Weil MD, Lamborn K, Edwards MSB, Wara WM. Influence of a Child's Sex on Medulloblastoma Outcome. JAMA. 1998;279(18):1474-1476. doi:10.1001/jama.279.18.1474
From the Departments of Radiation Oncology (Drs Weil and Wara) and Neurologic Surgery (Drs Lamborn and Edwards), University of California, San Francisco.
Context.— Aggressive treatment of medulloblastoma, the most common pediatric brain
tumor, has not improved survival. Identifying better prognostic indicators
may warrant less morbid therapy.
Objective.— To investigate the role of sex on outcome of medulloblastoma.
Design.— Retrospective study of significant factors for survival with a median
follow-up of 82 months.
Setting.— University medical center.
Patients.— A total of 109 consecutive, pediatric patients treated for primary medulloblastoma
from 1970 to 1995 with surgery and postoperative radiotherapy and, after 1979,
Main Outcome Measures.— Factors independently associated with survival.
Results.— The final multivariate model predicting improved survival included sex
(hazard ratio, 0.52; 95% confidence interval [CI], 0.29-0.92; P=.03; favoring female), metastases at presentation (hazard ratio,
2.01; 95% CI, 1.14-3.52; P=.02), and extent of surgical
resection (hazard ratio, 0.60; 95% CI, 0.34-1.04; P=.07;
favoring greater resection). The overall, 5-year freedom from progression
was 40% and survival was 49%. Radiotherapy dose (P=.72),
and chemotherapy (P=.90) did not significantly affect
a disease outcome.
Conclusions.— The sex of the child was an important predictor for survival of medulloblastoma;
girls had a much better outcome. The difference in survival between sexes
should be evaluated in prospective, clinical trials.
MEDULLOBLASTOMA, the most common brain tumor in children, is the only
disease where postoperative irradiation of the entire craniospinal axis is
considered standard of care. Children with the disease routinely undergo craniotomy
followed by high doses of craniospinal radiotherapy and, in many cases, a
year of intensive chemotherapy. Sadly, this aggressive approach is extremely
morbid and yet has not improved survival over the past 2 decades.1- 4 Therapy
inevitably has serious adverse effects on the developing central nervous and
skeletal systems,5,6 including
marked learning disabilities, hormonal and hearing abnormalities, short stature,
and induction of secondary tumors.7- 9
In fact, it is difficult to demonstrate that variations in outcome are
more than the result of variations in classification of the disease at presentation.
Medulloblastoma has been staged as low risk or high risk.10
Most trials demonstrate a 5-year survival of approximately 70% for low-risk
patients and 30% for high-risk patients. None of the staging or treatment
protocols take sex into account. Based on earlier work,10
we investigated whether factors other than residual tumor volume and the patient's
age influence the outcome of the malignancy.
We, retrospectively, evaluated all patients with primary medulloblastoma,
21 years or younger, treated with postoperative radiotherapy at the University
of California, San Francisco, between 1970 and 1995. Most patients underwent
spinal evaluation with examination of the cerebrospinal fluid, myelogram,
magnetic resonance imaging, or a combination of these tests. Following standard
clinical practice, patients were staged as low risk if they were older than
3 years, had undergone a gross total resection, and had negative evaluation
of the craniospinal axis.10 High-risk patients
were considered to be children 3 years old or younger, those who had undergone
less than complete resection, or patients found to have evidence of disease
beyond the posterior fossa.
Tumor volumes were localized with the aid of computed tomography (CT)
beginning in the mid-1970s, and later with magnetic resonance imaging. All
patients were treated with linear accelerators using 4-MV or 6-MV photons.
Until 1989, and most recently, radiation was delivered to the posterior fossa
in single daily fractions of 1.8 Gy to a total of 56 Gy or less. Between 1989
and 1992, patients were treated with 1 Gy twice daily to a total dose of 72
Gy to the posterior fossa.11 Patients treated
once a day received an average dose of 36 Gy to the craniospinal axis and
those treated twice daily received 24 to 40 Gy.
Combinations of chemotherapeutic agents changed over time. Prior to
1979, most patients received radiation only. Subsequently, procarbazine was
given postoperatively, followed by hydroxyurea plus radiation at reduced craniospinal
doses. After 1990 most high-risk patients older than 3 years were treated
with hyperfractionated radiotherapy, followed by cisplatin, lomustine, and
No patients were lost to follow-up. After treatment, patients were followed
up with regular CT or magnetic resonance scans and cerebrospinal fluid cytology.
Time to progression was measured from the start of radiotherapy until relapse,
and patients who died without evidence of disease were censored for this analysis.
Duration of survival was measured from the start of radiotherapy until last
follow-up or death. Estimates of time to progression and survival were computed
using the method of Kaplan and Meier.12 We
used χ2 or t test statistics (as appropriate
to the data) to compare patient characteristics by sex. Univariate and multivariate
analyses of survival were performed with the Cox proportional hazards regression
model13 using statistical software (Stata Corporation,
College Station, Tex). All variables in Table 1 were evaluated as potential prognostic factors by univariate
analyses. For the purpose of these analyses, the extent of surgical resection
was categorized as gross total resection or less than gross total resection.
Multivariate analyses used forward stepwise selection with inclusion based
on P=.05. We evaluated whether the hazard ratio for
any factor, eg, sex, metastasis, or surgery, changed with time from diagnosis
by graphing log (−log survival) vs log (time).
From 1970 to 1995, 109 patients were treated (Table 1), 62 patients were males, and 47 females. The median age
of the patients was 7 years (range, 5 months to 21 years), 25% were aged 3
years or younger. The spine was evaluated in 93%. Gross total resection was
performed on 54%. There were 39 low-risk patients and 70 high-risk. There
were 7 patients considered poor risk solely based on age younger than 3 years
at diagnosis. Adjuvant chemotherapy was used in 17 low-risk and 59 high-risk
patients. Standard radiotherapy was delivered to 80 patients and 29 patients
received hyperfractionation. Seven infants received chemotherapy and posterior
fossa irradiation only (3 of these patients are still alive without disease).
The median follow-up for living patients was 96 months (range, 3-275
months) and the median time to relapse was 24 months. The actuarial 5-year
freedom from progression was 40% (64% for low-risk patients and 27% for high-risk
patients). There were relapses in 61 patients; 15 low risk and 46 high risk.
Median overall survival was 59 months, and a total of 58 patients died. Five-year
survival was 64% for the low-risk patients vs 41% for the high-risk patients,
and 49% overall (Figure 1). The
data for time to progression overall and by sex parallel these curves (Figure 2). There were 6 late deaths (5-7
years following therapy) from disease, and 4 girls died of therapy-related
causes other than tumor recurrence. There was no significant difference in
time to progression or survival detected over the varying diagnostic and treatment
Prognostic factors that were significant for overall survival by univariate
analysis included stage (low risk vs high risk) (P=.01),
sex (P=.01), metastasis at presentation (P<.01), and extent of surgical resection (P<.01)
(Table 2). For the purpose of
the multivariate analysis of survival time, we chose to use the individual
factors of stage: age, extent of surgical resection, and disseminated disease
at presentation. Results using risk grouping provide a similar outcome with
regard to the effect of sex and are not presented. Cox stepwise analysis yielded
a final model with sex (hazard ratio, 0.52; 95% CI, 0.29-0.92; P=.03; favoring female), metastasis at presentation (hazard ratio,
2.01; 95% CI, 1.14-3.52; P=.02), and favoring increased
extent of surgery (hazard ratio, 0.60; 95% CI, 0.34-1.04; P=.07). Extent of surgery was left in the model (although the P value was slightly above the .05 cutoff) to ensure that
the apparent difference between the sexes was not due to a difference in extent
There was no indication that the hazard ratio changed over time for
either extent of resection or presence of metastases. This supports the belief
that use of the multivariate model adequately adjusted for any difference
between the sexes in these risk factors. There was some indication that the
hazard ratio for sex decreased with time (ie, the benefit for girls became
more apparent). This trend can also be seen in Figure 1, where the separation of the survival curves only became
apparent after 24 months of follow-up. To further confirm the result regarding
sex, comparison between the sexes was done separately within the 2 risk groups.
For the high-risk group, the hazard ratio was 0.47 favoring female (P=.03; 95% CI, 0.23-0.93). Results for the low-risk group
were similar with a hazard ratio of 0.65. However, with the fewer events,
this was not statistically significant. An overall test for interaction between
risk group and sex was not statistically significant (P=.56).
These results indicate that females had a significant survival advantage
compared with males. Males more often presented with high-risk disease, yet
there were no significant differences in adverse prognosticators noted for
males and males had poorer survival in both the low- and high-risk groups.
Multivariate analysis showed sex to be a major prognostic indicator even when
adjustment was made for standard risk factors. Radiotherapy dosage (P=.72), chemotherapy (P=.90),
and treatment era (P=.13) did not affect outcome.
Medulloblastoma is treated postoperatively with craniospinal axis irradiation
and, when indicated, with systemic chemotherapy. These nonspecific therapies
include a large volume of normal tissue and are, therefore, extremely toxic.
Acutely, patients suffer from fatigue, nausea, skin erythema, hair loss, and
low blood cell counts. However, it is the chronic side effects of decreased
intellect and stature, hearing, and hormonal deficits that can be devastating.
Attempts to decrease toxic effects by using combined modality therapy have
not demonstrated a survival benefit. Early reports of dramatic improvement
in outcome after cisplatin chemotherapy14,15
have not been reproduced.10
Prediction of outcome remains dependent on the accuracy of pathology
and staging. Thorough evaluation of the extent of disease at presentation
is performed to gauge the required intensity of treatment. The assignment
of patients to categories of low vs high risk of failure presently is predicted
by postoperative residual disease in the craniospinal axis and patient age.
Improved imaging with magnetic resonance imaging in addition to cytological
examination has improved staging.16 Unfortunately,
the advances in imaging have not yet produced longer survival. Our data suggest
that sex may be an important determinant of medulloblastoma outcome: girls
did remarkably better than boys.
Our results are from a retrospective analysis at a single institution.17,18 There were slightly more boys than
girls in our patient population, which is similar to other studies.19 Although boys generally presented with worse disease,
both sexes presented with a range of risk factors. It is clear from the separation
of the survival curves with time that without adequate follow-up the differences
based on sex will not be observed. Patients were treated over 2 decades, on
several different therapeutic regimens, and we cannot be certain what role
physician bias may have played in treatment decisions. However, there were
several advantages for this group. Children were aggressively studied prior
to therapy; 93% had craniospinal axis evaluation (88% were evaluated with
magnetic resonance imaging or CT). Patients were treated by a small group
of physicians at a single institution.20 Although
difficult to quantify, improved outcome in many studies is associated with
expertise acquired by treating a large number of patients.
There is a clinical axiom in oncology that "girls are good, boys are
bad." The effect of sex on the course of medulloblastoma has been previously
shown to be significant in epidemiological study.21
We do not know the mechanism for a potential influence of sex on the biology
of medulloblastoma. It might be that girls are more sensitive to therapy;
4 of the 5 patients who died of treatment-related causes were female. We hypothesize
that the improved outcome for girls might be the result of therapy-induced
precocious puberty. We have not documented the induction of precocious puberty
in this group; however, others have demonstrated early puberty following combined
modality therapy.22 There is no reference in
the literature regarding hormonal interactions for this central nervous system
tumor,23 nor do we know of studies demonstrating
a beneficial effect of female hormones on medulloblastoma. However, estrogen
and progesterone have been used to treat a 12-year-old boy with massive spinal
recurrence with equivocal results (M.D.W., and Carol A. Diamond, MD, unpublished
The treatment of medulloblastoma is not satisfactory; the sequelae of
craniospinal irradiation delivered to children are severe. To date, treatment
is based on the extent of primary resection, disease outside of the primary
area, and age of the patient. If in fact sex is significant, then it might
be justifiable to treat boys more aggressively and girls less extensively.
The data suggest that the difference in survival between sexes following medulloblastoma
should be evaluated in prospective, clinical trials.