SUCCESSFUL PHASE II TRIAL OF ETOPOSIDE AND HIGH DOSE IFOSFAMIDE IN NEWLY DIAGNOSED METASTATIC OSTEOSARCOMA: AN UPDATE. A PEDIATRIC ONCOLOGY GROUP TRIAL (POG)

A.M. Goorin, M. Devidas, P. Gieser, W. Ferguson, M. Harris, M. Link, M. Gebhardt, G.P. Siegal, R.C. Shamberger, M. Bernstein, C. Schwartz, H. Berrey, and H.E. Grier. Pediatric Oncology Group, Chicago, IL.

Patients with metastatic osteosarcoma (MOS) at presentation have a long term survival of <30% (POG 9259). Most active agents in MOS produce tumor regression in only 20-30% of patients with MOS. More effective chemotherapy to treat MOS is needed. An MTD of 500mg/M2 of etoposide (VP), and 17.5gms/M2 of ifosfamide (IFOS) was determined in POG 9170 for relapsed MOS. The objective of this Phase II trial was to estimate the RR and define toxicity of VP, IFOS, and G-CSF in newly diagnosed MOS. The study was closed September 15, 1997 having reached its accrual goal. A total of 43 patients were registered. Two patients were ineligible; 2 were inevaluable and 39 were evaluable for response. Patients received infusions of 100mg/M2/day of VP over 1 hour followed by 3.5gr/M2/day of IFOS over 4 hours for 5 days total. G-CSF was began on day 6. This was repeated in 3 weeks. Response was determined at week 6. Eligibility included: age < 30 years, biopsy proven newly diagnosed, previously untreated MOS, and ECOG performance status < 2. Twenty-eight of 41 (68%) have metastatic sites only in the lung, and 12 (29%) have synchronous MOS with metastatic sites in other bones. Toxicity was evaluated in 41. The most serious toxicities are; grade 5 sepsis (death) in 1; grade 3 and 4 sepsis in 9; grade 3 and 4 infections (non-sepsis) in an additional 10. Two patients developed congestive heart failure (1 died). Grade 4 neutropenia occurred in 37 (90%) and Grade 4 thrombocytopenia in 24 (59%). Grade 3 FanconiÕs Syndrome developed in 5 and one additional patient had grade 4 FanconiÕs. Response information is available on 39 patients. Four had CRÕs; 19 PRÕs; 4 MRÕs; 10 NR; 2PD. The RR (CR+PR) is 56% + 8% (SE). The two year event free and overall survival for all patients is 44% +10% and 53 + 11%. Two year event free survival for the 12 patients with synchronous MOS is 54% (+ 21%). We conclude that the combination of VP and high dose IFOS are very effective induction treatment for high risk MOS, particularly for patients with synchronous bone disease, despite significant associated myelosuppression, sometimes complicated by infection, and renal toxicity requiring electrolyte replacement.