ABSTRACT
To improve survival in young children with malignant brain tumors, irradiation-avoiding or -minimizing marrow-ablative chemotherapy (HDCx) with autologous hematopoietic cell transplantation (AuHCT) has been investigated. We evaluated the outcome of 44 children with malignant brain tumors treated with HDCx and tandem AuHCT at Children's Hospital Los Angeles between June 1999 and July 2012. Forty-four children with malignant brain tumors were studied. Twenty-one had medulloblastoma/primitive neuro-ectodermal tumor, eight atypical teratoid/rhabdoid tumor (ATRT), five high-grade glioma, four malignant germ cell tumor, three ependymoma and three choroid plexus carcinoma. Twenty-nine patients received three tandem transplants and 15 received two tandem transplants, respectively. The 5-year PFS and overall survivals (OS) for all patients were 46.3±8.2% and 51.7±8.5%, respectively. The PFS and OS for 27 newly diagnosed patients were 68.9±9.9% and 73.5±9.3%, respectively, compared with 17 transplanted at relapse 11.8±9.8% (P<0.001) and 15.1±12.3% (P=0.0231), respectively. The 5-year PFS and OS in 13 previously unirradiated patients were 74±13% and 74±13% versus 33.2±9.8% and 40.2±10.6% in 31 irradiated patients (P=0.11 and P=0.239), respectively. One patient died of transplant-related toxicity. HDCx with tandem AuHCT is feasible and safe in children with malignant brain tumors with encouraging irradiation-free survival in newly diagnosed children.
Subject(s)
Brain Neoplasms/therapy , Hematopoietic Stem Cell Transplantation/methods , Myeloablative Agonists/therapeutic use , Adolescent , Adult , Brain Neoplasms/mortality , Child , Child, Preschool , Disease-Free Survival , Humans , Infant , Survival Analysis , Transplantation, Autologous , Treatment Outcome , Young AdultABSTRACT
Since 1991, three sequential prospective clinical trials have been conducted by the 'Head Start' (HS) Consortium in which young children with newly-diagnosed malignant central nervous system (CNS) tumors were treated with induction chemotherapy followed by single-cycle marrow-ablative chemotherapy and autologous hematopoietic rescue as a means of improving disease cure rate and quality of survival through avoidance (<6 years old at diagnosis) or reduction (6-10 years old) of brain irradiation. Bone Marrow (HS I) or filgrastim-mobilized peripheral hematopoietic cells (HS II and III) were obtained following recovery from the first and/or second induction cycles. Radiotherapy was administered following all chemotherapy only for patients with residual tumor following completion of induction or with age greater than 6 years at diagnosis. Two hundred and twenty-six children were enrolled on three consecutive HS trials with primary malignant CNS tumors and underwent marrow-ablative chemotherapy. The 100-day treatment-related mortality (TRM) steadily declined as did grade IV transplant-related oropharyngeal mucositis. Factors most likely associated with the decrease in TRM and morbidity are increasing experience with the marrow-ablative chemotherapy regimen combined with improved leukapheresis and post-reinfusion supportive care techniques, contributing toward improved overall survival.
Subject(s)
Central Nervous System Neoplasms/therapy , Clinical Trials as Topic/standards , Hematopoietic Stem Cell Transplantation/methods , Central Nervous System Neoplasms/mortality , Central Nervous System Neoplasms/radiotherapy , Child , Combined Modality Therapy , Hematopoietic Stem Cell Transplantation/adverse effects , Hematopoietic Stem Cell Transplantation/mortality , Hematopoietic Stem Cell Transplantation/trends , Humans , Induction Chemotherapy/methods , Morbidity/trends , Mortality/trends , Myeloablative Agonists/therapeutic use , Retrospective Studies , Transplantation, AutologousABSTRACT
Recurrence of malignant brain tumors results in a poor prognosis with limited treatment options. High-dose chemotherapy with autologous hematopoietic cell rescue (AHCR) has been used in patients with recurrent malignant brain tumors and has shown improved outcomes compared with standard chemotherapy. Temozolomide is standard therapy for glioblastoma and has also shown activity in patients with medulloblastoma/primitive neuro-ectodermal tumor (PNET), particularly those with recurrent disease. Temozolomide was administered twice daily on days -10 to -6, followed by thiotepa 300 mg/m(2) per day and carboplatin dosed using the Calvert formula or body surface area on days -5 to -3, with AHCR day 0. Twenty-seven patients aged 3-46 years were enrolled. Diagnoses included high-grade glioma (n=12); medulloblastoma/PNET (n=9); central nervous system (CNS) germ cell tumor (n=4); ependymoma (n=1) and spinal cord PNET (n=1). Temozolomide doses ranged from 100 mg/m(2) per day to 400 mg/m(2) per day. There were no toxic deaths. Prolonged survival was noted in several patients including those with recurrent high-grade glioma, medulloblastoma and CNS germ cell tumor. Increased doses of temozolomide are feasible with AHCR. A phase II study using temozolomide, carboplatin and thiotepa with AHCR for children with recurrent malignant brain tumors is being conducted through the Pediatric Blood and Marrow Transplant Consortium.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Brain Neoplasms/mortality , Brain Neoplasms/therapy , Hematopoietic Stem Cell Transplantation , Adolescent , Adult , Autografts , Carboplatin/administration & dosage , Child , Child, Preschool , Dacarbazine/administration & dosage , Dacarbazine/analogs & derivatives , Disease-Free Survival , Female , Follow-Up Studies , Humans , Male , Middle Aged , Neoplasm, Residual , Survival Rate , Temozolomide , Thiotepa/administration & dosageABSTRACT
BACKGROUND AND PURPOSE: DIBSGs have the worst prognosis among pediatric brain tumors with no improvement of outcome for several decades. In this study, we determined whether diffusion imaging could improve patient stratification and our understanding of the impact of therapies. MATERIALS AND METHODS: Nine baseline and 24 follow-up DTI studies performed in 9 patients on a 1.5T clinical MR imaging scanner were reviewed. ADC and FA were measured for the whole lesion and at 5 anatomic levels: the rostral medulla, caudal pons, midpons, rostral pons, and caudal midbrain. Reference data were obtained from 8 controls with normal brain stem, 6 patients with medulloblastoma, and 7 patients with pilocytic astrocytoma. RESULTS: ADC was higher in untreated DIBSG than in normal brain stem and medulloblastoma (1.14 ± 0.18 [×10⻳ mm²/s] versus 0.75 ± 0.06 and 0.56 ± 0.05, both P < .001). FA was lower in DIBSG than in normal brain stem (0.24 ± 0.04 versus 0.43 ± 0.02, P < .001) but was higher than that in pilocytic astrocytoma (0.17 ± 0.05, P < .05). Lower baseline ADC and higher FA correlated with a worse clinical course. Correlations were more significant at the caudal midbrain than in other regions. ADC decreased and FA increased after RT. Changes of FA after RT at the caudal midbrain correlated with event-free survival. CONCLUSIONS: Baseline ADC and FA of DIBSG revealed hypocellular tumors with extensive edema. Diffusion changes after therapy implied reduced edema but did not support a significant response to therapy. The significance of diffusion properties varied with anatomic locations, the caudal midbrain being particularly important.
Subject(s)
Astrocytoma/pathology , Brain Stem Neoplasms/pathology , Diffusion Magnetic Resonance Imaging/methods , Medulloblastoma/pathology , Anisotropy , Child , Child, Preschool , Disease-Free Survival , Female , Humans , Male , Medulla Oblongata/pathology , Mesencephalon/pathology , Pons/pathology , Predictive Value of Tests , PrognosisABSTRACT
BACKGROUND: The authors report the experience at the Children's Hospital Los Angeles with brain tumors diagnosed before 6 months of age, describing the characteristics of the patients, their tumors, treatment strategies, and prognostic factors. METHODS: Thirty-three children who were identified between 1979 and 2005 were included. Twelve were female (36%). There were 11 gliomas, 9 choroid plexus tumors, 8 medulloblastomas and supratentorial primitive neuroectodermal tumors (PNET), 2 atypical teratoid/rhabdoid tumors (ATRT), and 1 each of ependymoma, craniopharyngioma, and immature teratoma. Locations of primary tumors included 21 supratentorial (64%) and 7 posterior fossa, and 5 tumors involved both compartments. The treatment strategies included 5 patients with biopsy only, 18 less than gross total resections (Subject(s)
Brain Neoplasms
, Brain Neoplasms/diagnosis
, Brain Neoplasms/epidemiology
, Brain Neoplasms/pathology
, Brain Neoplasms/therapy
, Female
, Hospitals, Pediatric
, Humans
, Infant
, Infant, Newborn
, Los Angeles/epidemiology
, Male
, Prognosis
, Survival Rate
, Treatment Outcome
ABSTRACT
BACKGROUND AND PURPOSE: In a subset of in vivo MR spectra acquired from pediatric brain tumors, we have observed an unassigned peak. The goal of this study was to determine the molecule of origin, and the prevalence and concentration of this chemical in various pediatric brain tumors. MATERIALS AND METHODS: Single-voxel point-resolved spectroscopy (PRESS) spectra from 85 patients with brain tumors and 469 control subjects were analyzed. Citrate seemed to be a likely candidate, and model spectra of citrate were added to the basis set of metabolites for automated processing with use of LCModel software. Absolute "apparent" concentrations of citrate and the Cramer-Rao lower bounds (CRLB), indicators for the reliability of detection, were determined. RESULTS: "Apparent" citrate was detected in 26 of 85 patients with CRLB of less than 25%. Diffuse intrinsic brain stem glioma (DIBSG) had the highest mean concentration (4.0 +/- 1.1 mmol/kg in all subjects), and 8 of 12 patients had CRLB less than 25%. A significant reduction of citrate (P < .01) was observed in 6 DIBSGs that had follow-up MR spectroscopy studies after radiation therapy. "Apparent" citrate with CRLB less than 25% was detected in 5 of 22 medulloblastomas (mean citrate, 2.9 +/- 2.2 mmol/kg), in 5 of 14 ependymomas (2.6 +/- 1.8 mmol/kg), 5 of 14 astrocytomas (1.9 +/- 1.2 mmol/kg), and 3 of 23 pilocytic astrocytomas (1.4 +/- 1.1 mmol/kg). In control subjects older than 6 months, CRLB less than 25% was not observed, whereas CRLB less than 25% was observed in 39 of 194 subjects younger than 6 months,. CONCLUSION: MR signal consistent with citrate was observed in pediatric brain tumors and in the developing brain of infants younger than 6 months.
Subject(s)
Brain Neoplasms/metabolism , Brain/metabolism , Citric Acid/metabolism , Magnetic Resonance Spectroscopy/methods , Adolescent , Adult , Biomarkers/metabolism , Child , Child, Preschool , Female , Humans , Infant , Infant, Newborn , MaleABSTRACT
PURPOSE: Our aims were to evaluate the metabolic profiles of pediatric brain tumors with short echo time (TE) MR spectroscopy and absolute quantitation of metabolite concentrations (in mmol/kg of tissue) and to describe metabolic features that distinguish individual tumor types and that may help to improve preoperative diagnosis of specific tumors. METHODS: MR imaging examinations of 60 patients with untreated brain tumors (14 medulloblastomas, 5 anaplastic astrocytomas, 3 low-grade astrocytomas, 17 pilocytic astrocytomas, 4 anaplastic ependymomas, 5 ependymomas, 3 choroid plexus papillomas, 3 choroid plexus carcinomas, and 6 pineal germinomas) were reviewed. Single-voxel proton MR spectroscopy with a TE of 35 ms was performed and absolute metabolite concentrations were determined by using fully automated quantitation. RESULTS: Taurine (Tau) was significantly elevated in medulloblastomas (P < .00001) compared with all other tumors pooled (All Other). Tau was also observed consistently, at lower concentration, in pineal germinomas. Creatine (Cr) was significantly reduced in pilocytic astrocytomas, distinguishing them from All Other (P < .000001). The MR spectra of choroid plexus papillomas exhibited low Cr (P < .01) concentrations; however, myoinositol was elevated (P < .01) and total choline (tCho) (P < .0001) was reduced relative to All Other. Choroid plexus carcinomas had low Cr (P < .01 versus All Other) and the lowest Cr/tCho ratio (P < .0001 versus All Other) among all tumors studied. Guanidinoacetate was reduced in low-grade astrocytomas and anaplastic astrocytomas (P < .00001) versus All Other, whereas ependymoma and anaplastic ependymomas exhibited particularly low N-acetylaspartate (P < .00001 versus All Other). CONCLUSION: Quantitative proton MR spectroscopy reveals features of pediatric brain tumors that are likely to improve preoperative diagnoses.
Subject(s)
Brain Neoplasms/diagnosis , Brain Neoplasms/metabolism , Magnetic Resonance Spectroscopy , Adolescent , Child , Child, Preschool , Humans , Infant , Magnetic Resonance Spectroscopy/methods , Preoperative CareABSTRACT
Early attempts to use high-dose chemotherapy technology in order to improve the effect of nitrosourea on high-grade gliomas resulted in minimal benefit as well as in severe toxicity. Since then, other drugs have been applied in conjunction with either autologous bone marrow or peripheral blood stem cells, including thiotepa, etoposide, melphalan, cyclophosphamide, and busulfan. The data suggest benefit in recurrent primitive neuroectodermal tumors (PNET), in newly diagnosed young children with PNET and possibly in young children with newly diagnosed ependymoma, as a strategy not only to improve tumor-free survival but also to avoid exposure of the young brain to irradiation. In other tumors such as recurrent ependymoma and newly diagnosed or recurrent brain stem glioma, high-dose chemotherapy remains ineffective. New protocols under evaluation include new agents, multiple cycles of high-dose chemotherapy and allogeneic transplantation as immunotherapeutic approach.
Subject(s)
Antineoplastic Agents/therapeutic use , Brain Neoplasms/drug therapy , Drug Therapy/methods , Brain Neoplasms/surgery , Child , Child, Preschool , Combined Modality Therapy/methods , Ependymoma/drug therapy , Ependymoma/surgery , Glioma/drug therapy , Glioma/surgery , Humans , Infant , Infant, Newborn , Medulloblastoma/drug therapy , Medulloblastoma/surgery , Neuroectodermal Tumors/drug therapy , Neuroectodermal Tumors/surgery , Practice Patterns, Physicians'ABSTRACT
Despite prolonged therapy (18 months), children with advanced non-lymphoblastic, non-Hodgkin's lymphoma (NHL) treated on previous Children's Cancer Group (CCG) trials achieved less than a 60% 5-year event-free survival (EFS). In this study we piloted a shorter but more intensive protocol ('Orange') to determine the feasibility, safety, and efficacy of this alternative treatment approach. Thirty-nine children received a CHOP-based induction, etoposide/ifosfamide consolidation, DECAL (dexamethasone, etoposide, cisplatin, cytosine arabinoside (Ara-C) and L-asparaginase) intensification, and either one or two similar but less intense maintenance courses. Patients were stratified to standard-risk (5 months) vs high-risk (7 months) treatment. High risk was defined as either bone marrow disease, CNS disease, mediastinal mass > or = one-third thoracic diameter at T5 and/or LDH > or =2 times institutional upper limits of normal. All other patients were considered to be standard risk. Results were compared with the previous CCG NHL study (CCG-503). Sixteen and 23 patients were considered standard- vs. high-risk, respectively. The 5-year EFS and overall survival (OS) were 77 +/- 7% and 80 +/- 7%, respectively. The 5-year EFS and OS were significantly better in the standard- vs. high-risk subgroups (100% vs. 61 +/- 11%) (P < 0.003) and (100% vs. 65 +/- 11%) (P < 0.01), respectively. Lactate dehydrogenase (LDH) > or =2 x normal (NL) was associated with significantly poorer outcomes (LDH > or =2 x NL vs. <2 x NL) (5-year EFS: 55 +/- 12% vs. 100%) (P < 0.0004). This CCG hybrid regimen, 'Orange', of short and more intensive therapy resulted in a significant improvement in outcomes compared with the previous CCG trial of more prolonged but less intense therapy. This regimen that deletes high-dose methotrexate, if confirmed in a larger trial, could be considered as an alternative treatment approach in children without high tumor burdens (LDH <2 x NL) and Murphy stage III disease.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Lymphoma, Non-Hodgkin/drug therapy , Adolescent , Adult , Child , Child, Preschool , Disease-Free Survival , Female , Follow-Up Studies , Humans , L-Lactate Dehydrogenase/metabolism , Lymphoma, Non-Hodgkin/enzymology , Lymphoma, Non-Hodgkin/pathology , Male , Methotrexate/administration & dosage , Neoplasm Staging , Pilot Projects , Prognosis , Treatment OutcomeABSTRACT
Malignant astrocytoma is one of the most deadly primary central nervous system tumors. Although significant progress has been made in understanding the molecular pathways that lead to the development of these tumors in adults, comparatively little analysis has been done in childhood astrocytomas, which are less common and have a more favorable prognosis. Our previous studies of an institutional cohort of children with malignant gliomas suggested the existence of distinct molecular pathways of tumorigenesis in younger versus older children, based on the finding of a high frequency of TP53 mutations in tumors from children >3 years of age at diagnosis, compared with those from younger children. In the current study, the association between TP53 mutations and age was examined in greater detail using the multi-institutional group of children enrolled in Children's Cancer Group Study 945, the largest cohort of childhood high-grade gliomas analyzed to date. Seventy-seven tumors with centrally reviewed diagnoses of anaplastic astrocytoma or glioblastoma multiforme had sufficient archival histopathological material for microdissection-based genotyping. Sections were examined histologically, and topographic targets that contained malignant tissue were isolated by microdissection and subjected to PCR-based amplification and sequencing of TP53 exons 5-8. Twenty-six tumors (33.8%) had mutations in those exons. Mutations were observed in 2 of 17 tumors (11.8%) from children <3 years of age at diagnosis versus 24 of 60 tumors (40%) from older children, a difference that was statistically significant (P = 0.04), in agreement with our previous results. Whereas malignant gliomas in older children have a frequency of mutations comparable to tumors that arise in young adults, those from children <3 years old do not. The association between age and frequency of TP53 mutations among pediatric malignant gliomas indicates the probable existence of two distinct pathways of molecular tumorigenesis in younger versus older children.
Subject(s)
Astrocytoma/genetics , Brain Neoplasms/genetics , Genes, p53/genetics , Glioblastoma/genetics , Mutation , Adolescent , Age Factors , Astrocytoma/pathology , Brain Neoplasms/pathology , Child , Child, Preschool , Cohort Studies , Glioblastoma/pathology , Humans , InfantABSTRACT
This study evaluated the quality of life and neuropsychologic functioning among patients enrolled between 1989 and 1993 in the First International CNS Germ-Cell Tumor Study. Quality-of-life questionnaires (Short Form-36 or Child Health Questionnaire) were completed on 43 patients at median follow-up of 6.1 years after diagnosis (range, 4.5-8.8 years), and intellectual and academic testing was performed on 22 patients. Psychosocial and physical functioning of patients aged 19 years and older at follow-up was within the average range, whereas the same functioning for patients aged 18 years and younger, as reported by their parents at follow-up, was low average and borderline, respectively. Overall psychosocial and physical health summary scores were positively correlated with age at diagnosis for both groups combined. Those who received CNS radiation therapy (n = 29) reported significantly worse physical health, but similar psychosocial health, compared with those treated without radiation. Neuropsychologic testing indicated full-scale and verbal IQ, reading, spelling, and math skills in the average range, and performance IQ in the low average range. Intelligence and math skills were positively correlated with age at diagnosis. Those with germinomas significantly outperformed those with nongerminomatous/ mixed tumors on all neuropsychological measures administered. Younger patients diagnosed with CNS germ-cell tumors are at increased risk for psychosocial and physical problems as well as neuropsychologic deficits. Exposure to irradiation adversely affects overall physical functioning, whereas tumor pathology appears to be a salient neurocognitive risk factor. Collaborative and randomized studies are required to further elucidate the late effects arising from factors such as age at diagnosis, tumor histology, level of irradiation therapy, and chemotherapy toxicity among these young and potentially curable patients.
Subject(s)
Central Nervous System Neoplasms/psychology , Intelligence , Neoplasms, Germ Cell and Embryonal/psychology , Quality of Life , Adolescent , Adult , Aged , Central Nervous System Neoplasms/pathology , Central Nervous System Neoplasms/radiotherapy , Child , Cognition Disorders/etiology , Female , Follow-Up Studies , Health Status , Humans , Male , Middle Aged , Neoplasms, Germ Cell and Embryonal/pathology , Neoplasms, Germ Cell and Embryonal/radiotherapy , Neuropsychological Tests , Radiotherapy/adverse effectsABSTRACT
BACKGROUND: In the past, patients with metastatic retinoblastoma have had a poor prognosis when treated with conventional modalities. In the current study, the authors evaluated the use of combined intensive conventional chemotherapy, high dose chemotherapy with autologous stem cell rescue (ASCR), and radiation therapy. METHODS: Four patients with metastatic retinoblastoma were treated. All had orbital and bone marrow metastases. In addition, three patients had bone metastases and two patients had liver metastases. None had central nervous system disease. Patients received intensive conventional chemotherapy that included vincristine, cyclophosphamide, etoposide, and either cisplatin or carboplatin. Stem cells were harvested after bone marrow disease was no longer detectable. High dose chemotherapy with carboplatin (500 mg/m(2)/day x 3 days or area under the curve = 7 via the Calvert formula) and thiotepa (300 mg/m(2)/day x 3 days) with (n = 3 patients) or without (n = 1 patient) etoposide (250 mg/m(2)/day x 3 days) was administered with ASCR. Sites that originally harbored bulky disease were irradiated after recovery from the high dose chemotherapy. RESULTS: The therapy was associated with substantial acute hematopoietic and mucosal toxicities. At last follow-up, all four patients had survived event free from 46-80 months after the diagnosis of metastatic disease. CONCLUSIONS: The treatment strategy described in the current study is effective for patients with metastatic retinoblastoma that does not involve the central nervous system. However, a multicenter trial should be considered to evaluate it in a larger group of patients.
Subject(s)
Antineoplastic Agents/therapeutic use , Bone Marrow Neoplasms/therapy , Hematopoietic Stem Cell Transplantation , Retinal Neoplasms/therapy , Retinoblastoma/therapy , Adolescent , Adult , Antineoplastic Agents/adverse effects , Bone Marrow Neoplasms/secondary , Combined Modality Therapy , Female , Follow-Up Studies , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Male , Retinal Neoplasms/mortality , Retinal Neoplasms/pathology , Retinal Neoplasms/radiotherapy , Retinoblastoma/mortality , Retinoblastoma/radiotherapy , Retinoblastoma/secondary , Survival Analysis , Treatment OutcomeABSTRACT
OBJECTIVE: This study was performed to evaluate the association between the type of neurosurgeon (general or pediatric) and either the extent of tumor removal or the frequency of complications in children undergoing malignant brain tumor resections. METHODS: Data were analyzed from three recent Children's Cancer Group studies: two on medulloblastomas/primitive neuroectodermal tumors and one on malignant gliomas. Neurosurgeons were classified as general neurosurgeons, as designated pediatric neurosurgeons in their institutions, or as members of the American Society of Pediatric Neurosurgeons (ASPN), which requires pediatric neurosurgical experience and practice standards. RESULTS: Data forms from 732 children were analyzed; 485 were from children with medulloblastomas/primitive neuroectodermal tumors, and 247 were from children with malignant gliomas. Operations were performed by 269 neurosurgeons, including 213 general neurosurgeons, 29 designated pediatric neurosurgeons, and 27 ASPN members. The mean number of operations per surgeon was 1.8, 4.9, and 7.6 for general neurosurgeons, designated pediatric neurosurgeons, and ASPN members, respectively. There was a significant relationship between the extent of tumor resection or the amount of residual tumor and the type of neurosurgeon. Designated pediatric neurosurgeons and ASPN members were more likely to remove more than 90% of the tumor and to leave less than 1.5 cc of residual tumor than were general neurosurgeons (P<0.05). In these studies, the probability of extensive tumor removal correlated with the number of operations the neurosurgeon performed (P<0.01). Neurological complications occurred in the following proportion of cases: general neurosurgeons, 23%; designated pediatric neurosurgeons, 32%; and ASPN members, 18%. CONCLUSION: Pediatric neurosurgeons are more likely than general neurosurgeons to extensively remove malignant pediatric brain tumors. In these tumors, extent of removal has been demonstrated to influence survival.
Subject(s)
Brain Neoplasms/surgery , Cerebellar Neoplasms/surgery , Glioma/surgery , Medulloblastoma/surgery , Neuroectodermal Tumors, Primitive/surgery , Neurosurgical Procedures , Pediatrics/methods , Child , Humans , Neoplasm, Residual , Treatment OutcomeABSTRACT
Forty-two patients (29 newly diagnosed) with high grade gliomas (n = 37), medulloblastoma (n = 2) or non-biopsied tumors (n = 3) with supratentorial (n = 24), brain stem (n = 11), posterior fossa (n = 5) or spinal (n = 2) location were eligible for this study with adequate organ function and no bone marrow tumor infiltration. Median patient age was 12.2 years (range, 0.7-46.8). A total of 600 mg/m2 BCNU, 900 mg/m2 thiotepa and 1500 or 750 mg/m2 etoposide (VP-16) was administered followed by autologous bone marrow reinfusion (ABMR). Twenty-one newly diagnosed patients received local irradiation (RT) post ABMR. Nine early deaths were observed (21%), as well as one secondary graft failure. Half of the patients aged 18 years or older experienced toxic deaths, whereas only 15% of patients younger than 18 years experienced toxic death (P = 0.05). Of 25 evaluable newly diagnosed patients, 20% achieved complete remission (CR) and 4% partial remission (PR), while 28% remained in continuing complete remission (CCR) and 44% remained with stable disease prior to RT. Of eight evaluable patients with recurrent disease, one achieved CR and two PR, while one remained in CCR and four with stable disease for 1 to 110.2 months. Overall survival was 36%, 24% and 17% at 1, 2 and 3 years following ABMR, with three newly diagnosed patients and one patient treated for recurrent disease being alive, without disease progression 64.4, 67.0, 86.3 and 110.2 months after ABMR, respectively. The combination of high-dose BCNU/ thiotepa/VP-16 has substantial toxicity but definite activity for high risk CNS tumors. Similar protocols with lower toxicity merit further evaluation in both newly diagnosed and recurrent CNS tumors.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/toxicity , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bone Marrow Transplantation , Central Nervous System Neoplasms/complications , Central Nervous System Neoplasms/therapy , Adolescent , Adult , Carmustine/administration & dosage , Carmustine/toxicity , Central Nervous System Neoplasms/mortality , Chemical and Drug Induced Liver Injury , Child , Child, Preschool , Combined Modality Therapy , Disease-Free Survival , Etoposide/administration & dosage , Etoposide/toxicity , Female , Graft Survival , Hematologic Diseases/chemically induced , Humans , Infant , Kidney Diseases/chemically induced , Lung Diseases/chemically induced , Male , Middle Aged , Multiple Organ Failure/chemically induced , Nervous System Diseases/chemically induced , Survival Rate , Thiotepa/administration & dosage , Thiotepa/toxicity , Transplantation, Autologous , Treatment OutcomeABSTRACT
PURPOSE: To evaluate prospectively the effects on survival, relapse-free survival, and patterns of relapse of reduced-dose (23.4 Gy in 13 fractions) compared with standard-dose (36 Gy in 20 fractions) neuraxis irradiation in patients 3 to 21 years of age with low-stage medulloblastoma, minimal postoperative residual disease, and no evidence of neuraxis disease. PATIENTS AND METHODS: The Pediatric Oncology Group and Children's Cancer Group randomized 126 patients to the study. All patients received posterior fossa irradiation to a total dose of 54 Gy in addition to the neuraxis treatment. Patients were staged postoperatively with contrast-enhanced cranial computed tomography, myelography, and CSF cytology. Of the registered patients, 38 were ineligible. RESULTS: The planned interim analysis that resulted in closure of the protocol showed that patients randomized to the reduced neuraxis treatment had increased frequency of relapse. In the final analysis, eligible patients receiving standard-dose neuraxis irradiation had 67% event-free survival (EFS) at 5 years (SE = 7.4%), whereas eligible patients receiving reduced-dose neuraxis irradiation had 52% event-free survival at 5 years (SE = 7.7%) (P =.080). At 8 years, the respective EFS proportions were also 67% (SE = 8.8%) and 52% (SE = 11%) (P =.141). These data confirm the original one-sided conclusions but suggest that differences are less marked with time. CONCLUSION: Reduced-dose neuraxis irradiation (23.4 Gy) is associated with increased risk of early relapse, early isolated neuraxis relapse, and lower 5-year EFS and overall survival than standard irradiation (36 Gy). The 5-year EFS for patients receiving standard-dose irradiation is suboptimal, and improved techniques and/or therapies are needed to improve ultimate outcome. Chemotherapy may contribute to this improvement.
Subject(s)
Central Nervous System/radiation effects , Infratentorial Neoplasms/radiotherapy , Medulloblastoma/radiotherapy , Skull Base Neoplasms/radiotherapy , Adolescent , Adult , Central Nervous System Neoplasms/secondary , Child , Child, Preschool , Cranial Fossa, Posterior , Disease-Free Survival , Dose-Response Relationship, Radiation , Female , Humans , Infratentorial Neoplasms/surgery , Male , Medulloblastoma/surgery , Neoplasm Staging , Neoplasm, Residual/radiotherapy , Prospective Studies , Radiotherapy Dosage , Radiotherapy, Adjuvant , Recurrence , Skull Base Neoplasms/surgery , Statistics, Nonparametric , Treatment FailureABSTRACT
Virtually all reports on the effects of focal brain lesions upon specific neuropsychological functions are based upon estimates of cognitive loss in persons following a lesion, without proof of premorbid capacity. This report presents the case of a 19-year-old left-handed male with assessment of Verbal and Performance I.Q. testing 1 year prior to a subsequent brain tumor for reasons unrelated to the neoplasm. The patient was then re-tested 23 months later, following the diagnosis and treatment of a supratentorial ependymoma in the right parietal region. His multi-modal treatment regimen included a partial surgical resection of the tumor, cranio-spinal irradiation with focal boost to the primary site, and chemotherapy. Results demonstrate a striking 58-point decline in the Wechsler Adult Intelligence Scale - Revised (WAIS - R) Performance I. Q. with no significant change in Verbal I.Q. These findings clearly document the important cognitive functions associated with the right parietal lobe.
Subject(s)
Antineoplastic Agents/therapeutic use , Brain Neoplasms/drug therapy , Brain Neoplasms/surgery , Cognition Disorders/etiology , Ependymoma/complications , Ependymoma/therapy , Parietal Lobe/surgery , Adult , Cognition Disorders/diagnosis , Combined Modality Therapy , Humans , Male , Wechsler ScalesABSTRACT
PURPOSE: To examine the impact of initial CNS involvement on outcome and patterns of failure in patients with disseminated small noncleaved-cell lymphoma and B-cell leukemia who were treated in four successive Children's Cancer Group trials. PATIENTS AND METHODS: Of 462 patients with disseminated disease, 49 (10.6%) had CNS disease at diagnosis (CNS+). CNS disease included meningeal disease or CNS parenchymal masses with or without cranial neuropathies (CSF+/Mass; CNPs) in 36 patients and isolated CNPs in 13. Of the CNS+ patients, 28 had M2 (5% to 25% blasts) or M3 (> 25% blasts) bone marrow involvement. All patients received protocol-based systemic and intrathecal chemotherapy. Thirty-six patients also received CNS irradiation. RESULTS: Relapses occurred in 21 (43%) of 49 patients, predominantly in the CNS (71%) and bone marrow (52%). The 3-year event-free survival +/- SE for all patients with CNS+ disease was 45% +/- 7%. Patients with CSF+/Mass had a nominally higher treatment failure rate compared with patients with CNS- after adjusting for marrow status and lactate dehydrogenase (LDH) diagnosis, with a relative failure rate (RFR) of 1.52 (95% confidence interval [CI], 0.88 to 2.6; P =.15). In comparison, the RFRs for patients with M2 or M3 marrow and for those with LDH levels greater than 500 IU/L after adjusting for CNS disease were 1.4 (95% CI, 0.96 to 2.0; P =.029) and 2.2 (95% CI, 1.5 to 3.0; P <.001), respectively. The RFR for patients with isolated CNPs was 0.87 (95% CI, 0.36 to 2.1; P =.76). CONCLUSION: We conclude that, with the treatments used during the period covered by these studies, the presence of CSF+/Mass CNS disease at diagnosis was associated with a nominally worse outcome independent of initial bone marrow status and LDH level, but the effect was not statistically significant.
Subject(s)
Central Nervous System Neoplasms/pathology , Leukemia, B-Cell/pathology , Lymphoma, Non-Hodgkin/pathology , Adolescent , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Central Nervous System Neoplasms/mortality , Central Nervous System Neoplasms/therapy , Child , Child, Preschool , Combined Modality Therapy , Cyclophosphamide/therapeutic use , Disease-Free Survival , Doxorubicin/therapeutic use , Female , Humans , Infant , Leukemia, B-Cell/drug therapy , Leukemia, B-Cell/mortality , Lymphoma, Non-Hodgkin/drug therapy , Lymphoma, Non-Hodgkin/mortality , Male , Methotrexate/therapeutic use , Prednisone/therapeutic use , Proportional Hazards Models , Survival Analysis , Treatment Outcome , Vincristine/therapeutic useABSTRACT
Surgery plays an important part in the overall management of primary central nervous system (CNS) germ cell tumors. While the general surgical objectives in patients with these neoplasms are similar to those with other types of CNS tumors, to obtain an accurate histopathologic diagnosis and to contribute towards improving patient survival the unique features of germ cell tumors have necessitated novel treatment strategies. Pure germinomas are exquisitely radiosensitive, and prior studies have shown no survival benefit from radical resection of such lesions. However, a significant proportion of CNS GCTs contain admixtures of nongerminomatous GCT (NGGCT) elements and are less responsive to aggressive chemotherapy and irradiation. Biopsy of these malignant GCTs carries the risk of histologic sampling error. Nevertheless, a proportion of NGGCTs produce tumor markers detectable in serum or CSF and may be accurately diagnosed without surgical intervention. Although the role of radical surgical resection has not been definitively demonstrated in the literature, recent data from an international cooperative trial suggest a survival benefit from radical resection of localized NGGCTs. Lastly, increasing experience has supported the role of delayed resective ("second-look") surgery for patients with negative tumor markers but residual radiographic abnormalities after initial chemotherapy. Resection of such lesions has typically yielded necrosis or teratoma, which may be cured by surgical resection, and obviated the need for additional chemotherapy or irradiation.
Subject(s)
Brain Neoplasms/surgery , Brain/pathology , Neoplasms, Complex and Mixed/surgery , Neoplasms, Germ Cell and Embryonal/surgery , Biomarkers, Tumor , Biopsy , Brain Neoplasms/diagnosis , Child , Humans , Neoplasm, Residual/diagnosis , Neoplasm, Residual/surgery , Neoplasms, Complex and Mixed/diagnosis , Neoplasms, Germ Cell and Embryonal/diagnosis , Reoperation , Selection BiasABSTRACT
Radical surgical resection of newly diagnosed glioblastoma multiforme (GBM) and anaplastic astrocytoma (AA) in children is the most powerful favorable predictor of outcome when followed by radiation therapy and chemotherapy. In the largest study of childhood malignant gliomas (Children's Cancer Group Study, CCG-945), which was conducted between 1985 and 1992, a radical surgical resection was defined as greater than 90% resection of tumor as seen on imaging studies, predominantly using MRI. Of note is that the training of the neurosurgeon (i.e. in pediatric versus adult neurosurgery) had a significant impact on the extent of surgical resection in patients enrolled on this study. In children with recurrent malignant glial tumors, radical surgical resection has been shown to predict a more favorable survival for children, both with GBM and AA, undergoing high-dose (marrow-ablative) chemotherapy with hematopoietic stem cell rescue. In these studies, radical surgical resection was defined as resection leaving less than 3 cm maximal diameter of enhancing tumor mass in place.
Subject(s)
Brain Neoplasms/surgery , Glioma/surgery , Neurosurgical Procedures/methods , Antineoplastic Agents/therapeutic use , Brain Neoplasms/drug therapy , Brain Neoplasms/radiotherapy , Chemotherapy, Adjuvant , Child , Glioma/drug therapy , Glioma/radiotherapy , Humans , Neoadjuvant Therapy , Radiotherapy, Adjuvant , Recurrence , Survival AnalysisABSTRACT
The outcome for children with malignant brain tumors has improved modestly in recent years. Notable is the improved 5-yr disease-free survival for those children with 'standard-risk' medulloblastoma and other primitive neuro-ectodermal tumors (PNET) (i.e. tumors without neuraxis dissemination at presentation). For other children with newly diagnosed malignant brain tumors, especially in the absence of radical surgical resection, the outcome remains poor despite surgery, irradiation and conventional chemotherapy. Patients whose tumors recur despite initial therapy continue to experience a dismal outlook with these conventional strategies of treatment. In an attempt to improve the outlook for such brain tumor patients with poor prognoses, strategies utilizing high-dose (potentially myeloablative) chemotherapy with autologous stem cell rescue have been developed. These studies, conducted initially in patients with recurrent tumors, were then extended to patients with newly diagnosed malignant gliomas and brain-stem tumors, as well as to young children with various malignant brain tumors at diagnosis in an attempt to avoid irradiation to the brain. The results of several of these studies are summarized, updating information reviewed in an earlier summary in 1996, demonstrating durable disease-free survival for a proportion of patients with recurrent malignant gliomas and medulloblastomas/PNET, as well as encouraging data in some of those patients with newly diagnosed brain tumors.