Local Control For High-Grade Nonrhabdomyosarcoma Soft Tissue Sarcoma Assigned to Radiation Therapy on ARST0332: A Report From the Childrens Oncology Group.

PURPOSE: The ARST0332 trial for pediatric and young adults with nonrhabdomyosarcoma soft tissue sarcoma (NRSTS) used risk-based treatment including primary resection with lower-than-standard radiation doses to optimize local control (LC) while minimizing long-term toxicity in those requiring radiation therapy (RT). RT for high-grade NRSTS was based on extent of resection (R0: negative margins, R1: microscopic margins, R2/U: gross disease/unresectable); those with >5 cm tumors received chemotherapy (CT; ifosfamide/doxorubicin). This analysis evaluates LC for patients assigned to RT and prognostic factors associated with local recurrence (LR). METHODS AND MATERIALS: Patients aged <30 years with high-grade NRSTS received RT (55.8 Gy) for R1 ≤5 cm tumor (arm B); RT (55.8 Gy)/CT for R0/R1 >5 cm tumor (arm C); or neoadjuvant RT (45 Gy)/CT plus delayed surgery, CT, and postoperative boost to 10.8 Gy R0 <5 mm margins/R1 or 19.8 Gy for R2/unresected tumors (arm D). RESULTS: One hundred ninety-three eligible patients had 24 LRs (arm B 1/15 [6.7%], arm C 7/65 [10.8%], arm D 16/113 [14.2%]) at median time to LR of 1.1 years (range, 0.11-5.27). Of 95 eligible for delayed surgery after neoadjuvant therapy, 89 (93.7%) achieved R0/R1 margins. Overall LC after RT were as follows: R0, 106 of 109 (97%); R1, 51 of 60 (85%); and R2/unresectable, 2 of 6 (33%). LR predictors include extent of delayed resection (P <.001), imaging response before delayed surgery (P < .001), histologic subtype (P <.001), and no RT (P = .046). The 5-year event-free survival was significantly lower (P = .0003) for patients unable to undergo R0/R1 resection. CONCLUSIONS: Risk-based treatment for young patients with high-grade NRSTS treated on ARST0332 produced very high LC, particularly after R0 resection (97%), despite lower-than-standard RT doses. Neoadjuvant CT/RT enabled delayed R0/R1 resection in most patients and is preferred over adjuvant therapy due to the lower RT dose delivered.

A phase II study of the farnesyl transferase inhibitor, tipifarnib, in children with recurrent or progressive high-grade glioma, medulloblastoma/primitive neuroectodermal tumor, or brainstem glioma: a Children's Oncology Group study.

BACKGROUND: An open-label Phase II study of tipifarnib was conducted to evaluate its safety and efficacy in children with recurrent or refractory medulloblastoma (MB)/primitive neuroectodermal tumor (PNET), high-grade glioma (HGG), and diffuse intrinsic brainstem glioma (BSG). METHODS: Between January 2004 and July 2005, patients were enrolled and stratified as follows: Stratum 1, recurrent or refractory MB/PNET; Stratum 2, recurrent or refractory HGG; and Stratum 3, recurrent or refractory BSG. Patients received tipifarnib 200 mg/m2 per dose twice daily for 21 days repeated every 28 days. Patients who received enzyme-inducing anticonvulsants and other CYP3A4/5 inducers or inhibitors were excluded. The primary objective was to estimate the sustained response rate in all strata. RESULTS: Ninety-seven patients with a median age of 11.2 years (range, 3.2-21.9 years) were enrolled on the study, and 81 patients were evaluable for response. One of 35 patients with BSG and 1 of 31 patients with HGG had a sustained partial response. No responses were observed in 15 patients with MB/PNET. Eight patients (3 HGG, 1 MB, and 4 BSG) remained stable for >or=4 courses (range, 4-25 courses). The median number of courses received was 2 (range, 1-25 courses). The most frequent grade 3 and 4 toxicities included neutropenia (18.7%), thrombocytopenia (14.3%), and leukopenia (14.3%). The 6-month progression-free survival rate (+/-standard deviation) was 14%+/-6% for HGG, 6%+/-6% for MB/PNET and 3%+/-3% for BSG. CONCLUSIONS: Tipifarnib tolerated well but had little activity as a single agent in children with recurrent central nervous system malignancies.

Phase I and pharmacokinetic study of gefitinib in children with refractory solid tumors: a Children's Oncology Group Study.

PURPOSE: Epidermal growth factor receptor is expressed in pediatric malignant solid tumors. We conducted a phase I trial of gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, in children with refractory solid tumors. PATIENTS AND METHODS: Gefitinib (150, 300, 400, or 500 mg/m2) was administered orally to cohorts of three to six patients once daily continuously until disease progression or significant toxicity. Pharmacokinetic studies were performed during course one (day 1 through 28). RESULTS: Of the 25 enrolled patients, 19 (median age, 15 years) were fully evaluable for toxicity and received 54 courses. Dose-limiting toxicity was rash in two patients treated with 500 mg/m2 and elevated ALT and AST in one patient treated with 400 mg/m2. The maximum-tolerated dose was 400 mg/m2/d. The most frequent non-dose-limiting toxicities were grade 1 or 2 dry skin, anemia, diarrhea, nausea, and vomiting. One patient with Ewing's sarcoma had a partial response. Disease stabilized for 8 to > or = 60 weeks in two patients with Wilms' tumor and two with brainstem glioma (one exophytic). At 400 mg/m2, the median peak gefitinib plasma concentration was 2.2 microg/mL (range, 1.2 to 3.6 microg/mL) and occurred at a median of 2.3 hours (range, 2.0 to 8.3 hours) after drug administration. The median apparent clearance and median half-life were 14.8 L/h/m2 (range, 3.8 to 24.8 L/h/m2) and 11.7 hours (range, 5.6 to 22.8 hours), respectively. Gefitinib systemic exposures were comparable with those associated with antitumor activity in adults. CONCLUSION: Oral gefitinib is well tolerated in children. Development of the drug in combination with cytotoxic chemotherapy will be pursued.