VOLUME

31

NUMBER

23

AUGUST

10

2013

JOURNAL OF CLINICAL ONCOLOGY

O R I G I N A L

R E P O R T

High-Risk Medulloblastoma: A Pediatric Oncology Group

Randomized Trial of Chemotherapy Before or After
Radiation Therapy (POG 9031)
Nancy J. Tarbell, Henry Friedman, William R. Polkinghorn, Torunn Yock, Tianni Zhou, Zhengjia Chen,
Peter Burger, Patrick Barnes, and Larry Kun
Nancy J. Tarbell and Torunn Yock,
Massachusetts General Hospital,
Boston, MA; Henry Friedman, Duke
University, Durham, NC; William R.
Polkinghorn, Memorial Sloan-Kettering
Cancer Center, New York, NY; Tianni
Zhou, California State University, Long
Beach; Patrick Barnes, Stanford University, Stanford, CA; Zhengjia Chen,
Emory University, Atlanta, GA; Peter
Burger, Johns Hopkins Hospital, Baltimore, MD; Larry Kun, St Jude
Research Hospital, Memphis, TN.
Published online ahead of print at
www.jco.org on July 15, 2013.
Presented in part at the 43rd Annual
Meeting of The American Society for
Therapeutic Radiology and Oncology,
November 4-8, 2001, San Francisco, CA.
Authors disclosures of potential conflicts of interest and author contributions are found at the end of this
article.
Clinical trial information: NCT00003573.
Corresponding author: Nancy J. Tarbell,
MD, Massachusetts General Hospital,
55 Fruit St, Boston, MA 02114; e-mail:
[email protected].
2013 by American Society of Clinical
Oncology
0732-183X/13/3123w-2936w/$20.00
DOI: 10.1200/JCO.2012.43.9984

2936

Purpose
To compare event-free survival (EFS) in children with high-risk medulloblastoma randomly
assigned to receive either chemotherapy before radiation or chemotherapy after radiation.
Patients and Methods
One hundred twelve patients were randomly assigned to each arm. Criteria used to categorize
patients as high risk included M1-4 disease by modified Chang staging classification, T3b/T4
disease, or greater than 1.5 cm3 of residual tumor after surgery. Postoperatively, children with
high-risk medulloblastoma were randomly assigned to two arms, either chemotherapy entailing
three cycles of cisplatin and etoposide before radiation (chemotherapy first [CT1]) or the same
chemotherapy regimen after radiation (radiation therapy first [RT1]). Both groups received
consolidation chemotherapy consisting of vincristine and cyclophosphamide.
Results
The median follow-up time was 6.4 years. Five-year EFS was 66.0% in the CT1 arm and 70.0% in
the RT1 arm (P .54), and 5-year overall survival in the two groups was 73.1% and 76.1%,
respectively (P .47). In the CT1 arm, 40 of the 62 patients with residual disease achieved either
complete or partial remission.
Conclusion
Five-year EFS did not differ significantly whether, after surgery, patients received chemotherapy
before or after radiotherapy.
J Clin Oncol 31:2936-2941. 2013 by American Society of Clinical Oncology

INTRODUCTION

Medulloblastoma is the most common pediatric

brain malignancy, with approximately 540 new patients diagnosed in the United States each year.1,2
For the purposes of treatment, patients are divided
by ageless than or greater than 3 years of age
with these groups further subdivided into standardrisk and high-risk groups. Patients greater than 3
years of age are stratified into risk groups based on
the extent of disease beyond the original tumor site,
as summarized in the M stage of the Chang staging
system, with M1 or greater and residual tumor size
after surgery of greater than 1.5 cm3 considered
high risk.3
Since medulloblastoma was first described in
1925 by Bailey and Cushing, the futility of surgical
resection alone has been recognized, and it was only
after the use of postsurgical craniospinal irradiation
(CSI) in the 1960s that significant survivability was
reported. In the 1970s, randomized trials conducted

by the Childrens Cancer Group and the International Society of Pediatric Oncology demonstrated
improved survival for the high-risk patient when
incorporating adjuvant chemotherapy,4,5 the results
of which Packer et al6 improved on by adding cisplatin to lomustine and vincristine. Current event-free
survival (EFS) rates for high-risk patients using fulldose CSI with or without the addition of chemotherapy range from 30% to 74%.6-11 Packer et al12 later
established the value of chemotherapy in the
standard-risk patient, for whom the dose of CSI
could be lowered to 23.4 Gy in the setting of similar
adjuvant chemotherapy without compromising
survivability. More recent trials treating standardrisk medulloblastoma using reduced-dose CSI and
adjuvant chemotherapy have produced EFS rates of
81% to 86%.11,13
To improve survival for high-risk medulloblastoma, a number of different strategies have been
investigated that attempt to combine chemotherapy
with radiation therapy in an optimized manner.

2013 by American Society of Clinical Oncology

Information downloaded from jco.ascopubs.org and provided by at University of Melbourne on February 23, 2016 from
Copyright 2013 American Society
of Clinical Oncology. All rights reserved.
128.250.144.144

High-Risk Medulloblastoma: POG 9031

Table 1. Demographic and Clinical Characteristics of Eligible Patients by Treatment Arm

Chemotherapy First
(n 112)
Demographic or Clinical Characteristic
Sex
Male
Female
M stage
0
1
2
3
4
T stage
1
2
3
3a
3b
4
Unknown
T stage/M0, no RD
3b
4
Race
White
Black
Hispanic
Asian
Hawaiian

No.

Radiotherapy First
(n 112)
No.

All Patients
(N 224)
No.

P
.28

62
50

55
45

70
42

62
38

132
92

59
41

58
16
19
15
4

52
14
17
13
4

58
13
17
19
5

52
12
15
17
4

116
29
36
34
9

52
13
16
15
4

1
8
18
2
43
39
1

1
7
16
2
38
35
1

1
5
23
4
47
31
1

1
4
20
4
42
28
1

2
13
41
6
90
70
2

1
6
18
3
40
31
1

27
13

68
32

26
6

81
19

53
19

74
26

88
17
5
1
1

79
15
4
1
1

83
17
7
4
1

74
15
6
4
1

171
34
12
5
2

76
15
5
2
1

.91

.80

.19

.72

Abbreviation: RD, residual disease.

Pearsons 2 test.
Fishers exact test.

One strategy has been to give preirradiation chemotherapy, the results

of which have been mixed.7-9 The primary objective of the Pediatric
Oncology Group (POG) 9031 multi-institutional study was to compare the clinical outcome of treating high-risk medulloblastoma patients with either preirradiation or postirradiation chemotherapy,
with both groups receiving identical consolidation chemotherapy. A
second objective was to evaluate whether response to preirradiation
chemotherapy in patients with residual disease possessed prognostic significance.
PATIENTS AND METHODS
Patient Population
For the purposes of this study, patients with medulloblastoma were
considered high risk if they had M1-4 disease by modified Chang staging
classification, exhibited T3b/T4 disease at time of surgery, or had greater than
1.5 cm3 of residual tumor after surgery. From July 1990 through March 1996,
patients with high-risk medulloblastoma were randomly assigned to receive either chemotherapy entailing three cycles of cisplatin and etoposide
before radiation or the same chemotherapy regimen after radiation; both
groups received consolidation chemotherapy consisting of vincristine and
cyclophosphamide. Patients were eligible if they were age 3 years to 21 years
at registration.
An enhanced computed tomography (CT) or magnetic resonance imaging (MRI) scan within 72 hours after surgery or between 10 and 21 days after
surgery was required. Patients had to be registered within 4 weeks of the initial
www.jco.org

diagnostic surgical procedure and were not eligible if they had received prior
chemotherapy. In addition, patients had to meet the following laboratory
criteria: serum creatinine less than 1.7 mg/dL, ALT less than 1.5 normal, total
bilirubin less than 1.5 mg/dL, absolute neutrophil count (ANC) more than
1,500/L, hemoglobin more than 10 g/dL, and platelets more than 100,000/
L. Informed consent was obtained from every patient enrolled, and each
participating institution opened the protocol after obtaining approval from his
or her local human investigation committee in compliance with the Declaration of Helsinki.
On central review, five patients were found to be ineligible. There were
112 eligible patients left in the analysis per treatment arm. Patient characteristics are listed in Table 1. As expected, more males (n 132) than females (n
92) were accrued to this study.
Random Assignment
Patients were assigned randomly to one of two treatments (Fig 1). The
chemotherapy first (CT1) arm consisted of three cycles of preirradiation chemotherapy followed by radiation therapy starting at week 10. The radiotherapy
first (RT1) arm consisted of radiation therapy followed by three cycles of
identical chemotherapy. Both treatment arms were followed with consolidation chemotherapy (Fig 2).
Chemotherapy
Two phases of chemotherapy were administered. The first phase consisted of three cycles of cisplatin 90 mg/m2 and etoposide 150 mg/m2 administered every 4 weeks intravenously on day 1 of each cycle. Etoposide was given
intravenously on days 3 and 4 of every cycle. Dose modifications were not
made for hematologic or renal toxicity. Chemotherapy was delayed until
blood counts or renal function recovered.
2013 by American Society of Clinical Oncology

Information downloaded from jco.ascopubs.org and provided by at University of Melbourne on February 23, 2016 from
Copyright 2013 American Society
of Clinical Oncology. All rights reserved.
128.250.144.144

2937

Tarbell et al

Assessed for eligibility

(N = 229)

Excluded
Did not meet inclusion
criteria; ineligible by review

(n = 5)
(n = 5)

Randomly allocated
(n = 224)

CT1 arm, intervention A, chemotherapy first

Allocated to intervention
(n = 112)
Received allocated intervention
(n = 112)
Did not receive allocated intervention
(n = 0)
(death, inadequate toxicity, refused treatment,
inadequate data)

RT1 arm, intervention B, radiation therapy first

Allocated to intervention
(n = 112)
Received allocated intervention
(n = 112)
Did not receive allocated intervention
(n = 0)
(death, inadequate toxicity, refused treatment,
inadequate data, protocol violation)

Lost to follow-up
Discontinued intervention as a result of toxicity,
patient or physician withdrawal, or other reason

Lost to follow-up
Discontinued intervention as a result of toxicity,
patient or physician withdrawal, or other reason

Analyzed
Excluded from analysis

(n = 14)
(n = 6)

(n = 112)*
(n = 0)

Analyzed
Excluded from analysis

(n = 16)
(n = 12)

(n = 112)
(n = 0)

Fig 1. CONSORT diagram. CT1, chemotherapy first; RT1, radiation therapy first. (*) Patients lost to follow-up or off study were censored at date last seen.

The consolidation phase of chemotherapy was given 3 weeks after radiation therapy in the CT1 arm or after blood counts had recovered in the RT1
arm; it consisted of seven cycles of cyclophosphamide 1,000 mg/m2 and vincristine 2.0 mg/m2 administered every 4 weeks. The vincristine was given on
day 1, and the cyclophosphamide was given on days 1 and 2, with mesna 360
mg/m2 administered to prevent cyclophosphamide-induced hemorrhagic
cystitis. No dose modification of maintenance chemotherapy was made for
neutropenia, but patients with platelet nadirs of less than 20,000/L received a
25% reduction in the cyclophosphamide dose at the next cycle and were
supported with platelet transfusions. Trimethoprim-sulfamethoxazole prophylaxis was given during chemotherapy.

Random allocation

Radiation
Radiation therapy was administered to all patients under treatment.
Patients on the CT1 arm received radiation therapy on weeks 10 to 16 after
three cycles of cisplatin and etoposide. Patients on the RT1 arm received

7 weeks cisplatin
and VP-16

XRT

28 weeks vincristine/
cyclophosphamide

XRT=
Craniospinal irradiation 35.2-44.0 Gy
Posterior fossa boost 53.2-54.4 Gy

XRT

7 weeks cisplatin
and VP-16

28 weeks vincristine/
cyclophosphamide

Fig 2. Pediatric Oncology Group 9031 study treatment schematic. VP-16,

etoposide; XRT, radiation therapy.
2938

2013 by American Society of Clinical Oncology

radiation therapy on weeks 1 to 7 before any chemotherapy was administered.

Details of radiation techniques and quality assurance have been published.14
The treatment volume consisted of the whole brain and spinal contents,
with a boost to the posterior fossa. Spinal metastases were boosted with
individual portals with a margin of one vertebral body on either side of
the lesion.
The whole brain and spinal cord for patients with M0-1 disease received
35.2 Gy in 22 fractions at 1.6 Gy per fraction prescribed to midplane for the
whole brain and to the midthoracic posterior edge of the vertebral body.
Patients with M2-3 disease received 40.0 Gy at 1.6 Gy per fraction in 25
fractions to the brain and spinal cord. The posterior fossa boost for patients
with M0-1 disease was 18.0 Gy in 10 fractions (1.8 Gy per fraction), for a total
of 53.2 Gy to the posterior fossa. In patients with M2-3 disease, the posterior
fossa received a boost of 14.4 Gy in 8 fractions (1.8 Gy per fraction), for a total
dose of 54.4 Gy. Spinal or brain metastases were boosted to a total dose of 44.8
Gy at 1.6 Gy per fraction. Cranial spinal irradiation was delayed if the absolute
neutrophil count decreased to less than 750/L or the platelet count decreased
to less than 50,000/L.
Follow-Up Protocol
On completion of treatment, patients were seen at 2-month intervals
until 6 months after treatment, at which time they were observed every 3
months until 2 years after treatment. Thereafter, they were observed every 6
months until 5 years after treatment and then yearly after the 5-year mark.
Imaging examinations were obtained 2 and 6 months after treatment, and then
biannually until 5 years after treatment, and then yearly; spinal MRI scans or
myelograms were obtained during the first 2 years of follow-up, after which
patients were monitored with brain MRI or CT only.
Statistical Considerations
The primary end point for this study is EFS, defined as the time to disease
progression, disease relapse, occurrence of a second neoplasm, or death from
JOURNAL OF CLINICAL ONCOLOGY

Information downloaded from jco.ascopubs.org and provided by at University of Melbourne on February 23, 2016 from
Copyright 2013 American Society
of Clinical Oncology. All rights reserved.
128.250.144.144

any cause, measured from the time of study enrollment. The comparison
involves all eligible randomly assigned patients. Progression is assessed at any
time during or after radiotherapy. This study assumed a 2-year EFS of 60%
10% and is sensitive to a 15% difference with a total enrollment of 220 patients
(110 patients to each arm) at P .05 (two-sided) and 80% power. The end
point of overall survival (OS) was defined as time to death from any cause.
Nonparametric log-rank tests and Kaplan-Meier curves were used to compare
the two groups. Cox regression analysis was used to analyze possible prognostic factors for the risk of recurrence. Response at the end of chemotherapy was
compared for the two treatment groups using the 2 test. Complete response
was defined as the disappearance of all radiographically discernible lesions, as
well as two consecutively negative CSF cytologic examinations. A partial response was defined as a 50% or greater reduction in tumor size as measured by
the sum of the products of the maximum perpendicular diameters of all
measurable lesions or two consecutively negative CSF cytologies in addition to
a less than 50% reduction in tumor size. Stable disease was defined as a less than
50% reduction in tumor size and a persistently negative or positive CSF
cytology. Progressive disease was defined as a more than 25% increase in the
size of any measurable lesion or the appearance of a new lesion.
Quality Control
The pathology, operative reports, radiology and radiation simulation
films, and port films all were reviewed centrally. Details of radiotherapy quality
control have been published separately.14

RESULTS

Two hundred twenty-nine patients were enrolled onto the POG 9031
study for high-risk medulloblastoma between July 1990 and March
1996. Five patients found to be ineligible were removed from the
study, leaving 224 patients eligible after random assignment. Three of
the ineligible patients were misdiagnosed with medulloblastoma, with
the other two patients failing to meet high-risk disease criteria. Central
review of images was performed at Quality Assurance Review Center.14 The CT1 and RT1 arms each accrued 112 eligible patients. The
median follow-up time was 6.4 years (range, 0.1 to 11.2 years). The
median age was 7.8 years, with a range of 3.0 to 21.4 years. There were
132 males and 92 females, with a variety of races represented (34 black,
171 white, 12 Hispanic, and seven Asian patients). The frequency of M
stage was as follows: M0, n 116; and M, n 108 (M1, n 29; M2,
n 36; M3, n 34; and M4, n 9). Seventy-two patients were
T3b/T4 M0 with no residual disease (40 patients in the CT1 arm and
32 patients in RT1 arm). Treatment groups were balanced at random
assignment with respect to sex, stage, and ethnicity (P .05). Table 1
lists more detailed patient characteristics in each group.
Outcome by Treatment Group
Fifty-four patients experienced recurrence or progression, with
43 experiencing subsequent death. Twenty-two patients died of disease without a reported overt progression before this time. Four patients experienced a second neoplasm as a first event. Two patients
developed myelodysplastic syndrome, one on each of the treatments,
at 3.3 and 2.4 months from study enrollment. Two patients in the RT1
arm had a fibroma and leiomyosarcoma at 5.1 and 5.7 years from
study enrollment, respectively. Five-year EFS and OS probabilities for
the entire patient cohort as determined by institutional review were
68.1% 3% and 74.6% 3%, respectively. Figure 3 shows EFS by
randomly assigned treatment. Five-year EFS was 66.0% 4.5% and
70.0% 4.4% in the CT1 and RT1 arms, respectively (log-rank, P
.54). Five-year OS was 73.1% 4.2% and 76.1% 4.1% in the CT1
www.jco.org

Estimated Proportion Event Free

High-Risk Medulloblastoma: POG 9031

1.0

Radiotherapy first
Chemotherapy first

0.8

0.6

0.4

0.2

10

12

Time (years)
Fig 3. Event-free survival by treatment arm for eligible patients.

and RT1 arms, respectively (log-rank, P .47). The log-rank test for
detecting differences between both the EFS and OS curves for the two
treatments indicate that these curves are not significantly different.
There was also no evidence of a difference in EFS between treatment
groups after stratifying for stage. In patients with M0 and residual
disease after surgery, the 5-year EFS was 59.6% 7.0% in the CT1 arm
and 65.1% 6.8% in the RT1 arm (log-rank, P .40). In patients
with M and residual disease, the 5-year EFS was 51.2% 9.2% in the
CT1 arm and 64.0% 9.3% in the RT1 arm (log-rank, P .20).
Response to Chemotherapy Treatment
Response was evaluated at the end of 7 weeks of chemotherapy
with cisplatin 90 mg/m2 and etoposide 150 mg/m2. Response data for
the 224 eligible patients are listed in Table 2. Of the 224 patients, 118
were evaluable for response. One-hundred six patients were not evaluable for response (99 patients did not have measurable disease after
surgery; one patient on the CT1 arm had an early death on study
enrollment; five patients on the RT1 arm had missing response data;
and one patient on the RT1 arm was not evaluable for response). The
objective response rate (complete response partial response) was
66% (40 of 61 patients) in the CT1 arm and 86% (49 of 57 patients) in
the RT1 arm (P .01, two-sided 2 test). There was no significant
difference in EFS between patients in the CT1 arm who achieved
complete or partial response and those who did not (5-year EFS:
73% 7% v 56% 17%, respectively; P .1).
Prognostic Factors
Table 3 lists 5-year EFS and OS within patient categories defined
by sex, race, regimen, and M stage. On the basis of a Cox regression
Table 2. Response Data for Eligible Patients
No. of Patients
Response
Complete response
Partial response
Stable disease/no response
Progressive disease
Not evaluable for response
Total

Chemotherapy First Radiotherapy First Total

19
21
9
12
51
112

25
24
8
0
55
112

2013 by American Society of Clinical Oncology

Information downloaded from jco.ascopubs.org and provided by at University of Melbourne on February 23, 2016 from
Copyright 2013 American Society
of Clinical Oncology. All rights reserved.
128.250.144.144

44
45
17
12
106
224

2939

Tarbell et al

(range, 0.16 to 10.75 years), whereas in the RT1 arm, it was 6.68 years
(range, 0.18 to 11.93 years). However, follow-up protocols only included spinal MRI within the first 2 years after diagnosis. Subsequent
follow-up imaging was by CT or MRI of the brain. This may have
skewed the initial site of relapse to intracranial and under-reported the
incidence of spinal failures.

Table 3. Five-Year EFS and OS by Treatment Group and Disease

Characteristics for Eligible Patients
5-Year EFS
Characteristic
Sex
Male
Female
Race
White
Black
Hispanic
Other
Randomly assigned regimen
CT1
RT1
M stage
M0
M1
M2
M3
M4
M (M1, M2, M3, or M4)

Rate
(%) SE (%)

5-Year OS
P

Rate
(%) SE (%)

.96
68.6
67.3

4.1
4.9

69.3
61.0
75.0
57.1

3.6
8.5
12.5
18.7

66.0
70.0

4.5
4.4

74.0
64.9
69.2
61.6
22.2
61.6

4.1
9.0
7.7
8.4
13.9
4.7

P
.90

73.7
75.9

3.9
4.5

75.7
66.6
82.5
71.4

3.3
8.3
11.3
17.1

73.1
76.1

4.2
4.1

81.6
68.3
77.6
64.5
33.3
67.1

3.6
8.8
7.0
8.3
15.7
4.6

.75

Radiation Therapy
Patients with M0-1 disease received a median of 35.2 Gy CSI and
53.2 Gy to the posterior fossa. Patients with M2-3 disease received a
median of 40 Gy CSI and 54.4 Gy to the posterior fossa. This did not
differ by treatment group. The average overall radiation therapy treatment times in the CT1 and RT1 arms were 46.3 days (standard deviation, 10.51 days) and 44.8 days (standard deviation, 8.98 days),
respectively. Twenty-two patients in CT1 group and 11 patients in
RT1 group had more than 50 treatment days. This comparison had a
P .06 based on the Fishers exact test.

.48

.54

.47

.001

.001

Toxicity
Regarding acute toxicity, there were more episodes of thrombocytopenia in the RT1 arm, but otherwise, the toxicity for the two
treatments was similar. Treatment-induced diseases include two patients with myelodysplastic syndrome and a third patient who developed an ossifying fibroma.

Abbreviations: CT1, chemotherapy first; EFS, event-free survival; OS, overall

survival; RT1, radiation therapy first.

Log-rank P value in comparing M4 v others (M0, M1, M2, or M3).

DISCUSSION

analysis, factors such as sex, race, and regimen were not statistically
significant predictors of EFS or OS, and M stage was the only factor
associated with outcome. The 5-year EFS rates for M4 patients and
patients with M0, M1, M2, or M3 disease were 22% 14% and
70% 3%, respectively (P .001). The relative risk for progression or
relapse was four times (95% CI, 1.9 to 8.9 times) higher for M4
patients than for those with M0, M1, M2, or M3 disease. The relative
risk for death was 4.3 times (95% CI, 2.0 to 9.4 times) higher for M4
patients than for those with M0, M1, M2, or M3 disease.

The OS and EFS rates in this study, both for all high-risk patients, as
defined in 1990, and for those with metastatic disease within the CNS
(M1-3), are comparable to data previously reported in this disease
setting.4,5,8,9,15 There was no difference in EFS or OS between immediate or delayed radiation therapy. The EFS rates observed in this study
were better than the 60% nominal rate at year 2, assumed in our power
calculations. However, the observed rate difference between study
arms was small, only 4% and 3% for EFS and OS, respectively, at year
5. Our lack of treatment effect contrasts with the results of the German
randomized controlled trial of patients with both low- and high-risk
medulloblastoma, in which the RT1 group did significantly better
than the CT1 group.9 Note that in the German study, patients in the
CT1 arm, which included M0-3 stages, had a prolonged radiation
therapy treatment time because of greater hematologic toxicity than
the patients in the RT1 arm. This is important because prolonged
treatment time has been associated with a decrease in EFS.8,16-19

Site of First Relapse

The site of first relapse was similar for the two treatments arms.
The most common site of first relapse was the posterior fossa (n 10),
and the second most common site was the supratentorium (n 9;
Table 4). Approximately one third of the relapses were in the posterior
fossa. The median time to relapse was 6.36 years (range, 0.16 to 11.93
years). In the CT1 arm, the median time to relapse was 6.22 years

Table 4. Site of First Relapse by Treatment Arm for Eligible Patients

No. of Patients
Chemotherapy First

Radiation Therapy First

Total

Site

Total

M0

M1-2

M3

Total

M0

M1-2

M3

Supratentorial (brain, cerebral hemispheres, corpus callosum)

Posterior fossa (cerebellum, cerebellar peduncles)
CSF/meninges/dural sinus/ventricular system
Spinal cord
Bone
Total

5
5
5
1
0
16

3
3
1
1
0
8

2
0
2
0
0
4

0
2
2
0
0
4

4
5
2
1
3
15

3
3
0
0
2
8

1
2
0
1
0
4

0
0
2
0
1
3

2940

2013 by American Society of Clinical Oncology

9
10
7
2
3
31

JOURNAL OF CLINICAL ONCOLOGY

Information downloaded from jco.ascopubs.org and provided by at University of Melbourne on February 23, 2016 from
Copyright 2013 American Society
of Clinical Oncology. All rights reserved.
128.250.144.144

High-Risk Medulloblastoma: POG 9031

There was no difference in EFS between the treatment arms for

patients with residual disease after surgery either in the posterior fossa
or elsewhere. Also, in contrast to the findings in other studies, the
presence of residual disease in the posterior fossa was not associated
with worse EFS for patients with M0 disease. Patients with M0 disease
and no significant residual disease after resection of their T3b or T4
lesion had EFS of approximately 73% 5.2%. Note that in the current
era of medulloblastoma treatment, these patients would be categorized as being standard risk.
The EFS and OS of patients with M0 and M1 disease compare
favorably with other randomized studies4,5,7,18,20 and are consistent
with their findings. However, the 5-year EFS for the patients with
M2-3 disease was higher than in previously published reports (EFS
of 60% compared with 30% in the German study).9 On the basis of
previously published relatively poor survival rates, some patients with
M2-3 disease have been assigned directly to high-dose chemotherapy
with stem-cell rescue regimens.15,21
It is important to note that the high EFS rates in the M2-3 patients
may be the result of a higher dose of radiation used. In these patients,
40 Gy to the whole brain and spinal cord were delivered with a boost of
4.8 Gy to the gross disease. The EFS rates are similar to a multiinstitutional phase II study demonstrating a 67% PFS in patients with
M disease in which 11 of the 15 patients had either M2 or M3
disease. A similar chemotherapy regimen was used consisting of loREFERENCES
1. Gurney JG, Davis S, Severson RK, et al:
Trends in cancer incidence among children in the
U.S. Cancer 78:532-541, 1996
2. McNeil DE, Cote TR, Clegg L, et al: Incidence and
trends in pediatric malignancies medulloblastoma/
primitive neuroectodermal tumor: A SEER update
Surveillance Epidemiology and End Results. Med Pediatr
Oncol 39:190-194, 2002
3. Polkinghorn WR, Tarbell NJ: Medulloblastoma: Tumorigenesis, current clinical paradigm, and
efforts to improve risk stratification. Nat Clin Pract
Oncol 4:295-304, 2007
4. Evans AE, Jenkin RD, Sposto R, et al: The
treatment of medulloblastoma: Results of a prospective randomized trial of radiation therapy with
and without CCNU, vincristine, and prednisone.
J Neurosurg 72:572-582, 1990
5. Tait DM, Thornton-Jones H, Bloom HJ, et al:
Adjuvant chemotherapy for medulloblastoma: The
first multi-centre control trial of the International
Society of Paediatric Oncology (SIOP I). Eur J Cancer 26:464-469, 1990
6. Packer RJ, Sutton LN, Elterman R, et al:
Outcome for children with medulloblastoma treated
with radiation and cisplatin, CCNU, and vincristine
chemotherapy. J Neurosurg 81:690-698, 1994
7. Bailey CC, Gnekow A, Wellek S, et al: Prospective randomised trial of chemotherapy given before
radiotherapy in childhood medulloblastoma: International Society of Paediatric Oncology (SIOP) and the
(German) Society of Paediatric Oncology (GPO)SIOP
II. Med Pediatr Oncol 25:166-178, 1995

mustine, cisplatin, and vincristine. In this study, patients received 36

Gy to the craniospinal axis with a boost to 45 Gy to areas of gross
disease outside of the posterior fossa.7 This approach in high-risk
patients may be a reasonable alternative to high-dose chemotherapy
with stem-cell rescue in the older child. However, the late effects of
increased radiation will need to be studied in long-term survivors.
The EFS and OS reported in this study compare favorably with
other trials examining high-risk medulloblastoma. Preirradiation
chemotherapy fails to confer a survival advantage over radiation
before chemotherapy.
AUTHORS DISCLOSURES OF POTENTIAL CONFLICTS
OF INTEREST
The author(s) indicated no potential conflicts of interest.

AUTHOR CONTRIBUTIONS
Conception and design: Nancy J. Tarbell, Henry Friedman, Larry Kun
Provision of study materials or patients: Nancy J. Tarbell
Collection and assembly of data: Peter Burger, Patrick Barnes
Data analysis and interpretation: Nancy J. Tarbell, William R.
Polkinghorn, Torunn Yock, Tianni Zhou, Zhengjia Chen, Larry Kun
Manuscript writing: All authors
Final approval of manuscript: All authors

8. Zeltzer PM, Boyett JM, Finlay JL, et al: Metastasis stage, adjuvant treatment, and residual tumor are prognostic factors for medulloblastoma in
children: Conclusions from the Childrens Cancer
Group 921 randomized phase III study. J Clin Oncol
17:832-845, 1999
9. Kortmann RD, Kuhl J, Timmermann B, et al:
Postoperative neoadjuvant chemotherapy before radiotherapy as compared to immediate radiotherapy
followed by maintenance chemotherapy in the treatment of medulloblastoma in childhood: Results of
the German prospective randomized trial HIT 91. Int
J Radiat Oncol Biol Phys 46:269-279, 2000
10. Taylor RE, Bailey CC, Robinson KJ, et al:
Outcome for patients with metastatic (M2-3) medulloblastoma treated with SIOP/UKCCSG PNET-3
chemotherapy. Eur J Cancer 41:727-734, 2005
11. Gajjar A, Chintagumpala M, Ashley D, et al:
Risk-adapted craniospinal radiotherapy followed by
high-dose chemotherapy and stem-cell rescue in children with newly diagnosed medulloblastoma (St Jude
Medulloblastoma-96): Long-term results from a prospective, multicentre trial. Lancet Oncol 7:813-820,
2006
12. Packer RJ, Goldwein J, Nicholson HS, et al:
Treatment of children with medulloblastomas with
reduced-dose craniospinal radiation therapy and adjuvant chemotherapy: A Childrens Cancer Group
study. J Clin Oncol 17:2127-2136, 1999
13. Packer RJ, Gajjar A, Vezina G, et al: Phase III
study of craniospinal radiation therapy followed by
adjuvant chemotherapy for newly diagnosed averagerisk medulloblastoma. J Clin Oncol 24:4202-4208,
2006
14. Miralbell R, Fitzgerald TJ, Laurie F, et al:
Radiotherapy in pediatric medulloblastoma: Quality

assessment of Pediatric Oncology Group Trial 9031.

Int J Radiat Oncol Biol Phys 64:1325-1330, 2006
15. Strother D, Ashley D, Kellie SJ, et al: Feasibility of four consecutive high-dose chemotherapy
cycles with stem-cell rescue for patients with newly
diagnosed medulloblastoma or supratentorial primitive neuroectodermal tumor after craniospinal radiotherapy: Results of a collaborative study. J Clin
Oncol 19:2696-2704, 2001
16. Chan AW, Tarbell NJ, Black PM, et al: Adult
medulloblastoma: Prognostic factors and patterns of
relapse. Neurosurgery 47:623-631, 2000
17. Miralbell R, Bleher A, Huguenin P, et al: Pediatric medulloblastoma: Radiation treatment technique
and patterns of failure. Int J Radiat Oncol Biol Phys
37:523-529, 1997
18. Thomas PR, Deutsch M, Kepner JL, et al: Lowstage medulloblastoma: Final analysis of trial comparing
standard-dose with reduced-dose neuraxis irradiation.
J Clin Oncol 18:3004-3011, 2000
19. del Charco JO, Bolek TW, McCollough WM,
et al: Medulloblastoma: Time-dose relationship
based on a 30-year review. Int J Radiat Oncol Biol
Phys 42:147-154, 1998
20. Taylor RE, Bailey CC, Robinson K, et al: Results of a randomized study of preradiation chemotherapy versus radiotherapy alone for nonmetastatic
medulloblastoma: The International Society of Paediatric Oncology/United Kingdom Childrens Cancer
Study Group PNET-3 Study. J Clin Oncol 21:15811591, 2003
21. Papadakis V, Dunkel IJ, Cramer LD, et al:
High-dose carmustine, thiotepa and etoposide followed by autologous bone marrow rescue for the
treatment of high risk central nervous system tumors. Bone Marrow Transplant 26:153-160, 2000

www.jco.org

2013 by American Society of Clinical Oncology

Information downloaded from jco.ascopubs.org and provided by at University of Melbourne on February 23, 2016 from
Copyright 2013 American Society
of Clinical Oncology. All rights reserved.
128.250.144.144

2941

Tarbell et al

Acknowledgment
We thank James Kepner, PhD, for statistical support throughout this trial, and Chris Williams-Hughes for her work in finalizing
the manuscript.

2013 by American Society of Clinical Oncology

JOURNAL OF CLINICAL ONCOLOGY

Information downloaded from jco.ascopubs.org and provided by at University of Melbourne on February 23, 2016 from
Copyright 2013 American Society
of Clinical Oncology. All rights reserved.
128.250.144.144