Faculty Bibliography

A poor-risk population of children with primary malignant central nervous system (CNS) tumors, other than gliomas, can be identified by their young age, by the presence of disease dissemination at diagnosis, and possibly by subtotal resection of the primary tumor. These children require at least neuraxis radiation therapy and possibly chemotherapy for disease control. Unfortunately, once neuraxis radiation is administered, tolerance of subsequent chemotherapy is limited. The authors have explored a multimodal treatment approach in 14 poor-risk patients initially consisting of a modified Phase II chemotherapy trial followed by neuraxis radiation. The diagnoses were medulloblastoma (5), pineoblastoma (3), cerebral primitive neuroectodermal tumor (3), germinoma (2), and choroid plexus carcinoma (1). Eleven patients had disseminated CNS disease, and two had bone marrow involvement at diagnosis. Nine patients received 2 courses of intravenous cyclophosphamide (80 mg/kg) alone over 8 weeks, and five others received three daily doses of intrathecal Ara-C (50 mg/m2) and oral hydroxyurea (40 mg/kg) with each course of cyclophosphamide. There were four complete responses (two dysgerminomas, one pineoblastoma, and one primitive neuroectodermal tumor), one partial response (medulloblastoma), and three mixed responses (two medulloblastomas, one pineoblastoma) to chemotherapy alone, for a response rate of 57%. Twelve patients subsequently tolerated the planned dose of neuraxis radiation. The median survival of all patients was 11 months, and seven of eight deaths were related to recurrent disease. The hematologic toxicity was appreciable, and one death resulted from gram-negative septicemia. Through the use of this type of Phase II trial, valuable information can be obtained on the response rates to specific chemotherapy agents administered prior to radiation. Although cyclophosphamide alone was an active agent in this context, these treatment regimens did not have an important affect on survival

We reviewed the records of 31 children under the age of 21 years with parenchymal brain metastases diagnosed by CT scan (13 patients) or necropsy (18). Brain metastases were found in 18 of 139 (13%) children with solid tumors in whom complete postmortem examinations were done. Osteogenic sarcoma and rhabdomyosarcoma were the most frequent primary tumors causing brain metastases in patients younger than 15 years, and testicular germ cell tumor, from age 15 to 21 years. Evidence of intratumoral hemorrhage was found in 50% of autopsy cases. Pulmonary metastases were present in 28 of 31 (90%). The median interval from recognition of pulmonary metastases to the development of brain metastases was 10 months. No patient had evidence of brain metastases at diagnosis of the systemic cancer. In only one patient was the brain the only site of relapse. Following detection of brain metastases, the median survival was seven months in six patients who underwent surgery and whole-brain radiation therapy and four months in 15 given radiotherapy (3000 rads) alone. Patients with relatively radioresistant brain metastases may benefit from surgical excision or higher doses of radiation, or both

Brainstem gliomas of children are variably malignant tumors that rarely have been reported to produce subarachnoid dissemination. Nevertheless, during a two-year period, 5 of 15 such patients treated by us developed symptoms of leptomeningeal metastases. The diagnosis of an anaplastic astrocytoma with meningeal gliomatosis was confirmed postmortem in all 5. In 3 children, meningeal symptoms preceded other signs of posterior fossa recurrence. Symptoms of meningeal gliomatosis included local or radiating back pain (5 patients), segmental weakness (3), paresthesia (2), and incontinence (2). Myelography, performed in 4 patients, was the most useful diagnostic technique, disclosing multiple intradural filling defects or a high degree of block in 3 patients. Although the cerebrospinal fluid was abnormal in all 4 examined patients, in only 1 were malignant cells detected. Prolonged survival, which appears to predispose to dissemination of adult malignant gliomas, was not an apparent factor in our patients

Osteosarcoma patients free of CNS metastases are at risk for acquiring leukoencephalopathy after receiving multiple courses of high dose intravenous methotrexate followed by oral leucovorin rescue (MTX-LV). A prospective study of the adequacy of CNS rescue of MTX biochemical toxicity by oral leucovorin was undertaken in newly diagnosed neurologically normal osteosarcoma patients. Prior to surgical resection of the primary tumor, ten patients received 4 weekly courses of MTX-LV. During the fourth weekly MTX-LV treatment, 0 and 72 hr serum and CSF determinations of MTX, 5-methyl-tetrahydrofolate (5-MTHF) and LV were made. No CSF MTX was detectable at 0 hr in any patient, but a significant elevation in CSF MTX occurred in 9/9 patients at 72 hr (mean 47.2 +/- 31.8 ng/ml or 1.04 +/- 0.7 X 10(-7) M). There was no significant change in mean CSF 5-MTHF over 72 hr despite a rise in serum 5-MTHF. MTX exceeded 5-MTHF in 6/9 patients in CSF, whereas only 3/8 patients had higher MTX in the serum at 72 hr. No acute systemic or neurotoxicity was seen. The failure of oral leucovorin to consistently elevate CSF 5-MTHF levels at 72 hr in the context of significant levels of CSF MTX may result in intermittent CNS folate deficiency. The clinical and pathological syndrome of leukoencephalopathy may be related to this phenomenon and may evolve after repeated MTX-LV treatments

A patient with Stage III paratesticular neuroblastoma diagnosed in infancy was treated with radiotherapy and chemotherapy. Typical depigmented 'ash leaf' skin lesions of tuberous sclerosis appeared during early childhood. At 7 years of age he underwent craniotomy for a subependymal giant cell astrocytoma. The occurrence of neuroblastoma, tuberous sclerosis, and astrocytoma is unique, and supports the suggested relationship between neural crest tumors and hamartoma syndromes