Biologic risk stratification of medulloblastoma: The real time is now

Many of us remember medulloblastoma as the prototype malignant childhood brain tumor we learned about in medical school [1]. Typically, a child aged approximately 5 years presents with several weeks to months of nausea, vomiting, headaches, ataxia, and sometimes a turned-in eye or abducens nerve paresis. Subsequent head computed tomography or magnetic resonance imaging reveals a somewhat circumscribed cerebellar tumor and obstructive hydrocephalus. Histologically, the WHO defines this small, round, blue-cell tumor with hyperchromatic nuclei and scant cytoplasm as a grade 4 neoplasm [2]. Because of its tendency to disseminate through the subarachnoid spaces and to form microscopic or bulky metastases in about a third of patients, craniospinal radiotherapy to a dosage of 36 Gy, with an additional radiation boost to the posterior fossa, had been the mainstay of adjuvant therapy following tumor resection. Five-year survival exceeded 50% by the late 1970s, for “better-risk” patients, using this approach [3]. However, much has changed in the classification and treatment of medulloblastoma during the past two decades. As articles by Gajjar et al [4] and Fernandez-Teijeiro et al [5] in the current issue of the Journal of Clinical Oncology make clear, in this era of molecular medicine, we must grapple with a new risk stratification for this disease, incorporating clinical features, histopathological subtype, and expression of specific genes and proteins. Use of chemotherapy was a major advance in the treatment of medulloblastoma. In the 1980s, the debilitating cognitive and endocrinologic sequelae of craniospinal radiotherapy, with the poor survival for children with residual tumor following surgery, led to successive randomized cooperative trials by the International Society of Pediatric Oncology (SIOP) [6], Children’s Cancer Group (CCG 942) [7], and Pediatric Oncology Group (POG 7909) [8], which introduced chemotherapy to improve survival and, later, reduce radiation dosage. At first, an increase in overall survival from chemotherapy was not apparent for all children, but only those who had bulky residual tumor or metastatic disease. Subsequently, in the 1990s, for children aged 3 to 10 years, without residual tumor or metastases, the single-arm study CCG 9892 was performed, and used 23.4 Gy craniospinal irradiation rather than the standard 36 Gy, followed by eight courses of lomustine, cisplatin, and vincristine. This study attained a remarkable 5-year event-free survival of 78% [9]. While it accrued just 65 eligible patients, it demonstrated that chemotherapy can be substituted for at least some amount of craniospinal irradiation in children with “favorable” or average-risk medulloblastoma. We await the final results of a much larger North American Children’s Oncology Group trial (COG A9961) to replicate this success with reduced dose irradiation. Through all these medulloblastoma trials, the risk classification for relapse and selection of treatment has remained strictly clinical. Since the mid-1990s in the COG, children aged 3 years and older have been stratified into two groups, based on resection extent and Chang metastasis staging [10]. In this classification, average-risk includes children with less than 1.5 cm of residual tumor, and no metastasis. High-risk is defined by more than 1.5 cm of residual disease, or any metastatic disease. The extent of tumor spread at diagnosis has always been the most robust predictor of outcome. However, the impact of only microscopic tumor cells in lumbar CSF on survival remains debatable. In both CCG 921 and the German trial HIT ’91, overall survival was not significantly different in children who were staged as having no metastasis or microscopic metastasis [11,12]. Children younger than 3 years are always considered to be at high-risk because of their wellestablished higher rates of recurrence [13]. Finally, brainstem invasion (described as Chang stage T3b), previously considered an indicator of high-risk, is now thought not to affect prognosis [11]. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 22 NUMBER 6 MARCH 15 2004