Darryl C. Longee

High-dose chemotherapy with autologous stem-cell rescue in patients with recurrent and high-risk pediatric brain tumors.

PURPOSE We treated 49 patients with recurrent or poor-prognosis CNS malignancies with high-dose chemotherapy regimens followed by autologous marrow rescue with or without peripheral-blood stem-cell augmentation to determine the toxicity of and event-free survival after these regimens. PATIENTS AND METHODS Nineteen patients had medulloblastomas, 12 had glial tumors, seven had pineoblastomas, five had ependymomas, three had primitive neuroectodermal tumors, two had germ cell tumors, and one had fibrosarcoma. Thirty-seven received chemotherapy with cyclophosphamide 1.5 g/m2 daily x 4 and melphalan 25 to 60 mg/m2 daily x 3. Nine received busulfan 37.5 mg/m2 every 6 hours x 16 and melphalan 180 mg/m2 (n = 7) or 140 mg/m2 (n = 2). Three received carboplatin 700 mg/m2/d on days -7, -5, and -3 and etoposide 500 mg/m2/d on days -6, -4, and -2. All patients received standard supportive care. RESULTS Eighteen of 49 patients survive event-free 22+ to 55+ months (median, 33+) after transplantation, including nine of 16 treated before recurrence and nine of 33 treated after recurrence. There was one transplant-related death from pulmonary aspergillosis. Of five patients assessable for disease response, one had a partial remission (2 months), one has had stable disease (55+ months), and three showed progression 2, 5, and 8 months after transplantation. CONCLUSION The toxicity of these regimens was tolerable. Certain patients with high-risk CNS malignancies may benefit from such a treatment approach. Subsequent trials should attempt to determine which patients are most likely to benefit from high-dose chemotherapy with autologous stem-cell rescue.

Response of recurrent medulloblastoma to low-dose oral etoposide.

PURPOSE The outcome for patients with recurrent medulloblastoma has historically been poor, with most patients dying of disseminated disease. Here, we report on seven patients with recurrent medulloblastoma, most heavily pretreated with a variety of chemotherapeutic agents, including parenteral etoposide (VP-16), who showed responses to the administration of repeated courses of low-dose oral VP-16. PATIENTS AND METHODS Seven patients age 4 to 16 years were treated with VP-16 after neuroradiographic and clinical evidence of tumor progression. Six had received prior irradiation. All seven had been pretreated with a variety of chemotherapeutic agents and schedules, including parenteral VP-16. VP-16 was administered orally as repeated 21-day courses at 50 mg/m2/d with a 7-day interval between courses. Evaluation consisted of neuroradiographic and clinical examination after completion of every two courses of therapy. Complete blood cell counts were performed weekly. RESULTS The major toxicity of oral VP-16 was hematologic, with two patients requiring platelet transfusions due to thrombocytopenia and two requiring RBC transfusions. All seven patients developed treatment-related neutropenia. Two patients were supported with granulocyte colony-stimulating factor (G-CSF) between courses. One patient developed infectious epididymitis after course 2 and required intravenous antibiotics; this illness was complicated by Clostridium difficile colitis. There was one episode of fever associated with neutropenia. There were no treatment-related deaths. Of seven patients assessed, six have demonstrated partial responses (PRs) and the remaining patient had stable disease (SD). CONCLUSION This report demonstrates the activity of oral VP-16 in the treatment of a small cohort of pretreated patients with recurrent medulloblastoma. This form of administration of oral VP-16 was well tolerated and produced modest toxicity.

Central nervous system atypical teratoid tumor/rhabdoid tumor: response to intensive therapy and review of the literature.

Central nervous system atypical teratoid/rhabdoid tumor (ATT/RT) of infancy and childhood is a unique histologic entity with an extremely aggressive natural history. Standard therapy for infant and childhood medulloblastoma, for which this entity is often mistaken, has been ineffective; most children survive less than 12 months after diagnosis. Intensified therapy has been recently used for children with this disease, with promising results [1,2].We report four cases of ATT/RT in young children; all had subtotal resections and localized disease at diagnosis. One child treated prior to bone marrow transplant availability died of progressive disease 9 months after diagnosis. Another child, treated with high-dose chemotherapy and radiotherapy in preparation for bone marrow transplant, had a recurrence and died 20 months after diagnosis, without undergoing the transplant. Two children received high-dose chemotherapy and autologous bone-marrow transplant and had a good response to treatment; one survived 19 months, the other child is free of disease 46 months from diagnosis. Intensified therapy has altered the natural history of central nervous system ATT/RT.

Malignant Supratentorial Ganglioglioma (Ganglion Cell-Giant Cell Glioblastoma) A Case Report and Review of the Literature

BACKGROUND From both epidemiologic and pathologic viewpoints, gangliogliomas exhibiting components of giant cell glioblastomas are extraordinary neoplasms. We report herein the case of a 6-year-old girl who presented initially with a World Health Organization grade IV anaplastic ganglioglioma (a mixed ganglion cell tumor-giant cell glioblastoma). Despite aggressive management, the patient died of disease in a relatively short period. METHODS Formalin-fixed, paraffin-embedded tissue blocks were sectioned at 5 microm for histochemical and immunohistochemical analyses. Hematoxylin-eosin-stained sections and immunohistochemically stained sections from the primary and secondary resections were reviewed. Reactivity for glial fibrillary acidic protein, neurofilament protein, synaptophysin, and Ki67 nuclear antigen was evaluated. RESULTS Histologically, 2 distinct cell populations were noted on both the primary and secondary resections. The primary resection revealed a neoplasm having a predominant glial component consistent with a glioblastoma. Interspersed were dysmorphic ganglion cells supporting a diagnosis of ganglioglioma. The second resection (following therapy) demonstrated a much more prominent dysmorphic ganglion cell component and a subdued glial component. CONCLUSION Although immunohistochemical analysis clearly distinguished the 2 tumor cell populations, the identification of Nissl substance in neurons proved to be equally helpful. Although other cases of grade III gangliogliomas and rare cases of grade IV gangliogliomas have been reported, the present case is exceptional in that, to our knowledge, it is the only report of a patient who presented initially with a composite grade IV ganglioglioma and who was clinically followed up to the time of death. This case allows direct comparison between the histologic findings in a giant cell glioblastoma and a ganglioglioma and documents the aggressive biologic behavior of this complex neoplasm.

Activity of high-dose cyclophosphamide in the treatment of childhood malignant gliomas

Seventeen patients less than or equal to 20 years of age with newly diagnosed (n = 10) or recurrent (n = 7) malignant gliomas (anaplastic astrocytoma and glioblastoma multiforme) were treated with cyclophosphamide in association with hematopoietic cytokines (GM-CSF or G-CSF). Cyclophosphamide was given at a dose of 2 g/m2 daily for 2 days at 4-week intervals. Toxicity consisted of grade IV neutropenia and thrombocytopenia in 95% and 48% of cycles, respectively. There were no cyclophosphamide-related cardiac, pulmonary, or urothelial toxicities observed. Four of 10 patients with newly diagnosed disease demonstrated responses (three complete and one partial responses; one CR was only of 2 months duration). None of the seven patients with recurrent tumors demonstrated a response. We conclude that high-dose cyclophosphamide warrants further evaluation in children with newly diagnosed malignant glioma.

Criteria for termination of phase II chemotherapy for patients with progressive or recurrent brain tumor

We report six patients with progressive primary tumors of the brain who had prolonged periods with stable contrast-enhancing CT lesions following initial responses to chemotherapy. Chemotherapy was discontinued after 21 to 36 months, despite the persistence of apparent disease in each patient. PET using (F-18) fluorodeoxyglucose was performed in three patients, revealing hypometabolic lesions. All six patients are alive and well, with no clinical or radiographic evidence of progressive disease at 24 to 57+ months following termination of treatment. The usual criteria for terminating phase II chemotherapy in patients with a recurrent brain tumor are evidence of progressive disease or unacceptable toxicity. However, chemotherapeutic success mandates that these criteria be expanded to include patients whose response following the initiation of phase II treatment is followed by prolonged (greater than 1 year) radiographic and clinical stability. Complete response, ie, disappearance of all evidence of disease, is unusual in patients with recurrent primary brain tumors, even with highly effective therapy. Continued improvement in the therapy of patients with these tumors will allow wider application of these criteria.

Metastatic rhabdomyosarcoma presenting as intracranial hemorrhage: imaging findings

The CNS is rarely the first site of metastasis for rhabdomyosarcoma. CNS involvement is uncommon, and usually seen as leptomeningeal spread after development of pulmonary metastases. We present the imaging findings in a 13-year-old boy in whom a large intracranial hemorrhage was the initial presentation of surgically documented metastatic prostatic rhabdomyosarcoma. Multiple chest CTs and radionuclide bone scans had previously shown no evidence of pulmonary or osseous metastases. The significance of this case in relation to the possible role of the need for use of chemotherapeutic agents that cross the blood-brain barriers to prevent brain metastasis is discussed.

Evaluation of Pre-radiotherapy Cyclophosphamide in Patients with Newly Diagnosed Glioblastoma Multiforme

Cyclophosphamide is an alkylating agent that has shown activity in the treatment of pediatric brain tumors, including high-grade gliomas. This study was designed to evaluate the response of patients with newly diagnosed glioblastoma multiforme to pre-radiotherapy cyclophosphamide. Fourteen patients with glioblastoma multiforme were treated with high-dose cyclophosphamide (2 g/m2/day for 2 doses every 28 days) followed by either sargramostim or filgrastin. Sargramostim was given 250 µg/m2 subcutaneously twice a day continuing through the leukocyte nadir until the absolute neutrophil count was more than 1000 cells/µl for 2 consecutive days. The filgrastin dose was 10 µg/kg given subcutaneously once daily until the post nadir absolute neutrophil count was ≥10,000 cells/µl. A total of 46 courses was given. Four patients received a total of 3 courses, 7 patients completed 4 courses and 3 patients received 2 courses. Three patients demonstrated complete response; 3 stable disease; and 8 progressive disease. The most common toxicity was hematologic, requiring platelet and packed red blood cell transfusions, with 13 admissions for neutropenia with fever. There were no deaths related to infection or bleeding. These results suggest that high-dose cyclophosphamide has modest activity with acceptable toxicity against newly diagnosed glioblastoma multiforme.

Transient late magnetic resonance imaging changes suggesting progression of brain stem glioma: implications for entry criteria for phase II trials.

An 8-year-old boy was treated with irradiation (66 Gy) for a brain stem glioma. Five months after the completion of radiotherapy, magnetic resonance imaging demonstrated apparent tumor progression despite the patients neurological improvement. The child continued to improve, with subsequent radiographic evidence of tumor regression, without additional therapeutic intervention. The evaluations of response and recurrence of brain tumors as well as entry criteria for Phase II studies are discussed.