Faculty Bibliography

The central midline location of the pineal gland, its intricate contact with cerebrospinal fluid pathways, and the generally large size of tumors in this area before they produce symptoms raise problems in the use of TNM classification. Biopsy was performed on 30 consecutive pineal region tumors seen in children detected over an 8-year period. The pathologic features did not conform to previous autopsy data. Germinomas comprised only 7% of tumors, whereas 23% were malignant germ cell tumors. Neither computerized tomography, magnetic resonance imaging scan, nor markers were shown to be diagnostic of pathologic type. It was concluded that the significant factors affecting outcome are tumor cell type and presence or absence or mitoses. Surgical biopsy is recommended for all pineal region tumors in children. At the current time, the data base is insufficient to devise a staging classification specific for pineal region tumors and the TNM system appears largely inappropriate. Thus, it is reasonable to develop a data base for tumors of this region that then may lead to a specific staging system

The orderly conduct of clinical research trials in pediatric oncology has laid the foundation for modern curative therapy in several childhood malignancies. Such types of large clinical trials are relatively new to pediatric neuro-oncology. New treatments such as single and combination chemotherapy agents are studied in a Phase II trial in children with specific recurrent primary brain tumors. Computerized tomography (CT) and magnetic resonance imaging (MRI) scans and myelography allow the accurate determination of objective responses. The relative lack of promising Phase II trials has hampered the design of new Phase III studies for a variety of primary childhood brain tumors. The results of several Phase II trials may be incorporated into a prospective randomized Phase III study in which the endpoint is disease-free survival rather than response rate. Because of the rarity of specific types of primary childhood brain tumors, randomized Phase III trials are conducted more easily by cooperative cancer study groups. This article suggests some guidelines for the conduct of these Phase II and III trials in children with primary brain tumors so that accurate data may be accrued in an efficient manner

Prior studies in adults have shown that metoclopramide (MCP), when given in high intravenous (IV) doses (2 mg/kg), is a highly effective antiemetic for chemotherapy-induced vomiting. It is well-tolerated in older adults, but younger adults have an increased disposition to acute extrapyramidal reactions (EPRs). Before studying the efficacy of MCP as an antiemetic in children, we first had to establish the safe dose range. We performed a dose-increase MCP toxicity study in children receiving highly emetic chemotherapy such as cisplatin (120 mg/m2) or cyclophosphamide (greater than 900 mg/m2), beginning with a dose of 0.2 mg/kg and increasing the dose in nine steps to 3 mg/kg. MCP was given every two hours for four doses beginning one-half hour before chemotherapy. To reduce the incidence of EPRs, we added concomitant diphenhydramine. In MCP doses less than 2 mg, toxicity was minimal. In doses greater than or equal to 2 mg, 4/27 (15%) had EPRs and 9/27 (33%) had akathisia. Children who received two consecutive days of MCP had a higher frequency of EPRs. Metoclopramide (2 mg/kg) had promising antiemetic efficacy in a preliminary nonrandomized trial. Chemotherapy-experienced children vomited fewer than five times in 9/21 (43%) trials, and new patients vomited fewer than five times in 7/10 (70%) trials. MCP will become more useful as an antiemetic in children if better measures to prevent EPRs can be developed. Chemotherapy-induced emesis has the same negative implications in children as it does in adults and optimum antiemetic regimens can only be discovered by conducting randomized clinical trials in children

Primary childhood brain tumors are the second most common form of childhood cancer. Though progress in this area has been slow, the field has evolved considerably over the past 10 years. This article focuses on new information that will influence our treatment of the more common pediatric brain tumors

Gonadal germ cell tumors respond favorably to chemotherapy either at diagnosis or when they recur. Histologically similar tumors may arise in the CNS usually in the pineal or suprasellar regions. Although radiation therapy may produce a 5 year disease-free survival in excess of 60% in localized pure germinoma, germ cell tumors of other histology tend to recur. We have conducted 14 chemotherapy trials in 8 patients with recurrent CNS germ cell tumors using 3 different single agent and 2 multi-agent chemotherapy regimens. The histologic diagnoses of the patients were germinoma (4), endodermal sinus tumor (2), embryonal carcinoma (1), and mixed tumor - germinoma plus choriocarcinoma (1). There were 7 males and 1 female with a median age of 13 years. The primary tumor arose in the pineal region in 6 and was multicentric in 2. Seven patients had local recurrences and one developed an initial recurrence in the spinal canal. Three patients had CNS metastases at relapse and 2 had systemic metastases. Objective responses were documented in 7 of 14 trials (50%). Responses were observed with cyclophosphamide (80 mg/kg) in 3 of 4 patients for 2+, 3, and 5 mos, cisplatin (120 mg/m2) in 1 of 2 patients for 2+ mos, and the VAB 6 protocol (vinblastine, bleomycin, cyclophosphamide, actinomycin-d, cisplatin) in 3 of 5 patients for 5, 8, and 18 mos. The median duration of response was 5 mos. (2+-18). High doses of single chemotherapy agents such as cyclophosphamide and cisplatin as well as VAB 6 regimen have definite activity in recurrent CNS germ cell tumors, especially germinoma. Good palliation may be achieved with chemotherapy alone with acceptable morbidity.(ABSTRACT TRUNCATED AT 250 WORDS)

In a recent survey of the recurrence pattern in 40 medulloblastoma patients treated at Memorial Hospital between 1970 and 1979, 15% of all recurrences were in the region of the cribriform plate, which is an area that is undertreated with commonly employed radiation therapy techniques. The authors, therefore, modified their technique to increase the dose in this area. They report on the initial results in 15 subsequent patients treated with this modification. Ten of the 15 patients had localized tumors (Groups I and II) and 8 of these patients are alive disease-free compared with 7 of 17 Group I and II patients treated between 1970 and 1979. Three of five patients with disseminated tumors (Groups III and IV) are alive disease-free compared with none in the previous series. Although the period of follow-up is relatively short (median, 32 months), the overall survival of patients with medulloblastoma seems to be improved with additional radiation to the region of the cribriform plate. No side effects attributable to this modification were observed. In the opinion of the authors, this modification should be used routinely in patients with medulloblastoma

Twenty-eight evaluable children with the diagnosis of brain stem glioma were treated with 5-fluorouracil and CCNU before posterior fossa irradiation (5500 rads); during irradiation, the children received hydroxyurea and misonidazole. The treatment was well tolerated, and minimal toxicity was produced. The median relapse-free survival was 32 weeks, and the median survival was 44 weeks. Analysis of covariates showed that, in patients between the ages of 2 and 19 years, survival was longest in the older children (P less than 0.02). Tumor histology, sex, extent of operation (if any), Karnofsky score, and radiation dose did not correlate with survival