Phase I study of ch14.18 with granulocyte-macrophage colony-stimulating factor and interleukin-2 in children with neuroblastoma after autologous bone marrow transplantation or stem-cell rescue: a report from the Children's Oncology Group.

PURPOSE: Recurrence of high-risk neuroblastoma is common despite multimodality therapy. ch14.18, a chimeric human/murine anti-G(D2) antibody, lyses neuroblastoma cells. This study determined the maximum tolerable dose (MTD) and toxicity of ch14.18 given in combination with interleukin-2 (IL-2) after high-dose chemotherapy (HDC)/stem-cell rescue (SCR). Biologic correlates including ch14.18 levels, soluble IL-2 receptor levels, and human antichimeric antibody (HACA) activity were evaluated. PATIENTS AND METHODS: Patients were given ch14.18 for 4 days at 28-day intervals. Patients received IL-2 during the second and fourth courses of ch14.18 and granulocyte-macrophage colony-stimulating factor (GM-CSF) during the first, third, and fifth courses. The MTD was determined based on toxicities occurring with the second course. After the determination of the MTD, additional patients were treated to confirm the MTD and to clarify appropriate supportive care. RESULTS: Twenty-five patients were enrolled. The MTD of ch14.18 was determined to be 25 mg/m(2)/d for 4 days given concurrently with 4.5 x 10(6) U/m(2)/d of IL-2 for 4 days. IL-2 was also given at a dose of 3 x 10(6) U/m(2)/d for 4 days starting 1 week before ch14.18. Two patients experienced dose-limiting toxicity due to ch14.18 and IL-2. Common toxicities included pain, fever, nausea, emesis, diarrhea, urticaria, mild elevation of hepatic transaminases, capillary leak syndrome, and hypotension. No death attributable to toxicity of therapy occurred. No additional toxicity was seen when cis-retinoic acid (cis-RA) was given between courses of ch14.18. No patient treated at the MTD developed HACA. CONCLUSION: ch14.18 in combination with IL-2 was tolerable in the early post-HDC/SCR period. cis-RA can be administered safely between courses of ch14.18 and cytokines.

Molecular characterization of the pediatric preclinical testing panel.

PURPOSE: Identifying novel therapeutic agents for the treatment of childhood cancers requires preclinical models that recapitulate the molecular characteristics of their respective clinical histotypes. EXPERIMENTAL DESIGN AND RESULTS: Here, we have applied Affymetrix HG-U133Plus2 profiling to an expanded panel of models in the Pediatric Preclinical Testing Program. Profiling led to exclusion of two tumor lines that were of mouse origin and five osteosarcoma lines that did not cluster with human or xenograft osteosarcoma samples. We compared expression profiles of the remaining 87 models with profiles from 112 clinical samples representing the same histologies and show that model tumors cluster with the appropriate clinical histotype, once "immunosurveillance" genes (contributed by infiltrating immune cells in clinical samples) are eliminated from the analysis. Analysis of copy number alterations using the Affymetrix 100K single nucleotide polymorphism GeneChip showed that the models have similar copy number alterations to their clinical counterparts. Several consistent copy number changes not reported previously were found (e.g., gain at 22q11.21 that was observed in 5 of 7 glioblastoma samples, loss at 16q22.3 that was observed in 5 of 9 Ewing's sarcoma and 4 of 12 rhabdomyosarcoma models, and amplification of 21q22.3 that was observed in 5 of 7 osteosarcoma models). We then asked whether changes in copy number were reflected by coordinate changes in gene expression. We identified 493 copy number-altered genes that are nonrandom and appear to identify histotype-specific programs of genetic alterations. CONCLUSIONS: These data indicate that the preclinical models accurately recapitulate expression profiles and genetic alterations common to childhood cancer, supporting their value in drug development.

Favorable prognosis for patients 12 to 18 months of age with stage 4 nonamplified MYCN neuroblastoma: a Children's Cancer Group Study.

PURPOSE: The long-term survival of children between age 12 and 24 months with stage 4 neuroblastoma and nonamplified MYCN (MYCN-NA) has not been defined previously. PATIENTS AND METHODS: Survival for stage 4 MYCN-NA neuroblastoma patients enrolled onto Children's Cancer Group (CCG) protocols 321P2 (1986 to 1991) and 3891 (1991 to 1996) was analyzed. Treatment consisted of intensive alkylator-based induction chemotherapy with or without autologous bone marrow transplantation (ABMT) with or without 13 cis-retinoic acid. Survival was analyzed by age strata less than 12, 12 to 18, 18 to 24, and more than 24 months at diagnosis. Patients younger than 12 months were treated on the moderate-intensity CCG protocol 3881. RESULTS: Forty-three patients with stage 4 MYCN-NA disease enrolled onto CCG-321P2 (n = 17) or CCG-3891 (n = 26) were between 12 and 24 months of age at diagnosis. After a median follow-up of 94 months (range, 4 to 140 months), the 6-year event-free survival (EFS) for the 12- to 18-month age group was superior to that of the 18- to 24-month age group (74% +/- 8% v 31% +/- 12%; P = .008). The EFS for children older than 24 months with stage 4 MYCN-NA neuroblastoma was 23% +/- 3%, and for children younger than 12 months was 92% +/- 3%. CONCLUSION: Children diagnosed with stage 4 MYCN-NA neuroblastoma in the second year of life form a transitional group between infants and older children in terms of prognosis. Patients between 12 and 18 months of age have significantly better long-term survival than that of older children treated with intensive chemotherapy with or without ABMT. These patients may not benefit from additional intensification of therapy beyond that provided in earlier clinical trials and may even maintain this high survival rate with less intensive therapy.

Impact of radiotherapy for high-risk neuroblastoma: a Children's Cancer Group study.

PURPOSE: To assess the effect of local radiation administered to primary disease sites in children with high-risk neuroblastoma. MATERIALS AND METHODS: A total of 539 eligible patients were entered on protocol CCG-3891, consisting of chemotherapy, primary surgery, and 10 Gy of external beam radiation therapy (EBRT) to gross residual disease, followed by randomized assignment to continuation chemotherapy (CC) or autologous bone marrow transplantation (ABMT). ABMT patients received total body irradiation (TBI). RESULTS: Estimated event-free survival and overall survival at 5 years were 25% +/- 2% and 35% +/- 2%, respectively. Estimated 5-year locoregional recurrence rates were 51% +/- 5% and 33% +/- 7% for CC and ABMT patients (p = 0.004). For patients who received 10 Gy of EBRT to the primary, the addition of 10 Gy of TBI and ABMT decreased local recurrence compared with CC (22% +/- 12% and 52% +/- 8%, p = 0.022). EBRT did not increase acute toxicity, except for increased total parenteral nutrition administration. CONCLUSIONS: In combination with EBRT to the primary tumor site, the addition of 10 Gy of TBI as a component of high-dose chemotherapy with ABMT improved local control compared with CC without TBI. Results suggest a dose-response relationship for local EBRT. Short-term toxicity of local EBRT is limited.