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© 1999 American Society for Clinical Oncology Treatment of Children With Medulloblastomas With Reduced-Dose Craniospinal Radiation Therapy and Adjuvant Chemotherapy: A Children's Cancer Group StudyFrom the Departments of Neurology and Radiology, Children's National Medical Center, Washington, DC; Departments of Neurology, Radiology, and Pediatrics, The George Washington University, Washington, DC; Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA; Department of Hematology-Oncology, University of Oregon, Portland, OR; Department of Neurology, Beth Israel Medical Center, New York, NY; Department of Psychology, Cincinnati Children's Hospital, University of Cincinnati, Cincinnati, OH; Department of Neurosurgery, University of Michigan, Ann Arbor, MI; Department of Pathology, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA; Department of Radiation Oncology, University of California at San Francisco, San Francisco, CA; Department of Neurology, Cleveland Clinic, Cleveland, OH; and Department of Biostatistics and Epidemiology, St. Jude Children's Research Hospital, Memphis, TN. Address reprint requests to Roger J. Packer, MD, Children's Cancer Group, PO Box 60012, Arcadia, CA 91066-6012; email rpacker{at}cnmc.org
PURPOSE: Medulloblastoma is the most common malignant brain tumor of childhood. After treatment with surgery and radiation therapy, approximately 60% of children with medulloblastoma are alive and free of progressive disease 5 years after diagnosis, but many have significant neurocognitive sequelae. This study was undertaken to determine the feasibility and efficacy of treating children with nondisseminated medulloblastoma with reduced-dose craniospinal radiotherapy plus adjuvant chemotherapy. PATIENTS AND METHODS: Over a 3-year period, 65 children between 3 and 10 years of age with nondisseminated medulloblastoma were treated with postoperative, reduced-dose craniospinal radiation therapy (23.4 Gy) and 55.8 Gy of local radiation therapy. Adjuvant vincristine chemotherapy was administered during radiotherapy, and lomustine, vincristine, and cisplatin chemotherapy was administered during and after radiation. RESULTS: Progression-free survival was 86% ± 4% at 3 years and 79% ± 7% at 5 years. Sites of relapse for the14 patients who developed progressive disease included the local tumor site alone in two patients, local tumor site and disseminated disease in nine, and nonprimary sites in three. Brainstem involvement did not adversely affect outcome. Therapy was relatively well tolerated; however, the dose of cisplatin had to be modified in more than 50% of patients before the completion of treatment. One child died of pneumonitis and sepsis during treatment. CONCLUSION: These overall survival rates compare favorably to those obtained in studies using full-dose radiation therapy alone or radiation therapy plus chemotherapy. The results suggest that reduced-dose craniospinal radiation therapy and adjuvant chemotherapy during and after radiation is a feasible approach for children with nondisseminated medulloblastoma.
THE MANAGEMENT OF medulloblastoma, the most common form of malignant childhood brain tumor, has slowly evolved over the past decade.1-4 The conventional treatment of children with medulloblastoma after surgery consists of 36 Gy of craniospinal irradiation supplemented with 18 to 20 Gy of local irradiation (total dose of 54 to 56 Gy).1 After such treatment, more than one half of patients can be expected to be alive and free of progressive disease 5 years after diagnosis.1,2 Children with medulloblastoma have been roughly separated into two major risk groups: (1) average-risk patients who have localized disease at the time of diagnosis and have had a total or near-total resection of their tumors; and (2) high-risk patients who have disseminated disease and/or tumors that are partially resected. Prospective randomized studies have not demonstrated a clear-cut benefit for the addition of adjuvant chemotherapy during or after radiotherapy in children with average-risk disease.1,2,5 In contradistinction, these same studies have demonstrated that the addition of chemotherapy, using a lomustine (CCNU) and vincristine regimen, statistically improves survival for children with high-risk medulloblastomas.2,5-7 A factor that complicates decisions regarding management is the potential for long-term sequelae associated with craniospinal irradiation.1,8 Children who survive medulloblastoma are at significant risk for serious neurocognitive and endocrinologic dysfunction.1,8 These permanent sequelae are secondary to a variety of factors, although the most causative is the craniospinal radiation therapy received. Concern over the degree of sequelae, especially intellectual loss, has led to attempts to reduce the dose of craniospinal irradiation in children with nondisseminated disease.8-10 The current study (CCG-9892) was undertaken to determine the feasibility of treating children who have nondisseminated medulloblastoma with reduced-dose craniospinal radiation therapy (23.4 Gy) and adjuvant chemotherapy, administered during and after radiation therapy, that consists of CCNU, vincristine, and cisplatin. This regimen was chosen after a prospective, nonrandomized study demonstrated a greater than 90% 5-year disease control rate using irradiation and identical chemotherapy in children with nondisseminated medulloblastoma.2 Patient entry was restricted to children between 3 and 10 years of age, because they were thought to be at high risk for the deleterious effects of full-dose craniospinal irradiation. Children younger than 3 years were excluded from the study and were treated with chemotherapy alone in a separate prospective study.
Children between 36 and 120 months of age (inclusive) at the time of diagnosis with medulloblastomas (primitive neuroectodermal tumors of the posterior fossa) were eligible for analysis. When the study initially opened in October 1989, children with nonposterior fossa primitive neuroectodermal tumors who met all other entry criteria were eligible for study. The protocol was amended in January 1990 to allow entry of children with posterior fossa tumors only. Pathology was centrally reviewed, and all primitive neuroectodermal tumors of the posterior fossa were eligible, including those tumors with foci of glial, neuronal, or ependymal differentiation. Before study entry, postoperative magnetic resonance imaging (MRI) of the entire brain and spine, performed with and without gadolinium enhancement, was required. The spinal axis had to be visualized in at least two planes. CSF cytologic examination, obtained by lumbar puncture, was required within 21 days of diagnosis. To be eligible, there had to be no evidence of spread, based on MRI and by CSF cytologic analysis, outside the primary tumor site. In cases deemed equivocal for leptomeningeal disease by the treating institution, the MRIs were centrally reviewed, although there was no mandated central review of initial imaging studies. If CSF cytology was found to be positive for free-floating tumor cells within the first 7 to 10 days after surgery, a repeat spinal tap was to be performed 3 weeks after surgery. If the spinal fluid was found to be negative for tumor cells at that point, then the patient was eligible for study. Within 3 days of surgery, patients were required to have postoperative imaging of the primary tumor site with either computed tomography (CT), with and without contrast, or an MRI, with or without gadolinium. The degree of tumor resection was determined by the postoperative image and the surgeon's impression at the time of completion of surgery. After these assessments, patients were designated a T stage per the Chang staging system for posterior fossa medulloblastomas.2,4 Based on the surgeon's impression at the time of surgery and the postoperative MRI or CT study, tumor resections were graded as total or near-total (no areas of lump or residual disease or only residual tumor rim enhancement); partial (residual lump disease but < 50% of the original tumor); or subtotal or biopsy (< 50% tumor resection). If tumor was not visible on the postoperative image, but the surgeon believed the tumor was incompletely resected, the degree of surgery was considered incomplete. However, patients were eligible independent of the degree of tumor resection or brainstem involvement. All eligible patients or their guardians were required to sign informed consent before study entry.
Treatment Protocol The chemotherapy consisted of three drugs: vincristine, CCNU, and cisplatin. During radiotherapy, weekly vincristine was given at a dose of 1.5 mg/m2 (up to a maximum dose of 2 mg) for a total of eight doses. Six weeks after completion of radiation therapy, patients were started on a regimen of CCNU at 75 mg/m2 orally and cisplatin at 75 mg/m2 intravenously every 6 weeks. Vincristine at a dose of 1.5 mg/m2 intravenously (up to a maximum dose of 2 mg) was given weekly for 3 consecutive weeks. Eight 6-week cycles of chemotherapy were planned. All patients underwent a formal audiologic examination and renal assessment (glomular filtration rate or creatinine clearance) before each cycle of chemotherapy. The chemotherapy dose was modified if there was any evidence of significant audiologic, renal, hematologic, or neural toxicity. The cisplatin dose was reduced by 50% for a hearing loss of between 10 and 20 decibels in the 500- to 3,000-Hz range, and/or for a 40 decibel or greater loss in the 4,000- to 8,000-Hz range, and/or for a 25% to 49% reduction in renal function (grade 3 toxicity).11 If hearing loss was greater than 20 decibels in the 500- to 3,000-Hz hearing range, or if loss of renal function was greater than 50%, the cisplatin was omitted for that cycle and only given, thereafter, if renal or hearing function improved to a grade 3 or lower toxicity. The CCNU dose was reduced by 50% if there was marked thrombocytopenia (platelet count < 50,000/mm3) or symptomatic neutropenia (absolute neutrophil count < 500/mm3 with associated fever or evidence of infection requiring hospitalization, ie, grade 3 to 4 toxicity). The vincristine dose was reduced by 50% if severe symptomatic paresthesias developed or was omitted for at least one dose for ileus or weakness greater than 1 (on a 1 to 5 grading system) and began again when weakness improved or when the ileus resolved. A contrast-enhanced MRI of the brain was performed every 6 weeks after radiotherapy and every 3 months (after every two cycles of chemotherapy) while the patient was receiving chemotherapy, and at 6-month intervals thereafter for the next 3 years after treatment. MRI imaging of the spine was to be performed only if there were clinical abnormalities suggestive of leptomeningeal tumor recurrence. At time of disease relapse, patients were to have MRI of the entire neuraxis and CSF cytology sampled.
Neurocognitive and Endocrinologic Sequelae
Statistical Methods
The amended protocol opened for accrual in January 1990 and was closed in December 1994. Eighty-five patients were registered on study, and 71 were found to be eligible. Reasons for ineligibility in 14 patients included the following: age (two patients, one younger than 3 years and one older than 10 years); evidence of tumor in more than one posterior fossa site or dissemination or leptomeningeal dissemination upon further review of data (seven patients); inadequate postsurgical MRI studies of the spine due to movement artifact (four patients); and withdrawal from study by parental request before initiation of treatment (one patient). Six other children with nonposterior fossa tumors were entered before the amendment was made restricting entry to posterior fossa tumors; they were not formally analyzed in the review. The 65 assessable patients were a mean of 6.0 years of age at diagnosis (range, 36 to 180 months). Central pathologic review was carried out in 62 of 65 eligible patients. On pathologic review, a discordant diagnosis was found in three patients, which included sarcoma in two and anaplastic ependymoma in one. Of the 59 patients whose tumors were centrally reviewed and considered to have medulloblastomas, the tumor was found to be primitive neuroectodermal not otherwise specified in 47 and showed evidence of neuronal differentiation in three, glial differentiation in five, and mixed differentiation in four. All patients, as by eligibility, had no evidence of tumor spread at the time of diagnosis. Forty-seven patients were male and 18 were female. Extent of tumor locally at the time of diagnosis, as designated by T stage, was T1 in five patients, T2 in 12 patients, and T4 in one patient. The remaining 47 patients were considered to have T3 tumors, with brainstem involvement in 17 (T3b). Although patients with subtotal resections were eligible for study, only two of the 65 patients had greater than 1.5 cm2 of residual disease on the postoperative scans.
PFS and EFS
During the period of observation, three patients died as a result of causes other than progression of the primary tumor. One developed a biopsy-proven brainstem glioma 4.8 years after diagnosis. A second child died of accidental causes at 5 years of age. The remaining child developed pneumonitis and overwhelming sepsis during the fifth cycle of chemotherapy at a time when the child was not neutropenic. An autopsy disclosed pneumonitis with alpha and gamma streptococcus cultured from the lung, pulmonary congestion, and hyaline membrane formation. There was no evidence of tumor recurrence. Thus the overall EFS in the 65 patients at risk was slightly lower and was 83% ± 5% at 3 years and 78% ± 5% at 5 years. There was no relationship between any clinical, neuroradiographic, or histologic parameter and outcome. Specifically, there was no difference in outcome in those patients who had brainstem involvement at the time of diagnosis and those who did not (Fig 2). Because only two patients had significant residual disease at the time of diagnosis and both are doing well, no judgment can be reached between extent of tumor resection or the amount of residual tumor and outcome. There was no relationship between tumor differentiation as seen on central pathologic review and PFS or EFS. However, it should be noted that in the majority of patients, only one or two slides stained with hematoxylin and eosin were available for central review, so assessment of the prognostic significance of cellular differentiation was quite limited. Children younger than 5 years fared as well as older patients.
Radiation Compliance
Toxicity
Toxicity of maintenance chemotherapy. Toxicity data reflect the experience of 65 patients who received a total of 464 cycles of maintenance chemotherapy (Table 1). Hearing loss, a known complication of cisplatin, occurred in 21 patients (32%). In these patients, hearing loss occurred as early as the third cycle of maintenance chemotherapy and as late as the seventh cycle (median, fifth cycle); renal toxicity occurred in 17% of patients. The dose of cisplatin delivered on each maintenance cycle is shown in Table 2. Infectious complications included sepsis in six patients (9%); overall, seven cycles of chemotherapy (1.5%) had sepsis as a complication. One child, as described earlier, died of probable bacterial pneumonitis and sepsis 2 weeks after beginning the fifth cycle of maintenance chemotherapy. The child was not neutropenic but was on chronic corticosteroids since diagnosis at the discretion of the treating physician for intermittent nausea and vomiting.
In addition, nine patients (14%) had varicella during maintenance therapy. No patient had more than one episode of varicella. Fever occurred in 26 patients (40%) and in 50 cycles of chemotherapy (11%). Anemia and thrombocytopenia requiring transfusion occurred in 36 (55%) and 27 (42%), respectively, of patients treated.
The results of this feasibility study are encouraging but must be interpreted cautiously. Children in this study were carefully selected to include only those with localized disease at the time of diagnosis, which comprises approximately 60% to 70% of children with medulloblastoma. The extent of surgical resection was not made an eligibility criteria, but only two of the 65 patients had extensive bulky disease after surgery. Brainstem involvement was found in 17 children, and as in other recent studies, the presence of brainstem involvement did not detrimentally affect PFS.4 Given the improvements in surgical and neuroimaging techniques over the past two decades, it is difficult to compare results in this series to those published in the literature.1,2,4,16 In the previous published experience using this same chemotherapy regimen for children with nondisseminated medulloblastoma, 63 children were treated, the majority of whom received full-dose craniospinal radiation therapy (36 Gy), although seven patients received radiation therapy as outlined in this study.2 The previous study had included children with metastatic disease at the time of diagnosis, and patients were primarily staged by myelography complemented with CSF cytology. The 5-year PFS was 85% ± 6% for the group as a whole and 90% ± 6% for those children without metastatic disease at the time of diagnosis, independent of the dose of craniospinal irradiation given. The results of the present series, in which all children received reduced-dose craniospinal irradiation, are quite similar. Other studies of children with nondisseminated or so-called average-risk medulloblastoma have demonstrated a variable 3- and 5-year survival rate. A prospective randomized study comparing 36 Gy of craniospinal irradiation to 23.4 Gy of craniospinal irradiation has been completed by the Children's Cancer Group (CCG) and the Pediatric Oncology Group (POG).9 Although 126 patients were randomized in this study, a significant number were found to be ineligible on central review, and 71 were considered completely assessable. This study was halted before the planned completion of the study because of the concern of increased disseminated relapses in those children who received reduced-dose craniospinal irradiation as compared with those who received full-dose craniospinal irradiation. On further follow-up of this cohort of patients, the difference between survival in the two groups has narrowed to a borderline statistical level of P < .058.16 In the initial report of this study in which no chemotherapy was used, the 3- and 5-year PFS rate was approximately 65%. The International Society of Pediatric Oncology and the German Society of Pediatric Oncology completed a randomized trial comparing 35 Gy to 25 Gy of craniospinal irradiation, with or without 6 weeks of preradiation chemotherapy (procarbazine, methotrexate, and vincristine), in children with nondisseminated medulloblastoma.10 The 5-year EFS in this study in children who received standard radiotherapy alone was 60% ± 7.8% and 69% ± 8% for those children who received reduced-dose craniospinal irradiation. The survival rate for those children who received preradiation chemotherapy followed by standard radiotherapy was 75% ± 7%. The only children who did not fare as well (5-year EFS of 41% ± 8%) were those who received preradiation chemotherapy followed by reduced-dose craniospinal irradiation. Other series reviewing patients treated over longer periods of time, usually dating back to the 1970s and early 1980s, have reported survival rates in the 50% to 70% range for those children with nondisseminated medulloblastoma who were treated with 36 Gy or more of craniospinal radiation therapy alone.4,17-27 The 3- and 5-year PFS results of the present study (> 80%) compare favorably with all of the previously mentioned studies. In previous experience with the CCNU, vincristine, and cisplatin postradiotherapy regimen, few patients relapsed 3 years after diagnosis. In our present series, there has been only one late relapse. The sites of failure of children with nondisseminated medulloblastoma in the present series are cause for concern. Of the 14 patients who experienced failure in the study, local relapse alone occurred in only two. In nine other patients, there was both local and disseminated relapse, and it is impossible to determine the initial site of loss of disease control. This pattern of disease relapse is similar to that seen in the initial study of 36 Gy of craniospinal irradiation and CCNU, vincristine, and cisplatin chemotherapy, in which leptomeningeal and local disease or leptomeningeal disease dissemination alone were more common than local relapse.2 There is no clear evidence that the reduced dose of craniospinal irradiation played a role in the tendency for tumor recurrence to occur outside the primary site. Another concern related to the pattern of disease relapse is the adequacy and interpretation of MRIs of the spine at the time of diagnosis. Eleven children who were initially registered on the study were made ineligible by their treating institutions after further review of the postoperative MRIs of the spine. This included four patients whose MRIs could not be fully evaluated because of movement artifact or postsurgical changes and seven children with evidence of leptomeningeal dissemination. This study did not mandate central review of the postsurgical preradiotherapy MRIs of the spine, although MRIs at the time of staging were requested for central review at the time of relapse. On review after relapse, five of the 14 children who relapsed either had evidence of dissemination on the initial MRIs (three) or had studies that could not be adequately assessed because of movement artifact or postoperative changes (two). These patients were not made unassessable for this analysis, because eligibility criteria was as determined by the referring institutions. All of the patients who were reviewed and who on central review were found to have an inadequate study, or a study that showed dissemination, ultimately developed disseminated disease as part of their relapse pattern. Because the staging MRIs on all patients who remain free of progressive disease were not reviewed, it is impossible to determine how many had inadequate studies or missed leptomeningeal disease. However, it is likely that, in any study that evaluates reduced-dose craniospinal irradiation, the failure to identify leptomeningeal disease at diagnosis will put children who receive reduced-dose radiation therapy at high risk for disease relapse. If patients with inadequate studies or known disseminated tumor are removed from analysis in the present study, then the 3-year PFS rate in patients with nondisseminated disease is greater than 90%, which compares favorably with the previous results using 36 Gy of craniospinal irradiation and similar chemotherapy or the results of any other published study. These difficulties with interpretation of postoperative MRIs highlight the fact that interpretations of spinal MRIs are still quite subjective and vary between institutions. Standardization of MRI techniques and central review of initial staging studies are needed for future studies; the lack of central review of staging studies is a major flaw of the present study. The wider use of preoperative MRI of the spine in children with presumed medulloblastoma may overcome some of the postoperative difficulties, but this contention has not been proved. Another concern is the compliance with radiation therapy guidelines. On central review, nearly one third of patients were believed to have some type of radiation treatment compliance variance: primarily, either part of the posterior fossa disease was shielded, or the treatment margins of the brain or spinal cord were assessed as inadequate. Despite this, there was no difference in PFS in those patients whose radiation therapy did not meet protocol standards as compared with those whose radiation therapy did. Some patients with shielded disease did experience recurrence in the leptomeninges or locally, but others did not. The chemotherapeutic approach used in this study was well tolerated. One child, who was on chronic corticosteroids due to nausea and vomiting, died as a result of sepsis and pneumonitis during the fifth cycle of chemotherapy at a time when the child was not neutropenic. No other child in this series was noted to be corticosteroid-dependent, and it is likely that the overwhelming sepsis was partially caused by the patient's chronic corticosteroid use. It is unclear why the child required long-term corticosteroid use and whether it was related to the initial location of the tumor, surgery, irradiation, and/or chemotherapy. As expected, a significant modification in the cisplatin dose was required in approximately one half of patients after the sixth cycle of chemotherapy. However, more than 60% of patients received eight cycles of cisplatin, and 41% of children entered onto the study completed the fully prescribed doses of cisplatin without difficulty. The present study needs to be viewed as a stepping stone for therapeutic approaches that will both maintain a high rate of disease control and further reduce treatment-related sequelae. When this study was initially developed, the dose of craniospinal irradiation was to be 18 Gy.28 A pilot study, which was the basis of this study, had entered 10 children at the time the present study was opened. Early in the 18-Gy pilot study, three children developed progressive disease: one outside the primary tumor site, another at both the local site and outside the primary tumor site, and one at the primary tumor site. In addition, the initial results of the randomized CCG and POG study that demonstrated a possible rate of poorer disease control at 23.4 Gy as compared with 36 Gy were reported. For these reasons, the study was amended to a higher dose of craniospinal irradiation (23.4 Gy). Interestingly, the other children treated with 18 Gy of craniospinal irradiation, full-dose local radiotherapy, and identical chemotherapy remain free of progressive disease well over 5 years after initiation of treatment, and the median full-scale intelligence quotient of this patient group is 100. In addition, the differences in overall disease control in the randomized CCG/POG study (23.4 Gy v 36 Gy) have narrowed to borderline statistical significance. On a nationwide basis, based partly on the results of this present study, a randomized study is underway that compares the treatment regimen used in this report to identical radiation therapy plus a different postradiotherapy adjuvant chemotherapy regimen that consists of cyclophosphamide, vincristine, and cisplatin. In the future, if this nationwide randomized study confirms the excellent disease control observed in our present study, it might be possible to either further reduce the dose of craniospinal irradiation or further reduce the dose of craniospinal irradiation and add alternative therapy (perhaps intrathecal chemotherapy) to both maintain disease control and reduce long-term sequelae. In any event, the results of this study suggest that reduced-dose craniospinal irradiation and adjuvant chemotherapy, during and after radiation therapy, are feasible approaches for children with nondisseminated medulloblastoma.
Supported by the Division of Cancer Treatment, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD. J.M.B. is supported by grant no. CA21765 and the American Lebanese Syrian Associated Charities. Contributing Children's Cancer Group investigators, institutions, and grant numbers are listed in the Appendix We thank Betsy Schaefer for her editorial assistance.
1. Packer RJ, Sutton LN, D'Angio G, et al: Management of children with primitive neuroectodermal tumors of the posterior fossa/medulloblastoma. Pediatr Neurosci 12:272-282, 1985-86 [Medline] 2. Evans AE, Jenkin RDT, Sposto R, et al: The treatment of medulloblastoma: Results of a prospective randomized trial of radiation therapy with and without CCNU, vincristine, and prednisone. J Neurosurg 72:572-582, 1990[Medline] 3. Packer RJ, Sutton LN, Elterman R, et al: Outcome for children with medulloblastoma treated with radiation and cisplatin, CCNU and vincristine chemotherapy. J Neurosurg 81:690-698, 1994[Medline] 4. Zeltzer P, Boyett J, Finlay J, et al: Prognostic factors for survival in high risk primitive neuroectodermal tumors (PNETs) in children: Report from the Childrens Cancer Group CCG-921. Proc Am Soc Clin Oncol 12:415, 1993 (abstr) 5. Tait DM, Thorton-Jones H, Bloom HJG, et al: Adjuvant chemotherapy for medulloblastoma: The first multi-centre control of the International Society of Paediatric Oncology (SIOP). Eur J Cancer 26:464-469, 1990 6. McIntosh S, Chen M, Sartain PA, et al: Adjuvant chemotherapy for medulloblastoma. Cancer 56:1316-1319, 1985[Medline] 7. Packer RJ: Chemotherapy for medulloblastoma/primitive neuroectodermal tumors of the posterior fossa. Ann Neurol 28:823-828, 1990[Medline] 8. Packer RJ, Sutton LN, Atkins TE, et al: A prospective study of cognitive function in children receiving wholebrain radiotherapy and chemotherapy: 2-year results. J Neurosurg 70:707-713, 1989[Medline] 9. Deutsch M, Thomas PR, Krischer J, et al: Results of a prospective randomized trial comparing standard dose neuraxis irradiation (3600 cGy/20) with reduced neuroaxis irradiation (2,340 cGy/13) in patients with low-stage medulloblastoma: A combined Children's Cancer Group-Pediatric Oncology Group study. Pediatr Neurosurg 24:167-177, 1996[Medline] 10. Bailey CC, Gnekow A, Welleks: Prospective randomised trial of chemotherapy given before radiotherapy in childhood medulloblastoma: International Society of Paediatric Oncology (SIOP) and the (German) Society of Paediatric Oncology (GPO)—SIOP II. Med Pediatr Oncol 25:166-178, 1995[Medline] 11. National Cancer Institute: Cancer Therapy Evaluation Program: Common Toxicity Criteria (version 2.0). Bethesda, MD, Division of Cancer Treatment, National Cancer Institute, March 1998 12. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 54:457-481, 1958 13. Peto R, Pike MC, Armitage P, et al: Design and analysis of randomized clinical trials requiring prolonged observation of each patient: I. Introduction and design. Br J Cancer 34:585-612, 1976[Medline] 14. Peto R, Pike MC, Armitage P, et al: Design and analysis of randomized clinical trials requiring prolonged observation of each patient: II. Analysis and examples. Br J Cancer 35:1-39, 1977[Medline] 15. Mantel N: Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 50:163-170, 1966[Medline] 16. Deutsch M, Reigel DM: Myelography and cytology in treatment of medulloblastoma. Int J Radiat Oncol Biol Phys 7:721-725, 1981[Medline] 17. Thomas PR, Deutsch M, Mulhern R, et al: Reduced dose vs standard dose neuraxis irradiation in low stage medulloblastoma: The POG and CCG study. Med Pediatr Oncol 25:277, 1995 (abstr) 18. Krischer JP, Ragab AH, Kun L, et al: Nitrogen mustard, vincristine, procarbazine, and prednisone as adjuvant chemotherapy in the treatment of medulloblastoma. J Neurosurg 74:905-909, 1991[Medline] 19. Prados MD, Wara W, Edwards MSB, et al: Treatment of high-risk medulloblastoma and other primitive neuroectodermal tumors with reduced dose craniospinal radiation therapy and multi-agent nitrosourea-based chemotherapy. Pediatr Neurosurg 25:174-181, 1996[Medline] 20. Jenkin D, Goddard K, Armstrong D, et al: Posterior fossa medulloblastoma in childhood: Treatment results and a proposal for a new staging system. Int J Radiat Oncol Biol Phys 19:265-274, 1990[Medline] 21. Kovnar EH, Kellie SJ, Horowitz ME, et al: Preirradiation cisplatin and etoposide in the treatment of high-risk medulloblastoma and other malignant embryonal tumors of the central nervous system: A phase II study. J Clin Oncol 8:330-336, 1990[Abstract] 22. Kretschmar CS, Tarbell NJ, Kupsky W, et al: Pre-irradiation chemotherapy for infants and children with medulloblastoma: A preliminary report. J Neurosurg 71:820-825, 1989[Medline] 23. Danjoux CE, Jenkin RDT, McLaughlin J, et al: Childhood medulloblastoma in Ontario, 1977-1987: Population-based results. Med Pediatr Oncol 26:1-9, 1996[Medline] 24. Brand WN, Schneider PA, Tokars RP: Long term results of a pilot study of low dose cranio-spinal irradiation for cerebellar medulloblastoma. Int J Radiat Oncol Biol Phys 13:1641-1645, 1987[Medline] 25. Levin VA, Rodriguez LA, Edwards MSB, et al: Treatment of medulloblastoma with procarbazine, hydroxyurea, and reduced radiation doses to whole brain and spine. J Neurosurg 68:383-387, 1988[Medline] 26. Halbert FE, Wara WM, Fippin LF, et al: Low-dose craniospinal radiation therapy for medulloblastoma. Int J Radiat Oncol Biol Phys 30:651-654, 1991 27. Prados MD, Wara WM, Edwards SB, et al: Hyperfractionated craniospinal radiation therapy for primitive neuroectodermal tumors: Early results of a pilot study. Int J Radiat Oncol Biol Phys 24:431-438, 1993 28. Goldwein JW, Radcliffe J, Johnson J, et al: Updated results of a pilot study of low dose craniospinal irradiation plus chemotherapy for children under five with cerebellar primitive neuroectodermal tumors (medulloblastoma). Int J Radiat Oncol 34:889-904, 1996 Submitted November 23, 1998; accepted March 12, 1999.
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
