gms | German Medical Science

Background: In the course of their disease approximately 20 % of patients (pts) diagnosed with pancreatic adenocarcinoma (PA) develop venous thromboembolism, which may contribute to the dismal prognosis of PA. In a recently published phase II trial the addition of low molecular weight heparin (LMWH) to chemotherapy with gemcitabine and cisplatin was reported to result in a higher response rate and improved survival compared with chemotherapy alone (Icli et al., ASCO 2003). These encouraging results prompted our group to examine the feasibility of gemcitabine, cisplatin, 5-fluorouracil and folinic acid (GFFC) with concomitant daily subcutaneous (s.c.) LMWH in pts with advanced PA.

Patients and Methods: Nineteen pts (13m, 6w) were treated; 12 were primarily inoperable (8 IVb, 4 IVa), and 7 had undergone pylorus-preserving pancreaticoduodenectomy (PPPD) and presented with local recurrence (2 pts) or distant metastasis (5 pts). Median age was 59 years. Chemotherapy consisted of gemcitabine 1000 mg/m2 (30 min), cisplatin 30 mg/m2 (90 min), 5-fluorouracil 750 mg/m2 (24 h) and folinic acid 200 mg/m2 (30 min) on days 1 + 8 q3w. Enoxaparin (Clexane®) 40 mg was given once daily s.c. Pts achieving at least stable disease (SD) as documented by CT scan after 12 weeks of treatment received maintenance chemotherapy with single agent gemcitabine 1000 mg/m2 (30 min) on days 1, 8 and 15 q4w until disease progression (PD).

Results: After median follow up of 2 years, pts have received a total of 71 cycles of GFFC (median 4, range 2-4) and 122 cycles of single agent gemcitabine (median 4, range 0-25). NCI grade 3/4 toxicity during treatment with GFFC was mostly hematologic and included neutropenia (12/2 pts) and thrombopenia (1/0 pts). The dose of cisplatin was temporarily reduced by 50% in 3 pts due to elevated serum creatinine. No grade 3/4 nausea or vomiting occurred, only one case of DVT with consecutive non lethal pulmonary embolism was observed. Among 17 pts undergoing a CT scan after 12 weeks of treatment with GFFC + LMWH, 15 had SD and 2 PD. Both PD pts had previously received PPPD.

Conclusions: Our results indicate that the addition of enoxaparin to GFFC is safe, does not change toxicity and maintains activity of chemotherapy in pts with advanced PA. To further investigate whether enoxaparin reduces the incidence of thromboembolic events and increases survival, we have initiated a randomized phase IIb trial of GFFC (or single agent gemcitabine for pts with poor performance status or elevated serum creatinine) with or without enoxaparin (PROSPECT trial).