Medulloblastoma - Challenges in radiation therapy and the addition of chemotherapy

Medulloblastoma is at once the most common and, perhaps, the most challenging malignant brain tumor in children. The disease is intricately linked to the history of radiation oncology, from the earliest observations of “radiosensitivity” to the current applications of 3-dimensional conformal and intensity modulation technologies. Pediatric oncology provided the testing ground for combined modality therapy in the 1960s; medulloblastoma has provided what may be one of the more successful models for testing applications of combined chemotherapy–irradiation in central nervous system tumors. There is increasing agreement in the literature regarding simplified recognition of features that define medulloblastoma as “favorable,” “average risk,” or “low-stage”: disease confined to the posterior fossa primary site (i.e., M0) in children over 3 years old (1–4). The role of surgical resection is important in the disease, best gauged by the degree of postoperative residual (5, 6). Even patients with previously defined “high-stage” local characteristics (i.e., significant local residual or brainstem invasion, but M0) enjoy high rates of disease control in an era when attempted gross resection is the standard and even those with “.1.5 cm residual” have had substantial resection of the primary tumors (1, 3–6). Most significant in identifying the “highrisk” or “high-stage” cohort of children is the presence of neuraxis dissemination at diagnosis (1–3, 6). In the current edition of the Journal, Kortmann and colleagues show similar outcome among M0 children with and without local disease residual, but a difference between those with and without imaging evidence of subarachnoid metastasis that is highly significant (7). Radiation therapy has been the primary therapeutic modality for the past seven decades. A contemporary estimate of the outcome following surgery and irradiation is provided by the first Pediatric Oncology Group–Children’s Cancer Group (POG–CCG) low-stage medulloblastoma trial (1986–1990). Reported initially in 1996, the update of this study shows event-free survival (EFS) of 70% at 5 years (60% at 8 years) for children with localized disease following near total or total resection and “conventional” radiation therapy: 36 Gy to the neuraxis and 54 Gy to the posterior fossa, initiated within 4 weeks of definitive surgery (8, 9). The trial documented a marginally significant benefit to the conventional radiation dose regimen at 5 years compared to the investigational reduced neuraxis-dose regimen (23.4 Gy craniospinal therapy), with no statistical difference at 8-year follow-up (9). Recent literature indicates inadequate radiation volumes, particularly about the cribriform plate, in up to 20–45% of cases; Miralbell’s detailed retrospective analysis demonstrated a significant correlation between incomplete subarachnoid coverage and an increased rate of recurrence, particularly in the supratentorial or subfrontal areas (10, 11). The Kortmann et al. series documents a prospective multiinstitutional trial conducted between 1991 and 1997, indicating inadequate irradiation at the cribriform region in 12% of cases and incomplete inclusion of the posterior fossa in 10% (7). Adequate irradiation is central to disease control in medulloblastoma. Medulloblastoma is a chemosensitive disease. Earlier controlled studies in CCG and the International Society of Paediatric Oncology (SIOP) demonstrated the efficacy of adjuvant, postirradiation chemotherapy in children with high-stage disease (12, 13). Controlled trials have failed to convincingly demonstrate a similar advantage in low-stage disease (2, 12, 13). POG and CCSG attempted to prospectively study the impact of chemotherapy in favorable disease presentations in 1993, opening a trial comparing conventional dose irradiation to reduced neuraxis-dose irradiation combined with chemotherapy. The study could not be completed due to investigator and parental biases in both directions. Subsequent published data have encouraged combined chemoradiation in most medulloblastoma presentations. Packer, in a limited-institution, single-arm trial accessioning “high-risk” cases, showed that conventional radiation therapy combined with vincristine, chloroethylcyclohexylnitrosourea (CCNU), and cisplatinum resulted in 90% 5-year EFS for M0 “high-risk” medulloblastoma (i.e., those with residual disease in the posterior fossa) (1). A recent report of an interim CCSG study in children , 10 years old with M0 presentations shows 79% 5-year progression-free survival (PFS) following reduced neuraxis-dose irradiation and the identical 3-drug regimen (4). Although not clearly superior to outcome following irradiation alone in “low-risk” settings, the study indicates disease control at least equal to that achieved with conventional radiation doses (2, 8, 9, 12, 13). Equally important, analysis of an Int. J. Radiation Oncology Biol. Phys., Vol. 46, No. 2, pp. 261–263, 2000 Copyright © 2000 Elsevier Science Inc. Printed in the USA. All rights reserved 0360-3016/00/$–see front matter