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High-dose cyclophosphamide chemotherapy for recurrent CNS tumors in children

Jeffrey C. Allen and Lawrence Helson

✓ A Phase II chemotherapy trial was conducted in 18 children with recurrent brain tumors, using high doses (80 mg/kg or greater) of intravenous cyclophosphamide. All eight patients with medulloblastomas responded; two patients with systemic metastases had complete responses and six others had partial responses. In seven patients with gliomas, there were one complete and four partial responses. In a third group, all three patients with intracranial germ-cell tumors had partial responses. The overall response rate was, therefore, 89% (16 of 18 patients), and the mean duration of response was 7 months (range 2 to 24 or more months). The hematological toxicity was considerable, with two deaths possibly related to chemotherapy: one patient, a recipient of unirradiated packed cells, died from a graft versus host reaction, and the other died from an intracranial hemorrhage during a thrombocytopenic episode. Four patients had prior chemotherapy, and 10 patients had prior neuraxis radiation therapy. These patients tolerated aggressive chemotherapy reasonably well. The results are sufficiently encouraging to justify a Phase III trial in patients with newly diagnosed disease.

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Medulloblastoma and other primary malignant neuroectodermal tumors of the CNS

The effect of patients' age and extent of disease on prognosis

Jeffrey C. Allen and Fred Epstein

✓ Studies to evaluate the extent of their disease were performed on 30 children with newly diagnosed malignant neuroectodermal tumors of the central nervous system, including 25 children with medulloblastomas. The studies consisted of postoperative computerized tomography scanning, cerebrospinal fluid (CSF) cytology, myelography, and bone marrow aspiration. In 11 patients (36%) one or more of these studies was positive, indicating disease dissemination (Group 1), and in 19 (64%) all four studies were negative (Group 2). The CSF cytology was positive for malignant cells in all 11 Group 1 patients; myelograms indicated subclinical filling defects in nine, and the bone marrow aspirate from two patients revealed extrinsic cells.

All patients received a conventional course of neuraxis radiation therapy as tolerated, and some also received chemotherapy. Patients with abnormal myelograms received additional radiation to areas of identifiable subarachnoid disease. The median survival time in Group 1 was 12 months, with five patients still surviving. The prognosis for Group 2 patients was considerably more favorable; only three of the 19 had died at the time of this report. Four of the six deaths in Group 1 were related to disease dissemination, the other two to chemotherapy toxicity. All three deaths in Group 2 were related to local tumor recurrence.

The mean age of Group 1 patients was 3.9 years compared to 11 years for Group 2. Of the 14 patients aged 5 years and under in both groups, nine presented with widely disseminated disease (Group 1), six of whom had a relatively short survival time. The performance of a postoperative extent-of-disease evaluation is especially important in young children with medulloblastoma. Knowledge of disease dissemination at diagnosis not only helps determine prognosis, but also assists in planning treatment. Aggressive multimodal therapy appears warranted in younger patients who present with widely disseminated disease.

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Neoadjuvant chemotherapy for newly diagnosed germ-cell tumors of the central nervous system

Jeffrey C. Allen, Jae Ho Kim, and Roger J. Packer

✓ A neoadjuvant (preradiotherapy) chemotherapy regimen consisting of either cyclophosphamide alone (60 to 80 mg/kg) or a modified multidrug regimen (vinblastine, bleomycin, cyclophosphamide, and cisplatin) was administered to 15 newly diagnosed patients with histologically confirmed, fully staged, primary germ-cell tumors (GCT's) of the central nervous system (CNS). There were 11 patients with germinomas and four with non-germinoma malignant GCT's. There were six females and nine males, whose median age was 13 years (range 4 months to 24 years). Seven germinoma patients (64%) had disseminated disease. For the germinoma patients, the subsequent radiotherapy dose was modified based on the response to the neoadjuvant chemotherapy, and craniospinal radiotherapy was given only to those with disseminated CNS disease at diagnosis. Ten of the 11 germinoma patients had complete disappearance of all evaluable disease after two courses of chemotherapy (cyclophosphamide in eight and multidrug in three) and one had a partial response. The planned dose of radiotherapy to the primary tumor was reduced from 5500 to 3000 rads, and the craniospinal dose was lowered from 3600 to 2000 rads. Ten patients remain in continuous disease-free remission 20+ to 89+ months after diagnosis (median follow-up period 47 months). All four patients with non-germinoma GCT's received the multidrug regimen, and two of three patients with evaluable disease had a partial response. High-dose regional and craniospinal radiotherapy was administered thereafter, but only two patients remain in their first remission.

Previously untreated germinoma is a highly chemosensitive disease and the neoadjuvant treatment strategy permits the identification of active chemotherapy regimens in newly diagnosed patients. Patients who have complete responses to neoadjuvant chemotherapy tolerate a significant radiotherapy dose reduction without compromising long-term survival, thereby allowing a reduction of some of the late effects of therapeutic radiation. Germinomas tend to disseminate early in the course of the disease and a pre-therapy staging evaluation permits individualized radiotherapy treatment planning.

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Malignant astrocytomas of the spinal cord

Alan R. Cohen, Jeffrey H. Wisoff, Jeffrey C. Allen, and Fred Epstein

✓ The authors review their experience with the operative management of 19 consecutive cases of malignant astrocytoma of the spinal cord. There was a male to female ratio of 1.1:1, and the median age of the population was 14 years (range 1 to 32 years). The median duration of symptoms prior to definitive diagnosis was 7 weeks. Radical excision was carried out in all cases, with 18 patients (95%) receiving radiotherapy and 10 patients (53%) receiving chemotherapy as well.

To date, 15 (79%) of the 19 patients in this series have died, with a median survival period of 6 months following surgery. No patient improved after operation. Hydrocephalus was present in 11 patients (58%), seven of whom underwent ventricular shunting procedures. Dissemination of disease was found in 11 patients (58%). Extraneural metastases did not occur in the absence of a ventricular shunt. The authors conclude that malignant astrocytomas of the spinal cord are heralded by a short history followed by rapid neurological deterioration and usually death. The rationale for operation is discussed, and an aggressive approach utilizing adjuvant therapy directed at the entire neuraxis is suggested.

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Radical excision of intramedullary spinal cord tumors: surgical morbidity and long-term follow-up evaluation in 164 children and young adults

Shlomi Constantini, Douglas C. Miller, Jeffrey C. Allen, Lucy B. Rorke, Diana Freed, and Fred J. Epstein

Object. The majority of intramedullary spinal cord tumors (IMSCT) in children and young adults are low-grade gliomas. Radical resection of similar tumors in the cerebral hemisphere or cerebellum is usually curative; however, the conventional management for IMSCTs remains partial resection followed by radiotherapy because of the concern for surgical morbidity. Nevertheless, radical resection of IMSCTs without routine adjuvant treatment has been the rule at our institution since 1980. In an attempt to resolve this controversy, the long-term morbidity and survival in a large series of children have been retrospectively reviewed.

Methods. The database records and current status of 164 patients 21 years of age and younger in whom an IMSCT was resected were reviewed. A gross-total resection (> 95%) was achieved in 76.8% of the surgical procedures. Subtotal resections (80–95%) were performed in 20.1%. The majority of patients (79.3%) had histologically low-grade lesions.

There were no deaths due to surgery. When comparing the preoperative and 3-month postoperative functional grades, 60.4% stayed the same, 15.8% improved, and 23.8% deteriorated. Only 13 patients deteriorated by more than one functional grade. Patients with either no deficits or only mild deficits before surgery were rarely injured by the procedure, reinforcing the importance of early diagnosis and treatment.

The major determinant of long-term patient survival was histological composition of the tumor. The 5-year progression-free survival rate was 78% for patients with low-grade gliomas and 30% for those with high-grade gliomas. Patients in whom an IMSCT was only partially resected (< 80%) fared significantly worse.

Conclusions. The long-term survival and quality of life for patients with low-grade gliomas treated by radical resection alone is comparable or superior to minimal resection and radiotherapy. The optimum therapy for patients with high-grade gliomas is yet to be determined.

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Central nervous system gangliogliomas

Part 2: Clinical outcome

Frederick F. Lang, Fred J. Epstein, Joseph Ransohoff, Jeffrey C. Allen, Jeffrey Wisoff, I. Richmond Abbott, and Douglas C. Miller

The records of 58 patients with gangliogliomas surgically treated between January 1, 1980, and June 30, 1990, were retrospectively reviewed in order to determine long-term survival, event-free survival, and functional outcome resulting after radical resection and to assess the impact of histological grading on outcome. Tumors were located in the cerebral hemisphere in 19 cases, the spinal cord in 30, and the brain stem in nine. Forty-four patients had gross total resection and 14 had radical subtotal resection. Only six patients underwent postoperative irradiation or chemotherapy and, therefore, the outcome was generally related to surgery alone. Of the 58 gangliogliomas, 40 were classified as histological grade I, 16 were grade II, and two were grade III. The median follow-up period was 56 months. There were no operative deaths, and the operative morbidity rate was 5%, 37%, and 33% for cerebral hemisphere, spinal cord, and brain-stem gangliogliomas, respectively. The 5-year actuarial survival rates for cerebral hemisphere, spinal cord, and brain-stem gangliogliomas were 93%, 84%, and 73%, respectively (p = 0.7). The event-free survival rate at 5 years was 95% for cerebral hemisphere gangliogliomas and 36% for spinal cord gangliogliomas (p < 0.05); for brain-stem gangliogliomas the event-free survival rate at 3 years was 53% (p < 0.05). Neurological function at recent follow-up evaluation was stable or improved in 81% of patients. Multivariate analysis (Cox linear regression) revealed tumor location to be the only variable predictive of outcome, with spinal cord and brain-stem gangliogliomas having a 3.5- and 5-fold increased relative risk of recurrence, respectively, compared to cerebral hemisphere gangliogliomas. Histological grade was not predictive of outcome, although in each location there was a trend for higher-grade tumors to have a shorter time to recurrence. It is concluded that radical surgery leads to long-term survival of patients with gangliogliomas, regardless of location, and adjuvant therapy can probably be reserved for special cases.

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Foreign body reaction to hemostatic materials mimicking recurrent brain tumor

Report of three cases

Karl F. Kothbauer, George I. Jallo, Joao Siffert, Elpidio Jimenez, Jeffrey C. Allen, and Fred J. Epstein

✓ Chemical agents routinely used in neurosurgery to achieve intraoperative hemostasis can cause a foreign body reaction, which appears on magnetic resonance (MR) images to be indistinguishable from recurrent tumor. Clinical and/or imaging evidence of progression of disease early after surgical resection or during aggressive treatment may actually be distinct features of granuloma in these circumstances.

A series of three cases was retrospectively analyzed for clinical, imaging, surgical, and pathological findings, and the consequences they held for further disease management.

All patients were boys (3, 3, and 6 years of age, respectively) and all harbored primitive neuroectodermal tumors. Two tumors were located in the posterior fossa and one was located in the right parietal lobe. Two boys exhibited clinical symptoms, which were unexpected under the circumstances and prompted new imaging studies. One patient was asymptomatic and imaging was performed at planned routine time intervals. The MR images revealed circumscribed, streaky enhancement in the resection cavity that was suggestive of recurrent disease. This occurred 2 to 7 months after the first surgery. At repeated surgery, the resected material had the macroscopic appearance of gelatin sponge in one case and firm scar tissue in the other cases. Histological analysis revealed foreign body granulomas in the resected material, with Gelfoam or Surgicel as the underlying cause. No recurrent tumor was found and the second surgery resulted in imaging-confirmed complete resection in all three patients. Because recurrent disease was absent, the patients continued to participate in their original treatment protocols. All patients remain free from disease 34, 32, and 19 months after the first operation, respectively.

During or after treatment for a central nervous system neoplasm, if unexpected clinical or imaging evidence of recurrence is found, a second-look operation may be necessary to determine the true nature of the findings. If the resection yields recurrent tumor, additional appropriate oncological treatment is warranted, but if a foreign body reaction is found, potentially harmful therapy can be withheld or postponed.

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Alphafetoprotein and human chorionic gonadotropin determination in cerebrospinal fluid

An aid to the diagnosis and management of intracranial germ-cell tumors

Jeffrey C. Allen, Jerome Nisselbaum, Fred Epstein, Gerald Rosen, and Morton K. Schwartz

✓ The cerebrospinal fluid (CSF) and serum of six patients with histologically verified intracranial germ-cell tumors were assayed serially for the presence of alphafetoprotein (AFP) and the beta subunit of human chorionic gonadotropin (HCG). Two patients had embryonal carcinomas, two had choriocarcinomas, and two had dysgerminomas. The marker profile for a given tumor in either CSF or serum correlated with the histological diagnosis; that is, embryonal carcinoma produced AFP and HCG, choriocarcinoma produced HCG, and dysgerminoma produced no markers. The marker levels in serum and CSF declined with therapy and rose usually prior to the development of overt clinical symptoms if the patient's tumor recurred. A CSF-to-serum gradient of the marker levels was present in three of four patients, and the serum levels were often normal when the CSF values were elevated. Ventricular marker levels were lower than the lumbar levels in two of two patients. The assay of these biological markers is a sensitive indicator of the success of therapy, and the presence of a CSF-to-serum gradient suggests that the major portion of the neoplasm rests within the central nervous system. A histological diagnosis can be inferred without the necessity of surgery in appropriate clinical contexts.

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Cumulative incidence of radiation-induced cavernomas in long-term survivors of medulloblastoma

Sean M. Lew, Joseph N. Morgan, Estee Psaty, Daniel R. Lefton, Jeffrey C. Allen, and Rick Abbott


The goal of this study was to determine the incidence of radiation-induced cavernomas in children treated for medulloblastoma.


A retrospective chart and film review was performed for all patients treated for medulloblastoma at the Insitute for Neurology and Neurosurgery/Beth Israel Medical Center between August 1996 and the present. The clinical and radiographic histories of pediatric patients (ages 3–21 years at diagnosis) with a histologically confirmed diagnosis of medulloblastoma who received craniospinal radiation therapy were reviewed.

Fifty-nine patients were identified, with a mean age at radiation treatment of 7.7 years and a mean follow-up time of 7.2 years. The dose to the craniospinal axis was 24 Gy (31 patients) or 36 Gy (28 patients). The radiation energy in the craniospinal axis was provided by photons in 55 patients and protons in four. All patients received a posterior fossa boost of 54 Gy (46 patients) or 72 Gy (13 patients). Twenty-six lesions developed in 18 patients (31%) during the observation period. The cumulative incidence of lesion development was 5.6, 14, and 43%, at 3, 5, and 10 years, respectively. The sites of occurrence were cerebral (20 cases) and cerebellar (six cases). There was no significant correlation between age at diagnosis, sex, craniospinal radiation dose or energy source, and lesion development. Only one patient required surgical intervention for a symptomatic hemorrhagic lesion in the frontal lobe. Histological analysis in this case was consistent with cavernoma.


Cavernomas are common after cranial irradiation in children, and their incidence increases over time. Most of these lesions follow a benign course and do not require intervention.

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The influence of central review on outcome in malignant gliomas of the spinal cord: the CCG-945 experience

Eric Bouffet, Jeffrey C. Allen, James M. Boyett, Allen Yates, Floyd Gilles, Peter C. Burger, Richard L. Davis, Laurence E. Becker, Ian F. Pollack, and Jonathan L. Finlay


The impact of central pathology review on outcome has been described in pediatric patients with high-grade glioma (HGG). The objective of this report was to analyze the impact of the central pathology review on outcome in the subgroup of patients with institutional diagnosis of HGG of the spinal cord enrolled in the Children's Cancer Group 945 cooperative study.


Five neuropathologists centrally reviewed the pathology of the 18 patients with HGG of the spinal cord who were enrolled in the study. These reviews were independent, and reviewers were blinded to clinical history and outcomes. A consensus diagnosis was established for each patient, based on the outcome of the review.


Of 18 patients, only 10 were confirmed to have HGG on central review. At a median follow-up of 12 years, event-free and overall survival for all 18 patients was 43.2% ± 13.3% and 50% ± 13.4%, respectively. After central review, 10-year event-free and overall survival for confirmed HGGs and discordant diagnoses was 30% ± 12.5% versus 58.3% ± 18.8% (p = 0.108) and 30% ± 12.5% versus 75% ± 14.2% (p = 0.0757), respectively.


The level of discordant diagnoses in children and adolescents with institutional diagnosis of HGG of the spinal cord was 44% in this experience. However, there was no significant difference in outcome between patients with confirmed and discordant diagnosis. This group of tumor deserves a specific attention in future trials.