Department of Medical Oncology and Hematology, Istituto Clinico Humanitas, Rozzano, Milan, Italy
*E-mail: massimo.magagnoli@humanitas.it
Randomized trials have demonstrated that the combination of 5-fluorouracil (5-FU) and folinic acid (FA) with oxaliplatin, the FOLFOX regimen, is highly active in metastatic colorectal cancer [1, 2]. In this regimen, 5FU is administered as a continuous infusion requiring a central venous catheter (CVC) implant with its inherent complications [3], such as venous thromboembolism (VTE). Prophylaxis with low-dose heparin or oral anticoagulants is recommended.
Two studies have shown that warfarin 1 mg/day (minidose) reduces catheter-related thrombosis without altering coagulative parameters or causing bleeding [4, 5]. On the other hand, some reports have described adverse interactions between warfarin and 5-FU [6, 7]. However, no data on CVC-VTE prophylaxis in patients receiving continuous infusion 5-FU in combination with oxaliplatin have so far been reported. Preliminary data on a small cohort of patients showed a high incidence of elevation of International Normalized Ratio (INR) during treatment with FOLFOX [8]. To confirm whether such an interaction exists, we decided to perform an analysis of the incidence of INR elevation in 72 patients receiving a FOLFOX regimen with concomitant prophylactic minidose warfarin, treated in our institution from April 2000 to August 2002.
Twenty-two patients were excluded from the analysis for the following reasons: lack of INR evaluation at baseline, seven patients; less than three determinations of INR during the treatment program, six patients; use of therapeutic warfarin (>1 mg/day), three patients; other reasons (platelet count <100 x 109/l, use of antiplatelet agents, refusal to start treatment), seven patients. All fifty evaluable patients had normal INR levels at the time of CVC insertion, received minidose warfarin (1 mg/day) and were treated with the FOLFOX-4 regimen (oxaliplatin 85 mg/m2 as a 2-h i.v. infusion on day 1, FA 100 mg/m2 as a 2-h i.v. infusion on days 1 and 2, 5-FU 400 mg/m2 as a short infusion on days 1 and 2; 5-FU 600 mg/m2 as a 22-h i.v. continuous infusion on days 1 and 2). Thirty-five patients had an external device such as Groshong CVC (Bard Access System, Salt Lake City, UT) and 15 patients had a completely internalized device such as Port-a Cath (BardPort; Bard Access System). Patient characteristics are listed in Table 1.
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Warfarin administration was discontinued if INR >2.0 and prothrombin time prolongation resolved within 48 h in all patients. Chemotherapy was continued thereafter without oral anticoagulant prophylaxis and none of these patients had any further prothrombin time alteration. In conclusion, these data confirm an adverse interaction between FOLFOX and warfarin and represent a relevant complication of minidose warfarin prophylaxis; the oncologist should be aware of this interaction and should regularly monitor the INR level in these patients.
Acknowledgements
We are indebted to Nordiana Marina Baruzzi for editing this letter.
M. Magagnoli*, G. Masci, C. Carnaghi, P. A. Zucali, L. Castagna, E. Morenghi & A. SantoroDepartment of Medical Oncology and Hematology, Istituto Clinico Humanitas, Rozzano, Milan, Italy (*E-mail: massimo.magagnoli@humanitas.it)
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