Serum Methotrexate (MTX) Concentrations and Prognosis in Patients with Osteosarcoma of the Extremities Treated with a Multidrug Neoadjuvant Regimen

Abstract

The relationship between the serum concentration of methotrexate and the prognosis has been studied in 108 patients with osteosarcoma of the extremities treated from September 1986 to December 1989 at the Chemotherapy Department of Rizzoli Hospital. The protocol of neoadjuvant chemotherapy included high doses of methotrexate (HDMTX) adriamycin, cisplatinum, ifosfamide and VP-16. After a median follow-up of 40.4 months (range 24-62), 84 (77.7%) of the patients studied remained continuously disease-free (CDF) and 24 relapsed. Significantly higher mean serum MTX concentrations were observed in the patients who remained CDF (669.5 mumol/l) than in the patients who relapsed (571.9 mumol/l) (p < .004). The breaking point of prognostic significance for the serum MTX levels seems to be 700 mumol/l. In fact, according to the mean MTX concentrations, the patients with less than 700 mumol/l showed a significantly lower disease-free survival than the patients with higher mean MTX concentrations (68.12% vs 94.87% p < .0013). The distribution of prognostic variables between the two groups was the same in terms of site and histological type of tumor and alkaline phosphatase serum levels at diagnosis. In the group which had more than 700 mumol/l MTX, a higher percentage of good histological response after primary chemotherapy was observed. This is probably independent from the MTX because no significant preoperative MTX serum levels between good and partially responding patients were observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Hyper-alkalinization without hyper-hydration for the prevention of high-dose methotrexate acute nephrotoxicity in patients with osteosarcoma

“…There was an obvious intra-patient and inter-patient variability in HDMTX serum concentrations, as previously described in the literature [21,22].…”

“…The median age was 18 years (range: [15][16][17][18][19][20][21][22][23][24][25]. A total of 344 cycles, including the pre-operative and post-operative treatments, were evaluable for toxicity and for HDMTX pharmacokinetics (Table 4).…”

High dose methotrexate in adult patients with osteosarcoma: Clinical and pharmacokinetic results

“…MTX optimal dosage per cycle fluctuates widely, ranging from 8 to 24 g/m 2 , the usual dose being 12 Á/ 15 g/m 2 [5]. HDMTX (200Á/ 500 mg/kg] with LV rescue was first used by Djerassi in 1967.…”

“…The present study investigates pk behavior in HDMTX and clinical response of adult patients to this regimen in neoadjuvant and adjuvant settings. [5,10,15]. All protocols comprised HDMTX, ADM, DDP and IFO but, depending on response to preoperative chemotherapy (rated as good/complete: /90% or poor/incomplete: B/90%), patients were given different postoperative cycles.…”

Chemotherapy for Osteosarcoma without High-Dose Methotrexate: A 12-Year Follow-Up on 53 Patients

“…Delepine et al further proved that high MTX serum levels were predictive for a better response and thus could positively impact overall prognosis [19]. Work done by the Rizzoli Institute and the Scandinavian Sarcoma Group pointed in the same direction [20,21]. The Cooperative Osteosarcoma Study Group analyzed 1,703 MTX doses in 198 patients.…”