Treatment of metastatic Ewing sarcoma/primitive neuroectodermal tumor of bone: evaluation of increasing the dose intensity of chemotherapy--a report from the Children's Oncology Group.

BACKGROUND: The outcome for patients with Ewing sarcoma family of tumors (ESFTs) of bone with metastases at diagnosis remains poor despite new approaches to treatment. We evaluated whether a dose-intensity chemotherapy regimen improved survival for patients with ESFTs of bone with metastases at diagnosis. METHODS: We entered 60 patients with metastatic ESFTs of bone onto a single arm trial of a new intensive therapy. Treatment consisted of 51-weeks of chemotherapy and local control of the primary with radiation, surgery, or both. The chemotherapeutic protocol included two alternating blocks: one with vincristine (2 mg/m(2)), doxorubicin (90 mg/m(2)), and cyclophosphamide (2,200 mg/m(2)); and the second with ifosfamide (2,800 mg/m(2)/day x 5 days) and etoposide (100 mg/m(2)/day x 5 days). RESULTS: Of the 60 patients with metastatic ESFTs of bone enrolled onto this single arm trial, 12 had metastasis to lung only, 7 to bone marrow or bone only, 38 to multiple sites, 2 in other sites and 3 not specified. There were three toxic deaths. Six patients (6-year cumulative incidence: 9%) developed second malignant neoplasms and died. The 6-year overall event-free survival (EFS) was 28% (standard error (SE) 6%) and survival (S) was 29% (SE 6%). CONCLUSION: An intensified treatment regimen using higher doses of cyclophosphamide, ifosfamide, and doxorubicin increased toxicity and risk of second malignancy without improving EFS and S.

Therapy-related myelodysplasia and acute myeloid leukemia after Ewing sarcoma and primitive neuroectodermal tumor of bone: A report from the Children's Oncology Group.

This study describes the magnitude of risk of therapy-related myelodysplasia and acute myeloid leukemia (t-MDS/AML) in 578 individuals diagnosed with Ewing sarcoma and enrolled on Children's Oncology Group therapeutic protocol, INT-0091. Between 1988 and 1992, patients with or without metastatic disease were randomized to receive doxorubicin, vincristine, cyclophosphamide, and dactinomycin (regimen A) or these 4 drugs alternating with etoposide and ifosfamide (regimen B). Between 1992 and 1994, patients with metastatic disease were nonrandomly assigned to receive high-intensity therapy (regimen C: regimen B therapy with higher doses of doxorubicin, cyclophosphamide, and ifosfamide). Median age at diagnosis of Ewing sarcoma was 12 years, and median length of follow-up, 8 years. Eleven patients developed t-MDS/AML, resulting in a cumulative incidence of 2% at 5 years. While patients treated on regimens A and B were at a low risk for development of t-MDS/AML (cumulative incidence: 0.4% and 0.9% at 5 years, respectively), patients treated on regimen C were at a 16-fold increased risk of developing t-MDS/AML (cumulative incidence: 11% at 5 years), when compared with those treated on regimen A. Increasing exposure to ifosfamide from 90 to 140 g/m2, cyclophosphamide from 9.6 to 17.6 g/m2, and doxorubicin from 375 to 450 mg/m2 increased the risk of t-MDS/AML significantly.

Treatment of metastatic Ewing's sarcoma or primitive neuroectodermal tumor of bone: evaluation of combination ifosfamide and etoposide--a Children's Cancer Group and Pediatric Oncology Group study.

PURPOSE: One hundred twenty patients with metastatic Ewing's sarcoma or primitive neuroectodermal tumor (PNET) of bone were entered onto a randomized trial evaluating whether the addition of ifosfamide and etoposide to vincristine, doxorubicin, cyclophosphamide, and dactinomycin improved outcomes. METHODS: Thirty-two patients had metastases to lungs only, 12 patients had metastases to bone marrow or bones only, 64 patients had metastases in multiple sites, and five patients had metastases in other sites; seven patients could not be assessed precisely. Treatment comprised 9 weeks of chemotherapy before local control and 42 weeks of chemotherapy; thereafter, regimen A consisted of vincristine 2 mg/m(2), cyclophosphamide 1,200 mg/m(2), and either doxorubicin 75 mg/m(2) or dactinomycin 1.25 mg/m(2). Regimen B consisted of regimen A alternating every 3 weeks with ifosfamide 1,800 mg/m(2)/d for 5 days and etoposide 100 mg/m(2)/d for 5 days. RESULTS: Patients treated on regimen B did not have significantly better survival than those treated on regimen A. The event-free survival (EFS) and survival (S) at 8 years were 20% (SE, 5%) and 32% (SE, 6%), respectively, for those treated on regimen A and 20% (SE, 6%) and 29% (SE, 6%), respectively, for those treated on regimen B. Patients who had only lung metastases had EFS and S of 32% (SE, 8%) and 41% (SE, 9%), respectively, at 8 years. There were six toxic deaths (5%), four from cardiac toxicity and two from sepsis (four treated on regimen B and two treated on regimen A). Two had second malignant neoplasms. CONCLUSION: Adding ifosfamide and etoposide to standard therapy does not improve outcomes of patients with Ewing's sarcoma or PNET of bone with metastases at diagnosis.

Phase I trial of rebeccamycin analog (NSC #655649) in children with refractory solid tumors: a pediatric oncology group study.

PURPOSE: To conduct a phase 1 trial of rebeccamycin analog (NSC #655649) in children with solid tumors to establish the dose-limiting toxicity (DLT) and maximum-tolerated dose (MTD); to establish the pharmacokinetic profile in children, and to document any evidence of antitumor activity. METHODS: A 1-hour infusion of NSC #655649 was administered every 21 days to 17 patients younger than 21 years who had malignant tumors refractory to conventional therapy. Doses ranged from 450 mg/m2 to 760 mg/m2. Pharmacokinetics were done in at least three patients per dose level. The first course was used to determine DLT and MTD. RESULTS: Sixteen patients on three dose levels were assessable for toxicities. At 760 mg/m2, four patients had dose-limiting neutropenia and thrombocytopenia. Pharmacokinetics were assessable in 13 patients. Plasma concentrations declined triexponentially and concentrations above the range of in vitro antitumor activity were maintained for 3 days. Analysis of urine extracts revealed the presence of an N-de-ethylated metabolite and probable involvement of cytochrome P450 isoenzyme(s) in the metabolism of NSC #655649. Pharmacodynamic studies showed a relationship between the area under the curve and percentage change in absolute neutrophil count in the E(max) model (r2 = 0.56, P = 0.001). CONCLUSIONS: The recommended phase 2 dose of NSC #655649 administered as a 1-hour infusion every 21 days to children with solid tumors is 585 mg/m2. Both neutropenia and thrombocytopenia were found to be dose-limiting toxicities.

Phase 1 study of Paclitaxel administered twice weekly to children with refractory solid tumors: a pediatric oncology group study.

PURPOSE: To perform a phase 1 trial to determine the maximum tolerated dose and the dose-limiting toxicities of paclitaxel in children with refractory or recurrent solid tumors. Paclitaxel was administered twice weekly, increasing from four to six doses every 21 to 28 days. METHODS: Paclitaxel was administered as a 3-hour intravenous infusion twice weekly. The initial dose was fixed at 50 mg/m2/dose twice weekly for 2 weeks (four doses), every 21 days. The number of twice-weekly doses per course was increased to six in the next cohort. In subsequent cohorts, the number of twice-weekly doses per course was fixed at six, every 28 days, and dosage was increased in 25% increments. RESULTS: Sixteen assessable patients were enrolled at three levels. Neutropenia was the dose-limiting toxicity at 65 mg/m2/dose, twice weekly x 6 doses, every 28 days. Nonhematologic toxicities were minor. No antitumor responses were observed. CONCLUSIONS: Protracted twice-weekly dosing of paclitaxel is limited by neutropenia. The maximum tolerated dose of paclitaxel administered twice weekly x 6 doses, every 28 days, was 50 mg/m2/dose.

Addition of ifosfamide and etoposide to standard chemotherapy for Ewing's sarcoma and primitive neuroectodermal tumor of bone.

BACKGROUND: Ewing's sarcoma and primitive neuroectodermal tumor of bone are closely related, highly malignant tumors of children, adolescents, and young adults. A new drug combination, ifosfamide and etoposide, was highly effective in patients with Ewing's sarcoma or primitive neuroectodermal tumor of bone who had a relapse after standard therapy. We designed a study to test whether the addition of these drugs to a standard regimen would improve the survival of patients with newly diagnosed disease. METHODS: Patients 30 years old or younger with Ewing's sarcoma, primitive neuroectodermal tumor of bone, or primitive sarcoma of bone were eligible. The patients were randomly assigned to receive 49 weeks of standard chemotherapy with doxorubicin, vincristine, cyclophosphamide, and dactinomycin or experimental therapy with these four drugs alternating with courses of ifosfamide and etoposide. RESULTS: A total of 518 patients met the eligibility requirements. Of 120 patients with metastatic disease, 62 were randomly assigned to the standard-therapy group and 58 to the experimental-therapy group. There was no significant difference in five-year event-free survival between the treatment groups (P=0.81). Among the 398 patients with nonmetastatic disease, the mean (+/-SE) five-year event-free survival among the 198 patients in the experimental-therapy group was 69+/-3 percent, as compared with 54+/-4 percent among the 200 patients in the standard-therapy group (P=0.005). Overall survival was also significantly better among patients in the experimental-therapy group (72+/-3.4 percent vs. 61+/-3.6 percent in the standard-therapy group, P=0.01). CONCLUSIONS: The addition of ifosfamide and etoposide to a standard regimen does not affect the outcome for patients with metastatic disease, but it significantly improves the outcome for patients with nonmetastatic Ewing's sarcoma, primitive neuroectodermal tumor of bone, or primitive sarcoma of bone.

Protracted intermittent schedule of topotecan in children with refractory acute leukemia: a pediatric oncology group study.

PURPOSE: To determine dose-limiting toxicity (DLT) and maximum-tolerated dose (MTD) of a protracted, intermittent schedule of daily 30-minute infusions of topotecan (TPT) for up to 12 consecutive days, every 3 weeks, in children with refractory leukemia. PATIENTS AND METHODS: Forty-nine children were enrolled onto this phase I trial (24 with acute nonlymphoblastic leukemia [ANLL] and 25 with acute lymphoblastic leukemia [ALL]). TPT dosage was escalated from 2.0 to 5.2 mg/m(2)/d for 5 days and 2.4 mg/m(2)/d from 7 days to the same dose for 9 and 12 days in cohorts of three to six patients when no DLT was identified. TPT pharmacokinetics were studied in 33 children once or twice (first and last doses in patients who received TPT for > 7 days). RESULTS: Seventy assessable courses of TPT were administered to 49 children who had refractory leukemia. DLTs were typhlitis, diarrhea, and mucositis, and the MTD was 2.4 mg/m(2)/d for 9 days in this group of heavily pretreated children. In 33 patients, the median TPT lactone clearance after the first dose was 19.2 L/h/m(2) (range, 9.4 to 45.9 L/h/m(2)) and did not change during the course. There were significant responses (one complete response [CR] and four partial responses [PR] in patients with ANLL and one CR and two PRs in patients with ALL), and all but one were at dosages of TPT given for at least 9 days. CONCLUSION: The MTD was 2.4 mg/m(2)/d for 9 days. Further testing is warranted of TPT's schedule dependence in children with leukemia.