Outpatient administration of high-dose methotrexate for osteosarcoma treatment in Brazil.

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Author(s): C. R. Macedo, A. M. Cappellano, D. T. Noguchi, A. P. Martinho, C. G. Dias, C. G. Dias, R. C. Malheiros, A. H. Dutra, M. Grings, A. L. Pires, A. S. Petrilli; Instituto de Oncologia Pediátrica, São Paulo, Brazil



Background: We describe the experience with outpatient administration of high dose methotrexate (HDMTX) and leucovorin rescue for osteosarcoma treatment at Instituto de Oncologia Pediátrica.


Methods: HDMTX (12g/m²) is administered as part of the Brazilian Osteosarcoma Treatment Group Protocol in an ambulatory basis. Daily MTX serum levels and fluid controls follows until the serum level is <0,2 µ/L. Families were oriented to measure urinary pH and volume, PO intake and to adjust leucovorin dose as needed. To achieve treatment adherence, a family education program was developed. Concomitantly to HD chemotherapy, low dose oral cyclophosphamide and MTX (metronomic treatment) were provided to metastatic (M) patients. This is a retrospective analysis of the HDMTX courses administered between 2006 and 2008.


Results: Out of 341 HDMTX infusions, administered to 42 patients, 42.5% had abnormal serum levels at hour 24, 8.8% at hour 48 and 33.2% at hour 72. After required interventions, 2.9% (n = 8) had serum levels >0.2 µ/L at hour 72 leading to delayed excretion. Of these, 7 had also creatinine elevation and main adverse events were mucositis, reversible transaminasis elevation and one sepsis. In the overall analysis, other toxicities included mucositis grade II (20%), nefrotoxicity (5.6%) and neutropenia grades III and IV (25.4%). Serious adverse events of seizure, allergic reaction, and Steven Johnson's Syndrome lead to suspension of future HDMTX administration in 4 patients (01 metastatic). The main differences found between M and non-M patients were 16.8% versus 8.7% of leucopenia grade IV and 12.1% versus 6.6% of anemia grades III and IV.


Conclusions: Similar to other authors' experience, outpatient administration of HDMTX lead to elevated serum levels in 42.5% of the infusions, demonstrating the importance of a well trained staff and early introduction of supportive therapies to avoid associated toxicities. To a developing country, this approach helps lowering treatment costs and infection risks and increases patient adherence to treatment, with acceptable toxicities, even with the introduction of metronomic treatment.