Piovella_edit.qxp 31/10/08 12:21 Page 39
Clinical Experience of Nadroparin in Patients with Cancer
Table 4: Nadroparin Studies in the Prolongation of Survival in Patients with Cancer
Study Setting Total Population Type of Cancer Nadroparin Comparator
Klerk et al.
5
Prolongation of 302 Various types 3,800 anti-Xa IU if <50kg Placebo
survival 5,700 anti-Xa IU between 50 and 70kg
7,500 anti-Xa IU if >70kg
Twice daily for 14 days then once daily for another 4 weeks
Icli et al.
86
Prolongation of 69 Pancreas cancer 2,850 anti-Xa IU No treatment
survival Once daily for 8 days every 3 weeks for a median of 6 cycles
INPACT (ongoing)
87
Prolongation of 500 Lung, pancreas or Therapeutic doses for 2 weeks followed by half therapeutic doses No treatment
survival prostate cancer for 4 weeks
After 4 weeks of wash-out, subsequent 2-week periods of
therapeutic doses of nadroparin
A total of 6 cycles, each separated by 4 weeks of wash-out
NVALT-8b (ongoing) Prolongation of 600 Resected non-small- Initiated 4–6 weeks after surgery No treatment
recurrence-free cell lung cancer Therapeutic doses for 2 weeks and half-therapeutic doses
survival with a high risk for 14 weeks
of recurrence
with these drugs was 40% lower than that in patients treated with course of subcutaneous nadroparin or placebo. Nadroparin was
unfractionated heparin.
81
Moreover, this analysis revealed that the mortality administered according to patient weight: 3,800 anti-Xa IU (0.4ml) in
reduction was present for various subtypes of malignancy; it was not due to patients below 50kg; 5,700 anti-Xa IU (0.6ml) in patients between 50 and
differences in death related to venous thromboembolism or bleeding and 70kg; and 7,600 anti-Xa IU (0.8ml) in patients above 70kg. It was
persisted after adjustment for several prognostic variables. Another administered subcutaneously twice daily for the first 14 days of treatment,
interesting fact was that in the treatment of venous thromboembolism, the then once daily for another four weeks. In total, 148 patients were
benefit of low-molecular-weight heparins relative to unfractionated heparin allocated to nadroparin and 154 patients to placebo. Mean follow-up was
on death reduction appeared to be specific to the subgroup of patients with one year. The overall hazard ratio of mortality was 0.75 (95% CI
cancer.
60
After this, two other meta-analyses and systematic reviews showed 0.59–0.96), with a median survival of 8.0 months in the nadroparin
that anticoagulants, particularly low-molecular-weight heparins, significantly recipients versus 6.6 months in the placebo group. After adjustment for
improved overall survival in cancer patients without venous thrombosis, potential confounders (life expectancy, World Health Organization [WHO]
suggesting that the beneficial effect of these drugs was partly independent performance status, concomitant treatment, type and histology of cancer),
of their antithrombotic effect.
82,83
the beneficial effect of nadroparin on survival remained significant (hazard
ratio, 0.76; 95% CI 0.58–0.99). In the a priori specified subgroup of
Nadroparin appears to be a very promising drug in this setting, as shown in patients with a life expectancy of six months or above at enrolment, the
various studies, both experimental and clinical (see Table 4). In vitro, it was hazard ratio of mortality was 0.64 (95% CI 0.45–0.90), with a median
shown that nadroparin may have antimetastatic activity by interfering with survival of 15.4 and 9.4 months in the nadroparin and placebo patients,
the adhesion and invasion of blood-borne metastatic cells: at equivalent respectively. For patients with a shorter life expectancy, the hazard ratio of
concentrations in terms of anti-factor Xa units, nadroparin but not mortality was 0.88 (95% CI 0.62–1.25). Major bleeding occurred in five
enoxaparin significantly inhibited P-selectin-dependent tumour cell nadroparin patients (3.4%) and in one placebo patient (0.6%; p=0.12).
interactions.
84
In a mouse experimental model, the dose (in anti-factor Xa None of these events were fatal. Of the major bleeding episodes in the
units) of nadroparin required to inhibit lung metastases by 50% was five- nadroparin group, three were spontaneous bleeds associated with the
fold lower than that of enoxaparin. The ability of nadroparin to inhibit P- malignancy; another occurred during an intervention (drainage of ascites).
selectin-dependent tumour cell interactions in vitro was positively correlated This was the first randomised, placebo-controlled study that showed that
with their ability to inhibit experimental lung metastases in vivo. This study a low-molecular-weight heparin may provide a survival benefit in the
confirmed previous data showing the ability of nadroparin to inhibit cancer population as a whole.
experimental metastases.
85
A second nadroparin trial in this context was performed to determine
The clinical value of nadroparin in prolonging the survival of patients whether the addition of this drug to gemcitabine and cisplatinum
with cancer was first suspected in a nadroparin trial in cancer patients with improved the response rate and survival of 69 patients with advanced
deep-vein thrombosis, in which only 7% of nadroparin patients died pancreatic cancer.
86
Gemcitabine 800mg/m
2
and cisplatinum 35mg/m
2
compared with 44% of unfractionated heparin patients (p=0.021).
63
were given on days one and eight: this was repeated every 21 days. No
However, this study was not primarily designed to investigate the effect of additional treatment was given to a first control group. Nadroparin was
nadroparin on cancer mortality. In addition, treatment lasted for only five administered subcutaneously at the once-daily dose of 2,850 anti-Xa IU
to 10 days and the follow-up period was generally limited to three (0.3ml) for each gemcitabine/cisplatinum cycle in a second group.
months. The prospective Malignancy And Low-molecular-weight heparin Nadroparin-treated patients received a median of six (range: two to nine)
Therapy (MALT) trial was performed in order to clarify the value of cycles; control patients received a median of three (range: two to eight)
nadroparin in prolonging the survival of cancer patients without cycles. The total response rate was 58.8% in patients treated with
thrombosis.
5
It was a randomised, double-blind, placebo-controlled study. nadroparin and 12.1% in control patients (p<0.001). Median times to
Patients with metastasised or locally advanced solid tumours but without progression and overall survival times were 7.3±2.1 and 13.0±3.8
venous thromboembolism were randomly assigned to receive a six-week months, respectively, in the nadroparin group versus 4.0±0.3 (p<0.001)
EUROPEAN ONCOLOGY 39
Page 1  |  Page 2  |  Page 3  |  Page 4  |  Page 5  |  Page 6  |  Page 7  |  Page 8  |  Page 9  |  Page 10  |  Page 11  |  Page 12  |  Page 13  |  Page 14  |  Page 15  |  Page 16  |  Page 17  |  Page 18  |  Page 19  |  Page 20  |  Page 21  |  Page 22  |  Page 23  |  Page 24  |  Page 25  |  Page 26  |  Page 27  |  Page 28  |  Page 29  |  Page 30  |  Page 31  |  Page 32  |  Page 33  |  Page 34  |  Page 35  |  Page 36  |  Page 37  |  Page 38  |  Page 39  |  Page 40  |  Page 41  |  Page 42  |  Page 43  |  Page 44  |  Page 45  |  Page 46  |  Page 47  |  Page 48  |  Page 49  |  Page 50  |  Page 51  |  Page 52  |  Page 53  |  Page 54  |  Page 55  |  Page 56  |  Page 57  |  Page 58  |  Page 59  |  Page 60  |  Page 61  |  Page 62  |  Page 63  |  Page 64  |  Page 65  |  Page 66  |  Page 67  |  Page 68  |  Page 69  |  Page 70  |  Page 71  |  Page 72  |  Page 73  |  Page 74  |  Page 75  |  Page 76  |  Page 77  |  Page 78  |  Page 79  |  Page 80  |  Page 81  |  Page 82  |  Page 83  |  Page 84  |  Page 85  |  Page 86  |  Page 87  |  Page 88  |  Page 89  |  Page 90  |  Page 91  |  Page 92  |  Page 93  |  Page 94  |  Page 95  |  Page 96  |  Page 97  |  Page 98  |  Page 99