A Phase II Study of Preradiotherapy Chemotherapy Followed by Hyperfractionated Radiotherapy for Newly Diagnosed High-Risk Medulloblastoma/Primitive Neuroectodermal Tumor: A Report From the Children's Oncology Group (CCG 9931)

Abstract

Corresponding author: Jeffrey Allen, NYU Medical Center, 160 E. 32 nd St, Hassenfeld Clinic, New York, NY 10016 Tel: (212) Fax (212) Conflicts of Interest Notification: nonePublisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptPurpose-Children with high risk medulloblastoma and non-cerebellar PNET's were treated on a phase II study of pre-radiotherapy chemotherapy (CHT) followed by high dose, hyperfractionated craniospinal radiotherapy (CSRT). The protocol objectives were to verify feasibility and monitor progression-free (PFS) and overall survival (OS).Methods and Materials-Eligibility criteria included age >3 years at diagnosis, medulloblastoma with either high M stage and/or >1.5 cm 2 post-op residual disease and all patients with non-cerebellar PNET. Treatment was initiated with 5 alternating monthly cycles of CHT [A (cisplatin, cyclophosphamide, etoposide and vincristine, B (carboplatin and etoposide), A, B and A] followed by hyperfractionated CSRT (40 Gy) with a boost to the primary tumor (72 Gy) given in twice daily 1 Gy fractions.Results-The valid study group consisted of 124 patients whose median age at diagnosis was 7.8 years. Eighty-four (68%) patients completed the entire protocol within the study guidelines of 9 months and the median time to complete CSRT was 1.6 months. Major reasons for failure to complete CHT included progressive disease (17%) and toxic death (2.4%). The 5-year PFS and OS were 43 ± 5% and 52 ± 5%. No significant differences were detected in subset analysis related to response to CHT, site of primary tumor, post-op residual disease or M-stage.Conclusions-The feasibility of this intensive multi-modality protocol was confirmed and response to pre-RT CHT did not impact on survival. Survival data from this protocol can not be compared to other studies, given the protocol design.

Relative survival of childhood and adult medulloblastomas and primitive neuroectodermal tumors (PNETs)

“…Although several epidemiologic studies have included medulloblastomas and PNETs together as a single entity, [22][23][24][25][26] a landmark study has identified genetic differences that point to a difference in cell origin between these 2 tumor types. 27 The inclusion of both histologic subtypes into the regression model was because PNETs were distributed similarly across age groups (see Table 1); therefore, any survival differences between tumor types would result in differences that were consistent across age categories and would not alter the overall differences between age groups, which was the key issue addressed in the current study.…”

Outcome of Children With Metastatic Medulloblastoma Treated With Carboplatin During Craniospinal Radiotherapy: A Children's Oncology Group Phase I/II Study

“…1,2 Whereas 80% of children with localized MB will be cured following treatment with reduced dose craniospinal radiation therapy (CSRT) and chemotherapy, 3 the success rate for patients with disseminated disease, as well as for those with supratentorial primitive neuroectodermal tumors (PNETs), has historically been poor despite full-dose CSRT and chemotherapy. 1,[4][5][6] The Goldie-Coldman model of therapeutic resistance states that the prompt elimination of tumor through the use of multiple drugs given concurrently reduces the likelihood of the emergence of resistant clones. 7 CSRT is the most effective treatment modality against MB and can be modeled as a non-cross-resistant chemotherapeutic agent.…”

Malignant Brain Tumors in Childhood

“…The German HIT'91 trial showed superior results with post operative RT followed by CCNU, vincristine and cisplatin compared to postoperative ifosfamide, etoposide, highdose methotrexate, cisplatin and cytosine arabinoside followed by irradiation: 83% 5-year EFS compared to 53%, respectively for M0 patients; no difference was noted in the M2-3 cohort, both at 40% EFS (127). CCG 9931 documented a 17% PD rate during a prolonged, 5 month preirradiation regimen, again showing only 43% EFS in high-risk disease (121). Similar trials have noted that outcome in average-risk patients receiving preirradiation CT correlates with response to CT; in the Milan trial, those with CR-PR to preirradiation CT enjoyed 94% PFS compared to 61% if only SD or PD attended CT (128).…”

“…The result is systematic reduction in CSI dosage to 23.4 Gy; with well documented efficacy now in average-risk disease when combined with contemporary cisplatin based CT (116,117). Agreement on combined chemo radiation is based on disease control rates that appear to be superior to those achieved with irradiation alone for both average-risk and high-risk presentations, a randomized European trial demonstrating improved outcome with chemo radiation compared to contemporary RT alone and several studies suggesting improvement in the risk: benefit ratio based on dose-volume modeling and evolving clinical data (118,119,120,121).…”