
In addition, accumulating clinical evidence suggests that LMWH significantly improves overall survival in
cancer patients without VTE. Intriguingly, however, this improved survival cannot simply be explained by
a reduction in fatal pulmonary embolism. Furthermore, the beneficial effects persist long after the LMWH
has been discontinued, suggesting that LMWH can directly influence tumour cell biology. This hypothesis
is entirely plausible, given the complex feedback mechanisms that exist between tumour cells, coagulation proteases, and vascular endothelial cells. Furthermore, an accumulating body of in vitro experimental
evidence suggests that both heparin and warfarin have direct antineoplastic effects. Further large randomized controlled trials will be required in order to validate these exciting preliminary data, and to
define whether anticoagulant therapy may constitute a useful adjunctive therapy in the management
of cancer patients without VTE.
Ó 2008 Elsevier Ltd. All rights reserved.
Introduction
Anticoagulant therapy in patients with cancer
For many years, it has been recognised that venous thromboembolism (VTE) represents a common complication of malignancy.
Recent studies have shown that the relative risk of VTE is increased
approximately four to sixfold in patients with cancer, compared to
age and sex matched controls.1,2 Clinically symptomatic deep vein
thrombosis (DVT) has been reported in up to 15% of patients with
cancer.3,4 However, post-mortem studies have demonstrated
asymptomatic VTE in as many as 50%.5 Indeed, underlying malignancy has been implicated in approximately 25% of all new cases
presenting with symptomatic VTE.6,7 Previous studies have also
clearly demonstrated that the development of symptomatic VTE
in a patient with cancer is associated with significantly reduced
overall survival.8,9 Nevertheless, it remains unclear whether this
increased mortality can be entirely attributed to fatal pulmonary
embolism (PE), or whether development of VTE may also serve
as a hallmark of more aggressive underlying tumour biology.
The clinical importance of anticoagulant therapy in this setting
is readily apparent, in view of the prevalence of VTE in cancer patients, together with its associated morbidity and mortality. In
non-cancer patients, acute VTE is generally managed using unfractionated heparin (UFH) or low molecular weight heparin (LMWH)
for 5–7 days, followed by ongoing oral anticoagulation with warfarin (target INR 2.5) for at least three months.10 Use of LMWH has
several important advantages over UFH, many of which are of particular importance in cancer patients.11 Firstly, the LMWHs have a
significantly longer half life than UFH, and thus can be administered as once daily subcutaneous injection. Secondly, because of
its more predictable pharmacokinetics, LMWH therapy does not
generally require laboratory monitoring.12 Finally, both heparininduced thrombocytopenia (HIT), and heparin-induced osteoporosis are both less common with LMWH compared to UFH.11,13 Consequently LMWH have become widely used as the treatment of
choice for the management of acute VTE in cancer.14 It remains unclear however, whether different LMWH preparations are equally
efficacious in this cohort of patients. Moreover, optimal LMWH
dosage regimens have not been defined, although recent studies
have suggested that twice daily administration may be more effective in preventing recurrent thrombotic events.15
* Corresponding author. Address: Haemostasis Research Group, Institute of
Molecular Medicine, Trinity Health Centre, St. James’s Hospital, Trinity College
Dublin, Ireland. Tel.: +353 1 416 2141; fax: +353 1 410 3570.
E-mail address: [email protected] (J.S. O’Donnell).
0268-960X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.blre.2008.10.002
130
M.S. Cunningham et al. / Blood Reviews 23 (2009) 129–135
Warfarin therapy in cancer patients is also associated with a
number of important clinical issues. In particular, gasto-intestinal
disturbances (vomiting and diarrhoea), hepatic dysfunction, and
concurrent chemotherapy can all cause significant fluctuations in
INR. Consequently, maintaining an INR within the target therapeutic range is more difficult. The risk of warfarin-induced major
bleeding will also be further exacerbated during any periods of
chemotherapy-induced thrombocytopenia. Finally, the delayed onset of anticoagulant effect, together with the long half life of warfarin, means that any surgical interventions must be carefully
planned in cancer patients maintained on warfarin. A further level
of complexity is involved in the effective management of anticoagulant therapy in cancer patients, because the risk of recurrent VTE
is significantly increased (two to threefold) compared to non-cancer patients, even when patients are maintained on therapeutic
levels of either warfarin or LMWH.6,16,17
In view of the inherent difficulties associated with warfarin use
in oncology patients, recent trials have investigated the efficacy
and safety of long-term LMWH as an alternative. In the CLOT (comparison of low molecular weight heparin versus oral anticoagulant
therapy for prevention of recurrent VTE in patients with cancer)
trial, Lee et al. studied 676 cancer patients with objectively-confirmed VTE.18 All patients were initially treated with LMWH (dalteparin 220 IU/kg once daily) for 5–7 days, and then randomized
to either 6 months of oral anticoagulation (target INR 2.5) or 6
months of LMWH (dalteparin 150 IU/kg), respectively. During the
6-month treatment period, recurrent episodes of VTE were significantly reduced in patients treated with LMWH (9% vs. 17%;
P = 0.002), resulting in a significant risk reduction of 52%. Moreover, despite the superior efficacy of LMWH, there was no significant difference in major bleeding rates between the two groups.
On the basis of these data, the authors calculated that one episode
of recurrent VTE would be prevented for every 13 cancer patients
treated with dalteparin. Other LMWH preparations (enoxaparin
and tinzaparin) have also demonstrated comparable long-term
efficacy in comparison to warfarin in patients with cancer.19–21
Consequently, expert consensus guidelines now specifically recommend the use of extended duration LMWH in this setting.14,22,23
Cancer, activation of coagulation, and VTE
The pathogenesis of cancer-related VTE is complex, involving
multiple interactions between malignant cells, endothelial cells,
and the coagulation cascade. Indeed, tumours can significantly impact upon all three components of Virchow’s triad (activation of
the coagulation cascade by neoplastic cells; direct damage to blood
vessel walls; and multi-factorial venous stasis). These different
mechanisms have been comprehensively discussed in other recent
reviews.24–27 Following vascular injury, coagulation is normally
initiated when tissue factor (TF) forms a complex with circulating
plasma FVIIa. In normal tissues, constitutive expression of TF is restricted to extra-vascular sites, such as fibroblasts in the adventitia
of arteries and veins, so that TF in effect acts as a haemostatic envelope.28 One of the most important mechanisms through which cancers induce coagulation cascade activation is due to aberrant TF
expression on tumour cell surfaces (including pancreatic cancer,
non-small cell lung cancer and leukaemia).28,29 Tumour cells also
trigger activation of host endothelial cells, monocytes and platelets. In view of these diverse effects, it is not surprising that persistent activation of the haemostatic pathway and increased
thrombin generation (e.g. thrombin–antithrombin complexes)
can be detected from an early stage in most patients with cancer.30–32 Moreover, plasma levels of coagulation activation markers
have been shown to correlate with overall survival.33 In addition to
these direct tumour effects, different aspects of cancer treatment
(including cancer surgery,34,35 treatment with oestrogen-related
compounds,36 use of specific chemotherapeutic agents,37–39 and
insertion of long-term central venous catheters40) can all synergistically interact to further increase the absolute risk of VTE.
Cross-talk between coagulation activation and tumour cell biology
Recent studies have demonstrated that the relationship between cancer and coagulation does not operate in only one direction. Rather, activated coagulation proteases can interact with
protease activated receptors (PARs) on tumour and host vascular
cells, leading to induction of genes important for angiogenesis,
apoptosis, and metastasis.28 Once again, a critical role for tumour
TF expression has been reported in determining tumour growth.
For example, TF expression on pancreatic cancer is associated with
the progression from a benign to malignant phenotype. Moreover
in colorectal cancer, TF expression is significantly correlated with
clinical stage and Dukes classification. TF expression has also been
clearly demonstrated to play a key role in promoting tumour
angiogenesis.41
These emerging data regarding the critical cross-talk that exists
in vivo between cancer cells and coagulation activation are not only
of scientific interest, but also be of direct translational significance.
In particular, these findings raise the question whether using anticoagulant therapies to down-regulate coagulation activation might
not only serve to reduce the risk of VTE, but also directly influence
cancer cell biology and tumour development, thereby offering a
novel therapeutic opportunity. This hypothesis is supported by
experiments performed in animal models dating back to the late
1960s and early 1970s, suggesting that oral vitamin K antagonists
could significantly modulate tumour metastasis. For example, in
rats inoculated with Walker 256 carcinosarcoma cells, warfarin
therapy for ten days significantly reduced the rate of pulmonary
metastases (9.8% vs. 85.8%; P < 0.001), and improved overall survival.42 Similarly, warfarin also significantly reduced pulmonary
metastases in mice, after the induction of autochthonous tumours,43 following injection of B16 melanoma cells,44 and after
subcutaneous injection of KHT tumour transplants.45 In contrast
however, warfarin therapy did not enhance the cytotoxic or antimetastatic effects of 5-flurouracil in murine models of adenocarcinoma or L210 leukaemia, respectively.46
Warfarin
Does warfarin influence survival in patients with cancer?
On the basis of in vitro and animal model data, a number of
groups have sought to investigate whether warfarin therapy influences survival in patients with cancer who do not have overt VTE.
Surprisingly, however, only three randomised trials have been
reported to date (Table 1).47–49
In the prospective randomized Veteran’s Administration (VA)
Cooperative Study No. 75, Zacharski et al. enrolled 431 patients
with a variety of different cancer types (including head and neck,
lung, colorectal and prostate).49,50 All patients received standard
chemotherapy and radiation therapy. In addition, patients were
randomised to receive either warfarin or placebo. In total 189 patients were actually treated with warfarin therapy, which was
administered in doses intended to prolong the prothrombin time
to approximately twofold the control value (mean dose 4.9 mg/
day). The mean duration of warfarin treatment was 26 weeks (ranged from only 8.2 weeks for patients with head and neck tumours,
to 85.9 weeks for patients with non-small cell lung cancer). Warfarin therapy did not improve overall survival for patients with colorectal, prostatic or head and neck tumours. However, subgroup
analysis did demonstrate a significant effect of warfarin on overall
M.S. Cunningham et al. / Blood Reviews 23 (2009) 129–135
131
Table 1
Cancer patients without clinical VTE-effect of warfarin on overall survival.
Study
n
Malignancy
Stage
Vitamin K
antagonist
Duration
Beneficial outcomes
Major bleeding
Zacharski
et al. 50
431
Head and neck; lung
(SCLC); colorectal; prostate
Limited and
extensive SCLC
Warfarin – prolong
PT twofold
Mean 26
weeks
SCLC –
warfarin 4%
Chahinian
et al.47
385
Small cell lung cancer
Extensive
Warfarin – prolong
PT 1.5 to twofold
N.R.
Maurer
et al.48
347
Small cell lung cancer
Limited
Warfarin – target
INR 1.4–1.6
113 days or
197 days
Significant increase in median survival for SCLC
(49.5 weeks vs. 23 weeks; P = 0.018)
No significant increase in survival for
colorectal; prostate; or head and neck
Significant increase in complete and partial
responses
Non-significant increase in median survival (9.3
months vs. 7.9 months; P = 0.09)
No significant increase in median survival
survival in patients with small cell lung cancer (SCLC). In this small
cohort (n = 50) which included patients with both limited and
extensive disease, patients randomised to receive warfarin and
chemotherapy (cyclophosphamide; vincristine and methotrexate)
demonstrated longer time to disease progression, and also had significantly improved median survival compared to those treated
with chemotherapy alone (49.5 weeks vs. 23 weeks; P = 0.018).
In addition, the warfarin-treated cohort also demonstrated significantly increased time to disease progression (P = 0.016). Interestingly, a significant beneficial effect of warfarin therapy on overall
survival was most marked in those patients with disseminated
SCLC (n = 25) at time of randomisation. Unsurprisingly, warfarin
therapy was associated with increased bleeding. Although the
majority of these episodes were mild, severe GI bleeding resulted
in permanent discontinuation of oral anticoagulant therapy in
two (4%) patients with SCLC.
On the basis of these preliminary data, the Cancer and Leukaemia Group B (CALGB) conducted a prospective randomised trial to
further investigate the effects of warfarin in a larger cohort of patients with extensive SCLC.47 Patients were stratified for sex and
performance status, and then randomised to receive combination
chemotherapy (methotrexate, adriamycin, cyclophosphamide,
and lomustine) with (n = 103) or without (n = 86) warfarin. Warfarin dose was adjusted to prolong the PT 1.5 to twofold the control
value. Statistically significant increases in both complete (CR) and
partial responses (PR) were observed for SCLC patients treated with
chemotherapy and warfarin (CR 17% and PR 50%) compared to
those randomised to chemotherapy only (CR 8% and PR 43%). In
addition, a modest prolongation in overall median survival was
observed in the warfarin-cohort, although this failed to achieve
statistical significance (9.3 months vs. 7.9 months; P = 0.09). Of
note, the combination chemotherapy regimen (without added
warfarin) used in this study was associated with a better outcome
than that used in the earlier VA study. Once again, the beneficial
effects of warfarin observed in this trial were offset by an increased
incidence of bleeding, including two fatal CNS bleeding
complications.
To investigate the potential benefit of warfarin therapy in patients with limited-stage SCLC, Maurer et al. studied 347 patients
who all received chemotherapy (cyclophosphamide, doxorubicin,
etoposide, and cisplatin) and concurrent radiation therapy.48 In
addition, these patients were randomised to warfarin or no warfarin. In an attempt to minimise further bleeding complications, warfarin dose was adjusted to maintain an INR between 1.4 and 1.6
times control, and was continued only until the completion of chemo-radiotherapy. In contrast to the previous reports, no significant
beneficial effect on response rates or overall survival was observed
using this reduced intensity warfarin regimen. However, interpretation of the results of this study is complicated by an enforced
amendment to the original study protocol introduced after only
179 patients had been randomised. Due to a high rate of fatal
Warfarin 7%
controls 0%
Warfarin 6.7%
controls 1.8%
pulmonary complications, the number of cycles of chemotherapy
was reduced from eight to five. Although no beneficial effect of
warfarin was apparent overall, subgroup analysis restricted to patients enrolled prior to the protocol amendment again demonstrated that warfarin therapy (n = 86) was associated with
improved median survival (21.4 months vs. 16.7 months;
P = 0.07). Moreover, among those pre-amendment patients who attained CR, warfarin therapy was associated with a doubling in
median survival time (41 months vs. 18 months; P = 0.05).
Does warfarin protect against cancer development?
In the context of studies suggesting that warfarin therapy may
influence overall survival in patients with objectively-confirmed
cancer, three more recent studies have investigated whether warfarin may influence the development of occult cancer.51–53
In the prospective duration of anticoagulation (DURAC) trial,
Schulman and Lindmarker studied 902 consecutive patients with
a confirmed idiopathic or precipitated first episode of VTE.52 Patients were randomised to receive oral anticoagulant therapy (warfarin 95% cases or dicumarol 5% cases) for either 6 weeks or 6
months duration, with a target INR range 2.0–2.85. The primary
objective of this trial was to compare the rate of VTE recurrence.
However, using the Swedish cancer registry, the number of new
diagnoses of cancer in both arms of the study was also assessed.
Patients (4.8%) enrolled in the study had received a diagnosis of
cancer before inclusion and were excluded. A total of 111 (13%) patients were newly diagnosed with cancer during the follow-up period (mean duration 8.1 years). On univariate analysis, cancer
diagnosis was significantly increased in patients who received 6
weeks anticoagulant therapy compared to those treated for 6
months (15.8% vs. 10.3%; P = 0.02). The principal difference between the two cohorts related to newly diagnosed urogenital tumours (including kidney, bladder, prostate, ovarian, and uterine),
which were diagnosed more than twice as commonly in those patients who received warfarin for only 6 weeks (6.7% vs. 2.8%;
P = 0.01). Interestingly, the difference in rates of newly diagnosed
cancers only first became apparent after two years of follow up.
Using a similar strategy, Taliani et al. investigated the effect of
extending duration of oral anticoagulation from 3 months to 12
months on the incidence of new, clinically overt cancers in 429 patients presenting with first, idiopathic VTE.53 Although the followup period in this study was considerably shorter (median 44
months), new cancers were diagnosed in 32 patients (7.5%) overall.
No significant difference was observed between patients treated
with warfarin for 3 months compared to those treated for 12
months (6.2% vs. 8.7%). Finally, a recent case–control study retrospectively evaluated warfarin exposure in 330 males with urogenital cancers compared to 1293 male controls.51 After adjusting for
smoking and age, no significant reduced risk of cancer was
observed in those treated with warfarin therapy.
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M.S. Cunningham et al. / Blood Reviews 23 (2009) 129–135
In summary, on the basis of the scant available evidence summarised above, it is not possible to confidently conclude that oral
anticoagulant therapy improves survival in cancer patients in the
absence of VTE. Equally, it is also impossible to definitively exclude
such an effect, particularly in patients with extensive small cell
lung cancer. Nevertheless, a recent systematic Cochrane review
concluded that warfarin had no significant effect in reducing mortality at six months (relative risk (RR) = 0.96; 95% CI 0.80–1.16), at
one year (RR = 0.95; 95% CI 0.86–1.05) or at five years (RR 0.91;
95% CI 0.83–1.01).54 However, warfarin did significantly increase
both major bleeding (RR = 4.24; 95% CI 1.85–9.68) and minor
bleeding (RR = 3.34; 95% CI 1.66–6.74). Similarly, a number of prospective cohort studies have concluded that the annual risk of major bleeding is 12–13% in patients with cancer whilst receiving oral
anticoagulant therapy,16,17 compared with 3–4% in patients without cancer. In view of the practical difficulties associated with
the use of warfarin in cancer patients, the significantly increased
bleeding risk associated with warfarin, and the observation that
long-term LMWH is more effective in preventing recurrent VTE
in these patients, more recent clinical trials have investigated
whether LMWH might have a role in directly determining cancer
survival.
Heparin
Does UFH influence survival in patients with cancer?
Five randomized controlled trials have directly tested the effect
of heparin on cancer survival as a primary endpoint (Table 2). One
of these trials examined the role of UFH in SCLC,55 whilst four more
recent trials have focussed on the potential benefits of LMWH in a
heterogeneous variety of different malignancies.56–59
In a prospective randomized multicenter trial, Lebeau et al.
studied the use of subcutaneous UFH as an adjunct to chemotherapy in 277 patients with either limited (44%) or extensive (56%)
SCLC.55 UFH was administered in two or three daily doses starting
at 500 U/kg per day, and adjusted to increase the APTT ratio two to
threefold for five weeks in total. Patients who received UFH demonstrated better complete response rates (37% vs. 23%; P = 0.004),
better median survival (317 days vs. 261 days; P = 0.01) and better
survival at 1, 2, and 3 years, respectively. Furthermore, subgroup
analysis demonstrated that the significant beneficial effects of
UFH were primarily due to improved survival in patients with limited-stage SCLC (P = 0.03) rather than those with more extensive
disease at initial randomisation (P = 0.31).
Does LMWH influence survival in patients with cancer?
In order to investigate whether LMWH influences survival in
cancer patients without VTE, the FAMOUS (Fragmin Advanced
Malignancy OUTcome Study) trial enrolled 385 patients with histologically confirmed, advanced (Stage III or IV) malignant disease of
breast, lung, gastrointestinal tract, pancreas, liver, genitourinary
tract, ovary or uterus.57 All patients had a minimum predicted life
expectancy of 3 months, and received chemotherapy (32%) and/or
radiotherapy (8%) at the discretion of the treating physician. In
addition, patients were randomized to receive either LMWH (dalteparin 5000 IU daily), or placebo for 12 months. A non-significant
trend towards a survival advantage was observed in the group of
patients treated with dalteparin (P = 0.19). Survival estimates at
1, 2, and 3 years after randomisation were 46%, 27%, and 21% for
the dalteparin group and 41%, 18%, and 12% for patients receiving
placebo. However, in a post-hoc analysis restricted to those patients surviving more than 17 months (n = 102) from randomisation, a significant beneficial effect of LMWH on survival became
apparent. Two years following randomisation, 78% of the dalteparin-cohort remained alive as opposed to only 55% in the placebo
group. Furthermore, median survival time was almost doubled in
the dalteparin-cohort compared to placebo controls (44 months
vs. 24 months; P = 0.03). Interestingly, this survival benefit could
not be explained by a reduction in symptomatic VTE (LMWH
2.4% vs. placebo 3.3%) which was generally low during the follow-up period. Low dose dalteparin administration in this heterogeneous group of patients with advanced malignancies was also
well tolerated, with no significant increase in major bleeding
complications.
In the MALT (malignancy and low molecular weight heparin
therapy) study, 302 patients with a variety of advanced solid tumours (including colorectal, breast, lung, gastric, liver, prostate,
pancreatic, renal, ovarian, and uterine) were recruited.58 To be eligible for enrolment, patients needed to have a predicted minimum
life expectancy of more than 1 month, and have no clinical evidence of VTE. Patients were randomised to receive either LMWH
(nadroparin) or placebo. Nadroparin (dose adjusted according to
weight) was administered twice daily for the initial 2 weeks, and
then once daily for a further 4 weeks. In addition, some patients received concomitant chemotherapy (29.8%), radiotherapy (25.2%),
or hormonal therapy (13.6%). A significant improvement in overall
survival was observed in those patients randomized to receive
nadroparin therapy compared to controls. At both 12 and 24
months, nadroparin administration was associated with 12% and
10% reductions in overall mortality. Median survival was 8.0
months in the nadroparin group and 6.6 months in the placebo
group. Furthermore, in keeping with the findings of the FAMOUS
trial,57 the beneficial effects of LMWH therapy were again more
pronounced in the subgroup of patients who had longer life expectancy (P6 months) at enrolment. In this cohort, use of nadroparin
was associated with an increase in median survival from 9.4
months to 15.4 months. Of note, the benefits of LMWH on overall
survival rates continued to be observed for months and years beyond discontinuation of the LMWH therapy, again suggesting that
the efficacy of LMWH is not simply mediated through thromboprophylaxis only. Once again, LMWH therapy was extremely well
tolerated, although there was a non-significant trend towards
increased major bleeding (3% vs. 1%).
A third study has further investigated the effects of LMWH on
survival in patients with advanced solid tumours.59 This study
was initially devised as a randomised double-blinded controlled
trial comparing dalteparin 5000 U to placebo in patients with
incurable cancers (breast, prostate, lung, and colorectal). However,
due to a low accrual rate, the placebo arm of the study was discontinued after only 52 patients had been enrolled. In contrast to the
previous two trials, no effect of LMWH on overall survival was observed, even in the subgroup of patients who had better prognosis.
Nevertheless, the value of these data is clearly difficult to interpret
given the protocol modification.
In view of the reports suggesting that oral anticoagulant therapy may have a particular beneficial effect in patients with SCLC,
Altinbas et al. further investigated whether LMWH may also influence survival in this particular malignancy type.56 Eighty-four
patients with histologically confirmed SCLC were treated with
combination chemotherapy (cyclophosphamide, epirubicin, and
vincristine) for 18 weeks. Patients with limited disease at entry
also received local thoracic radiotherapy. In addition, patients were
randomized to receive dalteparin 5000 U once daily or placebo
throughout their course of chemotherapy. Overall tumour response rate (69.2% vs. 42.5%; P = 0.07), and median overall survival
(13 months vs. 8.0 months; P = 0.01) were both significantly enhanced in the patients who received daltepain compared to placebo. Furthermore, in this study involving a single type of cancer,
133
M.S. Cunningham et al. / Blood Reviews 23 (2009) 129–135
Table 2
Cancer patients without clinical VTE-effect of heparin on overall survival.
Study
n
Malignancy
Stage
Heparin
Duration
Beneficial outcomes
Major bleeding
Lebeau
et al.55
277
Small cell lung
cancer
Limited and
extensive
UFH – adjusted
dose
5 weeks
N.R.
Kakkar et al.57
385
Breast, lung, GIT,
pancreas, GUT,
ovary, uterus
Small cell lung
cancer
Advanced
(stage III or
IV)
Limited and
extensive
Dalteparin
5000 IU daily
52 weeks or
until death
Significant increase in median survival (317 days vs.
261 days; P = 0.01)
Subgroup analysis – beneficial effect restricted to
limited-stage SCLC
In patients with better prognosis – significant increase
in median survival (44 months vs. 24 months; P = 0.03)
Dalteparin
5000 IU daily
18 weeks
Breast, lung, GIT,
pancreas, renal,
ovary, uterus
Breast, lung,
colorectal,
prostate
Advanced
Nadroparin –
adjusted dose
6 weeks
Advanced
Dalteparin5000 IU
daily
104 weeks
or until
death
Altinbas
et al.56
84
Klerk et al.58
302
Sideras
et al.59
138
the beneficial effect on survival was observed in patients with
either limited or extensive disease stages.
In summary, the limited evidence currently available form
these four randomized studies supports the hypothesis that LMWH
may indeed have a beneficial effect on survival in cancer patients.
In particular, both the FAMOUS and MALT studies suggest that
LMWH may significantly increase median survival in patients with
advanced solid tumour types and a favourable prognosis. In a
recent Cochrane review, Akl et al. systematically evaluated the
efficacy and safety of heparin (including UFH and LMWH) to improve survival of patients with cancer.60 Overall, they concluded
that heparin therapy was associated with a statistically and clinically significant survival benefit (hazard ratio = 0.77; CI: 0.65–
0.91). In contrast, the increased risk of bleeding with heparin did
not achieve statistical significance (RR = 1.78; CI: 0.73–4.38).
However, caution is necessary in the interpretation of these
exciting, preliminary findings. In total, all four trials on LMWH included only 909 patients. In view of the small numbers enrolled in
these studies, it is perhaps not surprising that some conflicting
conclusions were reported. In addition, the patients cohorts enrolled in the different studies demonstrate marked heterogeneity.
For example, they include a wide variety of different tumour types
and stages. Furthermore, as a consequence of the lack of patient
numbers, stratification for important confounding factors (e.g. type
of tumour; presence of metastasis; type of chemotherapy; concurrent radiotherapy or hormonal therapy) has not been possible.
Therefore, it is self-evident that larger randomized studies will
be required in order to confirm, and expand upon, these important
initial data. A number of other important issues will need to be
considered in the design of any future clinical trials. First, it is
important to recognise that significant differences exist between
different LMWH preparations.11,61 Consequently, it is not necessarily possible to extrapolate the results obtained using one LMWH in
the treatment of cancer patients to all others. Moreover, the optimal dose (treatment, intermediate, or prophylaxis), regimen (once
daily or twice daily) and duration of LMWH administration will require further study. Second, it is well established that different
types of malignant tumours influence in vivo coagulation through
different mechanisms and to varying degrees. Thus, it seems likely
that the relative effects of LMWH may differ markedly for different
types and stages of cancer. To date, the only specific tumour studied on an individual basis has been small cell lung cancer.
Antineoplastic effects of LMWH
Although the molecular mechanism(s) through which anticoagulant therapies may mediate direct antineoplastic effects have not
Significant increase in median survival (13 months vs.
8 months; P = 0.01)
Subgroup analysis – beneficial effect in both extensive
and limited-stage SCLC
Significant increase in median survival (8 months vs.
6.6 months; P = 0.02)
No significant effect on median survival
LMWH 0.5% vs.
placebo 0%
LMWH 2.4% vs.
control 0%
LMWH 3% vs.
placebo 1%
(P = 0.12)
LMWH 6% vs.
control 7%
been fully elucidated, a number of different mechanisms have been
proposed.31,32,62,63 Previous studies have shown that activated
coagulation proteases, particularly thrombin, can significantly
influence tumour proliferation and progression.31,32 Moreover,
fibrin generation has also been shown to play a critical role in
metastasis, by protecting cancer cells from immune attack,64 and
also mediating their attachment to vascular walls.65,66 Consequently, as a result of their anticoagulant effects in down-regulating thrombin generation and fibrin deposition, both heparin and
warfarin can directly influence tumour cell growth and metastasis.67 In addition, accumulating in vitro evidence has demonstrated
that heparins in particular can also influence cancer cell adhesion,
growth and angiogenesis through a number of different coagulation-independent mechanisms.68 These mechanisms have been
described in detail in a number of recent reviews.67,69 In brief however, LMWH has been shown to inhibit the adhesion of cancer cells
to extracellular matrix proteins (e.g. fibronectin or laminin),
endothelial cells, and platelets, all of which are important in the
metastatic process.70 These effects are mediated at least in part, because heparin can block P- and L-selectin binding to tumour mucin
ligands.70 LMWH can also significantly inhibit tumour-induced
angiogenesis, by inhibiting the binding of growth factors to their
endothelial receptors, and by decreasing TF expression.71,72 In
addition, studies have shown that LMWH can directly enhance
apoptosis and thereby reduce in vitro proliferation for a number
of different cancer cell lines, including primary high-grade
glioma,73 hepatoma (HepG2),30 and nasopharngeal carcinoma
(CNE2).30,74 Finally, LMWH can also inhibit heparanase, an enzyme
over-expressed by many tumours that is thought to play a key role
in facilitating extracellular matrix invasion.30,75 Further studies
will be necessary to determine the relative contributions of each
of these proposed mechanisms to the beneficial effects associated
with the use of LMWH in cancer patients.
Conclusions
In conclusion, it is clear that anticoagulant therapy has an
important role to play in the management of cancer patients
who develop acute VTE. In addition, animal studies dating back
to the 1960s have suggested that anticoagulant therapy may not
only reduce the risk of recurrent VTE, but also have other direct effects on tumour cell biology. This hypothesis has been supported
by human studies initially performed using warfarin, and more recently involving LMWH. However, only a small number of randomized controlled trials have been reported in which the designated
primary outcome was effect of anticoagulant therapy on overall
134
M.S. Cunningham et al. / Blood Reviews 23 (2009) 129–135
survival. Unfortunately, most of these studies have involved small
numbers of cancer patients. Also, the patients enrolled have often
had heterogeneous types and stages of cancer. Interpretation of the
data is further complicated by the fact that the patient cohorts enrolled in the different randomized studies were significantly different, and varied treatment regimens were employed.
Notwithstanding these limitations, it is important to note that
exciting novel data have been reported, particularly in the recent
LMWH studies. For example, based upon the findings of the MALT
trial, treatment of eight patients with advanced solid tumours with
nadroparin for 6 weeks would prevent one death at 12 months. If
this observation is validated, the efficacy of a short course of
LMWH would indeed be comparable to many recently introduced
anti-cancer therapies. Consequently, targeting the cross-talk between activated coagulation serine proteases and cancer cell biology may offer an entirely new therapeutic avenue. Moreover, it
remains unclear how the therapeutic efficacy and safety might
vary over a range of different LMWH dose regimens, in different
individual cancer types, and whether newer anticoagulant therapies will have similar in vivo effects.
On the basis of the data presented in this review, it is clear that
it is not possible to recommend using routine thromboprophylaxis
for all cancer patients. Nevertheless, there is certainly enough
encouraging data to highlight the need for new larger randomised
clinical trials. Several such trials (IMPACT, FOCUS, FRAGMATIC,
ABEL, and TILT) are already in progress, investigating the effects
of different LMWH preparations in different specific types of
malignancy (including ovarian, lung, small cell lung). The conclusions of these clinical trials, combined with emerging data from basic scientific research into this field, will be awaited with interest
and will be of major benefit in helping to design more informative
future clinical trials.
Conflict of interest statement
None.
Acknowledgements
This work was supported by a Health Research Board Ireland
Clinical Research Training Fellowship CRT/2006/03 (MC); a Health
Research Board Ireland Postdoctoral Fellowship RP/2006/44 (RJP);
and a Science Foundation Ireland President of Ireland Young
Researcher award 06/Y12/0925 (JSOD).
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