RESUMEN
BACKGROUND: We conducted a phase II study of oral capecitabine rapidly disintegrating tablets given concurrently with radiation therapy (RT) to assess progression-free survival (PFS) in children with newly diagnosed diffuse intrinsic pontine gliomas (DIPG). PATIENTS AND METHODS: Children 3-17 years with newly diagnosed DIPG were eligible. Capecitabine, 650 mg/m2 /dose BID (maximum tolerated dose [MTD] in children with concurrent radiation), was administered for 9 weeks starting the first day of RT. Following a 2-week break, three courses of capecitabine, 1,250 mg/m2 /dose BID for 14 days followed by a 7-day rest, were administered. As prospectively designed, 10 evaluable patients treated at the MTD on the phase I trial were included in the phase II analyses. The design was based on comparison of the PFS distribution to a contemporary historical control (n = 140) with 90% power to detect a 15% absolute improvement in the 1-year PFS with a type-1 error rate, α = 0.10. RESULTS: Forty-four patients were evaluable for the phase II objectives. Capecitabine and RT was well tolerated with low-grade palmar plantar erythrodyesthesia, increased alanine aminotransferase, cytopenias, and vomiting the most commonly reported toxicities. Findings were significant for earlier progression with 1-year PFS of 7.21% (SE = 3.47%) in the capecitabine-treated cohort versus 15.59% (SE = 3.05%) in the historical control (P = 0.007), but there was no difference for overall survival (OS) distributions (P = 0.30). Tumor enhancement at diagnosis was associated with shorter PFS and OS. Capecitabine was rapidly absorbed and converted to its metabolites. CONCLUSION: Capecitabine did not improve the outcome for children with newly diagnosed DIPG.
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Neoplasias del Tronco Encefálico/terapia , Capecitabina/administración & dosificación , Quimioradioterapia , Glioma/terapia , Administración Oral , Adolescente , Neoplasias del Tronco Encefálico/diagnóstico , Niño , Preescolar , Femenino , Estudios de Seguimiento , Glioma/diagnóstico , Humanos , Masculino , Estudios Prospectivos , ComprimidosRESUMEN
STUDY QUESTION: Does lower dose (<26 Gy) cranial radiation therapy (CRT) used for central nervous system prophylaxis in acute lymphoblastic leukemia (ALL) adversely affect sperm concentration or morphology? SUMMARY ANSWER: CRT doses <26 Gy had no demonstrable adverse effect on sperm concentration or morphology. WHAT IS KNOWN ALREADY: Treatment with alkylating agents produces oligospermia and azoospermia in some patients. No prior study has been large enough to evaluate the independent effects of alkylating agents and lower dose (<26 Gy) CRT on sperm concentration or morphology. STUDY DESIGN, SIZE, DURATION: This cross-sectional study included male adult survivors of pediatric ALL who had received alkylating agent chemotherapy with or without CRT and who enrolled in the St. Jude Lifetime Cohort Study (SJLIFE) from September 2007 to October 2013. PARTICIPANTS/MATERIALS, SETTING, METHODS: The inclusion criteria were males, ≥18 years of age, ≥10 years after diagnosis, treated at St. Jude Children's Research Hospital for ALL, and received alkylating agent chemotherapy. Semen analyses were performed on 173 of the 241 (78.1%) adult survivors of pediatric ALL who had received alkylating agent chemotherapy with or without CRT. Cumulative alkylating agent treatment was quantified using the cyclophosphamide equivalent dose (CED). Log-binomial multivariable models were used to calculate relative risks (RRs) and 95% CI. MAIN RESULTS AND THE ROLE OF CHANCE: Compared to those without CRT, risk of oligospermia or azoospermia was not increased for CRT <20 Gy (P = 0.95) or 20-26 Gy (P = 0.58). Participants 5-9 years of age at diagnosis compared to those 0-4 years of age (RR = 1.30, 95% CI, 1.05-.61) or those treated with 8-12 g/m2 CED (RR = 2.06, 95% CI, 1.08-3.94) or ≥12 g/m2 CED (RR = 2.12, 95% CI, 1.09-4.12) compared to those treated with >0 to <4 g/m2 CED had an increased risk for oligospermia or azoospermia. LIMITATIONS, REASONS FOR CAUTION: Our study relied on the results of one semen analysis. ALL survivors who did not participate in SJLIFE or who declined to submit a semen analysis may also have biased our results regarding the proportion with azoospermia or oligospermia, since those who provided a semen specimen were less likely to have previously fathered children compared to those who did not. The lower rate of previous parenthood among participants may have resulted in a higher observed frequency of azoospermia and oligospermia. WIDER IMPLICATIONS OF THE FINDINGS: Treatment with <26 Gy CRT did not increase the risk of oligospermia or azoospermia, although a CED exceeding 8 g/m2 and an age at diagnosis of 5-9 years did increase risk of oligospermia and azoospermia. These findings can be used to counsel adult survivors of pediatric ALL. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the National Institutes of Health (grant numbers CA 21765, CA 195547, CA00874) and the American Lebanese Syrian Associated Charities (ALSAC). The authors have no competing interests to declare.
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Azoospermia/etiología , Supervivientes de Cáncer , Neoplasias del Sistema Nervioso Central/prevención & control , Irradiación Craneana/efectos adversos , Oligospermia/etiología , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Traumatismos por Radiación/epidemiología , Adulto , Factores de Edad , Antineoplásicos Alquilantes/efectos adversos , Antineoplásicos Alquilantes/uso terapéutico , Azoospermia/epidemiología , Azoospermia/fisiopatología , Neoplasias del Sistema Nervioso Central/secundario , Quimioradioterapia/efectos adversos , Estudios de Cohortes , Estudios Transversales , Relación Dosis-Respuesta en la Radiación , Estudios de Seguimiento , Hospitales Pediátricos , Humanos , Masculino , Oligospermia/epidemiología , Oligospermia/fisiopatología , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Prevalencia , Traumatismos por Radiación/fisiopatología , Índice de Severidad de la Enfermedad , Recuento de Espermatozoides , Estados Unidos/epidemiologíaRESUMEN
BACKGROUND: Survivors of childhood non-Hodgkin lymphoma (NHL) are at increased risk for chronic health conditions. The objective of this study was to characterize health conditions, neurocognitive function, and physical performance among a clinically evaluated cohort of 200 childhood NHL survivors. METHOD: Chronic health and neurocognitive conditions were graded as per a modified version of the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) and impaired physical function defined as performance < 10th percentile of normative data. Multivariable regression was used to investigate associations between sociodemographic characteristics, therapeutic exposures, and outcomes. RESULTS: Survivors were a median age of 10 years (range 1-19) at diagnosis and 34 years (range 20-58) at evaluation. Eighty-eight (44%) received radiation, 46 (23%) cranial radiation, and 69 (35%) high-dose methotrexate. Most prevalent CTCAE Grades 3-4 (severe life-threatening) conditions were obesity (35%), hypertension (9%), and impairment of executive function (13%), attention (9%), and memory (4%). Many had impaired strength (48%), flexibility (39%), muscular endurance (36%), and mobility (36%). Demographic and treatment-related factors were associated with the development of individual chronic diseases and functional deficits. CONCLUSIONS: Clinical evaluation identified a high prevalence of chronic health conditions, neurocognitive deficits, and performance limitations in childhood NHL survivors.
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Atención , Hipertensión , Linfoma no Hodgkin , Memoria , Trastornos Neurocognitivos , Obesidad , Sobrevivientes , Adolescente , Adulto , Niño , Preescolar , Enfermedad Crónica , Femenino , Estudios de Seguimiento , Humanos , Hipertensión/epidemiología , Hipertensión/etiología , Hipertensión/fisiopatología , Lactante , Linfoma no Hodgkin/mortalidad , Linfoma no Hodgkin/fisiopatología , Linfoma no Hodgkin/terapia , Masculino , Trastornos Neurocognitivos/epidemiología , Trastornos Neurocognitivos/etiología , Trastornos Neurocognitivos/fisiopatología , Obesidad/epidemiología , Obesidad/etiología , Obesidad/fisiopatología , Factores de RiesgoRESUMEN
OBJECTIVES: To estimate the prevalence of central precocious puberty (CPP) after treatment for tumours and malignancies involving the central nervous system (CNS) and examine repercussions on growth and pubertal outcomes. DESIGN: Retrospective study of patients with tumours near and/or exposed to radiotherapy to the hypothalamus/pituitary axis (HPA). PATIENTS AND MEASUREMENTS: Patients with CPP were evaluated at puberty onset, completion of GnRH agonist treatment (GnRHa) and last follow-up. Multivariable analysis was used to test associations between tumour location, sex, age at CPP, GnRHa duration and a diagnosis of CPP with final height <-2SD score (SDS), gonadotropin deficiency (LH/FSHD) and obesity, respectively. RESULTS: Eighty patients (47 females) had CPP and were followed for 11·4 ± 5·0 years (mean ± SD). The prevalence of CPP was 15·2% overall, 29·2% following HPA tumours and 6·6% after radiotherapy for non-HPA tumours. Height <-2SDS was more common at the last follow-up than at the puberty onset (21·4% vs 2·4%, P = 0·005). Obesity was more prevalent at the last follow-up than at the completion of GnRHa or the puberty onset (37·7%, 22·6% and 20·8%, respectively, P = 0·03). Longer duration of GnRHa was associated with increased odds of final height <-2SDS (OR = 2·1, 95% CI 1·0-4·3) and longer follow-up with obesity (OR = 1·3, 95% CI 1·1-1·6). LH/FSHD was diagnosed in 32·6%. There was no independent association between CPP and final height <-2SDS, and LH/FSHD and obesity in the subset of patients with HPA low-grade gliomas. CONCLUSIONS: Patients with organic CPP experience an incomplete recovery of growth and a high prevalence of LH/FSHD and obesity. Early diagnosis and treatment of CPP may limit further deterioration of final height prospects.
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Neoplasias del Sistema Nervioso Central/diagnóstico , Neoplasias del Sistema Nervioso Central/radioterapia , Pubertad Precoz/diagnóstico , Estatura , Niño , Preescolar , Femenino , Hormona Folículo Estimulante/deficiencia , Estudios de Seguimiento , Trastornos del Crecimiento/etiología , Humanos , Hipotálamo/efectos de la radiación , Lactante , Hormona Luteinizante/deficiencia , Masculino , Obesidad/etiología , Evaluación de Resultado en la Atención de Salud/métodos , Evaluación de Resultado en la Atención de Salud/estadística & datos numéricos , Irradiación Hipofisaria/efectos adversos , Pubertad Precoz/etiología , Radioterapia/efectos adversos , Estudios Retrospectivos , Factores de TiempoRESUMEN
Survivors of childhood acute lymphoblastic leukemia (ALL) treated with cranial radiation therapy (CRT) are at risk for cognitive impairment, although whether impairment progresses with age into adulthood is unknown. We report change in intelligence for 102 adult survivors of childhood ALL (age range, 26.6-54.7 years) during a median interval of 28.5 years. Survivors demonstrated lower Performance intelligence (mean, 95.3; standard deviation, 16.5; P = .005) but not Verbal IQ (mean, 97.4; standard deviation, 15.44; P = .09) at initial testing. Verbal intelligence declined an average of 10.3 points (P < .0001) during the follow-up interval with no decline in Performance intelligence. Decline was associated with current attention problems (P = .002) but not gender, CRT dose, age at CRT exposure, or years between testing. Results suggest long-term survivors of childhood ALL treated with CRT are at risk for progressive decline in verbal intellect, which may be driven by attention deficits. This trial was registered at clinicaltrials.gov as no. NCT00760656.
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Trastornos del Conocimiento/epidemiología , Trastornos del Conocimiento/etiología , Irradiación Craneana/efectos adversos , Inteligencia/efectos de la radiación , Leucemia-Linfoma Linfoblástico de Células Precursoras/radioterapia , Sobrevivientes/psicología , Adulto , Edad de Inicio , Atención/efectos de la radiación , Conducta/efectos de la radiación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Sobrevivientes/estadística & datos numéricos , Factores de TiempoRESUMEN
PTC299 is a novel, orally-bioavailable small molecule that selectively inhibits vascular endothelial growth factor receptor protein synthesis at the post-transcriptional level. Based on promising preclinical results, we conducted a pediatric phase I study to estimate the maximum tolerated dose, describe dose-limiting toxicities (DLT) and characterize the pharmacokinetic profile of PTC299 in children with recurrent CNS tumors. PTC299 was administered orally twice or three times daily, depending on the regimen. Four regimens were evaluated using the rolling 6 design, starting with 1.2 mg/kg/dose twice daily and escalating to 2 mg/kg/dose three times daily. Pharmacokinetic studies were performed during the first two courses. Twenty-seven children (14 male, median age 11.2, range 5.5-21 years) with recurrent brain tumors were treated; 21 were fully evaluable for toxicity assessment. Therapy was well-tolerated, and the only DLT was grade 3 hyponatremia. Grade three and grade four toxicities were uncommon in subsequent cycles. Median AUC0-Tlast values at the 2 mg/kg were similar to those observed in adults. The study was terminated while patients were being treated at the highest planned dose, due to hepatotoxicity encountered in the ongoing adult phase I studies. No complete or partial responses were observed. Two patients with low-grade gliomas were noted to have minor responses, and at the time of the study's closure, 5 children with low-grade gliomas had been on therapy for 8 or more courses (range 8-16). PTC299 was well-tolerated at the highest dose level tested (2 mg/kg/dose TID) in children with recurrent brain tumors and prolonged disease stabilization was seen in children with low-grade gliomas.
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Antineoplásicos/administración & dosificación , Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Imidazoles/administración & dosificación , Tiazoles/administración & dosificación , Adolescente , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Niño , Preescolar , Femenino , Humanos , Hiponatremia/inducido químicamente , Imidazoles/efectos adversos , Imidazoles/farmacocinética , Masculino , Recurrencia Local de Neoplasia/tratamiento farmacológico , Tiazoles/efectos adversos , Tiazoles/farmacocinética , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Female survivors of central nervous system (CNS) tumors are at an increased risk for gonadal damage and variations in the timing of puberty following radiotherapy and alkylating agent-based chemotherapy. PROCEDURE: Clinical and laboratory data were obtained from 30 evaluable female patients with newly diagnosed embryonal CNS tumors treated on a prospective protocol (SJMB 96) at St. Jude Children's Research Hospital (SJCRH). Pubertal development was evaluated by Tanner staging. Primary ovarian insufficiency (POI) was determined by Tanner staging and FSH level. Females with Tanner stage I-II and FSH > 15 mIU/ml, or Tanner stage III-V, FSH > 25 mIU/ml and FSH greater than LH were defined to have ovarian insufficiency. Recovery of ovarian function was defined as normalization of FSH without therapeutic intervention. RESULTS: Median length of follow-up post completion of therapy was 7.2 years (4.0-10.8 years). The cumulative incidence of pubertal onset was 75.6% by the age of 13. Precocious puberty was observed in 11.1% and delayed puberty in 11.8%. The cumulative incidence of POI was 82.8%, though recovery was observed in 38.5%. CONCLUSIONS: Treatment for primary CNS embryonal tumors may cause variations in the timing of pubertal development, impacting physical and psychosocial development. Female survivors are at risk for POI, a subset of whom will recover function over time. Further refinement of therapies is needed in order to reduce late ovarian insufficiency. Pediatr Blood Cancer 2015;62:329-334. © 2014 Wiley Periodicals, Inc.
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Neoplasias Encefálicas/radioterapia , Irradiación Craneoespinal/efectos adversos , Neoplasias de Células Germinales y Embrionarias/radioterapia , Insuficiencia Ovárica Primaria/diagnóstico , Pubertad Tardía/diagnóstico , Pubertad Precoz/diagnóstico , Adolescente , Adulto , Alquilantes/uso terapéutico , Niño , Preescolar , Femenino , Hormona Folículo Estimulante/sangre , Humanos , Adulto JovenRESUMEN
BACKGROUND: Cediranib (AZD2171), an oral pan-vascular endothelial growth factor (VEGF) inhibitor, was evaluated in this phase I study to determine its toxicity profile, dose-limiting toxicities (DLTs), maximum-tolerated dose (MTD), pharmacokinetics, and pharmacodynamics in children and adolescents with recurrent or refractory primary central nervous system (CNS) tumors. METHODS: Children and adolescents <22 years were enrolled into one of two strata: stratum Ithose not receiving enzyme-inducing anticonvulsant drugs (EIACD) and stratum IIthose receiving EIACDs. Dose-level selection was based on the continual reassessment method (CRM). RESULTS: Thirty-six eligible patients with median age of 12.7 years (range, 5.4-21.7 years) in stratum I (24 males) and 12 patients (7 males) in stratum II with median age of 13.4 years (range, 8.9-19.5 years) were initially assessed over a 4-week DLT evaluation period, modified to 6 weeks during the study. An MTD of 32 mg/m(2)/day was declared; however, excessive toxicities (transaminitis, proteinuria, diarrhea, hemorrhage, palmer-planter syndrome, reversible posterior leukoencephalopathy) in the expansion cohort treated at this dose suggested that it might not be tolerated over a longer time period. An expansion cohort at 20 mg/m(2)/day also demonstrated poor longer-term tolerability. Diffusion and perfusion MRI and PET imaging variables as well as biomarker analysis were performed and correlated with outcome. At 20 mg/m(2)/day, the median plasma area under the concentration-time curve at steady state was lower than that observed in adults at similar dosages. CONCLUSIONS: While the MTD of once daily oral cediranib in children with recurrent or progressive CNS tumors was initially defined as 32 mg/m(2)/day, this dose and 20 mg/m(2)/day were not considered tolerable over a protracted time period.
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Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Quinazolinas/uso terapéutico , Administración Oral , Adolescente , Disponibilidad Biológica , Niño , Preescolar , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Lactante , Imagen por Resonancia Magnética , Masculino , Tomografía de Emisión de Positrones , Estadística como Asunto , Factores de Tiempo , Adulto JovenRESUMEN
PURPOSE: Amplification and high levels of NOTCH ligand expression have been identified in several types of pediatric brain tumors. A phase I trial of weekly MK-0752, an oral inhibitor of gamma-secretase, was conducted in children with recurrent central nervous system (CNS) malignancies to estimate the maximum tolerated dose, dose-limiting toxicities (DLT), pharmacokinetics (PK), and pharmacodynamics of weekly MK-0752. METHODS: MK-0752 was administered once weekly at 1000 and 1400 mg/m(2) using a rolling-6 design. PK analysis was performed during the first course. NOTCH and HES expression was assessed by immunohistochemistry and Western blot. RESULTS: Ten eligible patients were enrolled (median age 8.8 years; range 3.1-19.2) with diagnoses of brain stem glioma (n = 3), ependymoma (n = 2), anaplastic astrocytoma (n = 1), choroid plexus carcinoma (n = 2), medulloblastoma (n = 1), and primitive neuroectodermal tumor (n = 1). Nine were evaluable for toxicity. One DLT of fatigue occurred in the six evaluable patients enrolled at 1000 mg/m(2)/dose. No DLTs were experienced by three patients treated at 1400 mg/m(2)/dose. Non-dose-limiting grade 3 toxicities included lymphopenia, neutropenia, and anemia. Median number of treatment courses was 2 (range 1-10). Two patients continued on therapy for at least 6 months. The median (range) C(max) of MK-0752 was 88.2 µg/mL (40.6 to 109 µg/mL) and 60.3 µg/mL (59.2 to 91.9 µg/mL) in patients receiving 1000 and 1400 mg/m(2)/week, respectively. NOTCH expression was decreased in six of seven patients for whom tissue was available at 24 h post-MK-0752. CONCLUSION: MK-0752 is well tolerated and exhibits target inhibition at 1000 and 1400 mg/m(2)/week in children with recurrent CNS malignancies.
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Derivados del Benceno/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Enfermedades del Sistema Nervioso Central/tratamiento farmacológico , Inhibidores Enzimáticos/uso terapéutico , Propionatos/uso terapéutico , Sulfonas/uso terapéutico , Administración Oral , Adolescente , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Área Bajo la Curva , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Derivados del Benceno/sangre , Enfermedades del Sistema Nervioso Central/sangre , Niño , Preescolar , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/sangre , Femenino , Estudios de Seguimiento , Regulación de la Expresión Génica/efectos de los fármacos , Proteínas de Homeodominio/metabolismo , Humanos , Masculino , Propionatos/sangre , Receptor Notch1/metabolismo , Proteínas Represoras/metabolismo , Sulfonas/sangre , Factores de Tiempo , Factor de Transcripción HES-1 , Adulto JovenRESUMEN
INTRODUCTION: In diffuse intrinsic pontine gliomas (DIPG), subtracting pre-contrast from post-contrast T1-weighted images (T1WI) occasionally reveals subtle, "occult" enhancement. We hypothesized that this represents intravascular enhancement related to angiogenesis and hence that these tumors should have greater blood volume fractions than do non-enhancing tumors. METHODS: We retrospectively screened MR images of 66 patients initially diagnosed with DIPG and analyzed pretreatment conventional and dynamic susceptibility contrast (DSC) perfusion MRI studies of 61 patients. To determine the incidence of occult enhancement, cerebral blood volume (CBV) values were compared in areas of occult enhancement (OcE), no enhancement (NE), and normal-appearing deep cerebellar white matter (DCWM). RESULTS: Tumors of 10 patients (16.4 %) had occult enhancement; those of 6 patients (9.8 %) had no enhancement at all. The average CBV in areas of occult enhancement was significantly higher than that in non-enhancing areas of the same tumor (P = .03), within DCWM in the same patient (P = .03), and when compared to anatomically paired/similar regions of interest (ROI) in patients with non-enhancing tumors (P = .005). CONCLUSION: Areas of OcE correspond to areas of higher CBV in DIPG, which may be an MRI marker for angiogenesis, but larger scale studies may be needed to determine its potential relevance to grading by imaging, treatment stratification, biopsy guidance, and evaluation of response to targeted therapy.
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Neoplasias del Tronco Encefálico/irrigación sanguínea , Neoplasias del Tronco Encefálico/patología , Glioma/irrigación sanguínea , Glioma/patología , Imagen por Resonancia Magnética , Neovascularización Patológica , Adolescente , Niño , Preescolar , Medios de Contraste , Femenino , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Estudios RetrospectivosRESUMEN
BACKGROUND: The incidence and spectrum of acute toxicities related to the use of bevacizumab (BVZ)-containing regimens in children are largely unknown. This report describes the adverse events in a recently completed large phase 2 trial of BVZ plus irinotecan (CPT-11) in children with recurrent central nervous system tumors. METHODS: Pediatric Brain Tumor Consortium trial-022 evaluated the efficacy and toxicity of BVZ (10 mg/kg administered intravenously) as a single agent for 2 doses given 2 weeks apart and then combined with CPT-11 every 2 weeks (1 course = 4 weeks) in children with recurrent central nervous system tumors. Children were treated until they experienced progressive disease, unacceptable toxicity or completed up to a maximum of 2 years of therapy. Toxicities were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0. Patients who received at least 1 dose of BVZ were included for toxicity assessment. RESULTS: Between October 2006 and June 2010, 92 patients evaluable for toxicity were enrolled and received 687 treatment courses. The most common toxicities attributable to BVZ included grade I-III hypertension (38% of patients), grade I-III fatigue (30%), grade I-II epistaxis (24%), and grade I-IV proteinuria (22%). Twenty-two patients (24%) stopped therapy due to toxicity. CONCLUSIONS: The combination of BVZ and CPT-11 was fairly well-tolerated, and most severe BVZ-related toxicities were rare, self-limiting, and manageable.
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Inhibidores de la Angiogénesis/efectos adversos , Anticuerpos Monoclonales Humanizados/efectos adversos , Neoplasias Encefálicas/tratamiento farmacológico , Camptotecina/análogos & derivados , Adolescente , Inhibidores de la Angiogénesis/administración & dosificación , Anticuerpos Monoclonales Humanizados/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Bevacizumab , Camptotecina/administración & dosificación , Niño , Preescolar , Esquema de Medicación , Fatiga/inducido químicamente , Hemorragia/inducido químicamente , Humanos , Hipertensión/inducido químicamente , Lactante , Inyecciones Intravenosas , Irinotecán , Recurrencia Local de Neoplasia , Proteinuria/inducido químicamente , Adulto JovenRESUMEN
High expression of ERBB2 has been reported in medulloblastoma and ependymoma; EGFR is amplified and over-expressed in brainstem glioma suggesting these proteins as potential therapeutic targets. We conducted a molecular biology (MB) and phase II study to estimate inhibition of tumor ERBB signaling and sustained responses by lapatinib in children with recurrent CNS malignancies. In the MB study, patients with recurrent medulloblastoma, ependymoma, and high-grade glioma (HGG) undergoing resection were stratified and randomized to pre-resection treatment with lapatinib 900 mg/m² dose bid for 7-14 days or no treatment. Western blot analysis of ERBB expression and pathway activity in fresh tumor obtained at surgery estimated ERBB receptor signaling inhibition in vivo. Drug concentration was simultaneously assessed in tumor and plasma. In the phase II study, patients, stratified by histology, received lapatinib continuously, to assess sustained response. Eight patients, on the MB trial (four medulloblastomas, four ependymomas), received a median of two courses (range 1-6+). No intratumoral target inhibition by lapatinib was noted in any patient. Tumor-to-plasma ratios of lapatinib were 10-20 %. In the 34 patients (14 MB, 10 HGG, 10 ependymoma) in the phase II study, lapatinib was well-tolerated at 900 mg/m² dose bid. The median number of courses in the phase II trial was two (range 1-12). Seven patients (three medulloblastoma, four ependymoma) remained on therapy for at least four courses range (4-26). Lapatinib was well-tolerated in children with recurrent or CNS malignancies, but did not inhibit target in tumor and had little single agent activity.
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Antineoplásicos/uso terapéutico , Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Neoplasias del Sistema Nervioso Central/metabolismo , Receptores ErbB/metabolismo , Quinazolinas/uso terapéutico , Adolescente , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Western Blotting , Neoplasias del Sistema Nervioso Central/patología , Neoplasias del Sistema Nervioso Central/cirugía , Niño , Preescolar , Ependimoma/tratamiento farmacológico , Ependimoma/metabolismo , Ependimoma/cirugía , Receptores ErbB/antagonistas & inhibidores , Femenino , Glioma/tratamiento farmacológico , Glioma/metabolismo , Glioma/patología , Glioma/cirugía , Humanos , Lactante , Lapatinib , Masculino , Meduloblastoma/tratamiento farmacológico , Meduloblastoma/metabolismo , Meduloblastoma/cirugía , Clasificación del Tumor , Quinazolinas/efectos adversos , Quinazolinas/farmacocinética , Resultado del Tratamiento , Adulto JovenRESUMEN
PURPOSE: We performed a phase-1 pharmacokinetic optimal dosing study of intraventricular topotecan (IT), administered daily 5×, to determine whether, the maximum tolerated dose of IT topotecan was also the pharmacokinetic optimal dose. PATIENTS AND METHODS: Patients received topotecan administered through an intraventricular access device (0.1 or 0.2 mg/dose), daily × 5 every other week 2× (Induction); every 3 weeks × 2 (Consolidation); then every 4 weeks for up to 11 courses (Maintenance). Ventricular CSF pharmacokinetic studies were performed on day 1, week 1 of induction, and in a subset of patients after a single intralumbar topotecan dose on day 1, week 3. RESULTS: Nineteen patients were enrolled. All were evaluable for toxicity and 18 were assessable for pharmacokinetics. Arachnoiditis requiring corticosteroid therapy occurred in or one of three patients at the 0.1 mg dose level and two of the initial three patients enrolled at the 0.2 mg dose level. All subsequent patients were therefore treated with concomitant dexamethasone. Pharmacokinetic evaluation after accrual of the first seven patients revealed that a topotecan lactone concentration >1 ng/ml for 8 hours was attained in all patients and thus, further dose escalation was not pursued. Results of simulation studies showed that at the dose levels evaluated, >99.9% of patients are expected to achieve CSF topotecan lactone concentrations >1 ng/ml for at least 8 hours. CONCLUSION: Intraventricular topotecan, 0.2 mg, administered daily for 5 days with concomitant dexamethasone is well tolerated and was defined to be the pharmacokinetic optimal dose in this trial.
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Antineoplásicos/administración & dosificación , Antineoplásicos/farmacocinética , Meningitis Aséptica/tratamiento farmacológico , Topotecan/administración & dosificación , Topotecan/farmacocinética , Niño , Preescolar , Dexametasona/administración & dosificación , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Infusiones Intraventriculares , Masculino , Dosis Máxima Tolerada , Meningitis Aséptica/etiologíaRESUMEN
Children with solid tumors, most of which are malignant, have an excellent prognosis when treated on contemporary regimens. These regimens, which incorporate chemotherapeutic agents and treatment modalities used for many decades, have evolved to improve relapse-free survival and reduce long-term toxicity. This review discusses the evolution of the treatment regimens employed for management of the most common solid tumors, emphasizing the similarities between contemporary and historical regimens. These similarities allow the use of historical patient cohorts to identify the late effects of successful therapy and to evaluate remedial interventions for these adverse effects.
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Neoplasias/historia , Neoplasias/terapia , Niño , Historia del Siglo XX , Historia del Siglo XXI , HumanosRESUMEN
Criteria for new drug approval include demonstration of efficacy. In neuro-oncology, this is determined radiographically utilizing tumor measurements on MRI scans. Limitations of this method have been identified where drug activity is not reflected in decreased tumor size. The RANO (Response Assessment in Neuro-Oncology) working group was established to address limitations in defining endpoints for clinical trials in adult neuro-oncology and to develop standardized response criteria. RAPNO was subsequently established to address unique issues in pediatric neuro-oncology. The aim of this paper is to delineate response criteria issues in pediatric clinical trials as a basis for subsequent recommendations.
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Antineoplásicos/uso terapéutico , Ensayos Clínicos como Asunto/métodos , Neoplasias de Tejido Nervioso/tratamiento farmacológico , Adolescente , Adulto , Niño , Preescolar , Ensayos Clínicos como Asunto/normas , Femenino , Humanos , Lactante , Recién Nacido , MasculinoRESUMEN
BACKGROUND: Prophylactic cranial irradiation has been a standard treatment in children with acute lymphoblastic leukemia (ALL) who are at high risk for central nervous system (CNS) relapse. METHODS: We conducted a clinical trial to test whether prophylactic cranial irradiation could be omitted from treatment in all children with newly diagnosed ALL. A total of 498 patients who could be evaluated were enrolled. Treatment intensity was based on presenting features and the level of minimal residual disease after remission-induction treatment. The duration of continuous complete remission in the 71 patients who previously would have received prophylactic cranial irradiation was compared with that of 56 historical controls who received it. RESULTS: The 5-year event-free and overall survival probabilities for all 498 patients were 85.6% (95% confidence interval [CI], 79.9 to 91.3) and 93.5% (95% CI, 89.8 to 97.2), respectively. The 5-year cumulative risk of isolated CNS relapse was 2.7% (95% CI, 1.1 to 4.3), and that of any CNS relapse (including isolated relapse and combined relapse) was 3.9% (95% CI, 1.9 to 5.9). The 71 patients had significantly longer continuous complete remission than the 56 historical controls (P=0.04). All 11 patients with isolated CNS relapse remained in second remission for 0.4 to 5.5 years. CNS leukemia (CNS-3 status) or a traumatic lumbar puncture with blast cells at diagnosis and a high level of minimal residual disease (> or = 1%) after 6 weeks of remission induction were significantly associated with poorer event-free survival. Risk factors for CNS relapse included the genetic abnormality t(1;19)(TCF3-PBX1), any CNS involvement at diagnosis, and T-cell immunophenotype. Common adverse effects included allergic reactions to asparaginase, osteonecrosis, thrombosis, and disseminated fungal infection. CONCLUSIONS: With effective risk-adjusted chemotherapy, prophylactic cranial irradiation can be safely omitted from the treatment of childhood ALL. (ClinicalTrials.gov number, NCT00137111.)
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Asparaginasa/administración & dosificación , Asparaginasa/efectos adversos , Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Niño , Preescolar , Terapia Combinada , Irradiación Craneana , Ciclofosfamida/administración & dosificación , Daunorrubicina/administración & dosificación , Dexametasona/administración & dosificación , Trasplante de Células Madre Hematopoyéticas , Humanos , Lactante , Mercaptopurina/administración & dosificación , Metotrexato/efectos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Inducción de Remisión/métodos , Factores de Riesgo , Prevención Secundaria , Análisis de Supervivencia , Resultado del Tratamiento , Vincristina/administración & dosificaciónRESUMEN
To estimate the sustained (≥8 weeks) objective response rate in pediatric patients with recurrent or progressive high-grade gliomas (HGG, Stratum A) or brainstem gliomas (BSG, Stratum B) treated with the combination of O6-benzylguanine (O6BG) and temozolomide(®) (TMZ). Patients received O6BG 120 mg/m(2)/d IV followed by TMZ 75 mg/m(2)/d orally daily for 5 consecutive days of each 28-day course. The target objective response rate to consider the combination active was 17%. A two-stage design was employed. Forty-three patients were enrolled; 41 were evaluable for response, including 25 patients with HGG and 16 patients with BSG. The combination of O6BG and TMZ was tolerable, and the primary toxicities were myelosuppression and gastrointestinal symptoms. One sustained (≥8 weeks) partial response was observed in the HGG cohort; no sustained objective responses were observed in the BSG cohort. Long-term (≥6 courses) stable disease (SD) was observed in 4 patients in Stratum A and 1 patient in Stratum B. Of the 5 patients with objective response or long-term SD, 3 underwent central review with 2 reclassified as low-grade gliomas. The combination of O6BG and TMZ did not achieve the target response rate for activity in pediatric patients with recurrent or progressive HGG and BSG.
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Antineoplásicos/uso terapéutico , Neoplasias del Tronco Encefálico/tratamiento farmacológico , Dacarbazina/análogos & derivados , Glioma/tratamiento farmacológico , Guanina/análogos & derivados , Adolescente , Neoplasias del Tronco Encefálico/mortalidad , Niño , Preescolar , Metilasas de Modificación del ADN/metabolismo , Enzimas Reparadoras del ADN/metabolismo , Dacarbazina/uso terapéutico , Quimioterapia Combinada/métodos , Femenino , Glioma/mortalidad , Guanina/uso terapéutico , Humanos , Estimación de Kaplan-Meier , Antígeno Ki-67/metabolismo , Masculino , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Temozolomida , Proteínas Supresoras de Tumor/metabolismo , Adulto JovenRESUMEN
A pilot study to investigate the feasibility of the addition of intrathecal (IT) mafosfamide to a regimen of concomitant multi-agent systemic chemotherapy followed by conformal radiation therapy (RT) for children <3 years with newly diagnosed embryonal CNS tumors was performed. Ninety-three newly diagnosed infants and children (<3 years) with embryonal CNS tumors were enrolled. Twenty weeks of systemic multi-agent chemotherapy commenced within 35 days of surgery. Patients without CSF flow obstruction (n = 71) received IT mafosfamide (14 mg) with chemotherapy. Localized (M(0)) patients with SD or better subsequently received RT followed by 20 additional weeks of chemotherapy. Second look surgery was encouraged prior to RT if there was an incomplete surgical resection at diagnosis. 71 evaluable patients with normal CSF flow received IT Mafosfamide with systemic chemotherapy; patients with M + disease were removed from protocol therapy at 20 weeks and those with PD at the time of progression. One and 5-year progression free survival (PFS) and overall survival (OS) for the cohort of 71 evaluable patients were 52 ± 6.5 % and 33 ± 13 %, and 67 ± 6.2 % and 51 ± 11 %, respectively. The 1-year Progression Free Survival (PFS) for M0 patients with medulloblastoma (MB, n = 20), supratentorial primitive neuroectodermal tumor (PNET, n = 9), and atypical teratoid rhabdoid tumor (ATRT, n = 12) was 80 ± 7 %, 67 ± 15 % and 27 ± 13 % and 5-year PFS was 65 ± 19 %, 37 ± 29 %, and 0 ± 0 %, respectively. The addition of IT mafosfamide to systemic chemotherapy in infants with embryonal CNS tumors was feasible. The PFS for M0 patients appears comparable to or better than most prior historical comparisons and was excellent for those receiving conformal radiotherapy.
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Antineoplásicos/administración & dosificación , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/radioterapia , Ciclofosfamida/análogos & derivados , Antineoplásicos/efectos adversos , Neoplasias Encefálicas/patología , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Supervivencia sin Enfermedad , Estudios de Factibilidad , Femenino , Humanos , Lactante , Inyecciones Espinales , Masculino , Estadificación de Neoplasias , Proyectos Piloto , Radioterapia ConformacionalRESUMEN
Investigations of long-term outcomes have been instrumental in designing safer and more effective contemporary therapies for pediatric hematological malignancies. Despite the significant therapeutic changes that have occurred over the last five decades, therapy modifications largely represent refinements of treatment protocols using agents and modalities that have been available for more than 30 years. This review summarizes major trends in the evolution of treatment of pediatric hematological malignancies since 1960 to support the relevance of the study of late effects of historical therapeutic approaches to the design and evaluation of contemporary treatment protocols and the follow-up of present-day survivors.
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Protocolos Antineoplásicos , Neoplasias Hematológicas/terapia , Niño , Terapia Combinada/tendencias , Enfermedad de Hodgkin/terapia , Humanos , Leucemia Mieloide Aguda/terapia , Linfoma no Hodgkin/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Sobrevivientes , Resultado del TratamientoRESUMEN
CONTEXT: More than 90% of children with favorable-risk Hodgkin lymphoma can achieve long-term survival, yet many will experience toxic effects from radiation therapy. Pediatric oncologists strive for maintaining excellent cure rates while minimizing toxic effects. OBJECTIVE: To evaluate the efficacy of 4 cycles of vinblastine, Adriamycin (doxorubicin), methotrexate, and prednisone (VAMP) in patients with favorable-risk Hodgkin lymphoma who achieve a complete response after 2 cycles and do not receive radiotherapy. DESIGN, SETTING, AND PATIENTS: Multi-institutional, unblinded, nonrandomized single group phase 2 clinical trial to assess the need for radiotherapy based on early response to chemotherapy. Eighty-eight eligible patients with Hodgkin lymphoma stage I and II (<3 nodal sites, no B symptoms, mediastinal bulk, or extranodal extension) enrolled between March 3, 2000, and December 9, 2008. Follow-up data are current to March 12, 2012. INTERVENTIONS: The 47 patients who achieved a complete response after 2 cycles received no radiotherapy, and the 41 with less than a complete response were given 25.5 Gy-involved-field radiotherapy. MAIN OUTCOME MEASURES: Two-year event-free survival was the primary outcome measure. A 2-year event-free survival of greater than 90% was desired, and 80% was considered to be unacceptably low. RESULTS: Two-year event-free survival was 90.8% (95% CI, 84.7%-96.9%). For patients who did not require radiotherapy, it was 89.4% (95% CI, 80.8%-98.0%) compared with 92.5% (95% CI, 84.5%-100%) for those who did (P = .61). Most common acute adverse effects were neuropathic pain (2% of patients), nausea or vomiting (3% of patients), neutropenia (32% of cycles), and febrile neutropenia (2% of patients). Nine patients (10%) were hospitalized 11 times (3% of cycles) for febrile neutropenia or nonneutropenic infection. Long-term adverse effects after radiotherapy were asymptomatic compensated hypothyroidism in 9 patients (10%), osteonecrosis and moderate osteopenia in 2 patients each (2%), subclinical pulmonary dysfunction in 12 patients (14%), and asymptomatic left ventricular dysfunction in 4 patients (5%). No second malignant neoplasms were observed. CONCLUSIONS: Among patients with favorable-risk Hodgkin lymphoma and a complete early response to chemotherapy, the use of limited radiotherapy resulted in a high rate of 2-year event-free survival. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00145600.