How effective is dose-intensive/myeloablative therapy against Ewing's sarcoma/primitive neuroectodermal tumor metastatic to bone or bone marrow? The Memorial Sloan-Kettering experience and a literature review

Purpose: Attempts to improve outcomes of patients with Ewing's sarcoma/prim itive neuroectodermal tumor (ES/PNET) metastatic to bone/bone marrow (BM) h ave focused on chemotherapy dose intensification strategies, We now present results achieved with that approach, as carried out at Memorial Sloan-Kett ering Cancer Center (MSKCC) and as reported in the literature. Patients and Methods: Twenty-one unselected MSKCC patients with newly diagn osed ES/PNFT metastatic to bone/BM received the "P6" protocol which include s cycles of cyclaphosphamide (4.2 g/m(2))/doxorubicin (75 mg/m(2))/vincrist ine and cycles of ifosfamide (9 g/m(2))/etoposide (500 mg/m(2)), Patients i n complete/very good partial remission (CR/VGPR) after P6 received myeloabl ative therapy with either total-body irradiation (TBI) (hyperfractionated 1 5 Gy)/melphalan (180 mg/m(2)) or thiotepa (900 mg/m(2))/carboplatin (1,500 mg/m(2)). We reviewed the literature. Results: Only one MSKCC patient became a longterm event-free survivor; all but one relapse was in a distant site. Initial responses to P6 were CR/VGPR in 19 patients, but eight of them plus two others developed PD while recei ving or shortly after completing P6, Eight patients were treated with TBI/m elphalan: four relapsed 2 to 7 months after transplantation; two died early of toxicity; one died of pulmonary failure 17 months after transplantation (no evidence of ES/PNET); and one remains in CR at more than 7 years. The three patients treated with thiatepa/carbaplatin relapsed 3 to 4 months aft er transplantation. All reports on large series of unselected patients with ES/PNET metastatic to bone/BM showed similarly unsatisfactory results. Poo r outcome was seen with use of active agents for ES/PNET-cyclophosphamide, ifosfamide, doxarubicin, dactinamycin, vincristine, etoposide - at standard dosages for prolonged periods of time and at higher dosages in intensive r egimens for short or prolonged periods of time, No improvements in event-fr ee survival rates occurred with successive cooperative group or large singl e-institutional studies that used increasingly aggressive chemotherapeutic approaches. Inclusion of ifosfamide with or without etoposide made no diffe rence nor did consolidation of remission with myeloablative chemoradiothera py. Secondary leukemia emerged as a major risk with dose-intensive regimens . Conclusion: The MSKCC experience and findings reported in the literature su ggest that dose-intensive use of the chemotherapy agents with established a ctivity against ES/PNET is reaching its efficacy and toxicity limits, A maj or impact on prognosis awaits the development of entirely novel therapies. (C) 2001 by American Society of Clinical Oncology.