medulla blastoma

J Neurosurg 111:478–487, 2009
Survival and prognostic factors in a series of adults with
medulloblastomas
Clinical article
Laurent Riffaud, M.D.,1 Stephan Saikali, M.D., 2 Emmanuelle Leray, Ph.D., 3
Abderrahmane Hamlat, M.D.,1 Claire Haegelen, M.D.,1 Elodie Vauleon, M.D., 4
and Thierry Lesimple, M.D. 4
Departments of 1Neurosurgery, 2Neuropathology, and 3Epidemiology and Public Health,
Pontchaillou University Hospital; and 4Department of Medical Oncology, Eugene Marquis
Cancer Institute, Rennes, France
Object. In this article, the authors report their experience in the management of adult patients with medulloblastoma at their institution to identify prognostic factors important for survival and disease control.
Methods. Between 1977 and 2005, 27 patients who were ≥ 16 years old and had medulloblastoma were treated
consecutively. There were 16 women and 11 men with a median age of 21 years (range 16–54 years). Gross-total
resection was performed in 21 patients, subtotal (≥ 90%) in 2, incomplete in 1, and biopsy in 3 patients. Six patients
had the desmoplastic variant, and 21 patients presented with classic medulloblastoma. Staging according to the
Chang classification showed 4 patients with tumors invading the brainstem (2 with Stage T3b and 2 with Stage T4),
3 patients with metastases (2 with Stage M2 and 1 with Stage M3), and 1 patient in whom the stage was unknown
(Stage MX) who died 10 days postoperatively. Twenty patients were assigned to the standard-risk group and 7 to the
high-risk group. All patients except the one whose status was classified as Stage MX underwent craniospinal radiotherapy at our institution. Seven patients received chemotherapy before radiotherapy.
Results. The 5- and 10-year overall survival rates for the present study were 81 and 62%, respectively. The median
overall survival time was 17.7 years. The 5- and 10-year event-free survival rates were 72 and 57%, respectively. The
median event-free survival time was 17.9 years. Univariate analysis showed that survival was significantly correlated
with sex (women had a better prognosis than men) and M stage (patients without metastases had a better outcome).
Patient age, duration of symptoms, Karnofsky Performance Scale score at presentation, hydrocephalus, tumor location,
brainstem invasion, extent of resection, histological subtype, preradiotherapy chemotherapy, risk group, and period of
presentation were not significant variables. Multivariate analysis identified sex and M stage as well as the period of presentation as independent prognostic factors for overall and event-free survival times. Eleven patients suffered tumor recurrence within a median time of 4.2 years. The posterior fossa was not the most common site of recurrence, and delayed
recurrence was not rare. All patients in whom the tumor recurred have died despite aggressive treatments. The median
survival time after diagnosis of recurrence was 2.5 years. Questionnaires on quality of life and cognition showed high
scores in favor of limited negative effects in the perception of mental and physical health after treatment. The authors
observed 1 supposed second malignancy (thyroid carcinoma) and no evidence of pituitary dysfunction.
Conclusions. Long-term survival is possible in adults treated for medulloblastoma. Although rare, metastasis
seeding at presentation is a poor prognostic factor. The possibility of delayed recurrence necessitates close follow-up
of all patients. Tumor recurrences should be treated with aggressive therapies as some patients may have sustained
response. Adjuvant chemotherapy should be given to high-risk patients, but its role in reducing recurrences, particularly distant ones, remains unclear in the standard-risk group. (DOI: 10.3171/2009.1.JNS081004)
Key Words • medulloblastoma • prognostic factor • survival rate
M
is a malignant neuroepithelial
tumor that develops in the cerebellum from pluripotent cells. It is usually considered to be a tumor
of childhood. However, it can occur in patients of any age,
including the elderly,9 and ~ 25%41 to 40%43 of cases are
diagnosed in adults. Because of the relative infrequency
edulloblastoma
Abbreviations used in this paper: KPS = Karnofsky Performance
Scale; SF-36 = 36-Item Short Form Health Survey; VACA = vincristine/Adriamycin/cyclophosphamide/actinomycin.
478
of medulloblastoma in older patients, the treatment outcome and prognostic factors of this subgroup are less well
defined. The aim of this paper is to present experiences
gained from 27 patients who were ≥ 16 years old and who
were treated at our institution.
Methods
Between December 1977 and December 2005, 27 patients (age ≥ 16 years) were treated consecutively for newly
J Neurosurg / Volume 111 / September 2009
Survival and prognostic factors in adult medulloblastoma
diagnosed medulloblastoma at our institution; these patients comprise this retrospective analysis. Each patient was
treated by neurosurgeons, neurooncologists, and radiation
oncologists.
Patient Characteristics
Patients ranged in age from 16 to 54 years with a median age of 21 years. There were 16 women and 11 men.
The most common presenting symptoms were headache
(93%), nausea and vomiting (78%), and gait instability
(56%). There were 3 cases of cranial nerve palsies and 2
cases of torticollis at presentation. The median duration
of symptoms was 9 weeks (range 2–43 weeks; 11 weeks
for the 16 patients with midline lesions and 9 weeks for
the 11 patients with lateral lesions). The median KPS
score before surgery was 70 (range 50–90).
Initial neuroimaging consisted of CT scanning of the
brain in 7 patients before 1986, and CT scanning and MR
imaging in 20 patients since 1986. Hydrocephalus was
present in 16 patients (11 cases with midline location and
5 cases with lateral location).
Surgical Treatment and Outcome
Five patients required placement of a ventriculoperitoneal shunt before tumor surgery. Tumor surgery consisted of a suboccipital craniectomy with resection of as
much of the tumor as the surgeon considered prudent at the
time. The extent of resection was based on the surgeon’s
assessment at the time of the operation and a review of
the postoperative CT or MR images. Twenty-one patients
had a gross-total resection, 2 had a subtotal resection (≥
90% or when there were uncertainties about brainstem
invasion), 1 had an incomplete resection (< 90%), and 3
had only a biopsy. Perioperative death consisted of 1 sudden unexplained death 10 days after complete resection.
One patient experienced CSF leakage. Immediate postoperative clinical status showed functional improvement in
21 patients, no change in 4, and worsening in 1.
Histological Examination
All pathology slides were reviewed by a neuropathologist (S.S.) who had no knowledge of the patients’ clinical
course. Six patients (22%) had the desmoplastic variant:
3 patients had a lateral tumor (desmoplastic/lateral tumor
ratio 27%) and 3 patients had a midline tumor (desmoplastic/midline tumor ratio 19%). The remaining 21 patients presented with classic medulloblastoma.
Tumor Staging
Each patient underwent staging according to the classic Chang system11 definitions for tumor (T) and metastasis
(M) parameters (Table 1). The extent of spinal disease was
assessed using MR imaging in 16 patients (preoperatively
in 1). The cytological evaluation of CSF was conducted by
performing a lumbar puncture after tumor resection and
histopathological diagnosis of medulloblastoma in 25 patients. Two patients did not undergo CSF evaluation: 1 patient, whose status of metastasis was unknown (Stage MX),
died suddenly 10 days after surgery of an unexplained cause,
and the other had tonsillar herniation and spinal metastases
J Neurosurg / Volume 111 / September 2009
TABLE 1: Distribution of 27 adult patients with medulloblastoma
according to stage*
No. of Patients
Stage
T2
T3a
T3b
M0
M2
M3
MX
total
10
11
2
T4
2
1
11
1
12
2
2
Total
23
2
1
1
27
* Based on the staging system of Chang et al.
(classified as Chang Stage M3) that rendered CSF subtraction by lumbar puncture impossible. Cytological analysis
was negative in the remaining 25 patients, even in those with
medulloblastomas classified as Stage M2. No patient presented with symptoms of systemic metastasis at diagnosis,
but a complete evaluation was not routinely performed. The
preoperative tumor stage showed 4 tumors with brainstem
invasion (Chang Stages T3b and T4). Standard-risk patients
were those whose tumor was confined to the primary area
and who had undergone a gross-total resection. High-risk
patients were those who had less than a gross-total resection
of the primary lesion and those who had evidence of tumor
dissemination. The patient with Chang Stage MX medulloblastoma, who did not undergo a complete evaluation of the
spinal axis, was included in the high-risk group. Twenty
patients were assigned to the standard-risk group and 7 to
the high-risk group. With the exception of 1 patient, those
whose tumors did not invade the brainstem and who had no
metastasis underwent complete tumor resection.
Adjuvant Treatment
All patients, with the exception of the one who died
suddenly after surgery, received external-beam radiotherapy to the entire craniospinal axis as part of the curative
treatment at our institution. No patient had treatment interrupted by radiation-related toxicity. The median interval
from surgery to the initiation of radiotherapy was 45 days
(range 19–195 days). The median intervals from surgery
to radiotherapy for patients who did and did not receive
chemotherapy before radiotherapy were 133 days (range
87–195 days) and 39 days (range 19–122 days), respectively. The median dose to the entire brain was 30 Gy (range
24–54 Gy), to the posterior fossa 54 Gy (range 50–60 Gy),
and to the spine 30 Gy (range 24–39.6 Gy).
Seven patients received primary (preradiotherapy) chemotherapy after tumor surgery. The types of chemotherapy
were 8 drugs in 1 day (8-in-1) in 2 patients (2 cycles each),
VACA in 2 patients (2 and 4 cycles), intrathecal methotrexate plus vincristine/lomustine, carboplatin/VP-16 (3 cycles),
and cisplatin/VP-16 (3 cycles). Five patients who received
chemotherapy presented with more advanced disease or
incomplete resection of their tumors, and 2 were standardrisk patients (Stage T3aM0 and T2M0 medulloblastomas).
Statistical Analysis
The overall survival was calculated from the date of
479
L. Riffaud et al.
the first surgery to the date of death or to last follow-up for
living patients (censored observation). Event-free survival
was calculated from the date of the first surgery to the date
of recurrence or tumor progression on neuroimages or to
the date of last follow-up without progression (censored).
Survival probabilities were estimated using the KaplanMeier method,28 and the 95% CIs were calculated using
the Rothman formula.42 The log-rank test was used to assess the significance of the following prognostic variables:
age (≤ 21 years vs > 21 years), sex, duration of symptoms (≤
9 vs > 9 weeks), KPS score at presentation (≤ 70 vs ≥ 80),
hydrocephalus (present vs absent), tumor location (midline
vs lateral), histological type (desmoplastic vs classic), residual disease after surgery (complete resection vs subtotal, incomplete, or biopsy), metastasis or Chang M stage
(no metastasis [Stage M0] vs metastasis [Stages M2 and
M3] [MX excluded]), brainstem invasion or Chang T stage
(no invasion [Stages T2 and T3a] vs invasion [Stages T3b
and T4]), standard-risk or high-risk group, primary chemotherapy or not, and period of first presentation (1977–1985
vs 1986–1996 vs 1997–2005). Univariate analysis was performed to identify prognostic variables for overall survival
and progression-free survival. Independent prognostic
factors were identified by multivariate regression analysis
(Cox proportional hazards regression model).16 Statistical
analysis was performed using SPSS 15.0 software for Windows (SPSS, Inc.), and probability values < 0.05 were considered to be statistically significant.
Questionnaires on quality of life (Medical Outcomes
Study SF-366,46) and cognition (Mini-Mental State Examination), use of medication, presence of comorbidity, and
social status were studied for the patients alive at the latest
evaluation. The SF-36 questionnaire contains 36 questions
examining several aspects of general well-being during
the previous 4 weeks. The 36 questions are organized into
8 scales (physical functioning, physical problems, bodily
pain, social functioning, general mental health, emotional
problems, vitality, and general health perceptions), which
are linearly converted to a scale of 0–100. Higher scores
represent better quality of life.
Results
The median follow-up duration from diagnosis was 8.6
years (range 0–25.5 years). At the end of follow-up, 15 patients were alive, 11 patients had died of recurrence, and
1 patient had died in the perioperative period. The 5-year
overall survival rate for the entire population was 81% (95%
CI 63–92%), and the 10- and 20-year overall survival rates
were 62% (95% CI 42–79%) and 43% (95% CI 23–69%),
respectively (Fig. 1). The Kaplan-Meier estimated median overall survival time was 17.7 years (95% CI 1.0–34.3
years). The 5-year event-free survival (EFS) rate was 72%
(95% CI 52–86%), and the 10- and 20-year EFS rates were
57% (95% CI 37–75%) and 43% (95% CI 20–70%), respectively (Fig. 1). The Kaplan-Meier estimated median eventfree survival time was 17.9 years (95% CI 0–36.8 years).
Statistical Analysis of Prognostic Factors
Analysis of prognostic variables for overall and eventfree survival by univariate analysis is summarized in Table
480
Fig. 1. Graph depicting Kaplan-Meier curves for overall survival
(OS) and for event-free survival (EFS) rates in this series. % = percentage of patients.
2. We did not identify the prognostic value of age, duration
of symptoms, KPS score at presentation, hydrocephalus,
tumor location, brainstem involvement, extent of resection,
histological subtype, primary chemotherapy, or risk group.
The period of first presentation was a prognostic factor neither for overall survival nor for event-free survival (Fig. 2).
Prognostic factors that were significant for overall
survival by univariate analysis included sex (p < 0.004)
(Fig. 3) and M stage (p < 0.002) (Fig. 4). Sex and M stage
were also significantly associated with event-free survival
(p < 0.011 and p < 0.005, respectively). At 5 years, 87% of
patients with a Stage M0 metastasis were estimated to be
alive and 81% disease free, while none of the 3 patients
with Stage M2 and M3 metastases have reached 5 years
(the 2 patients with Stage M2 died before this point, and
at the latest evaluation, the patient with Stage M3 was
free of disease 3.7 years after diagnosis).
Multivariate analysis confirmed the independent prognostic value of sex and M stage, and identified the period
of presentation as a third independent prognostic factor for
overall and event-free survival times. The ORs and 95%
CIs are presented in Table 3.
Tumor Recurrence
A total of 18 recurrences have been observed in 11
patients (41%) (Table 4). The median time to first recurrence was 4.2 years (range 0.7–18 years). Overall survival
was strongly correlated with recurrence (p < 0.0001) (Fig.
5). All patients in whom the tumor recurred have died.
Only 1 patient’s tumor recurred after a period of time
corresponding to his age; the other tumors recurred much
more quickly (< 8.5 years). This patient was 18 years old
at the first presentation, and the tumor first recurred 18
years later exactly. Attempts at salvage treatments with
surgery, radiotherapy, chemotherapy, or a combination of
these were carried out for 10 of the 11 patients who experienced tumor recurrence, but the results of salvage therapy
J Neurosurg / Volume 111 / September 2009
Survival and prognostic factors in adult medulloblastoma
TABLE 2: Overall and event-free survival probabilities according to patient and tumor characteristics*
Overall Survival Probability % (95% CI)
Variable
age (yrs)
≤21
>21
sex
female
male
duration of symptoms (wks)
≤9
>9
KPS score
≤70
≥80
hydrocephalus
no
yes
tumor location
lateral
midline
operation
complete
subtotal, incomplete, or biopsy
brainstem involvement
no (T2 & T3a)
yes (T3b & T4)
metastases (MX excluded)
no (M0)
yes (M2 & M3)
histology subtype
classic
desmoplastic
risk
standard
high
primary chemotherapy
no
yes
period
1977–1985
1986–1996
1997–2005
Event-Free Survival Probability % (95% CI)
No. of Patients
5 Yrs
10 Yrs
p Value
5 Yrs
10 Yrs
p Value
13
14
77 (50–92)
86 (60–96)
52 (27–76)
75 (46–91)
0.060
67 (39–86)
76 (48–92)
40 (17–67)
76 (48–92)
0.063
16
11
100
55 (28–79)
91 (62–98)
27 (10–57)
0.004†
93 (68–99)
40 (17–69)
75 (46–91)
30 (11–60)
0.011†
15
12
86 (60–96)
75 (49–91)
55 (28–80)
67 (39–86)
0.679
71 (44–88)
73 (44–90)
62 (35–83)
55 (28–79)
0.696
15
12
66 (41–85)
100
51 (28–74)
75 (41–93)
0.108
56 (31–78)
90 (60–98)
40 (19–66)
79 (49–94)
0.094
11
16
91 (62–98)
74 (49–89)
80 (48–94)
49 (26–73)
0.129
91 (62–98)
55 (30–78)
72 (42–90)
46 (23–72)
0.134
11
16
82 (52–95)
81 (56–93)
57 (27–83)
66 (41–85)
0.806
73 (44–90)
72 (45–88)
47 (19–76)
64 (38–84)
0.600
21
6
85 (65–95)
67 (30–90)
62 (39–80)
67 (30–90)
0.938
74 (51–88)
67 (30–90)
55 (33–76)
67 (30–90)
0.993
23
4
87 (67–95)
50 (15–85)
64 (42–82)
NE
0.424
76 (54–89)
50 (15–85)
58 (36–77)
NE
0.464
23
3
91 (73–98)
NE
70 (48–86)
NE
0.002†
77 (57–90)
NE
62 (40–79)
NE
0.005†
21
6
80 (59–92)
83 (44–97)
62 (40–81)
63 (25–89)
0.372
68 (45–84)
83 (44–97)
55 (33–75)
67 (30–90)
0.504
20
7
85 (64–95)
71 (36–92)
65 (39–81)
54 (21–83)
0.516
78 (55–91)
57 (25–84)
58 (35–78)
57 (25–84)
0.540
20
7
85 (64–95)
71 (36–92)
59 (36–79)
71 (36–92)
0.750
72 (49–88)
71 (36–92)
60 (37–79)
54 (21–83)
0.731
7
7
13
86 (49–97)
71 (36–92)
85 (58–96)
57 (25–84)
57 (25–84)
71 (39–90)
0.633
57 (25–84)
67 (30–90)
85 (58–96)
29 (8–64)
67 (30–90)
74 (45–91)
0.174
* NE = not evaluable.
† Statistically significant.
for recurrent disease have been poor in the long term. The
Kaplan-Meier estimated median survival time after diagnosis of recurrence was 2.5 years (95% CI 1.8–3.2 years).
Eight patients whose tumors recurred had postoperative
craniospinal radiotherapy alone at first presentation, and
3 patients had preradiotherapy chemotherapy because of
advanced disease (1 patient following the 8-in-1 protocol,
1 with VACA [2 cycles], and 1 following an old protocol
of intrathecal methotrexate (Stage T2M0). The remaining
J Neurosurg / Volume 111 / September 2009
4 patients who have had preradiotherapy chemotherapy
did not experience recurrence (3 patients with advanced
disease and 1 patient with standard-risk disease).
Quality of Life
Fifteen patients alive and without evidence of disease
at last follow-up were available for late toxicity evaluation (median follow-up 10.0 years, range 2.8–25.5 years).
Among these 15 patients, 8 were asymptomatic and had a
481
L. Riffaud et al.
Fig. 3. Graph depicting Kaplan-Meier curves for overall survival
rates of women (n = 16) and men (n = 11).
out any sign of disease. This was the sole case of a supposed second malignancy. Routine endocrine assessments
were not performed for all patients, but no patient showed
evidence of pituitary dysfunction requiring hormonal supplements. Three patients had children 2, 15, and 20 years
after surgery.
Population Study
Discussion
This retrospective study reflects the clinical experience with treatment of adults with primary cerebellar
medulloblastoma at 1 institution over a 30-year time period. The definition of “adult” varies from author to author,
but most series include patients of ≥ 16 years in the adult
Fig. 2. Graph depicting Kaplan-Meier curves according to periods of
diagnosis. Upper: Overall survival rates. Lower: Event-free survival
rates.
normal life, 4 had minor chronic fatigue but were capable
of working full-time (KPS score of 90), and 3 were symptomatic (persistent cerebellar syndrome that was present
before surgery), with KPS scores of 50–60, and required
assistance. Results of the SF-36 questionnaire were as follows: median physical functioning score 100 (range 0–100),
median physical problems score 100 (range 0–100), median
bodily pain score 100 (range 10–100), median social functioning score 100 (range 0–100), median general mental
health score 76 (range 8–88), median emotional problems
score 100 (range 0–100), median vitality score 55 (range
0–75), and median general health perceptions score 80
(range 0–100). The scores obtained on the Mini-Mental
State Examination were 30 of 30 for 10 patients; 29 for
2 patients; and 28, 26, and 22 for the 3 symptomatic patients.
All the patients had occipital alopecia. A patient was
treated for a vesiculopapillary carcinoma of the thyroid 7
years after craniospinal radiotherapy and is still alive with482
Fig. 4. Graph depicting Kaplan-Meier curves for overall survival
rates of patients who had (Stages M2 and M3; 3 patients) or did not
have (Stage M0; 23 patients) metastases. The patient with an unknown
status of metastasis (Stage MX) is excluded.
J Neurosurg / Volume 111 / September 2009
Survival and prognostic factors in adult medulloblastoma
TABLE 3: Multivariate analysis
Variable
overall survival
sex
female
male
M stage
M0
M2 & M3
period
1977–1985
1986–1996
1997–2005
event-free survival
sex
female
male
M stage
M0
M2 & M3
period
1977–1985
1986–1996
1997–2005
OR (95% CI)
1
28.9 (2.9–291.0)
1
35.4 (1.6–796.6)
1
0.03 (0–0.41)
0.12 (0.01–1.32)
1
34.4 (3.5–341.9)
1
53.5 (2.2–1286.5)
1
0.02 (0–0.27)
0.07 (0.01–1.77)
population.1,3,10,19,20,23,26,27,29,43,44 Moreover, patients > 16
years were treated at our institution during this period using adult protocols. Although a retrospective analysis has
some restrictions, a single-institution study has the advantages of uniformity of staging and treatment for each time
period, and availability of more detailed and accurate patient-, disease-, and treatment-related information.
The patient population structure was similar to that in
previous studies for age, symptoms, duration of symptoms,
KPS score, and hydrocephalus at presentation.1,4,10,22,31,32,38,40
The distribution of histological variants was also comparable to that reported by other authors,1,7,10,19,24,26,31,34,36,38,43
with predominance of the classic histological phenotype.
However, our population showed some characteristics different from other series. We observed a female preponderance, unlike most previous reports that described a male
preponderance, as in childhood.1,3,4,7,8,10,15,19,26,32,33,43 This female preponderance is unusual but not exceptional as it has
also been reported in several other studies.14,22,24,38 Moreover, despite the fact that our retrospective study began in
the late 1970s before the modern era of neuroimaging and
surgical tools, we observed that a gross-total removal of the
primary tumor was achieved in 78% of all the patients, and
in 95% of patients whose tumors did not invade the brainstem or the surrounding structures. These findings contrast
with other authors’ reports of complete resection in about
half of the patients.10,19,22,24,26,31,33,36,45 For many years, our
general surgical principle has been to attempt as complete
a resection of the tumor as possible, but it was also guided
by what the surgeon considered prudent at the time: no attempts were made to remove the tumor from within the
brainstem in cases of infiltration into the floor of the fourth
ventricle or the cerebellar peduncles. This series also demJ Neurosurg / Volume 111 / September 2009
onstrated that adult patients with medulloblastoma generally present with symptoms and signs indicating a posterior
fossa lesion, and that the majority of patients have disease
limited to the posterior fossa at the time of initial staging.
None of our patients had extraneural disease at diagnosis.
Extraneural metastases are so unusual that routine systemic evaluation of asymptomatic patients is of very low yield
and probably unwarranted in this disease.
Survival Rate
This study documents high overall survival rates (median 17.7 years; 81 and 62% at 5 and 10 years, respectively)
that compare well with other recent series of patients with
adult medulloblastoma.1,4,5,7,10,26,31,33,36 The best outcomes
from medulloblastoma to date are from Kunschner et al.,31
who reported a 5-year overall rate of 84% for 28 adults
treated between 1978 and 1998. The event-free survival
rates (median 17.9 years; 72 and 57% at 5 and 10 years,
respectively) in the present study are also within the published range. Survival has improved in recent decades since
5-year survival rates of 50%3,25,29,30,39 to 60%19,27,44 were reported in studies published since the end of the 1980s. Our
study reflects the current tendency toward an improvement
in survival rates. The overall survival rate did not change
at 5 years between the first period (1977–1986) before the
era of MR imaging (86%) and the last period (1997–2005)
(85%), but it improved at 10 years from 57 to 71% between
the same periods, and at 20 years from 29 to 57% between
1977–1986 and 1987–1996. The difference was more obvious concerning the event-free survival times as we observed improvement of survival rates from 57 to 85% at
5 years and from 29 to 74% at 10 years between the first
and last periods. This observation was also confirmed by
the multivariate analysis that identified the period of presentation as an independent prognostic factor for overall
and event-free survival times. The high overall survival,
despite the number of recurrences, suggests that adult
medulloblastoma remains responsive to therapy even after
first relapse. Despite the small number of patients, salvage
treatment with surgery, radiotherapy, and chemotherapy
appears to have a role in recurrent disease in that several
patients showed durable responses after recurrence.
Prognostic Factors
The prognostic factors in childhood medulloblastomas have been extensively studied but have varied during
the last 20 years. The current consensus seems to be that
in patients < 2 years of age, metastatic disease, brainstem,
or fourth ventricular floor involvement are correlated with
a worse outcome.35,48
In the adult population, sex significantly affected survival in our study: female patients had better overall and
event-free survival times than male patients. This impact has
already been reported in other adult series12,18,32,40 as well as
in children.13,45,47 Others1,3,4,10,25,26,36 have found that sex did
not affect survival or, on the contrary, noted better outcome
for male patients.23 Some explanations for these findings
have been suggested as follows: a behavior of medulloblastoma intrinsically different between sexes, favoring a more
indolent, well-localized, and more easily resectable form in
483
L. Riffaud et al.
TABLE 4: Characteristics of 11 patients with relapse*
First Relapse
posterior fossa
pontocerebellar angle
4th ventricle
cerebellar hemi sphere
supratentorial
3rd ventricle
spinal axis
cervical
cervical
cervical
cervical & lumbar
extraneural axis
pelvis, femur, &
humerus
pelvis & femur
spine
No. of
Patients
3
No. & Location of
Recurrences
7
2 (same site)
3 (surgical bed)
Initial Characteristics (sex/stage/
location/histology/op)
F/T3aM0/midline/classic/total
M/T2M0/midline/classic/total
2 (2nd: spinal axis) F/T2M0/lateral/classic/total
1
4
3
3
2nd: surgical bed
3rd: spinal axis
F/T3aM0/midline/classic/total
Time from Op
Time from
to 1st/2nd/3rd
Op to Death
Recurrences (mos)
(mos)
Treatment of
1st/ 2nd/3rd
Recurrences
216/237
58/73/85
­
279
96
102/116
127
op & RT/chemo
78/125/168
213
chemo & RT/
chemo & RT/
chemo
op/chemo & RT
op & chemo/RT/
chemo
4
1
1
1
1
4
simultaneously
F/T3aM0/midline/classic/total
M/T4M2/lateral/classic/biopsy
M/T3aM0/midline/desmoplastic/total
M/T4 M2/lateral/classic/subtotal
51
13
8
9
82
25
8
14
chemo & RT
chemo
no treatment
chemo
M/T3aM0/lateral/classic/total
14
46
chemo & RT
simultaneously
2 (2nd: spine)
M/T3aM0/lateral/classic/total
M/T2M0/lateral/desmoplastic/total
37
70/88
64
115
chemo & RT
chemo/chemo
* chemo = chemotherapy; RT = radiotherapy.
female patients; the presence of female hormones, which
may provide protection against tumor recurrence; and the
precocious puberty induced by therapy that confers a survival advantage in children as well as the fact that girls were
usually more sensitive to therapy.32,45,47 However, we have
not been able to determine particular features of the tumors
in our female patients that might have suggested such different behavior. This sex-based difference for survival and
disease control remains an enigma and should be viewed
cautiously because of the small sample size of our series.
On the other hand, it sustains the clinical axiom in oncology
that “girls are good, boys are bad,” and may be evaluated in
the next prospective clinical trials.
Patients with metastases at presentation, although not
very common, have an unfavorable short-term prognosis.
In the current study, only 3 patients had evidence of metastases at diagnosis, a level similar to that observed in
other series.1,7,30,31 Among these patients, 2 had early relapse in the spinal axis despite more aggressive therapy.
In agreement with other reports on adults1,4,19,32,36,40 and
children,17,37,48 we found that the presence of metastatic
disease at presentation was an important prognostic factor for overall and event-free survival times. In a larger
multicenter series,7 metastatic disease did not appear to
be correlated with a worse prognosis, but data were available for only 61% of the patients, and half of the patients
with Stage M0 medulloblastomas received chemotherapy
either before or after, or both before and after, radiotherapy. Those authors suggested that the usual high dose
(30–36 Gy) of radiation administered to the entire brain
484
and spinal axis in adult patients, whether metastatic disease is present, could reduce the prognostic significance
of widespread disease. Nevertheless, we are convinced
that the presence of either microscopic or macroscopic
metastases at presentation remains one of the most important prognostic factors in adult medulloblastoma as
Fig. 5. Graph depicting Kaplan-Meier curves for overall survival
rates of patients whose tumors did (11 patients) or did not (16 patients)
recur.
J Neurosurg / Volume 111 / September 2009
Survival and prognostic factors in adult medulloblastoma
in the pediatric population, and that a careful systematic
staging is mandatory for this tumor with both neuroimaging and CSF analysis by lumbar puncture, and systemic
evaluation if symptoms are present.
Other patient characteristics such as brainstem insion,
incomplete resection, and high-risk group, previously reported to reach significance as unfavorable prognostic variables, especially among the pediatric population, were not
found to reach significance in our study. There are a few
studies that have evaluated survival stratified on the basis
of risk evaluation in adults with medulloblastoma.5,31,36,40
Our impression was similar to that of Brandes et al.5 and
Kunschner et al.31 who observed a comparable outcome for
both standard- and high-risk groups in terms of overall or
event-free survival. The fact that all the patients did not
undergo early postoperative MR imaging in this retrospective study, that patients with high-risk disease had more
aggressive therapies, and that therapies were not standardized may have confused our results. Like others,4,5,26 we are
convinced that adjuvant chemotherapy reduces the risk of
recurrence and death in patients with advanced disease, in
other words the high-risk group.
The value of clinical status at diagnosis, tumor location, or histology also remains unclear as discrepancies
were observed in most of the studies.4,7,10,24,26,36 The desmoplastic subtype has been observed more frequently in the
adult than in the pediatric population.21,23,43 It was suggested
as one of the explanations for the better prognosis reported
in the adult population because of lower growth rate parameters observed in the desmoplastic variant (decreased
proliferation index and/or increased apoptotic index).24,43
Not everyone will agree on this feature, but this histological distinctiveness should be kept in mind for the next trials
as desmoplastic subtype has already been associated with a
genetic disorder and a better outcome in children.2
Tumor Recurrence
The pattern of failure seen in the group of 27 patients
exhibits some interesting observations.
The first point is that recurrence did not develop most
often in the posterior fossa in our series, contrary to what
has been described in other studies.3,10,19,24,27,32,40,44 We observed only 1 supratentorial metastasis in an initial recurrence, in accordance with previous reports that recorded
this as a rare location.1,19,25,26,32 On the other hand, we observed, as other authors have,1,10,29,31,38 that the incidence of
extraneural metastasis at recurrence was proportionally
high. This seems to be characteristic of adults as opposed to
children and may represent a biological difference between
the tumor found in adults and that found in children.31 It
may also indicate that local tumor control has been brought
about by radiotherapy alone, and that a systemic adjuvant
treatment in the standard-risk group should be suggested
to reduce the number of recurrences at a distance from the
primary tumor. Indeed, the role of adjuvant chemotherapy
in high-risk patients has been demonstrated in terms of risk
of recurrence, delay of recurrence, and death,4,5 but it is still
unidentified in standard-risk patients. This relatively high
frequency of spinal and extraneural metastasis must also
be taken into account for regular clinical evaluation of the
patient during follow-up, and vigilance must be used conJ Neurosurg / Volume 111 / September 2009
cerning new symptoms, as recurrences may develop in isolation and at a distance from the posterior fossa although
the primary tumor is under control.
The second point is that delayed recurrences were not
particularly rare (median latency 4.2 years, range 0.7–18
years). This is also a characteristic of adult medulloblastoma, which has already been described, 5,10,25,38 and is unlike childhood medulloblastoma where recurrences develop more rapidly. However, no exceptions to the Collins
Law were observed, as only 1 of our patients suffered a
recurrence after a period of time exactly equal to his age
(18 years).
The third point is that all types of recurrence imply
an unfavorable prognosis whatever the treatment (all patients who had recurrences have died). However, survival
of patients suffering recurrence may be prolonged by several years by using aggressive treatment (median time to
death after diagnosis, 2.5 years). Gamma Knife surgery
has also been recently used in recurrent medulloblastoma
with promising results and should be considered part of the
range of therapeutic options.20 It therefore appears possible
to propose an optimum treatment in case of recurrence, taking into account the fact that other metastatic lesions may
occur at different sites during the evolution of the disease.
Spinal axis recurrence had the most unfavorable prognosis
with the shortest delays before the appearance of metastases
and the shortest survival times of all potential sites. Moreover unlike other authors3 we observed a higher frequency
of cervical recurrence.
The final point is that we do not deem it possible for
the moment to define a typical profile for patients with
medulloblastoma at risk for recurrence, be it for the stage
of disease, tumor location, histological subtype, quality of
resection, or postoperative treatment. There appear to be
multiple interrelated factors influencing prognosis; this
renders their identification difficult, and it is clear that we
are still far from understanding all the biological characteristics of this tumor.
Conclusions
Long-term survival is possible in adults treated for
cerebellar medulloblastoma. Surgery and postoperative
craniospinal radiotherapy are the mainstay treatments for
this disease. Prognostic factors vary from one study to
another but prospective trials should continue to analyze
classic factors such as sex, histological variants, or Chang
staging. Metastasis seeding at presentation, although rare,
is a poor prognostic factor for relapse. The very real possibility of delayed recurrence mandates close follow-up of all
patients with this disease, with prompt evaluation of new
symptoms. Recurrences should be treated with aggressive
therapies as some patients may have sustained response.
Adjuvant chemotherapy should be given to high-risk patients, but its role remains unclear in standard-risk adult
medulloblastoma. The question remains whether adjuvant
chemotherapy can reduce recurrences, particularly distant
ones, and improve survival with an acceptable toxicity.
Disclaimer
The authors report no conflict of interest concerning the mate-
485
L. Riffaud et al.
rials or methods used in this study or the findings specified in this
paper.
Acknowledgment
The authors thank Mrs. Deirdre McKeown for her help with the
English language.
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Manuscript submitted August 10, 2008.
Accepted January 9, 2009.
Please include this information when citing this paper: published
online February 20, 2009; DOI: 10.3171/2009.1.JNS081004.
Address correspondence to: Laurent Riffaud, M.D., Department
of Neurosurgery, Pontchaillou University Hospital, 35033 Rennes
cedex 09, France. email: [email protected].
487