This investigation was conducted to assess the use of intensified chemotherapy together with simultaneous application of heparin. The application of medical anticoagulation for cancer patients was still discussed over the last decade, even for inpatients or patients with confirmed thrombosis. The assumed higher incidence of severe bleeding events due to medical anticoagulation, especially in patients with advanced gastrointestinal malignancies, reduced the number of sufficient treated patients in the past and thus may lead to impaired overall survival [12, 19].
This open label phase II feasibility investigation used intensified chemotherapy and simultaneous enoxaparin treatment in patients with first line chemotherapy. The dosage of enoxaparin to be used in our trial has been intensively discussed in terms of pre-existing prevention studies in other indications. Results from the PRINCE  and MEDENOX [21, 22] studies demonstrated effective and well-tolerated VTE prevention in patients with severe cardiopulmonary disease using the LMWH enoxaparin. The given dosages in the MEDENOX trial were set at a high prophylactic level of 40 mg daily versus placebo and also in the PRINCE trial with 40 mg daily versus 5000 IU unfractioned heparin 3× daily. Thus 40 mg enoxaparin once a day was considered to be the minimal dose for primary symptomatic VTE prevention.
We used a safety step design to prevent patients from harmful increased toxicities due to the combination. The observed side effects were consistent with respect to the applied chemotherapy and were similar to those in our phase I trial . We therefore continued the investigation without need of modification of the regimen. Even the addition of heparin does not lead to increased toxicities. We suspected a raise in the local bleeding rate in our advanced pancreatic cancer patients by potential cancer infiltration of the stomach or duodenum. Major bleeding rates for patients with solid cancer using warfarin were 42% and 14% for controls in 431 patients , in our safety trial we therefore decided to accept no higher rate than 20% using prophylactic anticoagulation with enoxaparin. Fortunately we did not observe any patient with severe bleeding under concomitant application of 40 mg enoxaparin daily. Only one patient had a thromboembolic event while getting enoxaparin (5%), whereas the supposed rate of thromboembolic events without heparin use would be 15-20% .
We further observed a slightly increased overall survival compared to gemcitabine monotherapy [2, 9, 24]. This finding and the open discussion about an independent effect of heparins with regard to metastasis and cancer growth has to be investigated by a randomized trial in a larger setting . On the other hand this observed effect is commonly seen in phase II studies with the potential bias of unconscious patient selection and the addition of placebo effects [7, 10]. But besides these considerations we can at least assume that the efficacy of the treatment is not negatively affected.
The finding of this investigation regarding feasibility and safety gives us confidence for using the researched combination in a larger trial to investigate the effect of heparin in a randomized setting.