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Treatment of Children With Medulloblastomas With
Reduced-Dose Craniospinal Radiation Therapy and Adjuvant
Chemotherapy: A Children’s Cancer Group Study
By Roger J. Packer, Joel Goldwein, H. Stacy Nicholson, L. Gilbert Vezina, Jeffrey C. Allen, M. Douglas Ris,
Karin Muraszko, Lucy B. Rorke, William M. Wara, Bruce H. Cohen, and James M. Boyett
Purpose:
Medulloblastoma is the most common ma-
lignant brain tumor of childhood. After treatment with
surgery and radiation therapy, approximately 60% of
children with medulloblastoma are alive and free of
progressive disease 5 years after diagnosis, but many
have significant neurocognitive sequelae. This study
was undertaken to determine the feasibility and effi-
cacyoftreatingchildrenwithnondisseminatedmedullo-
blastoma with reduced-dose craniospinal radiotherapy
plus adjuvant chemotherapy.
Patients and Methods:
Overa3-yearperiod,65chil-
dren between 3 and 10 years of age with nondissemi-
nated medulloblastoma were treated with postopera-
tive, reduced-dose craniospinal radiation therapy (23.4
Gy) and 55.8 Gy of local radiation therapy. Adjuvant
vincristine chemotherapy was administered during ra-
diotherapy,andlomustine,vincristine,andcisplatinchemo-
therapy was administered during and after radiation.
Results:
Progression-free survival was 86% ⴞ4% at
3 years and 79% ⴞ7% at 5 years. Sites of relapse for the
14 patients who developed progressive disease in-
cluded the local tumor site alone in two patients, local
tumorsiteand disseminated disease in nine, and nonpri-
mary sites in three. Brainstem involvement did not
adversely affect outcome. Therapy was relatively well
tolerated; however, the dose of cisplatin had to be
modified in more than 50% of patients before the
completion of treatment. One child died of pneumonitis
and sepsis during treatment.
Conclusion:
These overall survival rates compare fa-
vorably to those obtained in studies using full-dose
radiation therapy alone or radiation therapy plus
chemotherapy. The results suggest that reduced-dose
craniospinalradiation therapy and adjuvant chemother-
apy during and after radiation is a feasible approach
for children with nondisseminated medulloblastoma.
J Clin Oncol 17:2127–2136.
r
1999 by American
Society of Clinical Oncology.
THE MANAGEMENT OF medulloblastoma, the most
common form of malignant childhood brain tumor, has
slowly evolved over the past decade.1-4 The conventional
treatment of children with medulloblastoma after surgery
consists of 36 Gy of craniospinal irradiation supplemented
with 18 to 20 Gy of local irradiation (total dose of 54 to 56
Gy).1After such treatment, more than one half of patients
can be expected to be alive and free of progressive disease 5
years after diagnosis.1,2 Children with medulloblastoma
have been roughly separated into two major risk groups: (1)
average-risk patients who have localized disease at the time
of diagnosis and have had a total or near-total resection of
their tumors; and (2) high-risk patients who have dissemi-
nated disease and/or tumors that are partially resected. Prospec-
tive randomized studies have not demonstrated a clear-cut
benefit for the addition of adjuvant chemotherapy during or
after radiotherapy in children with average-risk disease.1,2,5
In contradistinction, these same studies have demonstrated
that the addition of chemotherapy, using a lomustine (CCNU)
and vincristine regimen, statistically improves survival for
children with high-risk medulloblastomas.2,5-7
A factor that complicates decisions regarding manage-
ment is the potential for long-term sequelae associated with
craniospinal irradiation.1,8 Children who survive medulloblas-
toma are at significant risk for serious neurocognitive and
endocrinologic dysfunction.1,8 These permanent sequelae
are secondary to a variety of factors, although the most
causative is the craniospinal radiation therapy received.
Concern over the degree of sequelae, especially intellectual
From the Departments of Neurology and Radiology, Children’s National
Medical Center, Washington,DC; Departments of Neurology, Radiology, and
Pediatrics, The George Washington University, Washington, DC; Depart-
ment of Radiation Oncology, University of Pennsylvania, Philadelphia,
PA; Department of Hematology-Oncology, University of Oregon, Port-
land, OR; Department of Neurology, Beth Israel Medical Center, New
York, NY; Department of Psychology, Cincinnati Children’s Hospital,
University of Cincinnati, Cincinnati, OH; Department of Neurosurgery,
University of Michigan, Ann Arbor, MI; Department of Pathology,
Children’s Hospital of Philadelphia, University of Pennsylvania, Phila-
delphia, PA; Department of Radiation Oncology, University of Califor-
nia at San Francisco, San Francisco, CA; Department of Neurology,
Cleveland Clinic, Cleveland, OH; and Department of Biostatistics and
Epidemiology, St. Jude Children’s Research Hospital, Memphis, TN.
Submitted November 23, 1998; accepted March 12, 1999.
Supported by the Division of Cancer Treatment, National Cancer
Institute, National Institutes of Health, Department of Health and
Human Services, Bethesda, MD. J.M.B. is supported by grant no.
CA21765 and the American Lebanese Syrian Associated Charities.
Contributing Children’s Cancer Group investigators, institutions, and
grant numbers are listed in the Appendix.
Address reprint requests to Roger J. Packer, MD, Children’s Cancer
Group, PO Box 60012, Arcadia, CA91066-6012; email rpacker@cnmc.org.
r1999 by American Society of Clinical Oncology.
0732-183X/99/1707-2127
Journal of Clinical Oncology,
Vol 17, No 7 (July), 1999: pp 2127-2136 2127
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loss, has led to attempts to reduce the dose of craniospinal
irradiation in children with nondisseminated disease.8-10
The current study (CCG-9892) was undertaken to deter-
mine the feasibility of treating children who have nondissemi-
nated medulloblastoma with reduced-dose craniospinal radia-
tion therapy (23.4 Gy) and adjuvant chemotherapy,
administered during and after radiation therapy, that consists
of CCNU, vincristine, and cisplatin. This regimen was
chosen after a prospective, nonrandomized study demon-
strated a greater than 90% 5-year disease control rate using
irradiation and identical chemotherapy in children with
nondisseminated medulloblastoma.2Patient entry was re-
stricted to children between 3 and 10 years of age, because
they were thought to be at high risk for the deleterious
effects of full-dose craniospinal irradiation. Children youn-
ger than 3 years were excluded from the study and were
treated with chemotherapy alone in a separate prospective
study.
PATIENTS AND METHODS
Children between 36 and 120 months of age (inclusive) at the time of
diagnosis with medulloblastomas (primitive neuroectodermal tumors of
the posterior fossa) were eligible for analysis. When the study initially
opened in October 1989, children with nonposterior fossa primitive
neuroectodermal tumors who met all other entry criteria were eligible
for study. The protocol was amended in January 1990 to allow entry of
children with posterior fossa tumors only. Pathology was centrally
reviewed, and all primitive neuroectodermal tumors of the posterior
fossa were eligible, including those tumors with foci of glial, neuronal,
or ependymal differentiation.
Before study entry, postoperative magnetic resonance imaging (MRI)
of the entire brain and spine, performed with and without gadolinium
enhancement, was required. The spinal axis had to be visualized in at
least two planes. CSF cytologic examination, obtained by lumbar
puncture, was required within 21 days of diagnosis. To be eligible, there
had to be no evidence of spread, based on MRI and by CSF cytologic
analysis, outside the primary tumor site. In cases deemed equivocal for
leptomeningeal disease by the treating institution, the MRIs were
centrally reviewed, although there was no mandated central review of
initial imaging studies. If CSF cytology was found to be positive for
free-floating tumor cells within the first 7 to 10 days after surgery, a
repeat spinal tap was to be performed 3 weeks after surgery. If the spinal
fluid was found to be negative for tumor cells at that point, then the
patient was eligible for study.
Within 3 days of surgery, patients were required to have postoperative
imaging of the primary tumor site with either computed tomography
(CT), with and without contrast, or an MRI, with or without gadolinium.
The degree of tumor resection was determined by the postoperative
image and the surgeon’s impression at the time of completion of
surgery.After these assessments, patients were designated a T stage per
the Chang staging system for posterior fossa medulloblastomas.2,4
Based on the surgeon’s impression at the time of surgery and the
postoperative MRI or CT study, tumor resections were graded as total or
near-total (no areas of lump or residual disease or only residual tumor
rim enhancement); partial (residual lump disease but ⬍50% of the
original tumor); or subtotal or biopsy (⬍50% tumor resection). If tumor
was not visible on the postoperative image, but the surgeon believed the
tumor was incompletely resected, the degree of surgery was considered
incomplete. However, patients were eligible independent of the degree
of tumor resection or brainstem involvement.
All eligible patients or their guardians were required to sign informed
consent before study entry.
Treatment Protocol
Radiation therapy began within 28 days of surgery. The irradiation
dose for all patients was 23.4 Gy to the craniospinal axis, supplemented
by a local tumor dose of 31.8 Gy (total dose of 55.2 Gy). When the study
first opened in October 1989, the craniospinal axis dose was 18 Gy and
the supplemental local tumor dose was 36 Gy. This was amended in
January 1990 to 23.4 Gy of craniospinal irradiation, and only data on
those patients treated with 23.4 Gy of craniospinal irradiation were
analyzed. Daily fractions of 1.8 Gy were used. In the posterior fossa
boost, the treatment field included the entire tentorium, with the anterior
aspect of the field extending to the posterior clinoid process.
The chemotherapy consisted of three drugs: vincristine, CCNU, and
cisplatin. During radiotherapy, weekly vincristine was given at a dose of
1.5 mg/m2(up to a maximum dose of 2 mg) for a total of eight doses.
Six weeks after completion of radiation therapy, patients were started on
a regimen of CCNU at 75 mg/m2orally and cisplatin at 75 mg/m2
intravenously every 6 weeks. Vincristine at a dose of 1.5 mg/m2
intravenously (up to a maximum dose of 2 mg) was given weekly for 3
consecutive weeks. Eight 6-week cycles of chemotherapy were planned.
All patients underwent a formal audiologic examination and renal
assessment (glomular filtration rate or creatinine clearance) before each
cycle of chemotherapy. The chemotherapy dose was modified if there
was any evidence of significant audiologic, renal, hematologic, or
neural toxicity. The cisplatin dose was reduced by 50% for a hearing
loss of between 10 and 20 decibels in the 500- to 3,000-Hz range, and/or
for a 40 decibel or greater loss in the 4,000- to 8,000-Hz range, and/or
for a 25% to 49% reduction in renal function (grade 3 toxicity).11 If
hearing loss was greater than 20 decibels in the 500- to 3,000-Hz
hearing range, or if loss of renal function was greater than 50%, the
cisplatin was omitted for that cycle and only given, thereafter, if renal or
hearing function improved to a grade 3 or lower toxicity. The CCNU
dose was reduced by 50% if there was marked thrombocytopenia
(platelet count ⬍50,000/mm3) or symptomatic neutropenia (absolute
neutrophil count ⬍500/mm3with associated fever or evidence of
infection requiring hospitalization, ie, grade 3 to 4 toxicity). The
vincristine dose was reduced by 50% if severe symptomatic paresthe-
sias developed or was omitted for at least one dose for ileus or weakness
greater than 1 (ona1to5grading system) and began again when
weakness improved or when the ileus resolved.
A contrast-enhanced MRI of the brain was performed every 6 weeks
after radiotherapy and every 3 months (after every two cycles of
chemotherapy) while the patient was receiving chemotherapy, and at
6-month intervals thereafter for the next 3 years after treatment. MRI
imaging of the spine was to be performed only if there were clinical
abnormalities suggestive of leptomeningeal tumor recurrence. At time
of disease relapse, patients were to have MRI of the entire neuraxis and
CSF cytology sampled.
Neurocognitive and Endocrinologic Sequelae
All patients were to have neurocognitive testing performed, either
after surgery before radiation therapy or within 3 months of completion
of radiation therapy and at 1-year intervals thereafter for the first 3 years
after treatment. Patient height and weight were recorded at the time of
2128 PACKER ET AL
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Copyright © 1999 American Society of Clinical Oncology. All rights reserved.
diagnosis and were to be noted at yearly intervals after diagnosis. The
results of the neurocognitive and endocrinologic outcome will be
reported in a separate article.
Statistical Methods
Progression-free survival (PFS) was measured from the date of
registration to the first date of documented progressive disease for the
children who progressed and to the last date of contact for children who
survived without treatment failure. The two patients who experienced
treatment failure because of reasons unrelated to disease progression are
censored at the date of failure in the estimate of PFS but are considered
failures at these dates in the estimate of event-free survival (EFS).
Distributions of PFS, EFS, and survival were estimated using the
technique of Kaplan and Meier.12 SEs of the Kaplan-Meier estimates
were calculated as suggested by Peto et al13,14 and appear in the text
after estimates for specific points in time (estimate ⫾SE). Comparisons
between failure-time distributions were made using a stratified Mantel-
Haenszel statistic.15
RESULTS
The amended protocol opened for accrual in January 1990
and was closed in December 1994. Eighty-five patients were
registered on study, and 71 were found to be eligible.
Reasons for ineligibility in 14 patients included the follow-
ing: age (two patients, one younger than 3 years and one
older than 10 years); evidence of tumor in more than one
posterior fossa site or dissemination or leptomeningeal
dissemination upon further review of data (seven patients);
inadequate postsurgical MRI studies of the spine due to
movement artifact (four patients); and withdrawal from
study by parental request before initiation of treatment (one
patient). Six other children with nonposterior fossa tumors
were entered before the amendment was made restricting
entry to posterior fossa tumors; they were not formally
analyzed in the review. The 65 assessable patients were a
mean of 6.0 years of age at diagnosis (range, 36 to 180
months).
Central pathologic review was carried out in 62 of 65
eligible patients. On pathologic review, a discordant diagno-
sis was found in three patients, which included sarcoma in
two and anaplastic ependymoma in one. Of the 59 patients
whose tumors were centrally reviewed and considered to
have medulloblastomas, the tumor was found to be primitive
neuroectodermal not otherwise specified in 47 and showed
evidence of neuronal differentiation in three, glial differentia-
tion in five, and mixed differentiation in four.
All patients, as by eligibility, had no evidence of tumor
spread at the time of diagnosis. Forty-seven patients were
male and 18 were female. Extent of tumor locally at the time
of diagnosis, as designated by T stage, was T1 in five
patients, T2 in 12 patients, and T4 in one patient. The
remaining 47 patients were considered to have T3 tumors,
with brainstem involvement in 17 (T3b). Although patients
with subtotal resections were eligible for study, only two of
the 65 patients had greater than 1.5 cm2of residual disease
on the postoperative scans.
PFS and EFS
The 65 patients who were considered before central
pathologic review to be eligible have been observed for a
median of 56 months (range, 40 to 88 months). PFS in these
patients was 86% ⫾4% at 3 years and 79% ⫾7% at 5 years
(Fig 1). Of those 14 patients who developed progressive
disease, seven did so within the first 2 years of diagnosis. Of
the 59 patients on study who were considered eligible after
central pathologic review, PFS did not differ; survival at 3
years was 85% ⫾5%. Sites of relapse for the 14 patients
who developed progressive disease included the local tumor
site alone in two, local tumor site and disseminated disease
in nine, and outside the primary tumor site alone in three.
During the period of observation, three patients died as a
result of causes other than progression of the primary tumor.
One developed a biopsy-proven brainstem glioma 4.8 years
after diagnosis. Asecond child died of accidental causes at 5
years of age. The remaining child developed pneumonitis
and overwhelming sepsis during the fifth cycle of chemother-
apy at a time when the child was not neutropenic. An
autopsy disclosed pneumonitis with alpha and gamma
streptococcus cultured from the lung, pulmonary conges-
tion, and hyaline membrane formation. There was no
evidence of tumor recurrence. Thus the overall EFS in the 65
patients at risk was slightly lower and was 83% ⫾5% at 3
years and 78% ⫾5% at 5 years.
There was no relationship between any clinical, neurora-
diographic, or histologic parameter and outcome. Specifi-
cally, there was no difference in outcome in those patients
who had brainstem involvement at the time of diagnosis and
those who did not (Fig 2). Because only two patients had
significant residual disease at the time of diagnosis and both
are doing well, no judgment can be reached between extent
of tumor resection or the amount of residual tumor and
outcome. There was no relationship between tumor differen-
tiation as seen on central pathologic review and PFS or EFS.
However, it should be noted that in the majority of patients,
only one or two slides stained with hematoxylin and eosin
were available for central review, so assessment of the
prognostic significance of cellular differentiation was quite
limited. Children younger than 5 years fared as well as older
patients.
Radiation Compliance
Radiation fields and technical treatment records were
available and could be assessed in 63 of 65 assessable
patients entered on study. Radiation therapy fields were
REDUCED-DOSE RADIOTHERAPY IN MEDULLOBLASTOMA 2129
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Fig 1. Progression-free survival on all eligible patients (N ⴝ65) treated on the study.
Fig 2. Relationship between progression-free survival and T-stage; T3b patients had brain stem involvement at diagnosis.
2130 PACKER ET AL
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Copyright © 1999 American Society of Clinical Oncology. All rights reserved.
compared, when available, with presurgical MRI or CT
scans to assess disease location. In 20 (32%) of 63 patients,
the delivery of irradiation was considered to be in violation
of protocol guidelines, including fields arranged so that there
was shielding or a high potential for shielding of disease
(seven patients), an inadequately low radiotherapy dose (two
patients), or at least two margins that were too small for
protocol guidelines (11 patients). Four-year PFS was 81% ⫾
6% for patients with ‘‘adequate’’ radiation therapy and
70% ⫾10% for those whose radiation therapy did not meet
protocol guidelines (P⫽.42; Fig 3). There was no statistical
difference between patients who had radiotherapy outside
protocol guidelines of the whole brain, posterior fossa, or
spinal irradiation, analyzed together or separately, as com-
pared with those who did not. In addition, those patients with
radiotherapy reviews who demonstrated shielded (two pa-
tients), potentially shielded disease (two patients), or doses
of radiotherapy below those required by protocol (two
patients) had a survival similar to all others in the study.
Toxicity
Toxicity during radiotherapy. Few toxicities occurred
during induction, and included sepsis in one patient (1.5%),
varicella in four (6.2%), and interstitial pneumonitis in one
(1.5%) (Table 1).
Toxicity of maintenance chemotherapy. Toxicity data
reflect the experience of 65 patients who received a total of
464 cycles of maintenance chemotherapy (Table 1). Hearing
loss, a known complication of cisplatin, occurred in 21
patients (32%). In these patients, hearing loss occurred as
early as the third cycle of maintenance chemotherapy and as
late as the seventh cycle (median, fifth cycle); renal toxicity
occurred in 17% of patients. The dose of cisplatin delivered
on each maintenance cycle is shown in Table 2. Infectious
complications included sepsis in six patients (9%); overall,
Fig 3. Relationship between radiation compliance and progression-free survival; acceptable includes all patients whose radiation was within protocol
guidelines; not acceptable includes all patients with radiation protocol violations.
Table 1. Overall Toxicity (grades 3 or 4) on CCG-9892*
Toxicity
Induction Maintenance
CommentsNo. % No. %
Fever 4 6.2 26 40
Sepsis 1 1.5 6 9.2 One patient had sepsis on two
different maintenance cycles.
Varicella 4 6.2 9 13.8 No patient had varicella
more than once.
Ototoxicity — 21 32.3 One patient may have had
hearing loss before mainte-
nance chemotherapy. The
patient is included.
Interstitial pneumonitis 1 1.5 1 1.5
*The numbers in the table refer to patients, not maintenance cycles. The total
number of patients is 65.
REDUCED-DOSE RADIOTHERAPY IN MEDULLOBLASTOMA 2131
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Copyright © 1999 American Society of Clinical Oncology. All rights reserved.
seven cycles of chemotherapy (1.5%) had sepsis as a
complication. One child, as described earlier, died of
probable bacterial pneumonitis and sepsis 2 weeks after
beginning the fifth cycle of maintenance chemotherapy.The
child was not neutropenic but was on chronic corticosteroids
since diagnosis at the discretion of the treating physician for
intermittent nausea and vomiting.
In addition, nine patients (14%) had varicella during
maintenance therapy. No patient had more than one episode
of varicella. Fever occurred in 26 patients (40%) and in 50
cycles of chemotherapy (11%).Anemia and thrombocytope-
nia requiring transfusion occurred in 36 (55%) and 27
(42%), respectively, of patients treated.
DISCUSSION
The results of this feasibility study are encouraging but
must be interpreted cautiously. Children in this study were
carefully selected to include only those with localized
disease at the time of diagnosis, which comprises approxi-
mately 60% to 70% of children with medulloblastoma. The
extent of surgical resection was not made an eligibility
criteria, but only two of the 65 patients had extensive bulky
disease after surgery. Brainstem involvement was found in
17 children, and as in other recent studies, the presence of
brainstem involvement did not detrimentally affect PFS.4
Given the improvements in surgical and neuroimaging
techniques over the past two decades, it is difficult to
compare results in this series to those published in the
literature.1,2,4,16 In the previous published experience using
this same chemotherapy regimen for children with nondis-
seminated medulloblastoma, 63 children were treated, the
majority of whom received full-dose craniospinal radiation
therapy (36 Gy), although seven patients received radiation
therapy as outlined in this study.2The previous study had
included children with metastatic disease at the time of
diagnosis, and patients were primarily staged by myelogra-
phy complemented with CSF cytology.The 5-year PFS was
85% ⫾6% for the group as a whole and 90% ⫾6% for those
children without metastatic disease at the time of diagnosis,
independent of the dose of craniospinal irradiation given.
The results of the present series, in which all children
received reduced-dose craniospinal irradiation, are quite
similar.
Other studies of children with nondisseminated or so-
called average-risk medulloblastoma have demonstrated a
variable 3- and 5-year survival rate. A prospective random-
ized study comparing 36 Gy of craniospinal irradiation to
23.4 Gy of craniospinal irradiation has been completed by
the Children’s Cancer Group (CCG) and the Pediatric
Oncology Group (POG).9Although 126 patients were
randomized in this study, a significant number were found to
be ineligible on central review, and 71 were considered
completely assessable. This study was halted before the
planned completion of the study because of the concern of
increased disseminated relapses in those children who
received reduced-dose craniospinal irradiation as compared
with those who received full-dose craniospinal irradiation.
On further follow-up of this cohort of patients, the difference
between survival in the two groups has narrowed to a
borderline statistical level of P⬍.058.16 In the initial report
of this study in which no chemotherapy was used, the 3- and
5-year PFS rate was approximately 65%. The International
Society of Pediatric Oncology and the German Society of
Pediatric Oncology completed a randomized trial comparing
35 Gy to 25 Gy of craniospinal irradiation, with or without 6
weeks of preradiation chemotherapy (procarbazine, metho-
trexate, and vincristine), in children with nondisseminated
medulloblastoma.10 The 5-year EFS in this study in children
who received standard radiotherapy alone was 60% ⫾7.8%
and 69% ⫾8% for those children who received reduced-
dose craniospinal irradiation. The survival rate for those
children who received preradiation chemotherapy followed
by standard radiotherapy was 75% ⫾7%. The only children
who did not fare as well (5-year EFS of 41% ⫾8%) were
those who received preradiation chemotherapy followed by
reduced-dose craniospinal irradiation.
Other series reviewing patients treated over longer peri-
ods of time, usually dating back to the 1970s and early
1980s, have reported survival rates in the 50% to 70% range
for those children with nondisseminated medulloblastoma
who were treated with 36 Gy or more of craniospinal
radiation therapy alone.4,17-27 The 3- and 5-year PFS results
of the present study (⬎80%) compare favorably with all of
the previously mentioned studies. In previous experience
with the CCNU, vincristine, and cisplatin postradiotherapy
regimen, few patients relapsed 3 years after diagnosis. In our
present series, there has been only one late relapse.
Table 2. Dose of CDDP by Course of Maintenance Chemotherapy*
Course Number Full Dose Reduced Dose No CDDP
1 100 0 0
29722
39802
483134
575196
6711614
7552024
8412336
NOTE. For each row, only patients who actually received chemotherapy for
that course are considered in the denominator. Reduced-dose CDDP ⫽50%;
any dose of CDDP ⬎75% is considered to be a full dose.
*Numbers in table refer to the percentage of patients receiving CDDP at that
dose for that cycle. Numbers across a row may not total 100% due to rounding.
2132 PACKER ET AL
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The sites of failure of children with nondisseminated
medulloblastoma in the present series are cause for concern.
Of the 14 patients who experienced failure in the study, local
relapse alone occurred in only two. In nine other patients,
there was both local and disseminated relapse, and it is
impossible to determine the initial site of loss of disease
control. This pattern of disease relapse is similar to that seen
in the initial study of 36 Gy of craniospinal irradiation and
CCNU, vincristine, and cisplatin chemotherapy, in which
leptomeningeal and local disease or leptomeningeal disease
dissemination alone were more common than local relapse.2
There is no clear evidence that the reduced dose of
craniospinal irradiation played a role in the tendency for
tumor recurrence to occur outside the primary site.
Another concern related to the pattern of disease relapse is
the adequacy and interpretation of MRIs of the spine at the
time of diagnosis. Eleven children who were initially
registered on the study were made ineligible by their treating
institutions after further review of the postoperative MRIs of
the spine. This included four patients whose MRIs could not
be fully evaluated because of movement artifact or postsur-
gical changes and seven children with evidence of leptomen-
ingeal dissemination. This study did not mandate central
review of the postsurgical preradiotherapy MRIs of the
spine, although MRIs at the time of staging were requested
for central review at the time of relapse. On review after
relapse, five of the 14 children who relapsed either had
evidence of dissemination on the initial MRIs (three) or had
studies that could not be adequately assessed because of
movement artifact or postoperative changes (two). These
patients were not made unassessable for this analysis,
because eligibility criteria was as determined by the refer-
ring institutions. All of the patients who were reviewed and
who on central review were found to have an inadequate
study, or a study that showed dissemination, ultimately
developed disseminated disease as part of their relapse
pattern. Because the staging MRIs on all patients who
remain free of progressive disease were not reviewed, it is
impossible to determine how many had inadequate studies
or missed leptomeningeal disease. However, it is likely that,
in any study that evaluates reduced-dose craniospinal irradia-
tion, the failure to identify leptomeningeal disease at diagno-
sis will put children who receive reduced-dose radiation
therapy at high risk for disease relapse. If patients with
inadequate studies or known disseminated tumor are re-
moved from analysis in the present study, then the 3-year
PFS rate in patients with nondisseminated disease is greater
than 90%, which compares favorably with the previous
results using 36 Gy of craniospinal irradiation and similar
chemotherapy or the results of any other published study.
These difficulties with interpretation of postoperative MRIs
highlight the fact that interpretations of spinal MRIs are still
quite subjective and vary between institutions. Standardiza-
tion of MRI techniques and central review of initial staging
studies are needed for future studies; the lack of central
review of staging studies is a major flaw of the present study.The
wider use of preoperative MRI of the spine in children with
presumed medulloblastoma may overcome some of the postop-
erative difficulties, but this contention has not been proved.
Another concern is the compliance with radiation therapy
guidelines. On central review, nearly one third of patients
were believed to have some type of radiation treatment
compliance variance: primarily, either part of the posterior
fossa disease was shielded, or the treatment margins of the
brain or spinal cord were assessed as inadequate. Despite
this, there was no difference in PFS in those patients whose
radiation therapy did not meet protocol standards as com-
pared with those whose radiation therapy did. Some patients
with shielded disease did experience recurrence in the
leptomeninges or locally, but others did not.
The chemotherapeutic approach used in this study was
well tolerated. One child, who was on chronic corticoste-
roids due to nausea and vomiting, died as a result of sepsis
and pneumonitis during the fifth cycle of chemotherapy at a
time when the child was not neutropenic. No other child in
this series was noted to be corticosteroid-dependent, and it is
likely that the overwhelming sepsis was partially caused by
the patient’s chronic corticosteroid use. It is unclear why the
child required long-term corticosteroid use and whether it
was related to the initial location of the tumor, surgery,
irradiation, and/or chemotherapy.As expected, a significant
modification in the cisplatin dose was required in approxi-
mately one half of patients after the sixth cycle of chemother-
apy. However, more than 60% of patients received eight
cycles of cisplatin, and 41% of children entered onto the
study completed the fully prescribed doses of cisplatin
without difficulty.
The present study needs to be viewed as a stepping stone
for therapeutic approaches that will both maintain a high rate
of disease control and further reduce treatment-related
sequelae. When this study was initially developed, the dose
of craniospinal irradiation was to be 18 Gy.28 A pilot study,
which was the basis of this study, had entered 10 children at
the time the present study was opened. Early in the 18-Gy
pilot study, three children developed progressive disease:
one outside the primary tumor site, another at both the local
site and outside the primary tumor site, and one at the
primary tumor site. In addition, the initial results of the
randomized CCG and POG study that demonstrated a
possible rate of poorer disease control at 23.4 Gy as
compared with 36 Gy were reported. For these reasons, the
study was amended to a higher dose of craniospinal irradia-
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Copyright © 1999 American Society of Clinical Oncology. All rights reserved.
tion (23.4 Gy). Interestingly, the other children treated with
18 Gy of craniospinal irradiation, full-dose local radio-
therapy, and identical chemotherapy remain free of progres-
sive disease well over 5 years after initiation of treatment,
and the median full-scale intelligence quotient of this patient
group is 100. In addition, the differences in overall disease
control in the randomized CCG/POG study (23.4 Gy v36
Gy) have narrowed to borderline statistical significance. On
a nationwide basis, based partly on the results of this present
study, a randomized study is underway that compares the
treatment regimen used in this report to identical radiation
therapy plus a different postradiotherapy adjuvant chemother-
apy regimen that consists of cyclophosphamide, vincristine,
and cisplatin. In the future, if this nationwide randomized
study confirms the excellent disease control observed in our
present study, it might be possible to either further reduce
the dose of craniospinal irradiation or further reduce the
dose of craniospinal irradiation and add alternative therapy
(perhaps intrathecal chemotherapy) to both maintain disease
control and reduce long-term sequelae. In any event, the
results of this study suggest that reduced-dose craniospinal
irradiation and adjuvant chemotherapy, during and after
radiation therapy, are feasible approaches for children with
nondisseminated medulloblastoma.
ACKNOWLEDGMENT
We thank Betsy Schaefer for her editorial assistance.
APPENDIX
Participating Principal Investigators of the Children’s Cancer Group
Institution Investigators Grant No.
Group Operations Center
Arcadia, California W. Archie Bleyer, MD
Anita Khayat, PhD
Harland Sather, PhD
Mark Krailo, PhD
Jonathan Buckley, MBBS, PhD
Daniel Stram, PhD
Richard Sposto, PhD
CA 13539
University of Michigan Medical Center
Ann Arbor, MI Raymond Hutchinson, MD CA 02971
University of California Medical Center
San Francisco, CA Katherine Matthay, MD CA 17829
Children’s Hospital & Medical Center
Seattle, WA J. Russell Geyer, MD CA 10382
Rainbow Babies & Children’s Hospital
Cleveland, OH Susan Shurin, MD CA 20320
Children’s National Medical Center
Washington, DC Gregory Reaman, MD CA 03888
Children’s Hospital of Los Angeles
Los Angeles, CA Paul Gaynon, MD CA 02649
Children’s Hospital of Columbus
Columbus, OH Frederick Ruymann, MD CA 03750
Columbia Presbyterian College of Physicians & Surgeons
New York, NY Leonard H. Wexler, MD CA 03526
Children’s Hospital of Pittsburgh
Pittsburgh, PA A. Kim Ritchey, MD CA 36015
Vanderbilt University School of Medicine
Nashville, TN John Lukens, MD CA 26270
Doernbecher Memorial Hospital for Children
Portland, OR H. Stacy Nicholson, MD CA 26044
University of Minnesota Health Sciences Center
Minneapolis, MN Joseph Neglia, MD CA 07306
Children’s Hospital of Philadelphia
Philadelphia, PA Beverly Lange, MD CA 11796
Memorial Sloan-Kettering Cancer Center
New York, NY Peter Steinherz, MD CA 42764
James Whitcomb Riley Hospital for Children
Indianapolis, IN Philip Breitfeld, MD CA 13809
2134 PACKER ET AL
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Copyright © 1999 American Society of Clinical Oncology. All rights reserved.
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APPENDIX
Participating Principal Investigators of the Children’s Cancer Group (Cont’d)
Institution Investigators Grant No.
University of British Columbia
Vancouver, British Columbia, Canada Paul Rogers, MD CA 29013
Children’s Hospital Medical Center
Cincinnati, OH Robert Wells, MD CA 26126
Harbor/UCLA & Miller Children’s Medical Center
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University of California Medical Center (UCLA)
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University of Iowa Hospitals and Clinics
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Childrens Hospital of Denver
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Mayo Clinic and Foundation
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University of Medicine & Dentistry of New Jersey
Camden, NJ Richard Drachtman, MD —
Wyler Children’s Hospital
Chicago, IL James Nachman, MD —
M.D. Anderson Cancer Center
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Childrens Hospital of Orange County
Orange, CA Violet Shen, MD —
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