VERY-HIGH-DOSE SHORT-TERM CHEMOTHERAPY FOR POOR-RISK PERIPHERAL PRIMITIVE NEUROECTODERMAL TUMORS, INCLUDING EWINGS-SARCOMA, IN CHILDREN ANDYOUNG-ADULTS

Purpose: To improve the prognosis of patients with poor-risk periphera l primitive neuroectodermal tumors (pPNETs; including peripheral neuro epithelioma and Ewing's sarcoma), while testing the feasibility of int ensive use in adolescents and young adults of high-dose cyclophosphami de, doxorubicin, and vincristine (HD-CAV). Patients and Methods: This report concerns previously untreated patients with newly diagnosed pPN ET deemed poor-risk because of a tumor volume more than 100 cm(3) or m etastases to bone or bone marrow. The P6 protocol consists of seven co urses of chemotherapy. Courses 1, 2, 3, and 6 include 6-hour infusions of cyclophosphamide on days 1 and 2 for a total of 4,200 mg/m(2) per course (140 mg/kg per course for patients < 10 years old), plus 72-hou r infusions of doxorubicin 75 mg/m(2) and vincristine 2.0 mg/m(2) begi nning on day 1 (HD-CAV). Courses 4, 5, and 7 consist of 1-hour infusio ns of ifosfamide 1.8 g/m(2)/d and etoposide (VP-16) 100 mg/m(2)/d, for 5 days. Granulocyte colony-stimulating factor (G-CSF) and mesna are u sed. Courses start after neutrophil counts reach 500/mu L and platelet counts reach 100,000/uL. Surgical resection follows course 3 and radi otherapy follows completion of all chemotherapy. Results: Among the fi rst 36 consecutive assessable patients (median age, 17 years), HD-CAV achieved excellent histopathologic or clinical responses in 34 patient s and partial responses (PRs) in two patients. For 24 patients with lo coregional disease, the 2-year event-free survival rate was 77%; adver se events were two locoregional relapses, one distant relapse, and one secondary leukemia, All six patients with metastatic disease limited to lungs achieved a complete response (CR) and did not relapse; one is in remission 36+ months from diagnosis, but the other patients are no t assessable in terms of longterm efficacy of the P6 protocol because of short follow-up time (n = 3), additional systemic therapy (bone mar row transplantation), or septic death (autopsy showed no residual pPNE T). All six patients with widespread metastases had major responses, i ncluding eradication of extensive bone marrow involvement, but distant relapses ensued, Myelosuppression was severe, but most patients recei ved the first three courses of HD-CAV within 6 to 7 weeks. Major nonhe matologic toxicities were mucositis and peripheral neuropathy. Conclus ion: Excellent antitumor efficacy and manageable toxicity support the dose-intensive use of HD-CAV for pPNET in children, as well as in youn g adults. Consolidation of remissions of pPNET metastatic to bone and bone marrow remains a therapeutic challenge. (C) 1995 by American Soci ety of Clinical Oncology.