Patricia K. Duffner

Low-Stage Medulloblastoma: Final Analysis of Trial Comparing Standard-Dose With Reduced-Dose Neuraxis Irradiation

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 Childrens 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.

Prognostic Factors in Infants and Very Young Children with Intracranial Ependymomas

The Pediatric Oncology Group (1986–1990) conducted a study in which 48 children <3 years of age with intracranial ependymomas were treated with prolonged postoperative chemotherapy (CT) and delayed RT. Thirty-one children, 0–23 months of age at diagnosis (Gp A) received 2 years of CT followed by RT; while 17 children, 24–36 months of age at diagnosis (Gp B) received CT for 1 year followed by radiation. One-year survivals were 87% (Gp A) and 94% (Gp B) and 2-year survivals were 67% (Gp A) and 82% (Gp B). In subsequent years a significant divergence in survivals according to age has been noted (p = 0.04). Five-year survivals were 25.7% (Gp A) vs. 63.3% (Gp B). The curves began to diverge 1 year following diagnosis. Other than age, the only significant prognostic factor was degree of surgical resection: 5-year survivals were 66% (total resection) vs. 25% (subtotal resection). Neither the presence of metastases, degree of anaplasia nor the degree of surgical resection varied significantly according to age at diagnosis. The most likely reason for the difference in survivals between the two age groups relates to the timing of radiation following CT, i.e., 1-year delay in children 24–36 months of age compared to a 2-year delay in children 0–23 months of age. An alternative but less likely hypothesis is that ependymomas in the younger children have a more aggressive biology. In contrast, survivals in the 24- to 36-month group are much better than previous reports in the literature suggesting that prolonged postoperative CT may allow both a delay in CRT as well as provide improved survivals. Based on these results, future treatment trials should emphasize maximal surgical resection and a delay in radiation of no more than 1 year.

Results of a Prospective Randomized Trial Comparing Standard Dose Neuraxis Irradiation (3,600 cGy/20) with Reduced Neuraxis Irradiation (2,340 cGy/13) in Patients with Low-Stage Medulloblastoma

PURPOSE To determine in a prospective randomized trial the effect on survival, progression-free survival, and patterns of relapse of a decrease in the neuraxis radiation dose from 3,600 cGy in 20 fractions to 2,340 cGy in 13 fractions in patients with newly diagnosed medulloblastoma between 3 and 21 years of age with low T stage (T1, T2 and T3A), minimal postoperative residual tumor, and no evidence of dissemination (M0). METHODS AND MATERIALS Between June 1986 and November 1990, the Childrens Cancer Group and the Pediatric Oncology Group randomized 126 patients in a two-arm study comparing the two different doses of neuraxis irradiation. In both arms, the posterior fossa received 5,400 cGy in 30 fractions. All patients were staged with myelography, postoperative lumbar cerebrospinal fluid cytology, and postoperative contrast-enhanced cranial computerized tomography to ensure no evidence of dissemination and no more than 1.5 cm3 residual tumor volume. Overall survival, progression-free survival, and patterns of recurrence were carefully monitored. Prospective endocrine and psychometric studies were performed to determine the benefit of decreasing the neuraxis radiation dose. RESULTS Following an interim analysis at a median time on study of 16 months, the study was closed, since a statistically significant increase was observed in the number of all relapses as well as isolated neuraxis relapses in patients randomized to the lower dose of neuraxis radiation. CONCLUSIONS In patients with newly diagnosed medulloblastoma considered to have a good prognosis on the basis of low T stage, minimal residual tumor after at least subtotal resection, and no evidence of dissemination after thorough evaluation, there is an increased risk of early relapse associated with lowering the dose of neuraxis radiation from 3,600 cGy in 20 fractions to 2,340 cGy in 13 fractions.

Brain tumors in children : principles of diagnosis and treatment

The revised, updated, and expanded second edition of this book reflects the most recent advances in the diagnosis and treatment of childhood brain tumours. Major sections of the book focus on principles of diagnosis and treatment, specific brain tumours, and complications of therapy. All chapters have been updated to provide current information on topics such as noninvasive imaging; haematopoietic growth factors; new techniques in radiation, surgery, and chemotherapy; radiation-induced neurotoxicity in long-term survivors; and new molecular biologic techniques that will affect treatment in the future. New chapters on neuropathology and biologic response modifiers have also been added. The chapter on neuropathology includes discussions of immunohistochemistry, monoclonals, and other tumour markers. The chapter on biologic response modifiers discusses monoclonal antibodies, cytogenetic advances, oncogenes and anti-oncogenes, and immune modulation.

Treatment of infants with malignant gliomas: The Pediatric Oncology Group Experience

Although survivals of infants with malignant brain tumors are worse than any other age group, one possible exception to this rule are the malignant gliomas. Eighteen children less than 3 years of age with malignant gliomas (glioblastoma multiforme, anaplastic astrocytoma and malignant glioma) were treated on the Pediatric Oncology Group regimen of prolonged postoperative chemotherapy and delayed irradiation, (1986–1990). Of 10 children evaluable for neuroradiologic response, 6 had partial responses (> 50% reduction) to two cycles of cyclophosphamide and vincristine. Progression free survivals at l, 3 and 5 years were 54.25% ± 12, 43% ± 16 and 43% ± 23 respectively. Survivals at 5 years were 50% ± 14. Four children were not irradiated after 24 months of chemotherapy due to parental refusal and none have developed recurrent disease. Neither degree of surgical resection, presence or absence of metastases, nor pathology influenced survival but this may reflect small sample size. This study suggests that some malignant gliomas in infants are chemotherapy sensitive and may be associated with a good prognosis. Why infants with these high-grade gliomas fare better than adults is not clear. It is likely that there is something intrinsically different about them that cannot be identified on routine pathologic examination.

Postoperative Chemotherapy and Delayed Radiation in Infants and Very Young Children with Choroid Plexus Carcinomas

Eight infants with choroid plexus carcinomas were treated with surgery, prolonged postoperative chemotherapy and delayed radiation. The results suggest that some infants with choroid plexus carcinomas can be successfully treated with multimodality therapy, even allowing children with less than a gross total resection to have prolonged disease-free intervals.

Combination chemotherapy in recurrent medulloblastoma.

Five children with recurrent medulloblastomas were treated with Vincristine, BCNU, Methotrexate and Dexamethasone. All five patients responded to therapy. Two of the patients are alive and well 30 and 48 months later; one died of disease 19 months after first recurrence; one developed a further recurrence at 18 months but responded to additional chemotherapy and is alive; and the fifth patient developed a second recurrence after 28 months but has responded to repeat chemotherapy and radiotherapy and is now asymptomatic. These results support the concept that medulloblastomas are sensitive to chemotherapy and suggest that chemotherapy should be considered in cases of recurrent medulloblastomas. In addition, the importance of trials now in progress which employ both adjuvant chemotherapy and radiotherapy in newly diagnosed medulloblastomas is apparent.

Benefit from prolonged dose-intensive chemotherapy for infants with malignant brain tumors is restricted to patients with ependymoma: a report of the Pediatric Oncology Group randomized controlled trial 9233/34

BACKGROUND The randomized controlled Pediatric Oncology Group study 9233 tested the hypothesis that dose-intensive (DI) chemotherapy would improve event-free survival (EFS) for children <3 years of age with newly diagnosed malignant brain tumors. METHODS Of 328 enrolled eligible patients, diagnoses were medulloblastoma (n = 112), ependymoma (n = 82), supratentorial primitive neuroectodermal tumor (sPNET, n = 38) and other malignant brain tumors (n = 96), and were randomized to 72 weeks of standard dose chemotherapy (Regimen A, n = 162) or DI chemotherapy (Regimen B, n = 166). Radiation therapy (RT) was recommended for patients with evidence of disease at completion of chemotherapy or who relapsed within 6 months of chemotherapy completion. RESULTS Distributions of EFS for Regimens A and B were not significantly different (P = 0.32) with 2- and 10-year rates of 22.8% ± 3.3% and 15.4% ± 3.7%, and 27.1% ± 3.4% and 20.8% ± 3.8%, respectively. Thus, the study hypothesis was rejected. While distributions of EFS and OS were not significantly different between Regimens A and B for patients with medulloblastoma and sPNET, DI chemotherapy resulted in significantly improved EFS distribution (P = .0011) (2-year EFS rates of 42.1% vs. 19.6% with SD chemotherapy), but not OS distribution, for patients with centrally confirmed ependymoma. The degree of surgical resection affected EFS, OS or both for most tumor groups. Approximately 20%, 40% and 20% of patients with medulloblastoma, ependymoma treated with DI chemotherapy, and sPNET, respectively appear to have been cured without RT. Of 11 toxic deaths on study, 10 occurred on the DI chemotherapy arm. CONCLUSIONS Prolonged dose-intensive chemotherapy given to infants with malignant brain tumors resulted in increased EFS only for patients with ependymoma.

Myelopathy with severe structural derangement associated with combined modality therapy

Myelopathy is a known complication of radiation therapy, but its association with chemotherapy has been less well documented. The authors report the case of a 12‐year‐old boy with medulloblastoma who had been followed for an 8 1/2‐year period. In the context of accepted doses of intrathecal methotrexate and spinal irradiation, he developed an extensive myelopathy. At postmortem he was found to have profound fibrosis of the leptomeninges and necrosis with structural derangement of the spinal cord. It is speculated that these findings are secondary to a combination of radiation acting in synergism with methotrexate. The pertinent literature relating to myelopathy associated with radiation and chemotherapy is reviewed.

Brain tumors in children under 1 year of age: emphasis on the relationship of prognostic factors.

© Springer-Verlag 2003 We are fortunate to have received two interesting articles from Mexico. The first, “Stereotactically guided biopsies of brainstem tumors”, revisits an important controversy. Today, (in those countries where MRI is readily available), pontine gliomas are rarely biopsied, but at one time this was a highly controversial issue. Those in favor of biopsy raised concerns that without pathology one could misdiagnose inflammatory and vascular lesions, not to mention potentially radiosensitive tumors such as medulloblastomas and ependymomas. Those opposed to biopsy typically raised concerns regarding the morbidity of the procedure and the difficulty in making a pathologic diagnosis based on a tiny sample of tissue. This article demonstrates that in those countries where MRI is not available, experienced neurosurgeons can safely biopsy the brainstem using a stereotactic approach and obtain, in most cases, sufficient tissue for a pathologic diagnosis. This paper also demonstrates that more extensive lesions, i.e., those spreading beyond the pons to the mesencephalon, medulla, and cerebellum, are more likely to be unpredictable in their pathology and would merit biopsy even if MRI had been available. In contrast, those lesions completely confined to the pons were all astrocytomas and, if MRI had been available, would not have required biopsy. The second paper addresses the very important problem of brain tumors in children <12 months of age. This large retrospective study analyzes data from the two largest tertiary care pediatric institutions in Mexico and, as such, makes an important contribution regarding presenting signs and symptoms, pathology, location, and outcome of very young children with brain tumors. The survival curves are of interest, demonstrating the rapid failure rate in the first year following diagnosis and the extreme rarity of late failures. The most important aspect of this study is the significant survival benefit associated with a gross total resection, although the high operative mortality rate (26%) is also noted. This study inferentially emphasizes the need for experienced pediatric neurosurgeons to aggressively address brain tumors in the very young. As the authors point out, radiation is not an option at this time, and the ideal chemotherapeutic regimen has yet to be identified. A gross total resection has been shown in this and other studies to be the best predictor of survival, even among most of the malignant types of brain tumors. In addition to operative mortality, however, is the concern of perioperative morbidity, which has been shown to be a significant cause of long-term cognitive deficits. The treatment of babies and very young children with brain tumors remains a major challenge in pediatric neuro-oncology. Childs Nerv Syst (2003) 19:315 DOI 10.1007/s00381-003-0739-8 C O M M E N TA RY