Periprosthetic seromas and a third space effect after high-dose methotrexate

Background: Besides surgery, chemotherapy including high-dose methotrexate is a mainstay of osteosarcoma treatment. Methotrexate is known to accumulate in tissues and cavities, so-called third spaces (e.g., periprosthetic seromas) leading to local toxicity and delayed elimination (third space effect). We compared the concentrations of methotrexate in serum and periprosthetic seromas to evaluate a potential toxic risk based on a third space effect.

Methods: In 45 osteosarcoma patients who were treated with endoprosthesis and high-dose methotrexate (HDMTX) between 1991 and 2011 we retrospectively analyzed methotrexate concentrations in periprosthetic seromas and serum. Differences were assessed by means of the Wilcoxon test.

Results: A total of 112 periprosthetic seroma punctures were performed in 18 out of 45 patients. At 24 h the periprosthetic seroma concentrations were in median 14.86-fold (range 1.49-42.97-fold, p = 0.001), at 48 h in median 8.50-fold (range 1.36-52.56, p < 0.001) and at 72 h in median 2.66-fold (range 0.66-5.82, p = 0.015) of the corresponding serum concentrations. At 24 h highly toxic concentrations (≥ 20 μmol/l) were observed in 30% of all analyzed seromas (median 109.83 μmol/l, range 4.91-170.71 μmol/l). A significantly higher serum concentration (range 0.16-0.75 μmol/l, median 0.36 µmol/l) was found in patients with prior puncture than patients without puncture at 45 h after HDMTX.

Conclusion: Methotrexate concentrations of periprosthetic seromas are significantly higher than corresponding serum concentrations possibly contributing to a third space effect. To avoid severe adverse effects punctures of these effusions should be considered.