Phase I trial of intrathecal liposomal cytarabine in children with neoplastic meningitis.

PURPOSE: We performed a phase I trial of intrathecal (IT) liposomal cytarabine (DepoCyt; Enzon Pharmaceuticals, Piscataway, NJ and SkyePharma Inc, San Diego, CA) to determine the maximum-tolerated dose, the dose-limiting toxicities, and the plasma and CSF pharmacokinetics of IT lipsomal cytarabine in children >/= 3 years of age with advanced meningeal malignancies. PATIENTS AND METHODS: Eighteen assessable patients received IT liposomal cytarabine through either an indwelling ventricular access device or via lumbar puncture. Liposomal cytarabine was given once every 2 weeks during induction, once every 4 weeks during consolidation, and once every 8 weeks during the maintenance phase of treatment. The initial dose was 25 mg, with subsequent escalations to 35 and 50 mg. CSF pharmacokinetic samples were obtained in a subset of patients. RESULTS: Arachnoiditis, characterized by fever, headache, nausea, vomiting, and back pain was noted in the first two patients at the 25 mg dose level. Therefore, subsequent patients were treated with dexamethasone, beginning the day of liposomal cytarabine administration and continuing for 5 days. Headache (grade 3) was dose limiting in two of eight patients enrolled at the 50 mg dose level. Eight of the 14 patients assessable for response demonstrated evidence of benefit manifest as prolonged disease stabilization or response. CONCLUSION: The maximum-tolerated dose and recommended phase II dose of liposomal cytarabine in patients between the ages of 3 and 21 years is 35 mg, administered with dexamethasone (0.15 mg/kg/dose, twice a day for 5 days). A phase II trial of IT liposomal cytarabine in children with CNS leukemia in second or higher relapse is in development.

Deaths attributed to pediatric complex chronic conditions: national trends and implications for supportive care services.

BACKGROUND: Children with complex chronic conditions (CCCs) might benefit from pediatric supportive care services, such as home nursing, palliative care, or hospice, especially those children whose conditions are severe enough to cause death. We do not know, however, the extent of this population or how it is changing over time. OBJECTIVES: To identify trends over the past 2 decades in the pattern of deaths attributable to pediatric CCCs, examining counts and rates of CCC-attributed deaths by cause and age (infancy: <1 year old, childhood: 1-9 years old, adolescence or young adulthood: 10-24 years old) at the time of death, and to determine the average number of children living within the last 6 months of their lives. DESIGN/METHODS: We conducted a retrospective cohort study using national death certificate data and census estimates from the National Center for Health Statistics. Participants included all people 0 to 24 years old in the United States from 1979 to 1997. CCCs comprised a broad array of International Classification of Diseases, Ninth Revision codes for cardiac, malignancy, neuromuscular, respiratory, renal, gastrointestinal, immunodeficiency, metabolic, genetic, and other congenital anomalies. Trends of counts and rates were tested using negative binomial regression. RESULTS: Of the 1.75 million deaths that occurred in 0- to 24-year-olds from 1979 to 1997, 5% were attributed to cancer CCCs, 16% to noncancer CCCs, 43% to injuries, and 37% to all other causes of death. Overall, both counts and rates of CCC-attributed deaths have trended downward, with declines more pronounced and statistically significant for noncancer CCCs among infants and children, and for cancer CCCs among children, adolescents, and young adults. In 1997, deaths attributed to all CCCs accounted for 7242 infant deaths, 2835 childhood deaths, and 5109 adolescent deaths. Again, in 1997, the average numbers of children alive who would die because of a CCC within the ensuing 6-month period were 1097 infants, 1414 children, and 2548 adolescents or young adults. CONCLUSIONS: Population-based planning of pediatric supportive care services should use measures that best inform our need to provide care for time-limited events (perideath or bereavement care) versus care for ongoing needs (home nursing or hospice). Pediatric supportive care services will need to serve patients with a broad range of CCCs from infancy into adulthood.

O6-Methylguanine-DNA methyltransferase in pediatric primary brain tumors: relation to patient and tumor characteristics.

The DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) confers resistance to methylating and chloroethylating agents in pediatric medulloblastoma- and glioma-derived cell lines and xenografts. Here, we assayed MGMT activity in 110 pediatric brain tumors to establish correlates with patient and tumor characteristics. We also assayed MGMT in histologically normal brain adjacent to 22 tumors to characterize changes in activity accompanying neurocarcinogenesis. MGMT activity was detected in 94% of tumors, ranging ca. 1,500-fold from 0.34 to 498 fmol/10(6) cells (approximately 205-300,000 molecules/cell). Mean activity was 25 +/- 66 fmol/10(6) cells, including six specimens with undetectable activity (Mer- phenotype; <0.25 fmol/10(6) cells or 151 molecules/cell). MGMT content varied 10-fold among diagnostic groups and was associated with degree of malignancy, as evidenced by a 4-fold difference in activity between high- and low-grade tumors (P = 0.03). Tumor MGMT content was age dependent, being 5-fold higher in children 3-12 years old than in infants (P = 0.015) and adolescents (P = 0.015). Mean activity in tumors was 9-fold higher than in adjacent histologically normal brain (21 +/- 44 versus 2.4 +/- 4.0 fmol/10(6) cells; P = 0.05). By comparing tumor and adjacent normal tissue from the same patient, we found that 68% of cases exhibited an elevation of tumor activity that ranged from 2- to >590-fold. Moreover, 67% of Mer- normal tissue was accompanied by Mer+ tumor. These observations indicate that MGMT activity is frequently elevated during pediatric neurocarcinogenesis. Significantly, enhanced MGMT activity may heighten resistance to alkylating agents, suggesting a potential role for MGMT inhibitors in therapy.

Computed tomography in the evaluation of febrile neutropenic pediatric oncology patients.

AIM: To evaluate the diagnostic utility of computed tomography (CT) obtained during prolonged febrile neutropenia in pediatric oncology patients. METHODS: We evaluated the medical records of all patients with a malignant disease who had a CT examination during an episode of febrile neutropenia lasting for 4 days or more at Children's Hospital and Regional Medical Center in Seattle, WA, between January 1, 1997, and June 1, 1999. RESULTS: CT was performed on 83 patients to evaluate 109 episodes of prolonged febrile neutropenia. Sixty-eight (62%) of the initial CT scans demonstrated abnormalities, leading to changes in therapy in 42 (39%). The diagnostic and therapeutic utility of CT varied by anatomic site. Abdominal and head/neck CT detected abnormalities in only 19 and 8% of studies, respectively, resulting in therapy changes in 9 and 4%, respectively. Sinus CT demonstrated abnormalities in 41% of cases and altered therapy in 24%. Chest CT had the highest diagnostic utility, with 49% of cases demonstrating abnormalities, leading to therapy alteration in 30%. CT was rarely abnormal in the absence of localizing signs or symptoms. In 55 instances 1 or more follow-up scans were done. Thirteen follow-up CT scans showed abnormalities that led to a change in therapy. CONCLUSIONS: CT-detected abnormalities frequently lead to alterations in therapy, particularly sinus and thoracic CT. Most patients with CT-detected abnormalities have symptoms or signs referable to the site of abnormality. Asymptomatic febrile neutropenic children rarely have CT findings that lead to a change in therapy.

Neonatal brain tumors: a review.

This article presents two cases of infants with brain tumors and reviews the literature pertinent to congenital and neonatal brain tumors. Information regarding epidemiology, presentation, prognosis, and clinical management are also addressed with specific regard to differences between neonatal and childhood brain tumors. An appeal is made to consider (1) coordination of the care of these children through pediatric multidisciplinary neuro-oncology programs; (2) enrollment, whenever possible, in clinical trials; and (3) submission of available tumor tissue to pediatric tumor banks to assure its availability to interested researchers.

Lipid association increases the potency against primary medulloblastoma cells and systemic exposure of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) in rats.

PURPOSE: To reduce the systemic toxicity and prolong the systemic presence of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU), a lipid-based drug carrier was designed and characterized. METHODS: The degree of CCNU association with lipid vesicles composed of 1, 2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and 1,2-dimyristoyl-sn-glycero-3-phosphoglycerol (DMPG) (1:1, m/m) was characterized and the drug decomposition rates of lipid-drug complexes were monitored. Effects of lipid association on drug potency against medulloblastoma cells and total systemic drug exposure in rats were determined. RESULTS: At a CCNU:lipid molar ratio greater than 1:5, more than 90% of the drug was associated with the lipid vesicles. In aqueous suspensions, lipid association significantly reduced the first-order drug decomposition rate. In addition, lipid-associated CCNU exhibited a 4-fold increase in drug sensitivity with medulloblastoma cells. IC50 values for CCNU admixed and encapsulated with lipid vesicles were 18+/-4.9 and 14.0+/-2.2 microM, respectively, compared to 83+/-11.0 microM for free CCNU. When administered to rats, lipid-associated CCNU increased the AUC (area under the concentration-time curve) of CCNU by approximately 2-fold (20.46+/-2.15 compared to 39.59+/-1.87 microg x min/ml), and the terminal half-life (t1/2beta) by almost 9-fold (17+/-9 compared to 147+/-48 min) over free CCNU. Despite the increase in total systemic drug exposure, rats treated with lipid-associated CCNU exhibited a significantly lower frequency of acute neurotoxicity. CONCLUSIONS: These data indicate that CCNU associated with lipid vesicles may increase drug stability, potency, and systemic exposure in rats.

Metastasis stage, adjuvant treatment, and residual tumor are prognostic factors for medulloblastoma in children: conclusions from the Children's Cancer Group 921 randomized phase III study.

PURPOSE: From 1986 to 1992, "eight-drugs-in-one-day" (8-in-1) chemotherapy both before and after radiation therapy (XRT) (54 Gy tumor/36 Gy neuraxis) was compared with vincristine, lomustine (CCNU), and prednisone (VCP) after XRT in children with untreated, high-stage medulloblastoma (MB). PATIENTS AND METHODS: Two hundred three eligible patients with an institutional diagnosis of MB were stratified by local invasion and metastatic stage (Chang T/M) and randomized to therapy. Median time at risk from study entry was 7.0 years. RESULTS: Survival and progression-free survival (PFS) +/- SE at 7 years were 55%+/-5% and 54%+/-5%, respectively. VCP was superior to 8-in-1 chemotherapy, with 5-year PFS rates of 63%+/-5% versus 45%+/-5%, respectively (P = .006). Upon central neuropathology review, 188 patients were confirmed as having MB and were the subjects for analyses of prognostic factors. Children aged 1.5 to younger than 3 years had inferior 5-year estimates of PFS, compared with children 3 years old or older (P = .0014; 32%+/-10% v 58%+/-4%, respectively). For MB patients 3 years of age or older, the prognostic effect of tumor spread (MO v M1 v M2+) on PFS was powerful (P = .0006); 5-year PFS rates were 70%+/-5%, 57%+/-10%, and 40%+/-8%, respectively. PFS distributions at 5 years for patients with M0 tumors with less than 1.5 cm2 of residual tumor, versus > or = 1.5 cm2 of residual tumor by scan, were significantly different (P = .023; 78%+/-6% v 54%+/-11%, respectively). CONCLUSION: VCP plus XRT is a superior adjuvant combination compared with 8-in-1 chemotherapy plus XRT. For patients with M0 tumors, residual tumor bulk (not extent of resection) is a predictor for PFS. Patients with M0 tumors, > or = 3 years with < or = 1.5 cm2 residual tumor, had a 78%+/-6% 5-year PFS rate. Children younger than 3 years old who received a reduced XRT dosage had the lowest survival rate.

Predicting disease progression in childhood cerebellar astrocytoma.

Pediatric cerebellar astrocytomas are frequently curable by complete surgical resection. However, even incompletely resected tumors may lie dormant indefinitely or spontaneously involute, and tumors thought to be completely excised have reappeared in the same location several years later. Because of the unpredictable nature of some cerebellar astrocytomas, this study was designed to analyze several variables for their potential value in predicting disease progression. The charts of 78 children treated at a children's hospital between 1966 and 1993 were reviewed; 62 tumors were pilocytic, 13 were fibrillary, and 3 were mixed oligoastrocytomas. Four children had the additional diagnosis of neurofibromatosis type 1, and those children were considered separately. Of the remaining 74 children, 48 underwent postoperative contrast-enhanced computerized tomography or magnetic resonance imaging. Of those 48 children, 17 had residual disease, and in 15 cases the tumor volume could be measured. Frequently the surgeon's report conflicted with the postoperative scan regarding the presence of residual disease. However, the surgeon's report of brainstem infiltration correlated highly with residual disease on postoperative imaging. On univariate Cox analysis, sex, age, tumor location, and tumor morphology did not show prognostic significance. In spite of their differences, the surgeon's report of residual tumor and the presence of residual disease on postoperative imaging were similar in their correlation with disease progression. However, on multivariate analysis, the volume of residual tumor was most closely linked with disease progression. Only the presence of fibrillary histology significantly complemented the volume of residual tumor as a negative prognostic indicator.

Salvage therapy after postoperative chemotherapy for primary brain tumors in infants and very young children.

BACKGROUND: A trend toward the use of prolonged postoperative chemotherapy, with radiotherapy deferred until relapse, has emerged for very young children with malignant brain tumors. This study was undertaken to determine the failure patterns among infants who receive such treatment and to evaluate their responses to first salvage therapy, particularly radiotherapy, after postoperative chemotherapy. METHODS: A retrospective cohort was assembled, which comprised all children younger than 36 months with biopsy-proven malignant brain tumors diagnosed during the years 1987-1993 at 3 pediatric oncology referral centers. Fifty-eight children were treated with postoperative chemotherapy without irradiation, 40 of whom experienced relapse of their malignancy. These patients' charts were reviewed for failure patterns. Thirty-five of these children received salvage therapy. Statistical and survival analysis with the Cox proportional hazards regression model was performed. RESULTS: Among the 40 children who experienced relapse, 30 of 31 (97%) with solitary disease at initial diagnosis relapsed at the primary site of disease. Thirty-seven of 39 infants (95%) developed relapse that included their primary site of disease. Sixty percent of relapses were asymptomatic and were detected by magnetic resonance imaging (MRI) surveillance rather than by clinical examination. Two-year progression free survival (PFS) after relapse for infants who received salvage therapy was 29% (standard error [SE] = 8%). For infants who received radiotherapy alone, the 2-year PFS was 21% (SE = 9%). PFS did not differ according to whether relapses were detected clinically or radiographically or treated by radiotherapy, chemotherapy, surgery, or multimodal therapy. CONCLUSIONS: Relapse of brain tumors in infants after prolonged postoperative chemotherapy is largely a problem of local disease control. Salvage is possible after prolonged postoperative chemotherapy, but it yields few instances of long term, progression free survival. No therapeutic modality is superior for salvage at relapse. A strategy of reserving radiotherapy for the salvage of infants whose brain tumors relapse during postoperative chemotherapy demonstrated only limited effectiveness.

Survival and prognostic factors following radiation therapy and chemotherapy for ependymomas in children: a report of the Children's Cancer Group.

OBJECT: Ependymomas in children continue to generate controversy regarding their histological diagnosis and grading. optimal management, and possible prognostic factors. To increase our knowledge of these tumors the authors addressed these issues in a cohort of children with prospectively staged ependymomas treated with radiotherapy and chemotherapy. METHODS: Children between the ages of 2 and 17.3 years harboring an intracranial ependymoma confirmed by a central review of the tumor's pathological characteristics were treated according to Children's Cancer Group Protocol 921 from 1986 to 1992. Treatment following surgery and postoperative tumor staging (including brain computerized tomography or magnetic resonance [MR] imaging, spinal MR imaging or myelography, and cerebrospinal fluid cytological investigation) included craniospinal irradiation with a local boost to the primary tumor and patient randomization to receive adjuvant chemotherapy with either 1) CCNU, vincristine, and prednisone, or 2) the eight-drugs-in-1-day regimen. Centralized review of the tumor pathological characteristics revealed 20 ependymomas and 12 anaplastic ependymomas in the 32 children included in the study. Diagnoses made at the individual institutions included anaplastic (malignant) ependymoma (15 patients), ependymoma (four patients), ependymoblastoma (nine patients), ependymoastrocytoma (one patient), and primitive neuroectodermal tumor (three patients), which were discordant with the centralized review diagnosis in 22 of 32 cases. Only three of the 32 patients had metastatic disease (two with M and one with M3 stages). At surgery, 47% of tumors were estimated to be totally resected. Among the 14 of 17 patients who suffered a relapse and were evaluated for site of relapse, 10 (71%) had an isolated local relapse, three (21%) had concurrent local and metastatic relapse, and only one (7%) had an isolated metastatic relapse. Kaplan-Meier estimates of 5-year progression-free survival (PFS) and overall survival rates were 50 +/- 10% and 64 +/- 9%, respectively. CONCLUSIONS: Predictors of PFS duration included an estimate of the extent of resection made at surgery (total compared with less than total, p = 0.0001) and the amount of residual tumor on postoperative imaging as verified by centralized radiological review (< or = 1.5 cm2 compared with > 1.5 cm2, p < 0.0001). No other factors, including centrally reviewed tumor histopathological type, location, metastasis and tumor (M and T) stages, patient age, race, gender, or chemotherapy treatment regimen significantly correlated with PFS duration. The pattern of predominantly local relapse and the important influence of residual tumor or the extent of resection on PFS duration confirms a prevailing impression that local disease control is the major factor in the prediction of outcome of ependymoma. Survival rates were comparable with those reported by other investigators who have treated patients with similar doses of radiation and no chemotherapy.

Phase II study of daily oral etoposide in children with recurrent brain tumors and other solid tumors.

Pre-clinical data and adult experience suggests that topoisomerase targeted anti-cancer agents may be highly schedule dependent, and efficacy may improve with prolonged exposure. To investigate this hypothesis, 28 children with recurrent brain and solid tumors were enrolled in a phase II study of oral etoposide (ETP). Patients were prescribed ETP at 50 mg/m2/ day for 21 consecutive days. Courses were repeated every 28 days pending bone marrow recovery. Evaluation of response was initially performed after 8 weeks and then every 12 weeks either by CT or MRI. Three of 4 patients with PNET (primitive neuroectodermal tumor)/medulloblastora achieved a partial response (PR). Two of 5 with ependymoma responded, one with a complete response and one with a PR. Toxicity was manageable with only 1 admission for fever and neutropenia in 120 cycles of therapy. Five patients had grade 3 or 4 neutropenia. One had grade 4 thrombocytopenia and one grade 2 mucositis and withdrew as a result. One patient had grade 2 diarrhea. Two patients who achieved a PR had received ETP as part of prior combination chemotherapy regimens. Daily oral etoposide is active in recurrent PNET/medulloblastoma and ependymoma. Toxicity is manageable and rarely requires intervention. Daily oral etoposide in combination with crosslinking agents should be considered in future phase III trials. Determination of activity in glioma and solid tumors is not complete.

Asymptomatic recurrence detection with surveillance scanning in children with medulloblastoma.

PURPOSE: To assess the utility of surveillance neuroimaging in detecting recurrent disease in patients treated for medulloblastoma. PATIENTS AND METHODS: Records and scans of 59 consecutive patients treated for medulloblastoma between 1984 and 1993 in one institution were retrospectively reviewed. RESULTS: Nineteen of 59 patients had recurrence of tumor, of which 17 were available for this study. Eleven of the 17 recurrent patients were asymptomatic at the time of detection. The median time to recurrence was 13 months (range, 3 to 90). CONCLUSION: Surveillance scanning detected a majority of recurrences before onset of symptoms. Although the outcome of those with recurrent disease remains poor, early detection with minimum disease provides the best setting in which to test newer therapies. Patients and their parents also were more likely to elect pursuing further treatment when relapse was detected asymptomatically.

Pilot study of high-dose thiotepa and etoposide with autologous bone marrow rescue in children and young adults with recurrent CNS tumors. The Children's Cancer Group.

PURPOSE: This study was designed to determine the toxicity, radiographic response rate, and outcome following high-dose thiotepa, etoposide, and autologous bone marrow rescue (ABMR) for young patients with recurrent malignant brain tumors. METHODS: Eligibility criteria required adequate renal, hepatic, and pulmonary function, and no bone marrow infiltration. Thiotepa 300 mg/m2 and etoposide 500 mg/ m2 were infused on 3 consecutive days, and autologous bone marrow was infused 72 hours following chemotherapy. RESULTS: Forty-five patients with recurrent high-grade brain tumors, aged 8 months to 36 years (median, 8 years), were treated. Seven patients (16%) died of treatment-related toxicities within 56 days of marrow reinfusion. Delayed platelet engraftment occurred in 44% of patients who survived beyond day 56. Of 35 patients with radiographically measurable disease who survived at least 28 days following ABMR, there were two complete responses (CRs) and six partial responses (PRs), for an overall response (CRs plus PRs) rate of 23% (SE = 7%). Objective responses were observed in four of 14 assessable patients with high-grade glioma and in two of six with primitive neuroectodermal tumors (PNETs)/ medulloblastoma. Survival was significantly improved in patients treated with minimal residual disease (P < .0005). Five of 18 patients (28%) with high-grade gliomas remain free of disease at 39+, 44+, 49+, 52+, and 59+ months post-ABMR. CONCLUSION: The combination of high-dose thiotepa and etoposide has activity against a variety of recurrent childhood brain tumors. These results merit further evaluation in children and young adults with both recurrent and newly diagnosed high-grade brain tumors.

Spinal subdural enhancement after suboccipital craniectomy.

PURPOSE: To characterize transient intraspinal subdural enhancement (potentially mimicking the subarachnoid spread of tumor) seen on MR images in some children after suboccipital craniectomy for posterior fossa tumor resection. METHODS: Radiologic and medical records of 10 consecutive children who had MR imaging for spinal staging after resection of posterior fossa tumor during a 9-month period were reviewed retrospectively. In addition, one case with similar findings of intraspinal enhancement on spinal staging MR images obtained at another institution was included in the review. RESULTS: Intraspinal enhancement thought to be subdural was seen in four of 10 patients undergoing spinal staging MR imaging 6 to 12 days after surgery. In these four patients, MR studies 50 to 18 days later, without intervening treatment, showed resolution of the abnormal enhancement. A fifth patient (from another institution) with similar intraspinal enhancement underwent CT myelography 4 days later, which showed no subarachnoid lesions. No metastases have developed in any of these five patients during the 2.5- to 3.5-year follow-up period. conclusions: From analysis of the MR appearance and on the basis of prior myelographic experience, we suggest an extraarachnoid, probably subdural, location of this enhancement. Awareness of this phenomenon will reduce the rate of false-positive diagnoses of metastatic disease. Preoperative spinal staging should be considered for patients undergoing suboccipital craniectomy.

Prognostic significance of type 1 neurofibromatosis (von Recklinghausen Disease) in childhood optic glioma.

Although the association between optic glioma and neurofibromatosis is well recognized, few studies have systematically compared the outcomes of patients with optic gliomas and neurofibromatosis and patients with optic gliomas without neurofibromatosis. In the present study, patients with optic gliomas and Type 1 neurofibromatosis (NF-1) were compared with patients with optic gliomas without NF-1, with respect to survival, time to tumor progression, and tumor location. Forty-four patients with optic gliomas who were evaluated between 1949 and 1991 were studied retrospectively. Sixteen of 44 patients (36%) met the National Institutes of Health criteria for NF-1. The medical records of all patients were examined, and letters of inquiry were sent to every living patient to ascertain current health statuses. Death certificates were obtained to determine causes of death. Follow-up averaged 7.2 years (10.2 yr for patients with NF-1, 5.4 yr for patients without NF-1). The 5- and 10-year survival rates for patients with optic gliomas and NF-1 were 93 and 81%, respectively. For those patients with optic gliomas who did not have NF-1, 5- and 10-year survival rates were 83 and 76%, respectively. Seventeen patients experienced tumor progression (5 with NF-1, 12 without NF-1). A difference was observed in the mean time to tumor progression (first relapse) between the two groups (mean time with NF-1, 8.37 yr; without NF-1, 2.39 yr [P < 0.01]). However, no significant difference in overall survival, as evaluated by a log-rank test of the respective Kaplan-Meier survival curves, was observed between the two groups. A significant difference in distribution of tumor location between the group with NF-1 and the group without NF-1 was also noted (Fisher's exact test, P = 0.0338), although the number of patients evaluated in this series was too small to determine whether this difference in tumor location influenced relapse rate. We conclude that optic gliomas in patients with neurofibromatosis have a different distribution of location as opposed to those in patients without neurofibromatosis, and, for first relapse, the presence of neurofibromatosis is a significant favorable factor.

Long-term survival of a patient with primary sellar choriocarcinoma with pulmonary metastases: a case report.

Extracranial metastasis is an unusual complication of most types of primary intracranial tumor. Approximately one-third of reported cases of primary intracranial choriocarcinoma have been associated with pulmonary tumor metastasis. The prognosis of such patients has been uniformly fatal. This report describes a probable long-term survivor of primary intracranial choriocarcinoma wit pulmonary metastasis. The patient had a complete response to combination chemotherapy with cisplatin, etoposide, and bleomycin and is surviving free of disease >3 years from diagnosis.

A phase II study of thioTEPA in children with recurrent solid tumor malignancies: a Children's Cancer Group study.

A Phase II study of thioTEPA was performed by the Children's Cancer Group. ThioTEPA was administered intravenously every three weeks, at a dose of 65 mg/m2. Pediatric patients with recurrent sarcomas were targeted, but patients with other tumor diagnoses were also eligible. Toxicity was primarily hematopoietic, with thrombocytopenia being predominant. ThioTEPA did not demonstrate significant activity in the target tumor groups evaluated.

Prognostic factors and treatment results for supratentorial primitive neuroectodermal tumors in children using radiation and chemotherapy: a Childrens Cancer Group randomized trial.

PURPOSE: To determine clinical characteristics and response to treatment for children with supratentorial primitive neuroectodermal tumors (S-PNETs). PATIENTS AND METHODS: After surgery and staging, 55 patients aged 1.5 to 19.3 years with S-PNETs were randomized to receive craniospinal radiotherapy (RT) followed by eight cycles of 1-(2-chloro-ethyl)-3-cyclohexylnitrosourea (CCNU), vincristine (VCR), and prednisone (standard treatment) or two cycles of 8-in-1 chemotherapy followed by RT and then eight additional cycles of 8-in-1. RESULTS: Three-year Kaplan-Meier estimates (estimate +/- SE) of survival and progression-free survival (PFS) rates for patients with confirmed diagnoses of S-PNET were 57% +/- 8% and 45% +/- 8%, respectively; survival and PFS rates for children with PNETs located in the pineal region were 73% +/- 12% and 61% +/- 13%, respectively, and were significantly different from the other S-PNETs (P < .03). The 8-in-1 arm had greater toxicity than the standard-treatment arm. Distributions of PFS between the two treatment groups were not significantly different (P > .5). Other univariate prognostic factors that influenced PFS included metastasis (M) stage (P < .03: M0 50% +/- 9% v M1-4 0%) and age (P < .02: 1.5 to 2 years 25% +/- 13% v > or = 3 years 53% +/- 9%). CONCLUSION: In this first randomized treatment trial for S-PNETs in children, no significant differences were detected between the two treatment groups. M0 and pineal site of involvement were independent predictors of a better outcome. However, survival was better than previously reported.

Survival and prognostic factors following radiation and/or chemotherapy for primitive neuroectodermal tumors of the pineal region in infants and children: a report of the Childrens Cancer Group.

PURPOSE: To describe the biologic and clinical features of children with primitive neuroectodermal tumors (PNETs) arising in the pineal region (pineoblastomas) and evaluate prospectively the efficacy of radiation therapy (RT) and/or chemotherapy. PATIENTS AND METHODS: Between 1986 and 1992, 25 children with PNETs of the pineal region were treated as part of a Childrens Cancer Group study. Eight infants less than 18 months of age were nonrandomly treated with eight-drugs-in-1-day chemotherapy without RT. The remaining 17 patients were treated with craniospinal RT and randomized to receive either vincristine, lomustine (CCNU), and prednisone or the eight-drugs-in-1-day regimen. RESULTS: Of 24 completely staged patients, 20 (83%) had localized disease at diagnosis. All infants developed progressive disease a median of 4 months from the start of treatment. Of the 17 older patients treated with RT and chemotherapy, the Kaplan-Meier estimate of progression-free survival (PFS) at 3 years is 61% +/- 13%. This is superior to the PFS of children with other supratentorial PNETs (P = .026). Following RT, 12 of 17 patients (70.6%) had a residual pineal region mass, which persisted for as long as 5 years before resolving; only four subsequently developed progressive disease. CONCLUSION: (1) Eight-in-1 chemotherapy without RT appears to be ineffective therapy for young children with PNETs of the pineal region. (2) For children more than 18 months of age at diagnosis treated with craniospinal RT and chemotherapy, the PFS is superior to that of children with other supratentorial PNETs. (3) A residual enhancing mass following RT is not predictive of treatment failure.

Hematopoietic marrow regeneration in pediatric patients undergoing spinal irradiation: MR depiction.

PURPOSE: To evaluate changes in vertebral marrow signal intensity that occur over time in children undergoing craniospinal radiation therapy, specifically evaluating for the occurrence and timing of marrow regeneration. METHODS: MR images of nine pediatric patients (ages 4 to 12 years) with posterior fossa medulloblastoma who received total spinal irradiation (24 to 40 Gy) and had at least three MR examinations were reviewed. Signal intensity to vertebral body marrow was graded by two pediatric neuroradiologists who were blinded to patient identity and to the timing of the studies. RESULTS: Eight of nine patients demonstrated increasing signal intensity of the vertebral marrow after irradiation, consistent with conversion of hematopoietic to fatty marrow. In each of these patients, this was followed by subsequent decreasing signal intensity in a mottled or peripheral band pattern indicating recovery of hematopoietic marrow. CONCLUSION: Changes in vertebral body signal intensity consistent with marrow reconversion commonly are seen in pediatric patients 11 to 30 months after they undergo total spinal irradiation.