The prognosis for patients with newly diagnosed medulloblastoma has
improved dramatically over the past several decades. In contrast to the
dismal results of treatment during the first half of the 20th century,
current 5-year survival rates of better than 50% are now being reported,
and certain subsets of patients have more than a 70% chance of long-term
disease-free survival.[1,2] Although neurosurgeons and radiation oncologists
have proposed that this improvement is due to advances in their respective
specialties, probably multiple factors are involved. These include:
- decreased operative mortality and morbidity due to improvements in
surgical technique, allowing for more extensive resection of the primary
tumor, advances in anesthesia, the use of perioperative corticosteroids,
and better supportive care;
- advances in radiation therapy equipment, namely, the introduction of
- improved noninvasive diagnostic imaging modalities, such as CT and
MRI, which allow for earlier diagnosis, better assessment of tumor extent,
accurate assessment of disease beyond the posterior fossa, extent of tumor
resection, and response to therapy;
- increased use of MRI, CT, and cerebral spinal fluid (CSF) cytology
studies for staging and identification of high-risk patient subgroups;
- increased use of chemotherapy, which may be improving disease-free
survival in certain subsets.
Improvements in Radiotherapy
As Paulino has detailed so well, improvements in radiation therapy practice
(namely, the advent of supervoltage equipment) and technical advances now
allow for the administration of an accurate, uniform high dose to the cranio-spinal
axis. This is one of the most important factors accounting for the improvement
in prognosis. As he emphasizes, this more favorable outcome has been associated
with the use of whole craniospinal axis irradiation, as opposed to radiotherapy
just to the posterior fossa plus or minus the spinal cord.
However, equipment alone is not sufficient. There must be proper technique
and accurate placement of the radiation portals to avoid shielding the
cribriform plate region and to ensure adequate coverage of the lower spinal
cord. The junction of the portals used for cranial irradiation and the
posterior spinal portal must be determined and placed accurately in order
to avoid overdosage or underdosage to the upper cervical cord.
Prior to the availability of CT, relapse in the supratentorial region
as a first site of failure was certainly under-reported. This lack of appreciation
for the supratentorial region as a frequent site of failure prompted several
unsuccessful attempts to eliminate supratentorial irradiation from the
treatment of medulloblastoma.[3-5] Even though Cushing recognized the propensity
for medulloblastoma to disseminate via the CSF pathways, it was not until
1975 that thorough staging with myelography and CSF cytology studies were
suggested for all newly diagnosed patients with medulloblastoma. By
using thorough staging procedures, evidence of dissemination beyond the
posterior fossa was demonstrated in over 40% of newly diagnosed patients,
even though very few had symptoms suggestive of dissemination at diagnosis.
The M-stage is probably the most important predictor of prognosis in
patients with medulloblastoma. Other factors considered to be important
are T-stage, extent of resection, and age at diagnosis. Using such factors,
many investigators have divided the medulloblastoma population into "good-risk"
and "poor-risk" subgroups.
Is High-Dose Craniospinal Irradiation Needed?
With the improvement in long-term survival associated with high-dose
craniospinal axis irradiation has come the appreciation that radiotherapy
may cause severe late sequelae, such as neurocognitive and learning disorders,
lower IQ scores, endocrine dysfunction, and interference with normal growth
and development. These late sequelae are related mainly to irradiation
of the craniospinal axis and are dependent upon dose factors and age at
The problem of late sequelae from craniospinal radiotherapy, as well
as several retrospective reviews that questioned the need for high-dose
craniospinal axis irradiation, prompted the Children's Cancer Group (CCG)
and the Pediatric Oncology Group (POG) to evaluate a lower dose of neuraxis
irradiation, 2,340 cGy/13 fractions, vs a standard dose, 3,600 cGy/20 fractions,
with both arms receiving a posterior fossa dose of 5,400 cGy/30 fractions.
This study was carried out in the low-stage (T1-T3, M0), prognostically
favorable group of medulloblastoma patients. In neither arm was chemotherapy
used. The study was terminated in 1990 after an interim analysis demonstrated
an increased risk of early relapse overall and in the neuraxis among patients
receiving the lower neuraxis dose.
As Paulino states, most published series cite relapse in the posterior
fossa as the most common site of failure. However, when patients are followed
with CT scans of the head and MRI of the spine, the incidence of recurrence
beyond the posterior fossa, often clinically silent, increases. A series
reported in 1988, in which staging was attempted in all patients at relapse,
demonstrated an incidence of supratentorial and cord involvement about
equal to the incidence of relapse in the posterior fossa. Even in the
recently completed CCG-POG study carried out in a relatively good-risk
population with low T-stage and no evidence of dissemination, less than
one-half of all relapses involved the posterior fossa, both in the total
randomized population and completely eligible patients.
Important Unanswered Questions
Several important questions about radiotherapy for medulloblastoma remain:
- Would low-dose neuraxis irradiation plus chemotherapy be equivalent
to or perhaps even better than standard-dose neuraxis irradiation for a
good-risk, M0 population?
- What is the role of radiotherapy in infants? Chemotherapy alone after
surgery achieves a 3-year disease-free survival rate of less than 25% in
infants. Should all infants receive craniospinal axis irradiation when
they reach a specified age, perhaps 3 years? Should radiotherapy be reserved
just for relapse in the infant population? Hopefully, relapse would be
detected relatively early by intense surveillance.
- Would it be possible to increase the cure rate in the infant population
by using a very low dose of craniospinal axis irradiation in children who
are rendered clinically and radiographically disease-free by surgery and
chemotherapy? Perhaps radiotherapy just to the posterior fossa would be
adequate for a large proportion of infants who have M0 disease. For the
infant who has been treated with postoperative chemotherapy alone and who
still has detectable disease, there are still unanswered questions concerning
the proper radiation dose and the volume to be irradiated.
- Would hyperfractionation improve on or at least be equivalent to the
results of standard-dose irradiation while decreasing the incidence and
severity of late effects? A current CCG study is gathering data on hyperfractionation
after intense chemotherapy in a poor-risk population of patients with medulloblastoma
or supratentorial primitive neuroectodermal tumor. Although the data on
the relationship between hyperfractionation and late sequelae are rather
incomplete, I tend to use hyperfractionated radiotherapy for craniospinal
axis irradiation in children under age 7 years.
- Lastly, will advances in chemotherapy allow even the poor-risk patient
to be treated with a lower dose of craniospinal axis irradiation, thus
reducing late sequelae and hopefully also improving outcome?
Over the next decade, it will be important to determine optimal radiation
regimens for good- and poor-risk medulloblastoma patients and to determine
the optimal integration of radiotherapy with chemotherapy.
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in childhood: Treatment results and a proposal for a new staging system.
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