Rationale and design of PROSPECT-CONKO 004: a prospective, randomized trial of simultaneous pancreatic cancer treatment with enoxaparin and chemotherapy)

Abstract

Background: Advanced pancreatic cancer, in addition to its high mortality, is characterized by one of the highest rates of venous thromboembolic events (VTE) as compared to other types of cancer. Enoxaparin, a low molecular weight heparin (LMWH), has proven to be effective for the prevention and treatment of VTE in surgical and general medical patients. Results of some small studies suggest that this benefit might extend to patients with cancer, however, enoxaparin is not currently indicated for this use. This phase IIb study was designed to analyze the efficacy of enoxaparin in patients with locally advanced or metastatic pancreatic cancer undergoing systemic chemotherapy.

Methods: The aim of this prospective multicenter trial is to compare concomitant treatment with enoxaparin to no anticoagulation in 540 patients. Primary endpoint is the incidence of clinically relevant VTE (symptomatic deep venous thrombosis (DVT) of the leg and/or pelvic and/or pulmonary embolism (PE)) within the first 3 months. Secondary endpoints include the incidence of symptomatic and asymptomatic VTE after 6, 9 and 12 months as well as remission at 3, 6, 9 and 12 months, overall survival and bleeding.

Trial registration: isrctn.org identifier CCT-NAPN-16752, controlled-trials.com identifier: ISRCTN02140505.

Results: An interim analysis for safety performed after inclusion of 152 patients revealed no increased risk of bleeding (5 pts vs. 6 pts, Chi2: 0.763).

Conclusion: PROSPECT is a pivotal study in elucidating the role of low molecular weight heparins in advanced pancreatic cancer. Its results will lead to a new understanding of the role of heparins in the prevention of venous thromboembolism and of their effect on survival, remission rates and toxicity of chemotherapeutic regimens.

Figure 1

Initiation of the coagulation and angiogenic cascades by pancreatic tumour cells (modified from [61]). Figure legend text: TF, tissue factor; VEGF, vascular endothelial growth factor; PAR, protease-activated receptor; TSP, thrombospondin; HGBF2, heparin-binding growth factor 2 (previously called fibroblast growth factor 2 [FGF-2]).

Figure 2

Study design. Figure legend text: KPS, Karnowsky Performance Status; Crea, Creatinine; ULN, upper limit of normal (> 1.1 mg/dl for men and > 0.9 mg/dl for women); GFFC, combination of gemcitabine, 5-fluorouracil, folinic acid and cisplatin; GEM, gemcitabine monotherapy; PD, partial remission; CR, complete remission.

Figure 3

Treatment pathway. Figure legend text: GFFC, combination of gemcitabine, 5-fluorouracil, folinic acid and cisplatin; GEM, gemcitabine; CIS, cisplatin; FA, folinic acid; 5-FU, 5 fluorouracil; d, day.