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Michael S. B. Edwards, William M. Wara, Raul C. Urtasun, Michael Prados, Victor A. Levin, Dorcas Fulton, Charles B. Wilson, John Hannigan and Pamela Silver

✓ Fifty-three patients (19 adults and 34 children) harboring brain-stem glioma were treated with hyperfractionated radiation therapy (100 cGy twice a day, 5 days/wk, to a total dose of 7200 cGy). For the entire group, the median time to tumor progression (TTP) was 59 weeks (adults 66 weeks, children 44 weeks) and the median survival time was 74 weeks (adults 92 weeks, children 64 weeks). Statistically significant prognostic factors associated with a decrease in TTP and median survival times (adults < children) were: patient's age, a clinical history of less than 2 months, widespread brain-stem dysfunction, and a diffuse tumor as seen on magnetic resonance imaging. A finding of glioblastoma multiforme at histological analysis was associated with a statistical trend toward poorer survival, but in general tumor histology was not predictive of outcome. No evidence of an increase in acute or delayed radiation toxicity was seen with this fractionation schedule and total dose. This study suggests that hyperfractionation prolongs the TTP and survival time for many patients with brain-stem glioma. However, there remains a group of patients who are only moderately helped by this technique and for whom more aggressive treatment is warranted.

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Takao Hoshino, Luis A. Rodriguez, Kyung G. Cho, Kyu S. Lee, Charles B. Wilson, Michael S. B. Edwards, Victor A. Levin and Richard L. Davis

✓ The proliferative potential of low-grade astrocytomas was estimated in 47 patients. Each patient received an intravenous infusion of bromodeoxyuridine (BUdR), 150 to 200 mg/sq m, at the time of craniotomy to label cells in deoxyribonucleic acid (DNA) synthesis; the percentage of S-phase cells, or BUdR labeling index (LI), of each tumor was determined immunohistochemically. In 29 patients (60%), the tumors had BUdR LI's of less than 1%, indicating a slow growth rate; only three (10%) of these patients died of recurrent tumor during a follow-up period of up to 3½ years. In contrast, of the 18 patients (40%) whose tumors had BUdR LI's of 1% or more, 12 (67%) had a recurrence and nine died during the same follow-up period. These results show that the proliferative potential, as reflected by the BUdR LI, is an important prognostic factor that separates low-grade astrocytomas into two groups and provides a more scientific rationale for selecting treatment for individual patients.

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Michael S. B. Edwards, Roger J. Hudgins, Charles B. Wilson, Victor A. Levin and William M. Wara

✓ The authors believe that the preferred treatment for pineal region tumors in children requires definitive surgery with a histological diagnosis and that a conservative approach consisting of shunting and radiation therapy no longer seems to be appropriate. The results are reported of a retrospective review of the presentation, treatment, and outcome of 36 children under the age of 18 years treated between 1974 and 1986. Eleven children had germinomas (two-cell type), seven had astrocytomas, and the remaining 18 had 15 histologically different tumor types. Surgery was performed on 30 patients; there were no deaths, but a 10% rate of persistent morbidity was found. The median follow-up period was 4 years. Nine (82%) of 11 patients with germinomas are alive without evidence of recurrence; one child died from recurrent tumor in the pineal region and another is presently being treated for recurrent tumor of the spinal cord. Six (86%) of the seven patients with astrocytoma are well after biopsy and radiation therapy. Of the remaining 18 children, five (28%) died from tumor progression.

The cerebrospinal fluid (CSF) tumor markers α-fetoprotein and β-human chorionic gonadotropin were helpful in determining the presence of malignant germ-cell tumors, particularly those with a poor prognosis. Magnetic resonance imaging was useful for diagnosis and for planning the operative approach. Magnetic resonance images showed the presence of pineal region tumors in four children with hydrocephalus who had no evidence of tumor on computerized tomography scans.

Because the great variety of tumor types found in the pineal region must be treated in different ways and because improved microsurgical and stereotaxic surgical techniques have made mortality and morbidity rates acceptably low, a biopsy diagnosis should be obtained in all patients. Preoperative assessment of CSF tumor markers and cytology is useful for the identification of patients who have a poor prognosis.

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Victor A. Levin, Luis A. Rodriguez, Michael S. B. Edwards, William Wara, Hsiu-Chih Liu, Dorcas Fulton, Richard L. Davis, Charles B. Wilson and Pamela Silver

✓ Forty-seven patients with medulloblastoma were treated postoperatively with procarbazine, followed by craniospinal radiation therapy in combination with hydroxyurea. The radiation dose to the posterior fossa was 55 Gy; the spinal cord received 25 Gy and the whole brain 25 to 35 Gy (mean 33 Gy).

Seventeen tumors recurred. Only one initial recurrence was in the spinal subarachnoid space; 10 (59%) were in the posterior fossa, and four (24%) were supratentorial. The estimated 5-year disease-free survival probability was 55%; the 5-year overall survival rate was 66%. Myelotoxicity occurred in 38% of patients, but in only one case was it severe enough to warrant reducing the total dose of radiation. It was concluded that good-risk medulloblastoma patients may be treated with radiation dosages as low as 25 Gy to the spinal axis and to the whole brain without increasing the risk of recurrence outside the posterior fossa. Chemotherapy with procarbazine followed by radiation therapy and hydroxyurea during radiation therapy was well tolerated and may play a role in reducing radiation dosages outside the posterior fossa.

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Ali K. Choucair, Victor A. Levin, Philip H. Gutin, Richard L. Davis, Pamela Silver, Michael S. B. Edwards and Charles B. Wilson

✓ To determine the percentage of patients who developed multiple central nervous system (CNS) gliomas during postoperative radiation therapy and chemotherapy, the authors reviewed the records of 1047 patients treated between December 2, 1976, and August 16, 1985, who had an original diagnosis of supratentorial glioblastoma multiforme or other anaplastic glioma. The occurrence of multiple lesions was verified by neurodiagnostic studies (computerized tomography or myelography) or by findings at operation or autopsy. Twelve patients (1.1%) who presented with multiple lesions were excluded from this analysis. There were 405 patients with glioblastoma multiforme; their median age was 46.5 years (range 22 to 70 years). Eighteen (5%) of these patients had multiple CNS lesions, five of which were in the spinal cord. The median time from diagnosis to detection of the second lesion in this group was 59.5 weeks (range 10 to 182 weeks). There were 630 patients with anaplastic glioma (which included mixed malignant glioma and highly anaplastic, gemistocytic, moderately anaplastic, and anaplastic astrocytomas); their median age was 30 years (range 2 to 62 years). Fifty-four (8.6%) of these patients had multiple lesions, 10 of which were in the spinal cord; only one case of extraneural metastasis was found. The median time from diagnosis to detection of the second lesion in this group was 101 weeks (range 14 to 459 weeks). These results show that more than 90% of CNS gliomas recur at the site of the original tumor. Considering the high frequency of intellectual dysfunction after whole-brain radiation therapy, the use of focal radiation fields appears to be the most judicious approach to the treatment of patients with gliomas.

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Victor A. Levin, William M. Wara, Richard L. Davis, Pamela Vestnys, Kenneth J. Resser, Kathleen Yatsko, Stephen Nutik, Philip H. Gutin and Charles B. Wilson

✓ The authors report the results of a randomized study conducted to evaluate the relative benefit of treatment with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) or the combination of procarbazine, 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea, and vincristine (PCV) administered after radiation therapy with hydroxyurea to 76 evaluable patients with glioblastoma multiforme and 72 patients with other anaplastic gliomas. The primary end-point of the study was time to tumor progression. For better-risk patients with Karnofsky performance scores of 70 to 100, results suggest that PCV was of greater benefit than BCNU (p = 0.15 for glioblastoma multiforme; p = 0.13 for other anaplastic gliomas). Median times to tumor progression were 31 and 32 weeks for patients with glioblastoma multiforme; 25th percentile times to progression were 70 and 40 weeks for patients treated with PCV and BCNU, respectively. For patients with other anaplastic gliomas treated with PCV and BCNU, median times to progression were 123 and 77 weeks, respectively. Multivariate analysis showed that the prognostic variables of age and Karnofsky scores were important for patients with glioblastoma multiforme and other anaplastic gliomas, and that the extent of surgical resection was important for those with other anaplastic gliomas.

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Victor A. Levin, Michael S. B. Edwards, Philip H. Gutin, Pamela Vestnys, Dorcas Fulton, Margaret Seager and Charles B. Wilson

✓ The authors have conducted a Phase II trial to evaluate orally administered dibromodulcitol in the treatment of 40 evaluable patients with recurrent medulloblastoma, ependymoma, and malignant astrocytoma. Ten of 20 patients harboring medulloblastoma responded to therapy with a median time to tumor progression (MTP) of 40 weeks, and four of 20 patients had no sign of progression of disease 4 years after treatment was begun. The MTP for all 12 patients with ependymoma was 30 weeks. Nine of these 12 patients had stabilization of their disease with an MTP of 67 weeks; three of these 12 patients had no signs of progression for 1 to 3 years after treatment was begun. Of six patients harboring supratentorial gliomas, none responded to dibromodulcitol. Two patients, one with a primitive neuroectodermal tumor and the other with a metastatic carcinoma of the breast, had stabilization of disease for more than 4 and 2 years, respectively.

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Supratentorial malignant gliomas of childhood

Results of treatment with radiation therapy and chemotherapy

Surasak Phuphanich, Michael S. B. Edwards, Victor A. Levin, Pamela S. Vestnys, William M. Wara, Richard L. Davis and Charles B. Wilson

✓ Twenty-seven patients aged 1 to 18 years harboring supratentorial (20 in the cerebrum and seven in the thalamus) malignant gliomas were treated between 1975 and 1982. There were four glioblastomas multiforme, 14 anaplastic astrocytomas, and nine malignant gliomas. All patients had a subtotal resection or biopsy as the initial procedure and received postoperative radiation therapy (RT). Fifteen of 27 patients were treated by RT alone; 14 had tumor progression with a median time to tumor progression (MTP) of 65 weeks. Twelve patients were treated with chemotherapy as an adjuvant to RT; only seven had tumor recurrence, with an MTP of 130 weeks. Of the 21 patients with recurrent tumors in both groups, 18 were treated with chemotherapy alone, or chemotherapy with a second surgical procedure or second course of RT.

For all histological grades of tumor, the MTP for first recurrence was 75 weeks and the median survival time was 180 weeks. Age at initial diagnosis was found to be a statistically significant prognostic factor, with patients younger than 10 years of age surviving longer than patients aged over 10 years (p = 0.02).

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Primary cerebral neuroblastoma

Long-term follow-up review and therapeutic guidelines

Mitchel S. Berger, Michael S. B. Edwards, William M. Wara, Victor A. Levin and Charles B. Wilson

✓ Primary cerebral neuroblastoma is a distinct pathological and clinical entity that differs from other primitive neuroectodermal tumors. To characterize the clinical course of this lesion, the authors performed a retrospective analysis in 11 patients who ranged in age from 17 months to 26 years. The tumor had no predilection for either sex. Signs and symptoms were mostly those associated with increased intracranial pressure. The lesions commonly involved the parietal and occipital lobes. Computerized tomography scans of nine patients showed five solid and four cystic lesions; calcifications were found more commonly in the solid lesions. Contrast enhancement was seen in all tumors, yet angiograms typically showed an avascular mass. Total removal of tumor was possible in only two patients, both with cystic tumors. The remaining nine underwent subtotal resection of a solid lesion (in five) or a cystic lesion (in four). All 11 patients underwent postoperative irradiation that included the spinal axis in two cases; only one received adjuvant chemotherapy (solid tumor). Four patients, all with solid tumors that initially were subtotally resected, had evidence of tumor recurrence. The only patient with a subtotally resected solid lesion who did not have recurrence received adjuvant chemotherapy. The six patients who had cystic lesions are free of recurrent tumor at 26 to 109 months after surgery. Based on follow-up analysis of the 11 patients, recommendations are proposed for the treatment of primary cerebral neuroblastomas.

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Dorcas S. Fulton, Victor A. Levin, William M. Wara, Michael S. Edwards and Charles B. Wilson

✓ Forty-five children harboring brain-stem tumors were treated at the University of California, San Francisco, between 1969 and 1979. Pathological diagnoses were made in 19 patients. All patients received radiation therapy (RT). Thirteen patients received chemotherapy before, during, or immediately after RT. Twenty-four patients were treated with chemotherapy at the time of tumor progression, after initial treatment with RT alone. No statistically significant difference in time to tumor progression or survival was found for treatment with chemotherapy as an adjuvant to RT compared to treatment with RT alone followed by chemotherapy administered at the time of tumor progression. There were, however, more long-term survivors in the group that was first treated with chemotherapy at the time of tumor progression. There was no statistically significant correlation between survival and tumor pathology or location, although there were more long-term survivors among patients harboring low-grade gliomas and among patients with tumors confined to the midbrain. The authors documented the response of some brain-stem tumors to chemotherapy; however, cooperative controlled studies will be required to determine the optimum treatment for this disease.