Introduction
The influence of unfractionated heparin (UFH) and other anticoagulants on the spread
of cancer has been reported since the early 1960s.1 However, clinical studies investigating the use of heparins in cancer patients have
not produced consistent results.2 Intravenous, adjusted-dose UFH for 5 to 10 days has been the standard initial treatment
for venous thrombosis. More recently, subcutaneous, fixed-dose, low molecular weight
heparins (LMWHs), which are fractions of the parent compound, have been shown to be
safe and effective alternatives to UFH in the initial treatment for venous thromboembolism.3-5
In one of our randomized clinical trials comparing LMWH and UFH in the initial treatment
of deep vein thrombosis (DVT), we observed an unexpected difference in 6-month mortality
among cancer patients in favor of LMWH, which could not be attributed to a difference
in the incidence of thrombotic or bleeding complications.6 A similar observation in favor of LMWH was reported in a subsequent study and in
a meta-analysis of trials.7,8 The number of cancer patients included in these studies was small, and adjustment
of the observed effect for the baseline characteristics of the cancer patients was
not possible. However, these findings suggested an inhibitory effect of LMWH on tumor
growth or metastasis, which is less apparent or absent for UFH, resulting in a beneficial
effect on the survival of cancer patients. This hypothesis is supported by the observations,
in experimental studies, that LMWH and low molecular weight heparan sulfate, in comparison
to UFH, effectively suppressed angiogenesis, a process necessary for tumor growth
and metastasis.9,10
On the other hand, animal studies that investigated the effect of chemically-modified
heparins on the spread of cancer did not detect a superior anti-tumor effect of LMWH
compared to UFH; both were found to inhibit metastasis.11,12 To date, the effect of LMWH on cancer survival in humans has not been investigated
as a primary objective. If a consistent and beneficial effect of LMWH on mortality
is indeed present, such a study would be warranted.
We performed a meta-analysis of all available randomized clinical trials where LMWH
was compared with UFH in the treatment of venous thromboembolism (VTE) to estimate
the crude treatment effect of LMWH on mortality in cancer patients compared to UFH.
Subsequently, we adjusted this treatment effect for age, gender, and primary malignancy
site by reanalyzing data from three of those trials.3-5 This effect was further adjusted for other prognostic factors, including cancer histology,
tumor stage, presence of metastases, duration of cancer, and concomitant use of cancer
treatment, by analyzing individual patient data from the largest randomized trial.5
