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BACKGROUND: New, effective chemotherapeutic agents are needed for intraocular retinoblastoma. METHODS: This institutional clinical trial sought to estimate the rate of response to 2 courses of vincristine and topotecan (VT) window therapy in patients with bilateral retinoblastoma and advanced disease (Reese-Ellsworth group IV or V) in at least 1 eye. The topotecan dose started at 3 mg/m2/day for 5 days and was adjusted to target a systemic exposure of 140 ± 20 ng/mL · hour. The vincristine dose was 0.05 mg/kg for patients 12 months of age at diagnosis. RESULTS: From February 2005 to June 2010, 27 patients received VT window therapy. Median age at enrollment was 8.1 months (range, 0.7-22.1 months). Twenty-four patients (88.9%) responded to window therapy (95% confidence interval = 71.3%-96.9%). Hematologic toxicity comprised grade 4 neutropenia (n = 27), grade 3 anemia (n = 19), and grade 3/4 thrombocytopenia (n = 16). Thirteen patients had grade 3 nonhematologic toxicity. Granulocyte colony-stimulating factor support was added after 10 patients had been treated, and it significantly reduced the duration of grade 4 neutropenia (median, 7 vs 24 days; P < .001). Pharmacokinetic studies showed rapid changes in topotecan clearance rates during the first year of life. CONCLUSIONS: The combination of topotecan and vincristine is effective for the treatment of advanced intraocular retinoblastoma. Granulocyte colony-stimulating factor treatment alleviates the duration of grade 4 neutropenia. Appropriate topotecan starting doses for patients 0-3, 3-6, 6-9, 9-12, and >12 months of age are specified. Cancer 2012. © 2012 American Cancer Society.

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 ≥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. Cancer 2007. © 2007 American Cancer Society.

Background. The most frequent second malignant neoplasm after retinoblastoma is osteosarcoma, which may be associated with radiation therapy or arise de novo in patients with bilateral retinoblastoma. Methods. Clinical, pathologic, and diagnostic imaging findings in two patients with Ewing sarcoma (ES) and one with peripheral neuroepithelioma (PN) are presented. Results. Second malignant neoplasms located in the extremities or pelvis were seen 12–18 years after initial diagnosis of unilateral (two patients) or bilateral (one patient) retinoblastoma. The patients with unilateral retinoblastoma were treated by enucleation only; the other received ocular radiation therapy and chemotherapy. To the knowledge of the authors, this is the first documentation of round blue cell tumor after unilateral retinoblastoma. Conclusions. ES and PN should be included in the differential diagnosis of malignant neoplasms occurring after treatment of unilateral or bilateral retinoblastoma.

BACKGROUND Medullomyoblastoma (MMB) is a rare cerebellar embryonal neoplasm that occurs almost exclusively in children. It is biphasic by microscopy, containing myoblastic and primitive neuroectodermal components. METHODS The authors conducted a retrospective review of the radiographic and pathologic characteristics, treatment, and clinical outcomes of six children with MMB who were treated at St. Jude Children's Research Hospital (Memphis, TN) between 1984 and 2003. Fluorescence in situ hybridization (FISH) data were available for four children. A literature review also was conducted and focused on imaging and pathologic findings. RESULTS The median age at diagnosis was 4.5 years (range, 0.83–7.5 years). Radiographically, all tumors were cerebellar and exhibited variable enhancement, and 50% of tumors had necrotic foci. Three tumors contained discrete, magnetic resonance imaging (MRI) T2-weighted–hypointense/computed tomography (CT)-hyperdense enhancing regions and separate hyperintense/hypodense nonenhancing regions, which correlated microscopically with geographic islands of primitive neuroectodermal and rhabdomyoblastic cells. Large cell/anaplastic (five tumors), nodular/desmoplastic (two tumors), and classic (two tumors) medulloblastoma histologies were encountered either alone (five tumors) or in combination with each other (two tumors). All 4 tumors that were tested exhibited alterations in chromosome 17 or c-myc amplification. All patients underwent macroscopic total resection and subsequently received chemotherapy and craniospinal (five patients) or local conformal (one patient) radiotherapy. At a median follow-up of 92 months (range, 23–187 months), 3 patients remain alive with no evidence of disease, 2 patients have died of disease, and 1 patient has died of secondary acute lymphocytic leukemia. CONCLUSIONS The results of the current study demonstrated the frequent correlation of biphasic nodularity (as determined by MRI or CT) with discrete rhabdomyoblastic and primitive neuroectodermal islands (as revealed by microscopy) in MMB. These results also support the view that MMB and medulloblastoma may have common tumorigenic origins, given their similar histologic and molecular features. Cancer 2004. © 2004 American Cancer Society.

BACKGROUND Brain metastases of pediatric germ cell tumors are uncommon, and there is limited information regarding their incidence, clinical presentation, response to treatment, and influence on survival. METHODS The authors reviewed the experience with brain metastases from pediatric germ cell tumors at St. Jude Children's Research Hospital (Memphis, TN) over a 40-year period. RESULTS Between March 1962 and February 2002, 16 of 206 patients with germ cell tumors (7.8%) had brain metastases at the time of initial presentation (n = 2), later in the course of the illness (n = 12), or at autopsy (n = 2). Twelve of 16 patients (75%) had symptoms referable to the brain (nausea/emesis, headaches, or seizures), and 14 (88%) had pulmonary metastases at the time brain metastases were identified. Patients with brain metastases were more likely to have an extragonadal primary tumor (P = 0.013), advanced-stage disease at initial presentation (P = 0.016), and choriocarcinoma within the primary tumor (P < 0.001). The incidence of brain metastases was significantly lower in the second 2 decades of the study period (5 of 135 patients [3.7%]) than in the first 2 decades (11 of 71 patients [15.5%]; P = 0.005). Two of the 16 patients in the current study are long-term survivors. CONCLUSIONS Brain metastases are uncommon in childhood germ cell tumors, and their incidence appears to be decreasing. In the current study, most patients with such metastases were symptomatic and had pulmonary metastases at the time brain metastases were identified. Patients with the highest risk of developing brain metastases include those with extragonadal tumors, those with high disease stage at initial presentation, and those with choriocarcinoma as a component of the primary tumor. The probability of survival is poor, although a small proportion of patients may become long-term survivors. Cancer 2004. © 2004 American Cancer Society.