Posters— Medical Oncology

RESULTS OF A T10-DERIVED PROTOCOL BASED ON PREOPERATIVE HIGH-DOSE METHOTREXATE WITH INDIVIDUAL DOSE ADJUSTMENT IN THE TREATMENT OF PRIMITIVE OSTEOSARCOMA

Duffaud F, Digue L, Volot F, Bouvier C, Curvale G, Poitout D, Favre R (Hôpital La Timone, Marseille 13385, France)

From January 1987 to December 1997, 42 adolescents and adults with high-grade osteosarcoma were treated at La Timone University Adults Hospital with a T10-derived protocol using high-dose methotrexate (HDMTX) with individual dose-adjustment. The male/female ratio was 3:1 and the median age 24 years (14-53). Primary tumor sites included extremities (90.4%), axial bones (7.2%) and head and neck (2.4%). Seven patients (16.7%) presented with initial lung metastases. Preoperative chemotherapy included 4 weekly cycles of HDMTX with individual dose adjustment followed by citrovorum factor rescue. HDMTX was administered in 8 hour–perfusion to achieve a serum MTX concentration of 1.000 mMol/L (Cmax) at the end of the infusion. Definitive surgery was performed 10 to 14 days after the last HDMTX cycle. Twenty-nine patients (72.5%) had conservative surgery and 11 patients (27.5%) amputation. The histologic response to preoperative chemotherapy evaluated according to the method of Huvos grading system was rated “good” (³ 90% tumor necrosis) in 11.2% of patients or “poor” (< 90% tumor necrosis) in 88.8% of patients. “Good” responders received post-operative chemotherapy based on HDMTX, pirarubicin and BCD (Bleomycin-Cyclophosphamide-Dactinomycin) whereas “poor” responders received a “salvage” regimen including ifosfamide, pirarubicin, cisplatin +/- etoposide during 18 weeks. No toxic death occurred and severe toxicities (WHO grade III/IV) due to chemotherapy were moderate. Individual MTX dose-adjustment according to the patient’s pharmacokinetic profile was optimum (mean Cmax obtained was 1001 +- 75.4 &uumol;Mol/L). Mean delivered dose of HDMTX was higher than the one recommended by Rosen (13.1 g/m² versus 8 to 12 g/m²). With a median follow-up of 55 months (11-139), the 5-year and 8-year overall survival (OS) rates were 65.7% and 61.3% for the entire group. For the 35 patients with localized disease at diagnosis, the 5-year and 8-year OS rates were 75.8% and 70.4%. For the same group, event-free survival (EFS) rates were 64.6% and 55.5% at 5 years and 8 years. Fourteen patients (33.3%) relapsed: eight patients developed lung metastases, 2 developed a local recurrence and 4 presented both. The difference in OS and EFS rates at 5 years between “good” and “poor” responders was not significant. In multivariate analysis, tumor size, dose intensity and preoperative MTX dose intensity were independent prognostic factors for OS (P= 0.0004, 0.04, 0.007). Our OS and EFS rates are similar to those reported in recent studies despite the low rate of “good” responders to preoperative chemotherapy obtained. Our post-operative “alvage” chemotherapy regimen is effective for “poor” responders yielding identical EFS and OS rates as those of “good” responders.