Intensive Multimodality Therapy for Extraocular Retinoblastoma: A Children's Oncology Group Trial (ARET0321)

PURPOSE Metastatic retinoblastoma has a poor prognosis when treated with conventional chemotherapy and radiation therapy (RT). Intensified therapy may improve the outcome. METHODS A prospective, international trial enrolled patients with extraocular retinoblastoma. Patients with stage II or III (locoregional) retinoblastoma received four cycles of chemotherapy, followed by involved field RT (45 Gy). Patients with stage IVa or IVb (metastatic or trilateral) retinoblastoma also received four cycles of chemotherapy and those with $ partial response then received one cycle of high-dose carboplatin, thiotepa, and etoposide with autologous hematopoietic stem-cell support. Patients with stage IVa or IVb with residual tumor postchemotherapy received RT. The proportion of patients who achieved event-free survival would be reported and compared with historical controls separately for each of the three groups of patients. RESULTS Fifty-seven eligible patients were included in the analyses. Event-free survival at 1 year was 88.1% (90% CI, 66.6 to 96.2) for stage II-III, 82.6% (90% CI, 61.0 to 92.9) for stage IVa, and 28.3% (90% CI, 12.7 to 46.2) for stage IVb/trilateral. Toxicity was significant as expected and included two therapy-related deaths. CONCLUSION Intensive multimodality therapy is highly effective for patients with regional extraocular retinoblastoma and stage IVa metastatic retinoblastoma. Although the study met its aim for stage IVb, more effective therapy is still required for patients with CNS involvement (ClinicalTrials.gov identifier: NCT00554788).Fil: Dunkel, Ira J.. Memorial Sloan Kettering Cancer Center; Estados UnidosFil: Piao, Jin. University of Southern California; Estados UnidosFil: Chantada, Guillermo Luis. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Banerjee, Anuradha. University of California San Francisco; Estados UnidosFil: Abouelnaga, Sherif. Children's Cancer Hospital; EgiptoFil: Buchsbaum, Jeffrey C.. National Cancer Institute; Estados UnidosFil: Merchant, Thomas E.. St. Jude Children's Research Hospital; Estados UnidosFil: Granger, Meaghan M.. Cook Children's Hospital; Estados UnidosFil: Jubran, Rima F.. Children's Hospital Los Angeles; Estados UnidosFil: Weinstein, Joanna L.. Ann & Robert H. Lurie Children's Hospital of Chicago; Estados UnidosFil: Saguilig, Lauren. Children's Oncology Group; Estados UnidosFil: Abramson, David H.. Memorial Sloan-kettering Cancer Center; Estados UnidosFil: Krailo, Mark D.. University of Southern California; Estados UnidosFil: Rodriguez Galindo, Carlos. St. Jude Children's Research Hospital; Estados UnidosFil: Chintagumpala, Murali M.. Texas Children's Hospital Houston; Estados Unido

Enrichment of Targetable Mutations in the Relapsed Neuroblastoma Genome - Fig 1

<p><b>Study cohort overview</b> A) Tabulation of Children’s Oncology Group (COG) risk classification and treatment time points of biopsy for 151 samples. (Intermed. = intermediate risk group) B) Number of samples taken at each treatment time point for nine patients with serial biopsies. (HR = high risk, IR = intermediate risk, LR = low risk at time of biopsy; further information in <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1006501#pgen.1006501.s003" target="_blank">S2 Table</a>) C) Tabulation of all variants identified (VUS: variants of unknown significance) D) Total number of variants identified per sample, stratified by COG risk group. Inset shows a similar calculation for suspected driver variants only. Heavy line represents the median of the data. “n” indicates the number of patients in each risk group. E) Total number of variants in each sample. Each bar represents an individual sample; color corresponds to risk group (red = high, blue = intermediate, green = low).</p

Genetic variants from a single patient at different treatment time points.

<p>Each biopsy was at a different anatomic site. Red denotes suspected driver variants; gray denotes variants of unknown significance. Letter preceding tumor location indicates primary (P) or metastatic (M) site. Number in parentheses indicates inferred allelic fraction for mutation calls, or inferred copy number for amplification or deletion calls. See <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1006501#pgen.1006501.s003" target="_blank">S2 Table</a> for additional details. Note that this patient was treated with crizotinib following the 5^th relapse.</p

Phase II Trial of Alisertib in Combination with Irinotecan and Temozolomide for Patients with Relapsed or Refractory Neuroblastoma

PurposeIn phase I testing, alisertib tablets with irinotecan and temozolomide showed significant antitumor activity in patients with neuroblastoma. This study sought to confirm activity of this regimen; evaluate an alisertib oral solution; and evaluate biomarkers of clinical outcomes.Patients and methodsWe conducted a two-stage phase II trial of alisertib tablets (60 mg/m2/dose × 7 days), irinotecan (50 mg/m2/dose i.v. × 5 days), and temozolomide (100 mg/m2/dose orally × 5 days) in patients with relapsed or refractory neuroblastoma. The primary endpoint was best objective response. A separate cohort was treated with alisertib at 45 mg/m2 using oral solution instead of tablets. Exploratory analyses sought to identify predictors of toxicity, response, and progression-free survival (PFS) using pooled data from phase I, phase II, and oral solution cohorts.ResultsTwenty and 12 eligible patients were treated in the phase II and oral solution cohorts, respectively. Hematologic toxicities were the most common adverse events. In phase II, partial responses were observed in 19 evaluable patients (21%). The estimated PFS at 1 year was 34%. In the oral solution cohort, 3 patients (25%) had first cycle dose-limiting toxicity (DLT). Alisertib oral solution at 45 mg/m2 had significantly higher median C max and exposure compared with tablets at 60 mg/m2. Higher alisertib trough concentration was associated with first cycle DLT, whereas MYCN amplification was associated with inferior PFS.ConclusionsThis combination shows antitumor activity, particularly in patients with MYCN nonamplified tumors. Data on an alisertib oral solution expand the population able to be treated with this agent