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Chemotherapy for medulloblastomaprimitive neuroectodermal tumors of the posterior fossa.

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Chemotherapy for
Neuroectodermd Tumors of the
Posterior Fossa
Roger J. Packer, MD
Chemotherapy has only marginal efficacy in adult malignant brain tumors. In contrast, drug therapy is considerably
more effective in medulloblastomdprimitive neuroectodermal tumors (MBPNET) of the posterior fossa, the most
common childhood primary central nervous system tumor. At the time of disease recurrence, a variety of different
single agents and drug combinations result in tumor shrinkage and increased survival. The addition of chemotherapy
to standard radiotherapy improves the rate and length of disease-free survival for those children with MBPNET who
have the most extensive tumors at diagnosis. It remains to be determined which drug or drug combinations are the
most effective in MB/PNET, and which patients are most likely to benefit from chemotherapy. Chemotherapy may be
usefd to reduce or, in selected cases, obviate the need for radiotherapy and reduce treatment-related sequelae.
Packer RJ. Chemotherapy for medulloblastomdprimitive neuroectodermal
tumors of the posterior fossa. Ann Neurol 1990;28:823-828
Many different chemotherapeutic agents have been
used in the treatment of patients with newly diagnosed
and recurrent brain tumors [l). Experience with these
drugs for anaplastic glioma, by far the most common
adult malignant brain tumor, has been disappointing.
At the time of disease recurrence, chemotherapy has
been effective in only a minority of patients, and for
those who respond, benefit usually lasts less than 6
months [l}. When used in an adjuvant setting combined with surgery, radiation therapy, or both, drug
therapy has shown only marginal efficacy in proloinging
survival El]. In contrast, chemotherapy is often at least
transiently effective at the time of recurrence for children with medulloblastoma/primitive neuroectodermal
tumor (MB/PNET), the most common childhood
primary malignant brain tumor 12-71. The addition
of drug therapy to surgery and radiotherapy has improved the frequency and duration of disease-free survival in a subset of children with this tumor [8,9}. This
review summarizes the evidence that is
beneficial for children with MB/PNETs of the posterior fossa, and considers possible future applications of
drug therapy 18-101.
Medulloblastoma/Primit ive
Neuroectodermal Tumor
Medulloblastomaiprimitive neuroectodermal tumor is
composed predominantly of small cells with little cytoplasm and hyperchromatic nuclei. These tumors most
frequently arise in the posterior fossa where, traditionally, most small cell tumors have been called medulloblastomas [111. MB/PNETs frequently display
histological heterogeneity, with some regions within
the tumor having glial or other types of cellular differentiation on light microscopy. Immunohistochemical
analysis demonstrates that single MBlPNET cells may
have both neuronal and glial intermediate filaments,
staining with both neurofilament protein and glial
fibrillary acidic protein { 121. Recently, synaptophysin,
a cellular membrane protein, has been shown to be
selectively expressed in all “primitive neuroectodermal
tumors,” independent of site of origin but not in other
types of primary brain tumors {12). The cell of origin
of MBPNET has never been clearly elucidated, and
factors that control growth are largely unknown. Disagreement exists over the most appropriate classification for posterior fossa small cell tumors and histo-
From the Department of Neurology, Children’s National Medical
Center, Department of Neurology and Pediatrics, George Washington University, Washington, DC.
Address correspondence to Dr Packer, Department of Neurology,
Children’s National Medical Center, 111 Michigan Ave NW, Washington, DC 20010.
Received Jan 12, 1990, and in revlsed form May 2 and May 31.
Accepted for publication May 31, 1990.
Copyright 0 1990 by the American Neurological Association 823
Table 1 . Risk Grot@ for ChiUren with MBIPNET
Average Risk
Poor Risk (One or More)
Extent of disease
Size of primary tumor
Not disseminated
Tumor not causing marked internal
Extent of resection
Total resection or near total with only rim
enhancement on CTlMRI
4 years of age or older at diagnosis
Tumor causing internal hydrocephalus,
extending through foramen magnum, or
infiltrating brainstem
Subtotal resection
= computed tomography; MRI = magnetic resonance imaging
logically similar tumors that occur in other regions of
brain, such as the pineal (pineoblastomas) and cortex
(cerebral neuroblastoma) [l I]. Concepts of classification will no doubt change with the wider application
of immunohistochemical methods and the development of other (possibly molecular genetic) markers.
Nonetheless, since posterior fossa tumors comprise
the majority of MB/PNETs, more is known about
their clinical course and response to treatment than
for histologically similar tumors in other regions of
the brain.
A quarter century ago, fewer than one-third of patients with MB/PNET survived 5 years after treatment.
Due to several factors, including earlier diagnosis, safer
anesthesia, advances in surgical techniques, improved
postoperative care, and more effective use of radiotherapy, however, disease-free survival rates of at least
50% 5 years after diagnosis are now reported [lo, 13,
143. It is now well accepted that MB/PNETs have a
high likelihood of disseminating to other nervous system sites early in the course of illness, and 30 to 50%
of patients have either cerebrospinal ff uid cytological
or myelographic evidence of leptomeningeal spread at
diagnosis 1151. In the vast majority of patients, leptomeningeal disease at diagnosis is asymptomatic. The
clinical observation that many patients developed extensive tumor outside the primary tumor site after local radiotherapy led to delivery of prophylactic radiation to the entire neuroaxis at the time of diagnosis.
This improved long-term disease control [lo, 13, 141.
Conventionally, 3,600 cGy are given to the brain and
spine, and an additional 1,800 to 2,000 cGy to the site
of tumor (local dose 5,400-5,600 cGy). When regions
such as the subarachnoid space around the cribriform
plate have been inadvertently shielded from irradiation, localized disease relapse has occurred 161.
In the past decade, the usefulness of staging studies
has been demonstrated for MB/PNET, and these studies have become the backbone of on-going treatment
trials 18- 10, 171. Two large prospective randomized
treatment trials for children with MB/PNET (undertaken by the Children’s Cancer Study Group [CCSG}
and the International Society of Pediatric Oncology
Less than 4 years of age at diagnosis
{SIOP]) and single institutional reports strongly suggest that children can be stratified into at least two
groups based on the degree of surgical resection, size
of the tumor at the time of diagnosis, the extent of
tumor dissemination at diagnosis, and the age of the
patient E8,9, 171 (Table 1).For example, in the CCSG
study, children with localized disease at diagnosis had a
59% 5-year event-free survival, compared with 36%
for those with evidence of dissemination [8}. These
factors tend to concur in individual patients, and the
independent significance of any one factor, possibly
except for tumor metastasis, has been difficult to
prove. This is especially true for age. It is clear that
younger children, especially those younger than 3
years of age at diagnosis, have a lower survival rate [S101. Whether this is due to less aggressive treatment,
the tendency for younger patients to have disseminated disease at diagnosis, or inherent differences in
the biology of the tumor itself is unclear [S-101. It has
not yet been conclusively proven whether aggressive
resection can negate the significance of larger tumor
size at diagnosis [S]. As recommended by an American Cancer Society sponsored workshop on childhood
tumors, however, the two largest cooperative childhood cancer groups in the United States (CCSG and
the Pediatric Oncology Group) have adopted a postoperative staging system based on the extent of surgical
resection rather than on the preoperative size of local
tumor [ 181. Stratification into risk groups has taken on
increasing importance, since evidence now suggests
that some children with “poor-risk” parameters benefit
from the addition of chemotherapy, while children
with “average-risk” lesions do not. In most centers,
cerebrospinal fluid cytological analysis, myelography,
and neuroimaging of the surgical site (with either computed tomography [CT} o r magnetic resonance imaging [MRI]) are standard postoperative investigations.
Efficacy of Chemotherapy
in Recurrent MBFNET
MB/PNETs are theoretically excellent tumors for
chemotherapeutic intervention. They are usually well
vascuhzed and have a high growth fraction. In vitro
Annals of Neurology Vol 28 No 6 December 1990
Table 2. selected Chemotherapeutic Trials for Children with MBIPNET
When Given
Objective Response Rate"
Methotrexate (high-dose) 17)
Cyclophosphamide (high-dose) 131
Cisplatinum { 5 }
Carboplatinum {6]
CCNU, VCR, cisplatinum { 2 2 }
Eight-in-one (see text) [2 11
Vincristine, cisplatinum 1241
At recurrence
At recurrence
At recurrence
At recurrence
At recurrence
At recurrence
5 of 7
8 of 8
9 of 12
6 of 14
6 of 6
6 of 9
5 of 13
Median Time to Progression(mo)
10 +
Not given
Not applicable
+Reduction of tumor mass as seen on MRI or CT.
vincristine sulfate.
and in vivo studies of human medulloblastoma have
demonstrated responsiveness of the tumor to a variety
of chemotherapeutic agents {2). The recent development of multiple MB/PNET cell lines and improved in
vitro models of MBlPNET tumor growth should allow
for even better selection of agents [2). Clinical evidence for the benefit of chemotherapy has been substantiated by analysis of patients at the time of disease
recurrence, and by preirradiation therapy trials in
which therapy is given after surgery and before radiation therapy.
Since the 1960s, various chemotherapeutic agents
used singly have been shown effective in children with
relapsed MB/PNET [ 2 ) . The earliest studies, done in
the pre-CT-MRI era, usually involved only a small
number of patients and described clinical responses
without objective radiographic evidence of shrinkage.
Later studies, using CT, more convincingly demonstrated responses to chemotherapy (Table 2) [2-7).
High-dose intravenous methotrexate resulted in 50%
reduction in tumor size in 5 of 7 children with recurrent disease, and responses in 3 lasting for more than c)
months [7). The value of methotrexate is limited by
the risk of associated leukoencephalopathy, especially
when it is used after radiotherapy. High-dose intravenous cyclophosphamide was reported by Allen and
Helson [3] to result in objective evidence of tumor
shrinkage in 8 of 8 children with recurrent neuroectodermal tumors. The responses, however, were relatively transient, lasting for less than 6 months in most
patients. Recently, interest has centered on the platinum compounds. Cisplatinum has been shown to be
an effective agent, resulting in objective responses
(greater than 50% reduction in tumor size as seen
on CT) in as many as 75% of children treated for recurrent MB/PNET 14, 51. Although some children
treated with cisplatinum have had a relatively long response, most have relapsed within 1 year. Cisplatinum
may cause irreversible sensorineural hearing loss and
renal toxicity. For these reasons, a variety of platinum
derivatives have been evaluated, and one, carboplatin u n , in initial trials showed a similar therapeutic pro-
file at the time of relapse with much less ototoxicity
and nephrotoxicity [b).Unfortunately, in other clinical
trials, the efficacy of carboplatinum was not as great
[Kun, personal communication, 1990).
In 1979, Goldie and Coldman [19} proposed a
mathematical model that related curability of a malignancy to the appearance of resistant cell lines. They
proposed that control of a neoplasm was a function
of various factors favoring resistance, including the
tumor's spontaneous mutation rate. An outgrowth of
this theory was the concept that a tumor is less likely to
be resistant to multiple agents administered simultaneously than it is to be resistant to individual agents,
since cells are not given an opportunity to mutate and
develop pleiotropic multiple-drug resistance. Additionally, if drugs are given over a relatively short time,
myelosuppression should be less, because damage to
hematopoietic precursor cells is partially dependent on
duration of exposure. A variety of agents have been
used in combination (see Table 2) [2, 10, 20, 21).
These drug combinations have resulted in similar overall response rates for children with MB/PNET when
compared with single agents, and have somewhat
longer median times to recurrence. As was the case for
single agent trials, however, few if any patients have
experienced long-term disease control E2 1). At Children's Hospital of Philadelphia, a combination of l-(2chloroethyl)-3-cyclohexyl- 1-nitrosourea (CCNU), vincristine sulfate, and cisplatinum resulted in a 100%
objective response rate lasting for a median of 18.8
months [Zl]. This led to use of this drug combination
after radiotherapy in children with newly diagnosed
disease. The most aggressive application of rapid sequence, multiagent chemotherapy has been the use of
eight different drugs (so-called eight-drugs-in-one-day
therapy, which includes vincristine, CCNU, cisplatinum, hydroxyurea, prednisone, cyclophosphamide,
arabinosylcytosine, and procarbazine hydrochloride)
over a 24-hour period [20). Initial results with this
combination were encouraging, and toxicity was tolerable. Long-term therapeutic advantage in recurrent
MB/PNET for this combination when compared with
Brief Review: Packer: Chemotherapy for Medulloblastoma 825
other drug regimens, however, has yet to be shown.
The lack of long-term efficacy with this eight-drug
combination may be because some of the drugs used in
the regimen are of questionable usefulness in MB/
PNET and are used at suboptimal dosages.
Preirradiation Trials in MB/PNET
During the past decade, patients with newly diagnosed
MB/PNET have been given chemotherapy before
irradiation {19, 211 in an attempt to identify active
agents in MBIPNET and improve outcome. Potential
benefits of such trials include the following: (1) some
agents may be effective when used early in disease,
whereas the same drugs used after the patient has been
treated with other agents may have no benefit (this
effect has been demonstrated by Horowitz and coworkers 1221 in another childhood tumor, rhabdomyosarcoma), (2) side effects may be less intense because
of the lack of previous organ toxicity, allowing drugs to
be used at higher dosages, ( 3 ) microvascular changes
produced by previous radiotherapy, which may limit
drug delivery to the tumor site, may be avoided, (4)
there may be increased synergy with later radiotherapy, and (5) some drugs such as rnethotrexate and cisplatinum might be potentially less toxic to the nervous
system if used in this manner. As outlined in Table 2,
this “neoadjuvant” approach has demonstrated the efficacy of single drugs and drug combinations, primarily
eight-drugs-in-one-day therapy and the combination
of cisplatinum and vincristine. A major potential drawback of this type of therapy is the delay of radiotherapy, still the best proven form of treatment for
MB/PNET. To date, preirradiation therapy has not
been shown to improve survival for children with MB/
PNET, although in the series reported by Kretschmar
and colleagues [23}, 11 of 15 children treated with
preitradiation vincristine and cisplatinum remain alive
a median of 25 months after completion of treatment.
Adjuvant Trials in MEWNET
As stated previously, two large, independent, multiinstitutional randomized trials were undertaken in
the mid-1970s to determine the benefit of chernotherapy when used after radiation therapy for children with
MB/PNET {8, 91. In both studies, patients were randomized to receive either radiation therapy alone
(3,600 cGy craniospinal plus local boost, that is, a total
local dose 5,400-5,600 cGy) or identical radiation
therapy plus vincristine therapy during radiation and
postradiotherapy cycles of CCNU and vincristine. For
children in the CCSG trials, an addition to chemotherapy was the use of prednisone for the first 14 days
of each postradiation chemotherapy cycle. Although
these studies are flawed by today’s standards because
of the unavailability of CT scanning in some institutions and incomplete postoperative staging of other
826 Annals of Neurology
patients for residual primary site disease, they did for
the first time demonstrate a benefit of the addition of
chemotherapy in some children with MB/PNET. In
the SIOP trial, children with brainstem involvement at
diagnosis, ueated with radiation and chemotherapy,
had a significantly higher (p < 0.003) 5-year event-free
survival rate (64%) than children treated with radiation
therapy alone (36%) 191. For children treated on the
CCSG protocol, the estimated 5-year event-free survival probability was 60% for patients treated with
radiation therapy and chemotherapy, and 50% for patients treated with radiation therapy alone, a difference
that was not statistically significant 181. Patients with
higher T stages (T7-T*) alone did not statistically differ
in survival. The 5-year event-free survival for children
without metastases was 50%, compared with 36% for
children with metastases (p < 0.003). In the 30 patients with the most extensive tumor, both large primary site and metastatic event-free survival was markedly better in the group receiving chemotherapy (48%
vs. 0%, p = 0.006). Overall survival was also significantly prolonged by chemotherapy for patients with
the more extensive lesions.
Smaller nonrandomized trials have also suggested a
benefit of adjuvant chemotherapy. Mclntosh and colleagues 1241 reported 81% of 21 children ueated with
cyclophosphamide and vincristine after radiotherapy
were alive and free of disease at a median of 6 years
after diagnosis. Unfortunately, it is unclear what selection criteria were used to enter patients in this study
and how many of these patients fit current poor-risk
A study was begun in late 1983 at Children’s Hospital of Philadelphia using weekly vincristine during radiotherapy and cisplatinum, CCNU, and vincristine after radiotherapy in children with poor-risk MBIPNET
[25J. To date, 34 children with poor-risk MB/PNET
have been entered in this trial, and 32 remain alive
and free of disease at a median of 41.5 months from
diagnosis. When patients in this single-arm trial were
compared with historical controls matched for similar
poor-risk criteria, survival for children receiving the
cisplatinum regimen was statistically better than for
those treated with radiation alone or radiation plus
chemotherapy with CCNU and vincristine ( p < 0.001)
(Figure). There are obvious problems with a single-arm
study using historical controls, but this and other studies strongly suggest that chemotherapy improves the
short-term survival for children with poor-risk MB/
PNET when compared with outcome after radiotherapy alone. Presently, there are multiple single-arm and
randomized trials underway evaluating a variety of
agents both before and after radiotherapy. Results of
these trials will be very interesting, but only randomized trials pitting regimen against regimen will determine which is best.
Vol 28 N o 6 December 1990
- .
Months Post On Study
- Study Group
Disease-free survival in Children’s Hospital of Philadelphia
trial of “poor-risk” medulloblastomalprimiti~,e
tumor (MSIPNET) of the posteriorfossa with radiation therapy
plus adjuvant chemotherapy (1-{2-cbloroethyI}-3-cyclohexyl1-nitrosourea {CCNU). vincuistine sulfate {VCR}, and risplatinum {CPDD})versus disease-free survival far children
treated between 1975 and 1982 with identical radiotherapy but
no chemotherapy (or C C N U arid VCR).
Future Directions
Although the improvement in reported survival rates
is encouraging, many issues concerning the role of chemotherapy in patients with MB/PNET remain unsettled, including the question of which patients should
receive chemotherapy. As newer means of tumor characterization such as immunohistochemical staining, and
cytogenetic and molecular genetic studies are applied
to MBIPNET, better stratification is likely. Presently,
primarily children with poor-risk MB/PNET are receiving adjuvant chemotherapy. Recently reported
survival figures, however, suggest that patients with
poor-risk PNET treated with chemotherapy may survive at a rate equal to or higher than patients with
average-risk disease treated with radiotherapy alone. It
is thus unclear whether average-risk patients (who
probably still have no better than 60-70% rate of 5year survival) should be excluded from adjuvant drug
Many children, after treatment for MB/PNET, experience significant neurological, cognitive, and endocrinological sequelae [26]. Although many factors may
be responsible for these deficits, radiation therapy has
been identified as the major cause of damage. In a
prospective study of children with MB/PNET performed at Children’s Hospital of Philadelphia, children
younger than 6 years of age suffered a significant loss
of overall intelligence by 2 years after craniospinal radiotherapy (20-point decline average), which was not
seen in children with cerebellar astrocytomas treated
with surgery alone 1261. The amount of craniospinal
radiation necessary for tumor control has not been determined by carefully performed dose-response studies {lo, 261. It is conceivable that chemotherapy could
be used as a partial replacement for radiotherapy in
some patients with MB/PNET. There are presently
trials underway evaluating two doses of craniospinal
radiotherapy (2,400 cGy vs. 3,600 cGy) without chemotherapy in patients with average-risk MB/PNET.
We have undertaken a trial using a lower dose of
craniospinal radiation therapy (1,800 cGy) with fulldose posterior fossa radiation (5,580 cGy) in children
with MBIPNET, between 18 months and 6 years of
age at diagnosis, who have no evidence of leptomeningeal dissemination at diagnosis. In this trial, all
children receive adjuvant chemotherapy with CCNU,
vincristine, and cisplatinum. Only time will show, in
patients without dissemination, whether this reduced
dose of neural axis radiotherapy when coupled with
chemotherapy will be adequate to control disease and
will result in less long-term damage.
Possibly more important is the use of chemotherapy
in very young children who will probably be severely
damaged by therapeutic cranial radiation therapy. For
these patients, chemotherapy is being used in an attempt to delay or obviate the need for radiation. For
many years, workers at M. D. Anderson Hospital
(Houston, TX) have used MOPP (mechlorethamine
hydrochloride, vincristine, procarbazine, and prednisone) for infants with malignant tumors including
medulloblastoma. Eight of 18 children with MB/PNET
treated with MOPP are reported to be in complete
remission without radiotherapy for follow-up periods
ranging from 6 to 150 months (median 73 months)
1271. The Pediatric Oncology Group has used cisplatinum, high-dose cyclophosphamide, vasoetoposide
(VP lb), and vincristine for children younger than 3
years of age with a variety of malignant tumors including MB/PNET [28]. In this study, children were
treated for 12 months or until they reached 36 months
of age and then given full-dose radiotherapy. In the
majority of patients with MBIPNET, craniospinal and
local boost radiation could be delayed until the children were 24 to 36 months of age. Our experience in
the Philadelphia prospective study of neurocognitive
function, however, sumests that even at this slightly
older age, the dose of radiation delivered is still extremely damaging [26]. It is possible that further
intensification of chemotherapy may be more effective
in controlling disease and, in selected cases, permit
omission of radiotherapy.
MB/PNET is a chemoresponsive tumor. There is evidence that a subset of children with newly diagnosed
MB/PNET benefits from the addition of chemotherapy to radiation therapy. As stratification of children
with MBIPNET improves, a better understanding of
which children will benefit from drug therapy is likely.
Those drugs that are most efficacious and how they
Brief Review: Packer: Chemotherapy for Medulloblastoma 827
should be used can only be determined by prospective,
randomized, rnultiinstitutional clinical trials. The rational use of chemotherapy in the future may result in
less radiotherapy needed for some patients with MBI
PNET, resulting in fewer long-term sequelae.
We thank Delores Wider for her word processing assistance.
1. Levin VA. Chemotherapy of primary brain tumors. Neurol Clin
2. Friedman HS, Schold SC. Rational approaches to the chemotherapy of medulloblastoma. Neurol Clin 1985;3:843-854
3. Allen JC, Helson L. High-dose cyclophosphamide chemotherapy for recurrent CNS tumors in children. J Neurosurg 1981;
5 5 :749-756
4. Sexauer CL, Khan A, Burger PC, et al. Cisplatinum for recurrent pediatric brain tumors: a POG phase 11 study, a Pediatric
Oncology Group study. Cancer 1985;56:1497-1501
5. Walker RW, Allen JC. Cisplatinum in the treatment of recurrent childhood primary brain tumors. Clin Oncol 1988;6:62-66
6. Allen JC, Walker R, Luks E, et al. Carboplatin and recurrent
childhood brain tumors. J Clin Oncol 1987;5:459-463
7. Rosen G, Ghavimi F, Nirenberg A, et al. High dose methotrexate with citrovorum factor rescue for the treatment of central nervous system tumors in children. Cancer Treat Rep 1977;
6 1:681-690
8. Evans AE, Jenkin RDT, Sposto R, et al. The treatment of
medulloblastoma: the results of a prospective randomized trial
of radiation therapy with and without chloroethylcyclohexylnitrosourea, vincristine and prednisone. J Neurosurg 1990;72:
9. Allen JC, Bloom J, Ertel I, et al. Brain tumors in children:
current cooperative and institutional chemotherapy trials in
newly diagnosed and recurrent disease. Semin Oncol 1985;13:
10. Packer RJ, Sutton LN, DAngio G , et al. Management of children with primitive neuroectodermal tumors of the posterior
fossdmedulloblastoma. Pediatr Neurosci 1986;12:272-282
11. Rorke LB. The cerebellar medulloblastoma and its relationship
to primitive neuroectodermal tumors. J Neuropathol Exp
Neurol 1983;42:1-15
12. Molenaar WM, Jansson D, Gould VE, et al. Immunohistology
in the diagnosis of pediatric brain tumors. Pediatr Neurosci
13. Parks TS, Hoffman JH, Hendrich EB, et al. Medulloblastoma,
clinical presentation and management: experience at the Hospi-
tal for Sick Children, Toronto, 1950-1980. J Neurosurg 1983;
14. FaMIell JR, Dohrmann GJ, Fkdnnery JT: Medulloblastoma in
childhood: an epidemiologic study. J Neurosurg 1984;61:657664
15. Deutsch M, Reigel DM. Myelography and cytology in treatment
of medulloblastoma. Int J Radiat Oncol Biol Phys 1981;7:721725
16. Jereb B, Krishnaswasmi S, Reid A, Allen JC. Radiation for
medulloblastoma adjusted to prevent recurrence to the cribiform plate region. Cancer 1984;54:602-604
17. Chang CH, Housepian EM, Herbert C Jr. An operative staging
system and a megavoltage radiotherapeutic technique for cerebellar medulloblastoma. Radiology 1969;93:1351-1 359
18. Laurent JP, Chang CM, Cohen ME. A classification system for
primitive neuroectodermal tumors (medulloblasroma of the
posterior fossa). Cancer 1985;56:1807-1809
17. Goldie JM, Coldman A J. Quantitative model for multiple levels
of drug resistance in clinical tumors. Cancer Treat Rep 1983;
20. Pendergrass TW, Milstein JM, Geyer JR, et al. Eight-drugs-inone-day chemotherapy for brain tumors: experience in 107 children and rationale for preradiation chemotherapy. J Clin Oncol
21. Lefkowitz JB, Packer RJ, Siegel KR, et al. Results of treatment
of children with recurrent primitive neuroectodermal tumorsmedulloblastoma (PNET/MB) with CCNU, cisplatinum
(CPDD), and vincristine (VCR). Cancer 1990;65:412-417
22. Horowitz ME, Ecubanas E, Christensen ML, et al. Phase I1
testing of melphalan in children with newly diagnosed rhabdomyosarcoma: a model for anti-cancer drug development. J
Clin Oncol 1988;6:308-314
23. Kretschmar CS, Tartell N J , Kupsky W, et al. Pre-irradiation
chemotherapy for infants and children with medulloblastoma: a
preliminary report. J Neurosurg 1989;71:820-825
24. Mclntosh S, Chen M, Sartain PA, et al. Adjuvant chemotherapy
for medulloblastoma. Cancer 1985;56:1316-1319
25. Packer RJ, Siegel KR, Sutton LN, et al. Efficacy of adjuvant
chemotherapy for patients with poor-risk medulloblastoma: a
preliminary report. Ann Neurol 1988;24:503-508
26. Packer R J, Sutton LN, Atkins TA, et al. A prospective study of
cognitive deficits in children receiving whole brain radiotherapy:
2 year results. J Neurosurg 1989;70:707-713
27. Ater JL, Woo SY, Van Eyes J. Update on MOPP chemotherapy
as primary therapy for infant brain tumors. Pediatr Neurosci
28. Duffner PK, Cohen ME. Treatment of brain tumors in babies
and very young children. Pediatr Neurosci 1785-86;12:3043 10
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posterior, fossa, chemotherapy, medulloblastomaprimitive, neuroectodermal, tumors
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