Medulloblastoma: is the 5-year survival rate improving?

A review of 80 cases from a single institution

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✓ A series of 80 cases of medulloblastomas in children undergoing operation and postoperatively followed between 1980 and 1990 at Great Ormond Street Hospital for Children (GOSH) has been reviewed and compared to an earlier series reported from the same institution by McIntosh. The overall 5-year survival rate for the present series was 50%, although three patients died after surviving 5 years. The operative mortality rate was 5%. Survival analysis revealed that the presence or absence of spinal metastases and the necessity for some form of cerebrospinal fluid diversion within 30 days of the operation independently significantly affected survival in this series. Those patients with no spinal metastasis and total tumor removal had a 5-year survival rate of 73%, making this the most favorable subgroup in the series. Patient age and gender, duration of symptoms, Chang T stages, tumor volume, extent of resection, and postoperative chemotherapy were not significant variables.

Although these results are better than those reported in the earlier GOSH series, they are not significantly different from the results of the second 5-year cohort of patients described in that article. Radiotherapy remains the greatest advance in treatment, although it is hoped that further improvement will result from the various chemotherapy protocols now being studied and from increasing knowledge of the biological behavior of these tumors.

Abstract

✓ A series of 80 cases of medulloblastomas in children undergoing operation and postoperatively followed between 1980 and 1990 at Great Ormond Street Hospital for Children (GOSH) has been reviewed and compared to an earlier series reported from the same institution by McIntosh. The overall 5-year survival rate for the present series was 50%, although three patients died after surviving 5 years. The operative mortality rate was 5%. Survival analysis revealed that the presence or absence of spinal metastases and the necessity for some form of cerebrospinal fluid diversion within 30 days of the operation independently significantly affected survival in this series. Those patients with no spinal metastasis and total tumor removal had a 5-year survival rate of 73%, making this the most favorable subgroup in the series. Patient age and gender, duration of symptoms, Chang T stages, tumor volume, extent of resection, and postoperative chemotherapy were not significant variables.

Although these results are better than those reported in the earlier GOSH series, they are not significantly different from the results of the second 5-year cohort of patients described in that article. Radiotherapy remains the greatest advance in treatment, although it is hoped that further improvement will result from the various chemotherapy protocols now being studied and from increasing knowledge of the biological behavior of these tumors.

In 1925 Bailey and Cushing3 defined medulloblastomas as embryonic tumors of the central nervous system arising from undifferentiated neuroepithelial cells in the cerebellum. More recently, this definition has been confined to primitive neuroectodermal tumors of the posterior fossa, the etiology of which remains unknown.50

Medulloblastoma is the most common childhood intracranial tumor, accounting for 20 to 25% of pediatric intracranial tumors reported in the United Kingdom.55 During the past 30 years, radical surgical removal of the tumor followed by radiotherapy to the craniospinal axis, with or without complementary chemotherapy, has been responsible for an improvement in the 5-year survival rate to 50% or better (Tables 1 and 2).4,6,7,15,16,18,21,26–28,35,43,47,52

TABLE 1

Summary of contemporary surgical series of patients with medulloblastoma

Authors & Year*No. of Cases5-Year Survival (%)Periop Mortality (%)Result of Spinal Investigation
Hirsch, et al., 19795754 10.5 not given 
McIntosh, 1979   
 cohort 1 (no XRT)462 not given not given 
 cohort 2 (XRT)4139 not given not given 
Raimondi & Tomita, 19795134.5 8 not given 
Choux, et al., 19826037 not given not given 
Hoffman, et al., 198214447 not given not given 
Hoppe-Hirsch, et al., 199012060 6.5 3% (3 of 105) 
Jenkin, et al., 19907264 not given 13% (2 of 15) 
Di Rocco, et al., 19944544.4 not given not given 
Cervoni & Cantore, 19953560 14 not given 
Sure, et al., 19956650 not given 14% (9 of 66) 
David, et al., 19978050 5 33% (25 of 76) 
 (current article)   
metaanalysis81745.2 8.8 15% (39 of 262) 

XRT = radiotherapy.

The proportion of patients with positive myelography (the absolute number of positive myelography/all myelography; range 3–33%) where it was declared. In 67.9% (555 cases) the presence or absence of metastases was not declared.

TABLE 2

Summary of radiotherapy and/or chemotherapy series of patients with medulloblastoma*

Authors & YearNo. of Cases5-Year Survival (%)Adjuvant TherapyIndicationsResults of Spinal Investigation
Bloom, et al., 19698232XRTall patientsnot given
Harisiadis & Chang, 19775840.4XRTall patients26% (15 of 58)
Hughes, et al., 19886068XRTpartial removal, brainstem involvement, <2 yrs of agenot given
Evans, et al. (CCSG &23359XRT & CHTmetastases, advanced local disease, <4 yrs of age18% (42 of
 RTOG), 1990 233)
Tait, et al. (SIOP), 199028653XRT & CHTpartial removal, brainstem involvement, Chang stages T3 & T4not given
Halberg, et al., 19916573low-dose XRT & CHT>75% resection, no metastases, >2 yrs of agenot given
Krischer, et al., 19917168XRT & CHT>5 yrs of age, malesnot given
Duffner, et al., 19936246 (atCHT & XRTCHT <3 yrs of age, to delay XRTnot given
 2 yrs)
Packer, et al., 19946383XRT & CHTall patients17% (11 of 63)
Wara, et al., 19949252XRT & CHTall patientsnot given
Gentet, et al., 19956862XRT & CHTpartial removal, brainstem involvement, <2 yrs of age24% (16 of 68)
metaanalysis114058NANANA

CCSG = Children's Cancer Study Group; CHT = chemotherapy; NA = not applicable; RTOG = Radiation Therapy Oncology Group; SIOP = International Society of Pediatric Oncology; XRT = radiotherapy.

Recommendations for use of protocol concluded by study.

Proportion of patients with positive myelography (the absolute number of positive myelography/all myelography; range 17–26%) where it was declared.

In 1979 McIntosh35 reported 87 consecutive cases of medulloblastoma operated on at Great Ormond Street Hospital for Children (GOSH) between 1965 and 1974. The continuing large number of cases seen here allows us a unique opportunity to view longitudinally the effect that modern methods of investigation and therapy have had on the prognosis of this disease. We report here the details of 80 cases diagnosed, operated on, and followed in the 10 years from 1980 to 1990 at this hospital in an attempt to determine whether any improvement has occurred in the observed disease—free survival rate for medulloblastoma since McIntosh's earlier report.

Clinical Material and Methods
Patient Population

Patients with medulloblastoma diagnosed at our hospital in the 10-year period from 1980 to 1990 form the basis of this report. Hence a minimum 5-year follow-up period was available for all patients. All the data were collected and are stored in a database maintained and updated by a project-dedicated neurooncology research nurse (K.P.) for subsequent analysis. Variables considered as possible predictors of survival were age at diagnosis, gender, duration of symptoms, Chang T and M stages, presence of spinal metastases, tumor volume, extent of resection, postoperative adjuvant therapy, and cerebrospinal fluid (CSF) drainage procedure. Associations between these variables were investigated. The log-rank test was used to assess the significance of differences between groups. Kaplan—Meier survival curves are presented. Proportional hazards regression analysis was used to investigate the independent effects of all variables on survival. Although originally there were 87 patients with medulloblastoma who underwent operation during this period at GOSH, only 80 were included in the study. The remaining seven patients (whose presenting features, surgery, and postoperative treatment were comparable to the 80 patients reported here) came from overseas and there was insufficient information regarding the follow-up period to include them in the analysis. All the remaining 80 patients had a minimum of 5 years follow-up review from the date of study inclusion. Therefore, the 5-year survival figures are based on the entire data set, avoiding the need for actuarial estimation (percentages are presented with 95% confidence intervals [CIs] in parentheses).

Patient Gender and Age

There were 52 boys and 28 girls in this group (male/female ratio 1.85:1). The median age was 6.2 years, ranging from 8 months to 14.5 years. There were two age peaks: 4 and 8 years (Fig. 1).

Fig. 1.
Fig. 1.

Bar graph demonstrating bimodal age distribution in the 80 patients in the current series.

Duration of Symptoms Before Diagnosis

The median duration of symptoms was 1.75 months with a range of 3 days to 16 months.

Symptoms

Symptoms of raised intracranial pressure were present in 74 patients (92%). Truncal ataxia with nystagmus, diplopia, blurred vision, and an increasing head size in patients younger than 18 months were the most frequent signs noted at admission.

Operative Technique

All operations were performed, with the patient in the sitting position, by one of two consultant neurosurgeons. The operating microscope and the ultrasonic aspirator were available for every case. The operations consisted of a posterior fossa craniectomy with removal of as much tumor as the surgeon considered prudent at the time. Total, subtotal (> 90%), or partial (< 90% to > 50%) tumor removal was recorded by the operating surgeon in each case; in most cases this was confirmed by early postoperative computerized tomography (CT) scanning (see Results).

Postoperative Investigation and Therapies

For the detection of spinal secondary tumors, myelography was performed within 2 weeks of the operation. This was performed in all but four individuals who died in the early postoperative period.

The protocol used for postoperative craniospinal irradiation is detailed elsewhere.55 In summary, fractionated irradiation of the whole brain to a midline dose of 30 Gy in 3 weeks was conducted with boosting of the posterior fossa and midbrain as far anteriorly as the anterior clinoid process. At the same time, spinal irradiation was initiated. A single field was used wherever possible to avoid potentially dangerous areas of under- or overtreatment. A spinal dose of at least 30 Gy was given to the spine over a 5-week period. For the final part of the radiotherapy, a posterior fossa boost was given, providing the initial site of the tumor and its immediate surrounding area with a final dose of 50 to 55 Gy during a 7- to 8-week period. The final dose to the cerebral hemispheres and the anterior part of the brain was 35 Gy in 4 weeks, whereas that administered to the spine was a minimum of 30 Gy over 5 weeks. The whole treatment usually took 8 weeks to complete.

The policy concerning chemotherapy during the period of this study was to administer chemotherapy to patients under 2 years of age to avoid the deleterious effect of radiotherapy and to those with widespread metastatic disease and/or partial tumor removal. In these latter cases, the chemotherapy was given in combination with radiotherapy. The most frequently used agents were lomustine, vincristine, methotrexate, and cisplatinum, usually in combination. Chemotherapy was also used (together with palliative radiotherapy and reoperation) to treat tumor recurrences. The following decision-making process was used in the choice of treatment for patients with tumor recurrence: after patients had been deemed suitable for further treatment (on the basis of a joint medical and parental decision), symptomatic focal recurrence, that is, spinal with root pain, was usually treated by irradiation and diffuse recurrence by chemotherapy. Repeat surgery was advised for a solitary discrete recurrent mass in the posterior fossa and several patients received a combination of these treatments.

Results
Operative Results
Operative Staging and Tumor Volumes

The operative TM staging system of Chang, et al.,6 was applied to 71 (89%) of our patients (Table 3). We measured tumor volumes from preoperative CT scans using computer imaging software (NIH Image 1.57, developed by Wayne Rasband of the National Institutes of Health, Bethesda, MD, for processing, analysis, and display of images on Apple Macintosh computers). This method has previously been validated by Duong and colleagues.14 The mean tumor volume was 24.9 ml with a range from 1.5 to 85.1 ml. There was no significant correlation between patient age and gender, CSF drainage procedure, metastatic disease, Chang T stage, and tumor volume.

TABLE 3

Distribution of Chang tumor stages observed in 71 patients with medulloblastoma from 1980 to 1990*

No. of Patients
StageT1T2T3T4
M0, M1523221
M314123

In each case the more advanced proven M stage was applied. No patient with a Chang stage M2 or M4 was encountered.

Extent of Tumor Removal

Total tumor removal was achieved in 32 cases (40%). A subtotal removal was achieved in 33 cases (41%), partial removal in 14 cases (18%), and biopsy in one case. The operative mortality (death within 30 days of surgery) was 5% (four cases). Early CT scans were available for review in 71 cases (89%). In 56 (79%) of 71 cases, CT scans confirmed the surgeon's judgment of the extent of tumor removal. In eight cases, in which a thin layer of cells was left on the floor of the fourth ventricle, early postoperative scanning failed to detect this.

Perioperative Morbidity

Perioperative morbidity is listed in Table 4. Two patients were left with a permanent and severe hemiparesis and six displayed the syndrome described as transient cerebellar mutism.

TABLE 4

Perioperative complications in 29 patients with 41 complications

ComplicationNo. of Patients
pseudomeningocele9
meningitis9
cranial nerve palsy7
mutism6
CSF leak4
hemiparesis2
other infection4

Cerebrospinal Fluid Diversion Procedures

Seventeen patients (21%) required insertion of a perioperative external drain or ventriculoperitoneal (VP) shunt within 30 days of the operation. Only 10 patients (12.5%) needed a permanent VP shunt within 90 days of surgery and eight patients (10%) required a VP shunt more than 90 days after their operation, making a total of 18 cases (22.5%) that eventually required some form of permanent CSF diversion. The relation of CSF diversion procedures to the extent of tumor removal can be expressed in the following way: 12 of the 17 patients who required early shunting had undergone total tumor removal (71%), whereas this was achieved in 20 of the remaining 63 patients (32%).

Postoperative Investigation and Therapies
Myelography

Seventy-six children (95%) underwent postoperative myelography. The procedure was omitted in four patients (5%) due to their poor postoperative condition; all these patients subsequently died within 30 days of the operation. The investigation yielded positive results in 25 cases (33%) and negative results in 51 cases (67%).

Postoperative Adjuvant Therapy

Seventy-three patients (91%) received craniospinal radiation therapy, which was conducted at four different centers. Seven patients (9%) did not receive postoperative radiotherapy. Seven of the patients (10%) who received radiotherapy were given a reduced dose because of a variety of reasons (patient < 2 years of age, poor general condition, or deterioration during radiation therapy).

Twelve patients (15%) received chemotherapy with their initial postoperative treatment. Ten of these received chemotherapy with radiotherapy, whereas two only underwent chemotherapy; one 10-month-old patient died of septicemia during preirradiation chemotherapy 6 weeks after the operation. A 2-year-old patient with a small tumor and no metastasis received only chemotherapy.

Survival Analysis

The overall 5-year survival rate in our patients was 50% (Fig. 2). Three patients (ages 13.1, 6.8, and 8.5 years at surgery) died after surviving 5 years; they had been disease free for 2.8, 2.9, and 6.2 years, respectively. Thus, the 5-year disease-free survival rate was 47.5% (95% CI 36–59%). There was no significant difference between the survival data for boys and girls or for those of patients younger and older than 2 years of age at the time of presentation in this series.

Fig. 2.
Fig. 2.

Graph displaying a Kaplan—Meier curve for overall survival time in this series.

As expected, there was a statistically highly significant difference between the survival of those with positive and negative findings on myelography (p = 0.006) (Fig. 3 upper left). The 5-year survival rate was 60% (95% CI 46–74%) for those with negative myelography findings compared to 25% (95% CI 9–45%) for those with positive postoperative results. The overall mortality rate was increased by 138% (95% CI 26–353%) when myelography results were positive. A similar significant difference was observed between Chang stages M0 and M3.

Fig. 3.
Fig. 3.

Graphs depicting Kaplan—Meier survival curves of patients in this series. Upper Left: Patients with positive (25 patients) and negative (51 patients) findings on myelography. There is a highly significant difference (p = 0.006) between the survival of those with and without spinal metastases. Upper Right: Patients who did (yes; 17 patients) or did not (no; 63 patients) need CSF diversion within 30 days of the operation. There is a highly significant difference (p = 0.008) between the two groups of patients, with those patients undergoing CSF diversion experiencing a poorer 5-year survival rate. Lower Left: Patients with different Chang T stages divided into two groups according to invasion of the floor of the fourth ventricle (Chang T1–3A [40 patients] and T3B [31 patients]). The difference is statistically not significant. Lower Right: Patients with total (32 patients) and subtotal/partial (47 patients) tumor removal. The difference is not statistically significant.

Those patients who needed a CSF drainage procedure (either external ventricular drainage or a VP shunt) within 30 days of surgery had a significantly shorter survival time than those who did not require one (p = 0.008) (Fig. 3 upper right). The mortality rate was more than doubled (240% [95% CI 123–473%]) in those having early CSF drainage. There was no significant difference in the mean age of these patients (6.2 years) compared to others in the series, and although they were mostly males (15 [88%] of 17), inclusion of these variables in the Cox model did not significantly affect the findings.

Tumor size and infiltration (that is, the Chang T1–4 stages6) in themselves did not affect survival rates in our series. Post hoc analyses of various combinations of Chang stages (Chang T1–3A and T3B—4, according to the presence or absence of tumor arising from the floor of the fourth ventricle) failed to demonstrate any effect of this variable on survival, calling into question its usefulness (Fig. 3 lower left). Similarly, tumor volume did not influence survival.

Although the 5-year survival rate was slightly better for those with total tumor removal (56% vs. 47%) the difference did not reach statistical significance (Fig. 3 lower right). The mortality rate among those who had subtotal or partial removal was 120% (95% CI 64–226%) of that seen in patients with total tumor removal. Of those who had total tumor removal (32 patients), 22 had no metastases and their survival was 73% (95% CI 50–89%) at 5 years, making this the most favorable group in the series. In the subgroup with no spinal metastasis, the mortality rate among those with subtotal or partial removal was 139% (95% CI 55–354%) of that seen in the total tumor removal group (p = 0.48). More boys than girls had total tumor removal (26 vs. six; p < 0.01).

There was no significant difference between the survival of those treated with postoperative chemo- and radiotherapy and those treated only with radiotherapy. Two of the seven patients who had reduced doses of postoperative radiotherapy are still alive (survival time 9.7 and 11.3 years). The five who died did so after surviving between 0.125 and 6.4 years (median 2.2 years).

Five cases (6.2%) in this series had a histological diagnosis of desmoplastic medulloblastoma. All of these patients are still alive (median survival time 9.5 years, range 5–12.2 years).

Recurrence of Disease

Thirty-seven patients (46%) had a recurrence of their tumor and the outcome was fatal in all cases. The median time to recurrence was 14.6 months (range 2.3–74.7 months) and the mean time to death after diagnosis of the recurrence was 7.9 months (range 2 days–6 years; the recurrence occurred 2.8 years postoperatively in the latter case). Twenty-four of the recurrences occurred in the posterior fossa (65%) with or without other sites of disease (Table 5). Only one patient presented with extraneural (bone) metastases.

TABLE 5

Distribution of 37 patients with medulloblastoma accord ing to tumor recurrence

Site of RecurrenceNo. of Patients (%) 
posterior fossa24 (65) 
spine7 (19) 
supratentorial3 (8) 
CSF2 (5) 
extraneural1 (3) 

Twenty-three patients received additional treatment for their recurrence: 10 had chemotherapy, nine had palliative radiotherapy, and four had both. Three patients underwent additional surgery: two received chemotherapy and one chemo- and radiotherapy following the operation. A decision was made with the parents not to pursue further treatment in 14 cases. Patients who received treatment had a median survival time of 12.1 months from the time of diagnosis of their recurrence to death compared to 1.9 months for the 14 patients who had no further treatment.

Additional Follow-Up Information

Recurrence-free survival and 5-year survival times present only a limited picture of the disease and the sequelae of treatment. Many patients continue to have neuropsychological impairment, physical handicap, or medical problems. Of the 60 patients who underwent formal endocrinological assessment, 66% (95% CI 53–78%) developed growth-hormone deficiency. In terms of educational needs, 36% (95% CI 23–50%) of the 56 surviving patients either attended a special school (eight patients) or required some form of remedial assistance in a normal school (12 patients) 3 years after their initial diagnosis and treatment.

Discussion

Medulloblastomas represent approximately 4% of all brain tumors,23 18.2% of intracranial tumors in children, and roughly 30% of pediatric posterior fossa tumors;7 the patient's age at presentation, gender, and duration of symptoms have been well described.7,23 The pediatric cases reported in the literature show a peak of incidence between 3 and 8 years of age,7,49 and there is a well-known male predominance ranging from 1.33:1 to 2:1.2,16 The duration of preoperative symptoms is less than 3 months in the majority of cases.7,25 Our series demonstrates a typical pattern and these details will not be further discussed here.

Early surgical results of treating medulloblastoma were disappointing. In 1930, when Cushing9 reported his experience with 61 cases, his operative mortality rate was 32%. This has significantly improved and today it is usually under 10% in most series (Table 1).

Historically, the management of patients with medulloblastoma can be divided into four phases: 1) surgery alone; 2) surgery plus local radiotherapy; 3) surgery plus radiotherapy to the craniospinal axis; and 4) advent of chemotherapy. Improvement in the techniques and use of neuroimaging from 1965 to 1990, especially in regard to determination of the extent of tumor resection by use of postoperative CT or magnetic resonance (MR) imaging, may have contributed to more accurate tumor staging and survival analysis. The previous series from GOSH35 straddles Phases 2 and 3, when safe radiotherapy protocols were being established. Our present series demonstrates the success (or failure) of the management of cases treated between 1980 and 1990, and thus falls mainly into Phase 3, at the time when the regular use of chemotherapy protocols was only just being introduced.

Predictors of Survival

Our study focuses on a large series of patients who were all followed for a minimum of 5 years. Hence, our 5-year disease-free survival rates are the result of actual observation rather than statistical projection, which is often presented without reference to confidence limits. We have been able to identify the following variables that independently appeared to influence survival of children with medulloblastoma during this period: 1) the presence or absence of metastases at diagnosis; and 2) the need for CSF diversion within 30 days of the operation.

Metastatic Disease

In 1969 Chang, et al.,6 reported an operative staging system for medulloblastoma. Although this was modified by incorporating age and pathological characteristics,33 the value of the T staging proved disappointing not only in our series but in others.7,15,23,44 On the other hand the Chang M staging (presence or absence of metastatic disease) plays a very definite role in predicting recurrence-free survival4,15,19,23,25,53 and it soon became the “best practice” for all children with medulloblastoma to have either myelography or spinal MR imaging performed as soon after diagnosis as practical.10,41 Ninety-five percent of our patients underwent myelography within 2 weeks of the operation and we have confirmed a statistically highly significant difference between the survival of those with positive and negative findings on myelography. Today we use MR imaging (T1-weighted imaging performed both before and after gadolinium injection) as the investigation of choice preoperatively because on postoperative MR imaging studies, blood in the CSF and other postoperative changes can make interpretation difficult.8 The major influence that the presence of metastases has on survival makes it unsafe to draw any firm conclusion from those studies in which postoperative myelographic staging for spinal metastases was not performed.4,5,7,24,25,47 In our study the 5-year survival rate of patients without metastases, independent of the extent of surgical resection or tumor volume, was more than twice that of patients with metastases.

Cerebrospinal Fluid Diversion

Mild-to-severe hydrocephalus exists in at least 80 to 90% of moderate-to-large posterior fossa tumors.1 Despite earlier preferences for precraniotomy VP shunting,47 this procedure is rarely performed today.20,25 In fact, it has been reported that shunts can make subsequent tumor excision more difficult and hazardous.20 Most of our patients who required early CSF drainage (either external ventricular drainage or VP shunt) were in the younger age group, were male, and had a significantly shorter survival time. It is possible that the failure of hydrocephalus to respond to the removal of the tumor in these patients correlates with disease severity as reported by Lee and associates,34 who, in their recent study of the management of hydrocephalus in children with medulloblastoma, found that younger patients with moderate or severe preoperative hydrocephalus and extensive tumor are those most likely to benefit from preoperative CSF diversion.

Nonpredictors of Survival

In our series the following factors did not appear to have a significant influence on survival: 1) age, gender, and duration of symptoms; 2) Chang T stages; 3) tumor volume; 4) extent of tumor removal; and 5) postoperative chemotherapy.

Patient Age and Gender and Duration of Symptoms

Choux, et al.,7 also concluded that the prognosis is no better for girls in childhood medulloblastoma and there is no direct correlation between the duration of symptoms and survival time. They also reached a conclusion similar to others36 that, in children younger than 5 years, the 5-year survival rate is lower. However, several studies,5,18,19 including our own, have found no difference in survival related to age.

Chang T Stages

Similar to Choux,7 Evans,15 Hirsch,23 and Packer44 and their colleagues, we have observed that the T stages of the Chang system had no influence at all on survival. One might expect a difference between those patients who had no infiltration of the floor of the fourth ventricle compared to those who had (T1–3A and T3B—4, respectively) but our figures do not support this and we, therefore, suggest that use of Chang T staging as a predictor for survival time in medulloblastoma is not reliable. New grading systems such as those proposed by Jenkin, et al.,28 and Sure and coworkers53 also incorporate features such as the extent of resection, patient age, and tumor site as well as the presence of metastases. However, in light of our experience, we would suggest that in an analysis of a uniform cohort of patients (excluding those with the desmoplastic variant) collected over a relatively brief period, the presence or absence of metastatic disease is likely to remain the most potent perioperative factor influencing long-term survival.

Tumor Volume

We could not find any influence of tumor volume on survival time in our patients. This is perhaps not surprising considering that it is one of the variables used in the Chang T staging, which proved to have no correlation with survival.

Extent of Tumor Removal

The extent of tumor removal has been reported as one of the most significant variables affecting survival,4,5,7,25,28,40,47,53 and it has also been shown that radical tumor removal of a medulloblastoma carries lower operative mortality and morbidity rates.1,58 However, Evans and colleagues15 found that extent of tumor removal is not an independent prognostic factor and others did not find differences in long-term survival between those with total or subtotal/partial resection.18,19,26,52 Although our series appeared to suggest some benefit of total tumor removal, the difference was not statistically significant.

We observed six cases of transient cerebellar mutism postoperatively in our series. This peculiar phenomenon has been described as a most extreme form of dysarthria38,56 for which cerebellar damage is an important factor in the pathogenesis. As in our cases, it usually develops within 3 days of surgery and lasts a few weeks to a few months. The patients may have unimpaired consciousness, no deficits of the lower cranial nerves, and no disturbances of the phonatory organs.17 Psychological factors may play a role but possible organic factors include arterial spasm or edema, disturbances of CSF circulation, and postoperative meningitis.17,38 Recently bilateral edema within the brachium pontis was found to be significantly associated with the mutism syndrome.45 Another possible cause may be the sudden collapse of the aqueduct after its slow and extensive dilation due to CSF obstruction within the fourth ventricle itself. Medulloblastoma surgery has also been associated with transient peduncular hallucinations.37

Postoperative Adjuvant Therapy

The absolute necessity for postoperative craniospinal megavoltage irradiation is now generally accepted. The technique and dosages have been described by several authors6,55 and it has been emphasized that 5000 cGy or more must be directed at the posterior fossa, because that is the predominant site of recurrence.27 However, with increasing recognition of the long-term deleterious effects of irradiation, particularly on younger patients,26,29,31,39,46,48,51 alternative treatment regimes are now being studied.18,21,44

Chemotherapy has been shown to improve the survival rate of patients in poor risk categories (evidence of metastases, advanced local disease, and young age)15,42,43 and has also been used to delay radiotherapy in children less than 3 years of age who have undergone total resections and were without perioperative metastases.13,18 Chemotherapy has also been used as a preoperative measure to improve the patient's clinical condition and to facilitate tumor removal.11 In our series chemotherapy was used in younger patients and in those with advanced disease and/or partial tumor removal. However, survival time in these patients was identical to the rest of the series.

Whether the histological variant of desmoplastic medulloblastoma carries a better prognosis remains controversial. There are reports of better53 and worse25 prognosis; however, in most series the desmoplastic type did not significantly influence survival.4,5,7,26,36 That was the reason why we have not excluded these patients from the survival analysis.

The overall 5-year survival rate was 50% in our series; however, three patients died after surviving 5 years, confirming that 5-year survival does not equate with cure. Recent reports document better results,5,15,18,21,26–28,43 but the effects of selection, small patient numbers, and limited follow-up durations make interpretation difficult (Tables 1 and 2).

In 1979 McIntosh35 presented 87 consecutive cases of medulloblastoma treated at this hospital in the 10-year period from 1965 to 1974. The 46 patients undergoing surgery during the first 5 years (1965–1969) had a 5-year survival rate of only 2%, whereas the 41 patients undergoing surgery during the second 5 years (1970–1974) had a 5-year survival rate of 39%. He concluded that this improvement in prognosis was mainly due to improved radiotherapy techniques.35 Although our results appear better (50% vs. 39%), they represent no statistically significant improvement over McIntosh's second 5-year cohort of patients (Fig. 4).

Fig. 4.
Fig. 4.

Bar graph comparing 2-year and 5-year survival rates of 167 patients with medulloblastoma treated at GOSH over two decades.

How Can This Outlook Be Improved?
Earlier Diagnosis

The relatively short time between the onset of symptoms and diagnosis in most series makes it unlikely that this is a fruitful area for future effort.

Safer Surgery

It is now recognized that problems that occur around the time of surgery have a strong influence on the eventual quality of life of surviving children, especially the very young.26,30,31 Only by concentrating cases in specialized pediatric neurooncology centers can the short- and long-term morbidity of treatment be kept to an acceptable minimum.

Greater Knowledge of the Biological Behavior of Individual Tumors

Given the similar macroscopic and microscopic appearances of nondesmoplastic medulloblastomas, we do not yet have an explanation to account for their different behaviors in terms of their propensity to metastasize and their responses to radiotherapy and chemotherapy. Greater knowledge of the molecular and genetic biology of these tumors hopefully will enable us to categorize them in ways that would allow treatment to be tailored to the individual patient.

Adjuvant Treatments

Modern methods of investigation and therapy have clearly improved the outlook for patients with medulloblastoma compared to 20 years ago. However, the greatest advance lies in the changes that have been made to radiotherapy regimes introduced in the 1960s, and the impression from our series is that the effects of surgery and conventional radiotherapy (Phase 3 in our “history of medulloblastoma treatment”) have reached a plateau. It remains to be seen whether the various chemotherapy protocols that constitute the current phase of medulloblastoma management will be able to demonstrate any beneficial effect in a uniform cohort of nonselected patients.

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  • 6.

    Chang CHHousepian EMHerbert C Jr: An operative staging system and a megavoltage radiotherapeutic technic for cerebellar medulloblastomas. Radiology 93:135113591969Radiology 93:

  • 7.

    Choux MLena GHassoun J: Prognosis and long-term follow-up in patients with medulloblastoma. Clin Neurosurg 30:2462771982Clin Neurosurg 30:

  • 8.

    Cronqvist SGreitz DMaeder P: Spread of blood in cerebrospinal fluid following craniotomy simulates spinal metastases. Neuroradiology 35:5925951993Neuroradiology 35:

  • 9.

    Cushing H: Experiences with the cerebellar medulloblastomas: a critical review. Acta Pathol Microbiol Scand 7:1861930Cushing H: Experiences with the cerebellar medulloblastomas: a critical review. Acta Pathol Microbiol Scand 7:

  • 10.

    Deutsch MLaurent JPCohen ME: Myelography for staging medulloblastoma. Cancer 56:176317661985Cancer 56:

  • 11.

    Di Rocco CIannelli ALa Marca Fet al: Preoperative chemotherapy with carboplatin alone in high risk medulloblastoma. Childs Nerv Syst 11:5745781995Childs Nerv Syst 11:

  • 12.

    Di Rocco CIannelli ATancredi Aet al: Modalità delle recidive nel medulloblastoma. Pediatr Med Chir 16:2412451994Pediatr Med Chir 16:

  • 13.

    Duffner PKHorowitz MEKrischer JPet al: Postoperative chemotherapy and delayed radiation in children less than three years of age with malignant brain tumors. N Engl J Med 328:172517311993N Engl J Med 328:

  • 14.

    Duong DHRostomily RCHaynor DRet al: Measurement of tumor resection volumes from computerized images. Technical note. J Neurosurg 77:1511541992J Neurosurg 77:

  • 15.

    Evans AEJenkin RDTSposto Ret al: The treatment of medulloblastoma. Results of a prospective randomized trial of radiation therapy with and without CCNU, vincristine, and prednisone. J Neurosurg 72:5725821990J Neurosurg 72:

  • 16.

    Farwell JRDohrmann GJFlannery JT: Medulloblastoma in childhood: an epidemiological study. J Neurosurg 61:6576641984J Neurosurg 61:

  • 17.

    Ferrante LMastronardi LAcqui Met al: Mutism after posterior fossa surgery in children. Report of three cases. J Neurosurg 72:9599631990J Neurosurg 72:

  • 18.

    Gentet JCBouffet EDoz Fet al: Preirradiation chemotherapy including “eight drugs in 1 day” regimen and high-dose methotrexate in childhood medulloblastoma: results of the M7 French Cooperative Study. J Neurosurg 82:6086141995J Neurosurg 82:

  • 19.

    Geyer RLevy MBerger MSet al: Infants with medulloblastoma: a single institution review of survival. Neurosurgery 29:7077111991Neurosurgery 29:

  • 20.

    Goel A: Whither preoperative shunts for posterior fossa tumours? Br J Neurosurg 7:3953991993Goel A: Whither preoperative shunts for posterior fossa tumours? Br J Neurosurg 7:

  • 21.

    Halberg FEWara WMFippin LFet al: Low-dose craniospinal radiation therapy for medulloblastoma. Int J Radiat Oncol Biol Phys 20:6516541991Int J Radiat Oncol Biol Phys 20:

  • 22.

    Harisiadis LChang CH: Medulloblastoma in children: a correlation between staging and results of treatment. Int J Radiat Oncol Biol Phys 2:8338411977Int J Radiat Oncol Biol Phys 2:

  • 23.

    Hirsch JFHoppe-Hirsch E: Medulloblastoma. Adv Tech Stand Neurosurg 20:1651961993Adv Tech Stand Neurosurg 20:

  • 24.

    Hirsch JFRenier DCzernichow Pet al: Medulloblastoma in childhood. Survival and functional results. Acta Neurochir 48:1151979Acta Neurochir 48:

  • 25.

    Hoffman HJHendrick EBHumphreys RP: Management of medulloblastoma in childhood. Clin Neurosurg 30:2262451982Clin Neurosurg 30:

  • 26.

    Hoppe-Hirsch ERenier DLellouch-Tubiana Aet al: Medulloblastoma in childhood: progressive intellectual deterioration. Childs Nerv Syst 6:60651990Childs Nerv Syst 6:

  • 27.

    Hughes ENShillito JSallan SEet al: Medulloblastoma at the Joint Center for Radiation Therapy between 1968 and 1984. The influence of radiation dose on the patterns of failure and survival. Cancer 61:199219981988Cancer 61:

  • 28.

    Jenkin DGoddard KArmstrong Det al: Posterior fossa medulloblastoma in childhood: treatment results and a proposal for a new staging system. Int J Radiat Oncol Biol Phys 19:2652741990Int J Radiat Oncol Biol Phys 19:

  • 29.

    Johnson DLMcCabe MANicholson HSet al: Quality of long-term survival in young children with medulloblastoma. J Neurosurg 80:100410101994J Neurosurg 80:

  • 30.

    Kao GDGoldwein JWSchultz DJet al: The impact of perioperative factors on subsequent intelligence quotient deficits in children treated for medulloblastoma/posterior fossa primitive neuroectodermal tumors. Cancer 74:9659711994Cancer 74:

  • 31.

    Kimmings EKleinlugtebeld ATHCasey Aet al: Medulloblastoma: factors influencing the educational potential of surviving children. Br J Neurosurg 9:6116171995Br J Neurosurg 9:

  • 32.

    Krischer JPRagab AHKun Let al: Nitrogen mustard, vincristine, procarbazine, and prednisone as adjuvant chemotherapy in the treatment of medulloblastoma. A Pediatric Oncology Group Study. J Neurosurg 74:9059091991J Neurosurg 74:

  • 33.

    Laurent JPChang CHCohen ME: A classification system for primitive neuroectodermal tumors (medulloblastoma) of the posterior fossa. Cancer 56:180718091985Cancer 56:

  • 34.

    Lee MWisoff JHAbbott Ret al: Management of hydrocephalus in children with medulloblastoma: prognostic factors for shunting. Pediatr Neurosurg 20:2402471994Pediatr Neurosurg 20:

  • 35.

    McIntosh N: Medulloblastoma—a changing prognosis? Arch Dis Child 54:2002031979McIntosh N: Medulloblastoma—a changing prognosis? Arch Dis Child 54:

  • 36.

    Müller WÁfra DSchröder Ret al: Medulloblastoma: survey of factors possibly influencing the prognosis. Acta Neurochir 64:2152241982Acta Neurochir 64:

  • 37.

    Nadvi SSvan Dellen JR: Transient peduncular hallucinations secondary to brain stem compression by a medulloblastoma. Surg Neurol 41:2502521994Surg Neurol 41:

  • 38.

    Nagatani KWaga SNakagawa Y: Mutism after removal of a vermian medulloblastoma: cerebellar mutism. Surg Neurol 36:3073091991Surg Neurol 36:

  • 39.

    Nishiyama KFunakoshi SIzumoto Set al: Long-term effects of radiation for medulloblastoma on intellectual and physical development. A case report of monozygotic twins. Cancer 73:245024551994Cancer 73:

  • 40.

    Norris DGBruce DAByrd RLet al: Improved relapse-free survival in medulloblastoma utilizing modern techniques. Neurosurgery 9:6616641981Neurosurgery 9:

  • 41.

    O'Reilly GHayward RDHarkness WFJ: Myelography in the assessment of children with medulloblastoma. Br J Neurosurg 7:1831881993Br J Neurosurg 7:

  • 42.

    Packer RJ: Chemotherapy for medulloblastoma/primitive neuroectodermal tumors of the posterior fossa. Ann Neurol 28:8238281990Packer RJ: Chemotherapy for medulloblastoma/primitive neuroectodermal tumors of the posterior fossa. Ann Neurol 28:

  • 43.

    Packer RJSutton LNElterman Ret al: Outcome for children with medulloblastoma treated with radiation and cisplatin, CCNU, and vincristine chemotherapy. J Neurosurg 81:6906981994J Neurosurg 81:

  • 44.

    Packer RJSutton LNGoldwein JWet al: Improved survival with the use of adjuvant chemotherapy in the treatment of medulloblastoma. J Neurosurg 74:4334401991J Neurosurg 74:

  • 45.

    Pollack IFPolinko PAlbright ALet al: Mutism and pseudobulbar symptoms after resection of posterior fossa tumors in children: incidence and pathophysiology. Neurosurgery 37:8858931995Neurosurgery 37:

  • 46.

    Radcliffe JPacker RJAtkins TEet al: Three- and four-year cognitive outcome in children with noncortical brain tumors treated with whole-brain radiotherapy. Ann Neurol 32:5515541992Ann Neurol 32:

  • 47.

    Raimondi AJTomita T: Medulloblastoma in childhood. Acta Neurochir 50:1271381979Acta Neurochir 50:

  • 48.

    Riva DPantaleoni CMilani Net al: Impairment of neuropsychological functions in children with medulloblastomas and astrocytomas in the posterior fossa. Childs Nerv Syst 5:1071101989Childs Nerv Syst 5:

  • 49.

    Roberts ROLynch CFJones MPet al: Medulloblastoma: a population-based study of 532 cases. J Neuropathol Exp Neurol 50:1341441991J Neuropathol Exp Neurol 50:

  • 50.

    Rorke LB: The cerebellar medulloblastoma and its relationship to primitive neuroectodermal tumors. J Neuropathol Exp Neurol 42:1151983Rorke LB: The cerebellar medulloblastoma and its relationship to primitive neuroectodermal tumors. J Neuropathol Exp Neurol 42:

  • 51.

    Seaver EGeyer RSulzbacher Set al: Psychosocial adjustment in long-term survivors of childhood medulloblastoma and ependymoma treated with craniospinal irradiation. Pediatr Neurosurg 20:2482531994Pediatr Neurosurg 20:

  • 52.

    Stiller CALennox EL: Childhood medulloblastoma in Britain 1971–1977: analysis of treatment and survival. Br J Cancer 48:8358411983Br J Cancer 48:

  • 53.

    Sure UBerghorn WJBertalanffy Het al: Staging, scoring and grading of medulloblastoma. A postoperative prognosis predicting system based on the cases of a single institute. Acta Neurochir 132:59651995Acta Neurochir 132:

  • 54.

    Tait DMThornton-Jones HBloom HJGet al: Adjuvant chemotherapy for medulloblastoma: the first multi-centre control trial of the International Society of Paediatric Oncology (SIOP I). Eur J Cancer 26:4644691990Eur J Cancer 26:

  • 55.

    Tobias JSHayward RD: Brain and spinal cord tumors in childrenThomas DGT (ed): Neuro-Oncology. Primary Malignant Brain Tumors. London: Edward Arnold1990164190Neuro-Oncology. Primary Malignant Brain Tumors.

  • 56.

    Van Calenbergh FVan De Laar APlets Cet al: Transient cerebellar mutism after posterior fossa surgery in children. Neurosurgery 37:8948981995Neurosurgery 37:

  • 57.

    Wara WMLe QTXSneed PKet al: Pattern of recurrence of medulloblastoma after low-dose craniospinal radiotherapy. Int J Radiat Oncol Biol Phys 30:5515561994Int J Radiat Oncol Biol Phys 30:

  • 58.

    Wilson CB: Medulloblastoma. Current views regarding the tumor and its treatment. Oncology 24:2732901970Wilson CB: Medulloblastoma. Current views regarding the tumor and its treatment. Oncology 24:

Dr. David's work was supported by the Department of Neurosurgery, University of Péecs Medical School, Hungary, while he served as a registrar at GOSH.

Article Information

Address reprint requests to: Richard D. Hayward, F.R.C.S., Department of Neurosurgery, Great Ormond Street Hospital for Children, Great Ormond Street, London, WC1N 3JH, England.

© AANS, except where prohibited by US copyright law.

Headings

Figures

  • View in gallery

    Bar graph demonstrating bimodal age distribution in the 80 patients in the current series.

  • View in gallery

    Graph displaying a Kaplan—Meier curve for overall survival time in this series.

  • View in gallery

    Graphs depicting Kaplan—Meier survival curves of patients in this series. Upper Left: Patients with positive (25 patients) and negative (51 patients) findings on myelography. There is a highly significant difference (p = 0.006) between the survival of those with and without spinal metastases. Upper Right: Patients who did (yes; 17 patients) or did not (no; 63 patients) need CSF diversion within 30 days of the operation. There is a highly significant difference (p = 0.008) between the two groups of patients, with those patients undergoing CSF diversion experiencing a poorer 5-year survival rate. Lower Left: Patients with different Chang T stages divided into two groups according to invasion of the floor of the fourth ventricle (Chang T1–3A [40 patients] and T3B [31 patients]). The difference is statistically not significant. Lower Right: Patients with total (32 patients) and subtotal/partial (47 patients) tumor removal. The difference is not statistically significant.

  • View in gallery

    Bar graph comparing 2-year and 5-year survival rates of 167 patients with medulloblastoma treated at GOSH over two decades.

References

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Chang CHHousepian EMHerbert C Jr: An operative staging system and a megavoltage radiotherapeutic technic for cerebellar medulloblastomas. Radiology 93:135113591969Radiology 93:

7.

Choux MLena GHassoun J: Prognosis and long-term follow-up in patients with medulloblastoma. Clin Neurosurg 30:2462771982Clin Neurosurg 30:

8.

Cronqvist SGreitz DMaeder P: Spread of blood in cerebrospinal fluid following craniotomy simulates spinal metastases. Neuroradiology 35:5925951993Neuroradiology 35:

9.

Cushing H: Experiences with the cerebellar medulloblastomas: a critical review. Acta Pathol Microbiol Scand 7:1861930Cushing H: Experiences with the cerebellar medulloblastomas: a critical review. Acta Pathol Microbiol Scand 7:

10.

Deutsch MLaurent JPCohen ME: Myelography for staging medulloblastoma. Cancer 56:176317661985Cancer 56:

11.

Di Rocco CIannelli ALa Marca Fet al: Preoperative chemotherapy with carboplatin alone in high risk medulloblastoma. Childs Nerv Syst 11:5745781995Childs Nerv Syst 11:

12.

Di Rocco CIannelli ATancredi Aet al: Modalità delle recidive nel medulloblastoma. Pediatr Med Chir 16:2412451994Pediatr Med Chir 16:

13.

Duffner PKHorowitz MEKrischer JPet al: Postoperative chemotherapy and delayed radiation in children less than three years of age with malignant brain tumors. N Engl J Med 328:172517311993N Engl J Med 328:

14.

Duong DHRostomily RCHaynor DRet al: Measurement of tumor resection volumes from computerized images. Technical note. J Neurosurg 77:1511541992J Neurosurg 77:

15.

Evans AEJenkin RDTSposto Ret al: The treatment of medulloblastoma. Results of a prospective randomized trial of radiation therapy with and without CCNU, vincristine, and prednisone. J Neurosurg 72:5725821990J Neurosurg 72:

16.

Farwell JRDohrmann GJFlannery JT: Medulloblastoma in childhood: an epidemiological study. J Neurosurg 61:6576641984J Neurosurg 61:

17.

Ferrante LMastronardi LAcqui Met al: Mutism after posterior fossa surgery in children. Report of three cases. J Neurosurg 72:9599631990J Neurosurg 72:

18.

Gentet JCBouffet EDoz Fet al: Preirradiation chemotherapy including “eight drugs in 1 day” regimen and high-dose methotrexate in childhood medulloblastoma: results of the M7 French Cooperative Study. J Neurosurg 82:6086141995J Neurosurg 82:

19.

Geyer RLevy MBerger MSet al: Infants with medulloblastoma: a single institution review of survival. Neurosurgery 29:7077111991Neurosurgery 29:

20.

Goel A: Whither preoperative shunts for posterior fossa tumours? Br J Neurosurg 7:3953991993Goel A: Whither preoperative shunts for posterior fossa tumours? Br J Neurosurg 7:

21.

Halberg FEWara WMFippin LFet al: Low-dose craniospinal radiation therapy for medulloblastoma. Int J Radiat Oncol Biol Phys 20:6516541991Int J Radiat Oncol Biol Phys 20:

22.

Harisiadis LChang CH: Medulloblastoma in children: a correlation between staging and results of treatment. Int J Radiat Oncol Biol Phys 2:8338411977Int J Radiat Oncol Biol Phys 2:

23.

Hirsch JFHoppe-Hirsch E: Medulloblastoma. Adv Tech Stand Neurosurg 20:1651961993Adv Tech Stand Neurosurg 20:

24.

Hirsch JFRenier DCzernichow Pet al: Medulloblastoma in childhood. Survival and functional results. Acta Neurochir 48:1151979Acta Neurochir 48:

25.

Hoffman HJHendrick EBHumphreys RP: Management of medulloblastoma in childhood. Clin Neurosurg 30:2262451982Clin Neurosurg 30:

26.

Hoppe-Hirsch ERenier DLellouch-Tubiana Aet al: Medulloblastoma in childhood: progressive intellectual deterioration. Childs Nerv Syst 6:60651990Childs Nerv Syst 6:

27.

Hughes ENShillito JSallan SEet al: Medulloblastoma at the Joint Center for Radiation Therapy between 1968 and 1984. The influence of radiation dose on the patterns of failure and survival. Cancer 61:199219981988Cancer 61:

28.

Jenkin DGoddard KArmstrong Det al: Posterior fossa medulloblastoma in childhood: treatment results and a proposal for a new staging system. Int J Radiat Oncol Biol Phys 19:2652741990Int J Radiat Oncol Biol Phys 19:

29.

Johnson DLMcCabe MANicholson HSet al: Quality of long-term survival in young children with medulloblastoma. J Neurosurg 80:100410101994J Neurosurg 80:

30.

Kao GDGoldwein JWSchultz DJet al: The impact of perioperative factors on subsequent intelligence quotient deficits in children treated for medulloblastoma/posterior fossa primitive neuroectodermal tumors. Cancer 74:9659711994Cancer 74:

31.

Kimmings EKleinlugtebeld ATHCasey Aet al: Medulloblastoma: factors influencing the educational potential of surviving children. Br J Neurosurg 9:6116171995Br J Neurosurg 9:

32.

Krischer JPRagab AHKun Let al: Nitrogen mustard, vincristine, procarbazine, and prednisone as adjuvant chemotherapy in the treatment of medulloblastoma. A Pediatric Oncology Group Study. J Neurosurg 74:9059091991J Neurosurg 74:

33.

Laurent JPChang CHCohen ME: A classification system for primitive neuroectodermal tumors (medulloblastoma) of the posterior fossa. Cancer 56:180718091985Cancer 56:

34.

Lee MWisoff JHAbbott Ret al: Management of hydrocephalus in children with medulloblastoma: prognostic factors for shunting. Pediatr Neurosurg 20:2402471994Pediatr Neurosurg 20:

35.

McIntosh N: Medulloblastoma—a changing prognosis? Arch Dis Child 54:2002031979McIntosh N: Medulloblastoma—a changing prognosis? Arch Dis Child 54:

36.

Müller WÁfra DSchröder Ret al: Medulloblastoma: survey of factors possibly influencing the prognosis. Acta Neurochir 64:2152241982Acta Neurochir 64:

37.

Nadvi SSvan Dellen JR: Transient peduncular hallucinations secondary to brain stem compression by a medulloblastoma. Surg Neurol 41:2502521994Surg Neurol 41:

38.

Nagatani KWaga SNakagawa Y: Mutism after removal of a vermian medulloblastoma: cerebellar mutism. Surg Neurol 36:3073091991Surg Neurol 36:

39.

Nishiyama KFunakoshi SIzumoto Set al: Long-term effects of radiation for medulloblastoma on intellectual and physical development. A case report of monozygotic twins. Cancer 73:245024551994Cancer 73:

40.

Norris DGBruce DAByrd RLet al: Improved relapse-free survival in medulloblastoma utilizing modern techniques. Neurosurgery 9:6616641981Neurosurgery 9:

41.

O'Reilly GHayward RDHarkness WFJ: Myelography in the assessment of children with medulloblastoma. Br J Neurosurg 7:1831881993Br J Neurosurg 7:

42.

Packer RJ: Chemotherapy for medulloblastoma/primitive neuroectodermal tumors of the posterior fossa. Ann Neurol 28:8238281990Packer RJ: Chemotherapy for medulloblastoma/primitive neuroectodermal tumors of the posterior fossa. Ann Neurol 28:

43.

Packer RJSutton LNElterman Ret al: Outcome for children with medulloblastoma treated with radiation and cisplatin, CCNU, and vincristine chemotherapy. J Neurosurg 81:6906981994J Neurosurg 81:

44.

Packer RJSutton LNGoldwein JWet al: Improved survival with the use of adjuvant chemotherapy in the treatment of medulloblastoma. J Neurosurg 74:4334401991J Neurosurg 74:

45.

Pollack IFPolinko PAlbright ALet al: Mutism and pseudobulbar symptoms after resection of posterior fossa tumors in children: incidence and pathophysiology. Neurosurgery 37:8858931995Neurosurgery 37:

46.

Radcliffe JPacker RJAtkins TEet al: Three- and four-year cognitive outcome in children with noncortical brain tumors treated with whole-brain radiotherapy. Ann Neurol 32:5515541992Ann Neurol 32:

47.

Raimondi AJTomita T: Medulloblastoma in childhood. Acta Neurochir 50:1271381979Acta Neurochir 50:

48.

Riva DPantaleoni CMilani Net al: Impairment of neuropsychological functions in children with medulloblastomas and astrocytomas in the posterior fossa. Childs Nerv Syst 5:1071101989Childs Nerv Syst 5:

49.

Roberts ROLynch CFJones MPet al: Medulloblastoma: a population-based study of 532 cases. J Neuropathol Exp Neurol 50:1341441991J Neuropathol Exp Neurol 50:

50.

Rorke LB: The cerebellar medulloblastoma and its relationship to primitive neuroectodermal tumors. J Neuropathol Exp Neurol 42:1151983Rorke LB: The cerebellar medulloblastoma and its relationship to primitive neuroectodermal tumors. J Neuropathol Exp Neurol 42:

51.

Seaver EGeyer RSulzbacher Set al: Psychosocial adjustment in long-term survivors of childhood medulloblastoma and ependymoma treated with craniospinal irradiation. Pediatr Neurosurg 20:2482531994Pediatr Neurosurg 20:

52.

Stiller CALennox EL: Childhood medulloblastoma in Britain 1971–1977: analysis of treatment and survival. Br J Cancer 48:8358411983Br J Cancer 48:

53.

Sure UBerghorn WJBertalanffy Het al: Staging, scoring and grading of medulloblastoma. A postoperative prognosis predicting system based on the cases of a single institute. Acta Neurochir 132:59651995Acta Neurochir 132:

54.

Tait DMThornton-Jones HBloom HJGet al: Adjuvant chemotherapy for medulloblastoma: the first multi-centre control trial of the International Society of Paediatric Oncology (SIOP I). Eur J Cancer 26:4644691990Eur J Cancer 26:

55.

Tobias JSHayward RD: Brain and spinal cord tumors in childrenThomas DGT (ed): Neuro-Oncology. Primary Malignant Brain Tumors. London: Edward Arnold1990164190Neuro-Oncology. Primary Malignant Brain Tumors.

56.

Van Calenbergh FVan De Laar APlets Cet al: Transient cerebellar mutism after posterior fossa surgery in children. Neurosurgery 37:8948981995Neurosurgery 37:

57.

Wara WMLe QTXSneed PKet al: Pattern of recurrence of medulloblastoma after low-dose craniospinal radiotherapy. Int J Radiat Oncol Biol Phys 30:5515561994Int J Radiat Oncol Biol Phys 30:

58.

Wilson CB: Medulloblastoma. Current views regarding the tumor and its treatment. Oncology 24:2732901970Wilson CB: Medulloblastoma. Current views regarding the tumor and its treatment. Oncology 24:

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