Extended phase I evaluation of vincristine, irinotecan, temozolomide, and antibiotic in children with refractory solid tumors.

BACKGROUND: The combination of irinotecan, temozolomide, and vincristine is appealing because of potentially synergistic mechanisms of action and non-overlapping toxicities. This phase I study was designed to determine the toxicity and maximum tolerated dose (MTD) of escalating daily protracted doses of irinotecan given in this combination. With extended accrual, we more fully explored the toxicity of multiple courses at the MTD. PROCEDURE: Patients under 22 years with recurrent or refractory solid tumors were eligible. A course of chemotherapy was given every 28 days. Cefpodoxime was given for diarrhea prophylaxis. Vincristine (1.5 mg/m2, max 2 mg) was given intravenously (IV) on days 1 and 8. Temozolomide (100 mg/m2/day) was given orally on days 1-5. Irinotecan was given IV over 1 hr on days 1-5 and 8-12. Dose escalation was done in the standard 3 + 3 cohort design, starting at 15 mg/m2/day. RESULTS: Twenty-five of 26 eligible patients were evaluable for toxicity and response. They received 111 courses (1-13, median 4). Dose limiting toxicity (DLT-pancreatitis, transaminitis) was seen in two of three patients at dose level 2 (20 mg/m2). No patients at level 1 had DLT during the first two cycles. Thus, the MTD of irinotecan in this combination is 15 mg/m2/day x 10 doses. Hematologic toxicity was mild and not prolonged. Grade 3 diarrhea was seen in five courses. Responses included two complete and two partial with 12 stable disease (SD) (median 6 months). CONCLUSIONS: This combination is safe and shows activity in pediatric patients with recurrent malignancy.

Two new patients with Curry-Jones syndrome with trichoblastoma and medulloblastoma suggest an etiologic role of the sonic hedgehog-patched-GLI pathway.

Curry-Jones syndrome (OMIM #601707) is a rare multiple malformation disorder of unknown etiology, associated with brain and skull abnormalities, polysyndactyly, and defects of the eyes, skin and gastrointestinal tract. We report on two new cases of Curry-Jones syndrome with previously unreported features, including benign and malignant neoplasms. The first patient had typical features of Curry-Jones syndrome as well as multiple intra-abdominal smooth muscle hamartomas and trichoblastoma of the skin. The second patient was born with occipital meningoceles and developed a desmoplastic medulloblastoma. Routine lymphocyte karyotype, GLI3 gene analysis and Patched (PTCH) gene analysis on both patients and chromosome microarray analysis on the first patient were normal. We review the previously reported cases of Curry-Jones syndrome and compare our patients' findings. In view of the association of trichoblastoma with basal cell carcinoma and desmoplastic medulloblastoma with nevoid basal cell carcinoma syndrome (NBCCS) and PTCH mutations, we hypothesize that Curry-Jones syndrome is caused by malfunction of an element in the sonic hedgehog pathway.

Risk determinants for catheter-associated blood stream infections in children and young adults with cancer.

BACKGROUND: Catheter-associated blood stream infections (CABSI) are frequent complications encountered with cancer treatment. In order to understand which factors might predispose to CABSIs in children and young adults, we evaluated risk for infection in association with tumor type, catheter type, and setting of occurrence. METHODS: All pediatric oncology patients having a central venous catheter (CVC) with a tunneled external (TE) or totally implantable design (TID) were prospectively followed for the occurrence of a CABSI for 12 months. CABSIs were defined in accordance with the guidelines published by the Centers for Disease Control, and were quantified as the number of occurrences per 1,000 device days. Rates of CABSIs were stratified by tumor histology, type of catheter design, and setting of occurrence. Statistical comparisons were made using the Mantel-Haenzel statistic and the Cox proportional hazard model. RESULTS: A total of 58 CABSIs were identified in 139 patients over a period of 35,935 CVC days. The overall CABSI rate was 1.6 infections per 1,000 CVC days (95% CI 1.2, 2.1). Stratified analysis demonstrated increased risk for CABSIs in hospitalized patients having TEs, and while patients with solid tumors were also at higher risk; this association was not supported by the Cox proportional hazard model. CONCLUSION: While our baseline CABSI rate was comparatively lower than for other institutions, subset analyses identified that hospitalized cancer patients having TEs are at the highest risk for developing CABSIs. Our findings may help to guide improved methods of anticipating and controlling infections in immunocompromised patients.

Phase I study of combination topotecan and carboplatin in pediatric solid tumors.

PURPOSE: We conducted a phase I trial of escalating doses of topotecan (TOPO) in association with a fixed systemic exposure of carboplatin (CARBO) with or without granulocyte colony-stimulating factor (G-CSF) in children. PATIENTS AND METHODS: Two separate cohorts of patients (pts) with solid tumors were studied: (A) pts with refractory or recurrent disease and (B) pts with no prior myelosuppressive therapy or newly diagnosed tumors for which there was no standard chemotherapy. CARBO was given on day 1 at an area under the curve of 6.5, followed by TOPO as a continuous infusion for 3 days; the starting dose of TOPO was 0.50 mg/m(2)/d. Cycles were repeated every 21 days. G-CSF was given at a dose of 5 microg/kg/d starting on day 4. RESULTS: Forty-eight of 51 pts were assessable for toxicity. In group A, dose-limiting myelosuppression persisted despite de-escalation of TOPO to 0.3 mg/m(2)/d and use of G-CSF. In group B, the maximum-tolerated dose of TOPO was 0.5 mg/m(2)/d for 3 days, and 0.6 mg/m(2)/d for 3 days with G-CSF. No significant nonhematologic toxicities were observed. Among 46 pts assessable for response, one had complete response, five had partial response, and 18 had stable disease. CONCLUSION: Although this combination possesses antineoplastic activity in pediatric solid tumors, hematologic toxicity precluded any meaningful TOPO dose escalation. The addition of G-CSF did not alter this. The potential for preservation of activity and diminution of toxicity with alternative sequences and schedules of administration (topoisomerase followed by alkylating or platinating agents) should be evaluated.

Altered irinotecan pharmacokinetics in pediatric high-grade glioma patients receiving enzyme-inducing anticonvulsant therapy.

PURPOSE: The purpose of this study was to determine the effect of enzyme-inducing anticonvulsants (EIAs) on the disposition of irinotecan and metabolites in pediatric patients with high-grade glioma. EXPERIMENTAL DESIGN: Pediatric patients with newly diagnosed high-grade glioma were enrolled on this study between March 1999 and February 2001. During course 1, irinotecan was administered as a 60-min i.v. infusion at a dosage of 20 mg/m(2)/day for 5 days of 2 consecutive weeks. On days 1 and 12 of course 1, we collected serial plasma samples to measure the concentrations of the lactone and total forms of irinotecan and its metabolites SN-38 (7-ethyl-10-hydroxycamptothecin), SN-38 glucuronide (7-ethyl-10-[3,4,5-trihydroxy-pyran-2-carboxylic acid]camptothecin), and 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]carbonyloxycamptothecin. RESULTS: Thirty-one patients were enrolled. In patients receiving EIAs, the area under the concentration versus time curve (AUC) of irinotecan lactone and SN-38 lactone was significantly lower (P = 0.01 and P = 0.002, respectively), and the irinotecan lactone clearance was significantly higher (P = 0.0003), as compared with those in patients who received no EIAs. The glucuronidation ratio was higher (P = 0.0009), and the ratio of SN-38 AUC to irinotecan AUC was lower (P = 0.02) in patients who received EIAs. Two patients receiving EIAs tolerated increased irinotecan dosages of 30 and 40 mg/m(2)/day without toxicity. One patient receiving EIAs experienced grade 3 diarrhea when the dosage of irinotecan was increased to 60 mg/m(2)/day. CONCLUSIONS: EIAs increase the clearance of irinotecan and cause a decrease in systemic exposure to the active metabolite SN-38. Patients who are receiving irinotecan and who require anticonvulsants should be placed on non-EIA therapy, when possible.

Phase 2 study of idarubicin in pediatric brain tumors: Pediatric Oncology Group study POG 9237.

Idarubicin (IDA), the 4-demethoxy analog of daunomycin, has had significant cytotoxicity in many malignancies. In previous reports, the alcohol metabolite of IDA, 4-demethoxydaunorubicinol (idarubicinol, or IDOL), had cytotoxic activity and the ability to penetrate the blood-brain barrier. For this reason, the Pediatric Oncology Group conducted a Phase 2 trial of IDA for children with recurrent or progressive brain tumors. Ninety-one eligible children were entered on this study, with ages ranging from 3 months to 19 years. Patients were stratified by tumor types into 6 categories: stratum 1, low-grade astrocytoma; stratum 2, malignant glioma (glioblastoma multiforme and anaplastic astrocytoma); stratum 3, medulloblastoma; stratum 4, brainstem glioma; stratum 5, ependymoma; and stratum 6, miscellaneous malignant tumors not included in the previous diagnoses. IDA(18 mg/m2) was infused over 4 h and followed by granulocyte colony-stimulating factor (G-CSF) beginning day 5 after infusion of IDA. G-CSF was continued until blood cell count recovery. Cycles were repeated at approximately 21-day intervals until patients developed progressive disease or had completed 6 cycles with stable or improved disease. Pharmacokinetic plasma and cerebrospinal fluid (CSF) samples were collected from a subset of these patients. Response was poor in all strata. Most patients developed progressive disease; however, in 21 patients with medulloblastoma there was 1 partial response, and 6 patients had stable disease (SD) that in 4 patients lasted more than 20 weeks. Grades 3/4 hematopoietic toxicities were the most common toxic events, and 14 infection-related events resulted in hospitalization of patients. Only 1 patient developed reduced cardiac function. The systemic clearance data for IDA and IDOL were nearly identical to those published on patients with leukemia, and the plasma elimination of the IDOL metabolite was substantially longer than that of the parent drug IDA. The peak CSF:plasma ratios of IDA and IDOL were very low. The overall response rates to IDA were disappointing despite periods of prolonged SD in nearly a fourth of the patients. We conclude from this data and from that in nonhuman primates that it is unlikely that IDA, daunomycin, or other related anthracyclines will be useful for treating primary CNS tumors.

Preliminary results from a Phase II trail of conformal radiation therapy for pediatric patients with localised low-grade astrocytoma and ependymoma.

PURPOSE: To estimate the local control and patterns of failure for pediatric patients with low-grade astroglial tumors (LGA) and ependymoma (EP) treated with three-dimensional conformal radiation therapy (CRT) using an anatomically defined clinical target volume (CTV). METHODS AND MATERIALS: From an ongoing, prospective Phase II trial initiated in July 1997, 102 pediatric patients with LGA (n = 38) and EP (n = 64) have been treated with CRT using an anatomically defined CTV extending 1.0 cm beyond the gross tumor volume and a 0.5-cm margin (planning target volume) extending outside of the CTV. The prescribed dose was 54 Gy (LGA) and 59.4 Gy (EP). RESULTS: Patients with EP have been followed for a median of 17 months (range 3--43 months), and six failures have occurred. Patients with LGA have been followed for a median of 17 months (3--44 months), and four failures have occurred. Three-dimensional magnetic resonance (MR) studies performed to document treatment failure were registered with the MR and computed tomography (CT) data used in the treatment planning process. Failure occurred within the CTV for 5 patients with EP, including 3 with concurrent subarachnoid dissemination. One patient with EP developed metastatic disease with no evidence of local failure. Three patients with LGA failed within the CTV and one failed immediately outside of the CTV. CONCLUSIONS: Treatment of an anatomically defined CTV, encompassing 1.0 cm of non-involved brain beyond the margin of resection or neuroimaging-defined tumor, appears to be safe for pediatric patients with LGA and EP based on these preliminary data. Normal tissue sparing through the use of advanced radiation therapy treatment planning and delivery techniques should be beneficial to pediatric patients if the rate and patterns of failure are similar to conventional techniques and toxicity reduction can be objectively documented.

Early neuro-otologic effects of three-dimensional irradiation in children with primary brain tumors.

PURPOSE: Central nervous system (CNS) irradiation can cause sensorineural hearing loss. The relationship between the dose to the cochlea and the development of hearing loss is unknown. Conformal radiation therapy (CRT) techniques facilitate accurate cochlear dosimetry. We modeled hearing threshold levels (HTL) after CRT in children with localized primary brain tumors (ependymoma, low- or high-grade astrocytoma, craniopharyngioma, or CNS germinoma) by using cochlear dose and clinical variables. PATIENTS AND METHODS: We evaluated 72 children (median age, 9.5 years) with audiograms before and every 6 months after CRT (median follow-up, 16.6 months; range, 4.3-42.6 months). We used a mixed-effects model to predict change in hearing for each ear as a function of time, cochlear dose, and clinical variables. RESULTS: Hearing was affected the greatest in patients with CSF shunts and pre-CRT ototoxic chemotherapy, enhanced by cochlear dose, and was more prominent on the right side. Hearing impairment after CRT alone occurred at low and intermediate frequencies in patients with shunts and supratentorial tumors when the cochlear dose exceeded 32 Gy. Patients with shunts and central supratentorial tumors developed intermediate-frequency hearing loss after CRT alone regardless of dose. CONCLUSIONS: Hearing loss during the first 4 years after CRT alone is uncommon, although patients with shunts and supratentorial tumors appear to be at increased risk for low- and intermediate-frequency effects. CSF shunting and increased cochlear dose enhance the effect of ototoxic chemotherapy. If possible, the average cochlear dose should be <32 Gy over a 6-week course of treatment until more specific dose data become available.

Influence of tumor grade on time to progression after irradiation for localized ependymoma in children.

PURPOSE: To investigate the influence of histologic grade on progression-free survival (PFS) after irradiation (RT) for pediatric patients with localized ependymoma. METHODS AND MATERIALS: Fifty patients with localized ependymoma (median age 3.6 years, range 1-18 years at the time of RT) were treated with RT between December 1982 and June 1999. Anaplastic features were identified in 14 of 50 patients. The extent of resection was characterized as gross-total in 36 patients, near-total in 5, and subtotal in 9. The median dose to the primary site was 54 Gy. Of the 50 patients, 23 received pre-RT chemotherapy. RESULTS: Thirty-nine patients were alive at a median follow-up of 46 months (range 21-214) from diagnosis. Thirty-four patients remained progression free at a median follow-up of 35 months (range 13-183) after the initiation of RT. Progression occurred in 16 patients (12 local and 4 local and distant), with a median time to failure of 21.2 months (range 4.6-65.0). The tumor grade significantly influenced the PFS after RT (p < 0.0005). The estimated 3-year PFS rate was 28% +/- 14% for patients with anaplastic ependymoma compared with 84% +/- 8% for patients with differentiated ependymoma. These results remained significant when corrected for age at diagnosis (<3 years), pre-RT chemotherapy, and extent of resection. Patients who received pre-RT chemotherapy had an inferior 3-year PFS estimate after RT (49 +/- 12%) compared with those who did not (84% +/- 10%; p = 0.056). Anaplastic ependymoma was found more frequently in the supratentorial brain (p = 0.002). Six of 12 patients with supratentorial tumor developed recurrence; recurrence was restricted to patients with anaplastic ependymoma. CONCLUSION: Tumor grade influences outcome for patients with ependymoma independent of other factors and should be considered in the design and analysis of prospective trials involving pediatric patients treated with RT. Chemotherapy before RT influences the PFS and overall survival after RT. The effect is more pronounced when progression occurs during chemotherapy.

Population pharmacokinetics of temozolomide and metabolites in infants and children with primary central nervous system tumors.

PURPOSE: To construct a population pharmacokinetic model for temozolomide (TMZ), a novel imidazo-tetrazine methylating agent and its metabolites MTIC and AIC in infants and children with primary central nervous system tumors. METHODS: We evaluated the pharmacokinetics of TMZ and MTIC in 39 children (20 boys and 19 girls) with 132 pharmacokinetic studies (109 in the training set and 23 in the validation set). The median age was 7.1 years (range 0.7 to 21.9 years). Children received oral TMZ dosages ranging from 145 to 200 mg/m(2) per day for 5 days in each course of therapy. Serial plasma samples were collected after the first and fifth doses of the first and third courses. Approximately eight plasma samples were collected up to 8 h after each dose, and assayed for TMZ, MTIC, and AIC by HPLC with UV detection. A one-compartment model was fitted to the TMZ and metabolite plasma concentrations using maximum likelihood estimation. Covariates, including demographics and biochemical data were tested for their effects on TMZ clearance (CL/F) and MTIC AUC utilizing a two-stage approach via linear mixed-effects modeling. RESULTS: The population mean (inter- and intrapatient variability expressed as %CV) for the pharmacokinetic parameters (based on the training set) were as follows: TMZ CL/F 5.4 l/h (53.4, 17.5), Vc/F 14.0 l (48.5, 39.2), C(max) 9.1 mg/l (20.8, 29.1), and MTIC AUC 1.0 microg/ml.h (13.9, 30.0). Covariate analysis showed that increasing age and body surface area (BSA) were associated with a significant increases in TMZ CL, Vc, and C(max) ( P<0.05), and that increasing age was associated with significant decreases in TMZ and MTIC AUC. Indicators of liver and renal function were not significantly associated with TMZ pharmacokinetics or MTIC AUC. The final model with the significant covariates was validated using the remaining 23 pharmacokinetic studies. CONCLUSIONS: This study extends previous work done in adults, and identified BSA and age as covariates that account for variability in TMZ disposition in infants and children with primary CNS malignancies.

Temozolomide in the treatment of children with newly diagnosed diffuse intrinsic pontine gliomas: a report from the Children's Oncology Group.

An open-label phase II study (ACNS0126) testing the efficacy of chemoradiotherapy with temozolomide (TMZ) followed by adjuvant TMZ was conducted by the Children's Oncology Group. During the period from July 6, 2004 through September 6, 2005, 63 children with newly diagnosed diffuse intrinsic pontine glioma (DIPG) were enrolled in the study. All patients received TMZ at a dosage of 90 mg/m(2)/day for 42 days to a dose of 59.4 Gy. Four weeks following irradiation, TMZ was given at a dosage of 200 mg/m(2)/day for 5 days every 28 days, for a total of 10 cycles. The primary objective of the statistical analysis was to determine whether the current treatment produced a 1-year event-free survival (EFS) rate higher than the historical baseline of 21.9% observed in CCG-9941. The mean 1-year EFS (± standard deviation) was 14% ± 4.5%, compared with 21.9% ± 5% for CCG-9941. The P value of the test of comparison of 1-year EFS, based on a 1-sided, 1-sample test of proportions, was .96. There was no evidence that temozolomide produced a 1-year EFS rate higher than 21.9%. The mean 1-year OS (± standard deviation) was 40% ± 6.5%, compared with 32% ± 6% for CCG-9941. The median time to death was 9.6 months. Chemoradiotherapy with TMZ followed by adjuvant TMZ is not more effective than previously reported regimens for the treatment of children with DIPG.

Temozolomide in the treatment of high-grade gliomas in children: a report from the Children's Oncology Group.

To determine whether temozolomide is an active agent in the treatment of children with high-grade astrocytomas and whether survival is influenced by the expression of the O6-methylguanine-methyltransferase gene (MGMT) in these patients. In the Children's Oncology Group study ACNS0126, 107 patients with a diagnosis of anaplastic astrocytoma (AA), glioblastoma multiforme (GBM), or gliosarcoma were enrolled. All patients underwent concomitant chemoradiotherapy with temozolomide, followed by adjuvant chemotherapy with temozolomide. The outcomes were compared with those of children treated in Children's Cancer Group (CCG) study CCG-945. Formalin-fixed, paraffin-embedded tumor tissue was available in 71 cases for immunohistochemical analysis of MGMT expression. Ninety patients were deemed eligible, 31 with AA, 55 with GBM, and 4 with other eligible diagnoses. The 3-year event-free survival (EFS) and overall survival (OS) rates were 11 ± 3% and 22 ± 5%, respectively. There was no evidence that temozolomide given during radiation therapy and as adjuvant therapy resulted in improved EFS compared with that found in CCG-945 (p = 0.98). The 3-year EFS rate for AA was 13 ± 6% in ACNS0126 compared with 22 ± 5.5% in CCG-945 (p = 0.95). The 3-year EFS rate for GBM was 7 ± 4% in ACNS0126 compared with 15 ± 5% in CCG-945 (p = 0.77). The 2-year EFS rate was 17 ± 5% among patients without MGMT overexpression and 5 ± 4% among those with MGMT overexpression (p = 0.045). Temozolomide failed to improve outcome in children with high-grade astrocytomas. MGMT overexpression was adversely associated with survival.

Successful treatment of an unresectable choroid plexus carcinoma in a patient with Li-Fraumeni syndrome.

Choroid plexus carcinoma (CPC) is an uncommon central nervous system tumor requiring complete surgical excision for favorable outcome. The authors report the successful treatment of a 2-year-old patient with widely disseminated CPC and Li-Fraumeni syndrome. Following a partial resection of the tumor the patient received chemotherapy consisting of cyclophosphamide, etoposide, and carboplatin. There were no additional surgical procedures and radiation was not administered. Remarkably, the patient remains without evidence of active disease more than 3 years from the completion of therapy. Additional studies are necessary to determine whether this treatment plan can be beneficial to other patients with CPC and whether the patient's p53 mutation had an effect on outcome.

Clinically evident venous thromboembolic events in children with brain tumors.

We evaluated the incidence and significance of central venous access device dysfunction and symptomatic major thrombosis in 253 pediatric patients with brain tumors. Central venous access device dysfunction was a common complication (28.4%) and was associated with major thrombosis development and a reduced overall survival rate. Major thrombosis was relatively uncommon (2.8%).

Survival and functional outcome of children with hypothalamic/chiasmatic tumors.

BACKGROUND: The management of children with hypothalamic (H) and/or chiasmatic (C) tumors remains controversial. We evaluated the impact of clinical and neuroimaging parameters and primary therapy on overall (OS) and progression-free (PFS) survival and on neuroendocrine and neurocognitive outcome in children with H and/or C tumors. METHODS: Records were reviewed for 73 children with H and/or C tumors treated at St. Jude Children's Research Hospital between October 1981 and December 1999. RESULTS: Thirty-six patients received irradiation or chemotherapy immediately postdiagnosis and 37 were observed. The 6-year OS and PFS rates were 86 +/- 5%; and 36 +/- 7%, respectively. The 6-year PFS rates for the irradiation, chemotherapy, and observation groups were 69 +/- 16%, 12 +/- 11%, and 37 +/- 9%, respectively. In multivariate analysis, intracranial NF1 lesions (P = 0.015) and initial irradiation (P = 0.056) led to better PFS rates. There was no difference in OS between those initially treated or observed. Mean serial intelligence quotient (IQ) scores were 86 and 86 at diagnosis and at 6 years later, respectively. Patients younger than 5 years old had a lower mean IQ score at diagnosis (79.1) than older patients (96.3; P = 0.003). Patients who were irradiated at diagnosis had a significantly higher cumulative incidence of endocrinopathy at 3 years (P = 0.008). CONCLUSIONS: Overall survival for children with H and/or C tumors is excellent. Initial treatment with radiation and the presence of intracranial NF1 lesions were positive predictors of PFS. Mean IQ is significantly compromised at diagnosis, but does not change over time or with irradiation. Overall survival is not affected by initial observation. We recommend observation in asymptomatic patients, platinum-based chemotherapy in younger patients, and irradiation in older symptomatic patients.