MEDULLOBLASTOMA: AN ANALYSIS OF

TIME-DOSE RELATIONSHIPS AND

RECURRENCE PATTERNS
CHARLESE. SMITH, MD,* DONLINM. LONG,MD,+
THOMAS
K. JONES, JR., MD,$ SEYMOUR
H. LEVITT,MD*

Forty-three cases of medulloblastoma were retro spectively evaluated. Patients

who initially received irradiation to the entire central nervous system had
a better survival than those receiving limited irradiation. Patient survival was
improved with a dose of 4500 to 5500 rads to the posterior fossa, 3500 rads to
the remainder of the brain, and 3000 rads to the spinal cord. There was a
27% complication incidence in 11 patients who received supplemental intrathe-
cal radiogold and their survival has not been significantly better than those who
received only external beam therapy to the spinal cord. Reirradiation of
intracranial recurrences improved survival, while reirradiation of spinal core
recurrences did little to improve survival. Proven intracranial recurrences
were all anterior to the posterior fossa. We have concluded that the entire
brain should receive 5000 rads, the spine should receive 3500 rads, and re-
currences should be accurately localized and retreated by irradiation.

F ORTY-THREE CASES OF MEDULLOBLASTOMA

have been retrospectively evaluated. T h e
cases include all patients treated at the Uni-
versity of Minnesota since 1942, with his-
tologic proof of medulloblastoma.
T h e study was undertaken to evaluate the
incidence, site, and prognosis in those patients
who developed recurrences. Because a variety
of radiotherapeu tic approaches have been em-
ployed over these years, the number of cases
in each treatment group is small and statis-
tically significant figures cannot be obtained.
MATERIALS
AND METHODS
Thirty-seven of the 43 cases received irradia-
tion and were examined retrospectively for
irradiation dose and method of therapy, recur-
rence pattern with respect to the primary ther-
Presented at the 14th Annual Meeting of the Arneri-
can Society of Therapeutic Radiologists, Phoenix, Ariz..
Kov. 1-5, 1972.
From the University of Minnesota Hospitals, Minne-
apolis, Minn.
+ Medical Fellow, Department of Therapeutic Ra-
diology.
t Associate Professor, Department of Neurosurry.
t Assistant Professor, Department of Therapeuc Ra-
diology.
0 Professor and Head, Departmcnt of Therapeutic
Radiology.
.4cldress for reprints: Seymour H. Levit. MD, Depart-
ment of Therapeutic Radiology. University of Minnc-
sota Hospitals, Box 187. Minneapolis. hlinn. 55455.
Received for publication June 5 . 1973.
722
apy, and the usefulness of irradiation. All pa-
tients, including three treated within the past
year, have been included in the study.
During recent years, methods have become
available and utilized to localize accurately in-
tracranial and spinal recurrences. Prior to
this, most recurrences were diagnosed and lo-
calized by clinical signs and symptomatology.
I n this paper, the diagnosis of recurrence was
accepted as such whether it was made on clini-
cal grounds alone or supported by other diag-
nostic techniques. Special mention will be
made of those recurrences which were sup-
ported by biopsy or diagnostic procedures.
T h e surgery consisted of removal of all
grossly visible tumor unless invasion of vital
structures precluded its removal. T h e external
beam radiotherapy was delivered by orthovol-
tage equipment or cobalt teletherapy employ-
ing a wide variety of treatment techniques.
T h e doses delivered at tumor depth have been
calculated in rads. T h e radioactive gold was
given intrathecally, and no attempt was made
to estimate its contribution to the total dose
to the spinal cord. Survival is presented in
months.
RESULTS
Extent of central nervous system ( C N S ) irra-
dintion and suroiual: T e n patients received ir-
No. 3 MEDULLOBLASTOMA
* Smith et al. 723
radiation to only a portion of the CNS, and dose range is too small for statistically signifi-
27 patients had complete CNS irradiation. cant differences to be demonstrable. Two of
Of the 10 patients in the partially irra- five patients who received less than 3500 rads
diated group, three (30%) are currently alive, and 9 of 16 who received 3500 to 4500 rads to
having survived 9 to 15% years. These three the whole brain are currently alive. The sur-
patients received irradiation to the whole vival range in months for these two groups of
brain, posterior fossa and spine, and posterior patients is comparable. Five patients received
fossa only. greater than 4500 rads to the whole brain, and
Twenty-six of 27 patients received some ex- all are currently alive from 3 to 43 months.
ternal beam therapy to the entire CNS. The Three have been followed for less than 12
other patient received only radioactive gold months. Further follow-up will be necessary
therapy to the spine and has survived 43 to determine whether this dose will improve
months. Fifty-nine per cent of those receiving survival.
complete CNS irradiation are presently alive. Spinal cord irradiation and survival: Thir-
If the three patients who had been followed ty-seven patients received external beam irra-
for less than one year are excluded, the sur- diation. The irradition dose delivered to the
vival is 547& This is approximately twice the spinal cord is presented in Table 3. Fifteen
survival for the nine patients receiving irra- patients received less than 3000 rads, and five
diation to only a portion of the CNS. (33%) are currently alive. Twenty-two pa-
Posterior fossa irradiation dose and tients received more than 3000 rads, and 15
survival: Twenty-three patients who have (68%'are currently alive. The 13 patients in
been followed for more than one year received the 3000 to 3500 rad group include 10 patients
external beam therapy to the entire CNS. The who had supplemental intrathecal radiogold
total dose to the posterior fossa was calculated and no estimate of the dose contribution from
and the patients divided into three dose the gold has been included in the table. Thus
ranges (Table 1). There were five patients in the total dose to the spinal cord has been un-
both the 2500 to 3500 rad and 3500 to 4500 derestimated for these patients.
rad ranges. When these groups are combined, External beam us. external beam plus radio-
the survival was 3 of 10, or 30%. gold and survival: The comparison of the pa-
Thirteen patients received between 4500 tients followed for more than 12 months who
and 5500 rads to the posterior fossa. Their received greater than 3000 rads external beam
survival is 77% or more than twice that of the alone, to those who received a similar dose
low dose groups. It should be noted that these plus intrathecal gold, is shown in Table 4.
13 patients received at least 3000 rads to the The per cent survival for the former group is
remainder of the CNS which may in part ac- 60% compared to 70Y0 for the latter. Three of
count for their better survival. the survivors who received radioactive gold
Seven patients received external irradiation have the serious side effect of a clinically sig-
to only the posterior fossa. One patient who nificant and debilitating cauda equina syn-
received 4800 rads is currently alive 15y2years drome. This represents a complication inci-
after irradiation. dence of 27% for the 11 patients who received
Whole brain irradiation dose and survival: the gold therapy as it was employed in the pa-
Twenty-six patients, including three treated tients in this study. (One patient received only
recently, are evaluated for survival in relation radiogold therapy to the spine.)
to the minimal dose which the whole brain re- Zntracranial recurrences: Twenty patients
ceived (Table 2). The number of cases in each were considered to have intracranial recur-

TABLE
1. Total Dose to Posterior Fossa, Complete CNS Irradiation
-
Minimum dose to remainder of CNS
Dose to 0- 2000- 3000- Total Range (rnos.)
posterior fossa 2000 3000 4000
2 500- 2 Alive 2/5 (40% Alive 58-86
3500 2 Dead 1 Dead 3/5 (60%) Dead 10-49
3500- 1 Alive 1/5 (2070) Alive 76
4500 1 Dead 3 Dead 4/5 (80%) Dead 4-33
4500- 10 Alive 10/13 (77%) Alive 12-57
5500 3 Dead 3/13 (23%) Dead 6-24
724 CANCERSeptember 1973 Vol. 32

2. Total Dose to Whole Brain, Complete CNS Irradiation

TABLE
Minimum dose t o remainder of CNS
Dose to 0- 2000- 3000- Total Ranger (mos.)
whole brain 2000 3000 4000
2800- 1 ..\live 1 Alive 2/5 (40%) Alive 58-86
3500 2 Dead 1 Dead 3/5 (60%) Dead 10-49
3500- 9 Alive 9/16 (56%) Alive 24-1 10
4500 1 Dead 6 Dead 7/16 (44%) Dead 4-33
4500- 5 Alive 5/5 ( 1 0 0 ~ oAlive
) 3-43
5500

rences. T h e mean time to the presentation
was 21 months with a range of 4 to 51 months.
Seven of these patients also developed spinal
recurrences. It should be stressed that many of
these patients did not have evidence for recur-
rence other than signs and symptoms of in-
creased intracranial pressure or disease pro-
gression. More recently, patients suspected of
having recurrences have been evaluated with
various diagnostic techniques and they will be
discussed below.
Retreatment of intracranial recurrences:
Eleven of the patients were considered to be
candidates for reirradiation. There were 13
reirradiation attempts for these 11 patients.
Survival was calculated for these patients from
the completion of reirradiation to the next
CNS recurrence, their death, or July 1972.
T h e mean survival was 19 months with a me-
dian of 13 months and a range of 0 to 92
months.
T h e reirradiation was directed to various
portions of the CNS and given a variety of
doses (Table 5). There are two patients alive
without evidence of disease at 38 and 92
months from the completion of the irradia-
tion.
T h e problem of recurrence localization has
been alluded to above. There were six recur-
rences demonstrated in five patients prior to
death by contrast studies or scan, and three of
these were confirmed by biopsy (Table 6). One
of the patients had a concomitant spinal cord
recurrence. All proven recurrences were lo-
cated anterior to the posterior fossa. I n all
cases, the area of the recurrence received 3500
rads by initial therapy except for one who re-
ceived 4000 rads.
One patient (# 22) showed that a positive
scan cannot be completely relied upon when
that scan is obtained after the initial surgery
and irradiation. This patient’s scan showed in-
creased uptake in the right middle fossa and
left posterior fossa. A ventriculogram showed
a mass in the right lateral ventricle, and the
posterior fossa was not visualized. Subsequent
craniotomy showed a mass in the right lateral
ventricle; however, posterior fossa exploration
revealed only adhesions.
SpinaZ recurrences: Eight patients had
spinal recurrences and again not all were sub-
stantiated by myelogram. T h e average time to
the recurrence was 16 months with a median
of 12 months and a range of 4 to 36 months.
Seven of the eight patients had or developed
intracranial recurrences.
Retreatment of spinal cord recurrences:
These eight patients underwent 11 reirradia-
tion attempts. T h e mean survival from the
completion of irradiation to the next spinal
recurrence, their death, or July 1972, was 6
months with a median of 4 months and a
range of 2 to 22 months.
Three of the eight spinal recurrences were
proven by myelogram. One of these three had
3500 rads external beam therapy to the spinal
canal but had uncontrolled intracranial dis-
ease proven by scan a t the time of the spinal
recurrence.
Consideration of the dose to the spinal

TABLE
3. Spinal Irradiation i n All Patients
Per cent Survival Survival
No. patients survival mean (mos.) range (rnos.)
External beam 0-2000 11* 3/11 (27%) 114 43-188
dose (rads)
2000-3000 4 214 (50%) 90 58-1 22
3000-3500 13 9/13 (69%) 47 24-86
3500-4000 9 6/9 (67%) 19 3-76
* One received only.
A11198
No. 3 MEDULLOBLASTOMA -
Smith et al. 725
4. Radiogold vs. External Beam, Complete CNS Irradiation
TABLE
Therapy Survival Mean Median Range
3000 rads plus Au'O8 7/10 (70%) 49 mos. 47 mos. 40-58 mos.
3000 rads only 6/10 (60%) 26 mos. 22 rnos. 12-86 mos.

canal prior to the spinal recurrence is shown
in Table 7. Four of the eight patients had un-
controlled intracranial disesae at the time of
the spinal recurrence. Only one patient with a
spinal recurrence remained free of intracra-
nial disease until his death. Two patients had
adequate spinal irradiation, i.e.. 3000 rads,
prior to their spinal recurrence. However,
both had uncontrolled intracranial disease at
the time of their recurrence.
DISCUSSION
Medulloblastoma has a high potential for
seeding through the cerebrospinal fluid.
Cutler2 and Jenkin,4 among others, have
shown improved survival with irradiation di-
rected toward the entire CNS. Our data con-
firm that survival is greatly improved when
the entire CNS is irradiated. This entire vol-
ume must be irradiated because of the pro-
pensity for medulloblastoma to metastasize by
the cerebrospinal fluid. It is important to de-
liver this irradiation in a homogeneous fash-
ion and at the time of initial therapy so that
any circulating and hence potential recurrence
causing cells are included within the treat-
ment fields.
Our present survival is 54% for patients fol-
lowed for more than one year who received
complete CNS irradiation, vs. 30% for those
receiving partial CNS irradiation. These sta-
tistics may change somewhat with longer fol-
low-up and larger case numbers but do tend
to support the data of others2.4 that the entire
CNS must be initially irradiated.
Medulloblasoma is a sensitive tumor to ir-
radiation. Nevertheless, rather high doses are
required for local control. Bloom1 has pub-
lished results indicating that the optimum dose
to the primary is in the 40004500 Roentgens
range. Although we have not used the same
dose grouping, our results (Table 1) indicate
that a dose between 4500-5500 rads in 6-7
weeks is the optimum dose to the primary
tumor. This is also supported by the results
for the patients receiving irradiation to only
the posterior fossa. One patient received 4800
rads to the posterior fossa and is alive at 15%
years.
Because of the large volume and important
structures which must be included in these
fields covering the entire CNS, it is also im-
portant to find the optimum dose to the por-
tions of the CNS outside the posterior fossa.
Our figures (Table 2). although not statisti-
cally significant due to small numbers, show
that survival is improved to 56% from 40%

TABLE
5. Reirradiation of Intracranial Recurrences
Patients Original therapy Reirradiation Survival after reirradiation
3 2780 rads CNS 3840 rads post. fossa 14 mos. (Dead)
8 3840 rads posterior fossa 4150 rads post. fossa 20 mos. (CNS recurrence)
3840 rads post. fossa 6 mos. (Dead)
12 4000 rads whole brain 3500 rads CNS 38 mos. (NED)*
13 3500 rads CNS 2400 rads whole brain 6 rnos. (Dead)
1500 rads posterior fossa
15 3840 rads posterior fossa 2000 rads post. fossa 12 rnos. (CNS recurrence)
2680 rads post. fossa 17 rnos. (Dead)
20 3170 rads posterior fossa 3460 rads post. fossa 92 rnos. (NED)
22 3500 rads CNS 3000 rads mid-brain 15 mos. (Active intracranial disease)
1500 rads posterior fossa
29 3500 rads CNS 3300 rads CNS 3 mos. (CNS recurrence)
1000 rads posterior fossa 13 mos. (Dead)
31 3300 rads posterior fossa 3400 rads CNS 10 mos. (Dead)
33 3260 rads whole brain 3120 rads post. fossa 0 mo. (Lost)
40 3500 rads CNS 3500 rads mid-brain 8 mos. (Active intracranial disease)
1500 rads Dosterior fossa
* No evidence of disease.
726 CANCER
September 1973
when the dose to the remainder of the intra-
cranial cavity is raised to a minimum of 3500
rads. Another reason for increasing the dose to
the entire brain is the location of the intra-
cranial recurrences.
Prior papers such as Bloom’s have shown a
high incidence of tumor present in the poster-
ior fossa at the time of autopsy (I3 of 14 cases
in Bloom’s series). In our series, an autopsy
was performed on six patients. Tumor was
found in the posterior fossa in five of the pa-
tients but it was also found in the cerebrum
and cord in four of the five patients. Whether
the posterior fossa tumor was persistent or
represented, reseeding could not be deter-
mined from the postmortem studies.
A finding of great interest was the location
of antimortem intracranial recurrences which
were confirmed by diagnostic studies and/or
biopsy (Table 6). All six of the recurrences
were anterior to the posterior fossa and would
not have been included in the usual posterior
fossa field. Although these recurrences may
represent tumor spread from persistent poster-
ior fossa tumor, clinical examination and di-
agnostic studies failed to reveal any evidence
of posterior fossa disease at the time.
T h e other possibility is that these initial re-
currences represent tumor which was persist-
ent after the initial course of therapy. For this
reason, we have begun to raise the dose to the
entire brain rather than only the posterior
fossa. It is hoped that this dose will decrease
the incidence of anterior intracranial recur-
rences which may result from persistent tumor
after the initial therapy.
Four recent patients have been treated to a
total cranial dose of 5000 rads. Follow-up has
not been long enough to allow conclusions,
but if the current survival pattern is main-
tained, it would indicate that the whole brain
Vol. 32
should be irradiated to a dose equivalent to
that directed to the posterior fossa.
Dose and survival relationships for spinal
irradiation were presented in Table 3. For
those who received less than 3000 rads, the
survival was definitely worse than those receiv-
ing more than 3000 rads.
While there was no difference in survival
between those receiving 3000 to 3500 rads and
3500 to 4000 rads, it must be remembered that
the true dose to the former group of patients
was greater than the stated dose because of
the contribution of intrathecal gold in 10 of
the patients. It does seem clear, however, that
the minimum dose which should be delivered
to the spinal canal is 3000 rads and perhaps
higher if only external beam therapy is used.
We currently favor a minimum dose of 3500
rads to the spinal cord, delivered only by qx-
ternal beam therapy.
T h e patients treated with supplemental ra-
dioactive gold were treated in the mi+le
1960’s.3.5+6More recently, treated patients
have received only external beam to the spinal
canal. We have adopted this technique for
the following two reasons: 1. at present, we
have not observed a significant difference in
survival between these two groups, although
the latter patients have not been followed for
as long as the gold patients (Table 4), and 2.
the 27% incidence of cauda equina syndrome
produced by the technique employed by
D’Angio in these patients would seem to be a
high price to accept for a questionable small
gain in therapeutic benefit.
Reirradiation for intracranial recurrences
was found to be effective because it produced
palliation and an occasional cure. T h e aver-
age survival after reirradiation was 19 months
compared to 7 months for those not reirra-
diated. T w o of the patients are long-term sur-

TABLE
6. Proven Intracranial Recurrences
Patient Location Diagnostic technique Prior therapy to the area

12 Right lateral ventricle and Pneumoeiicephalogram, biopsy 4000 rads yhole brain
third ventricle
13 Right frontal area Scan 3500 rads C N S and 1500 rads
posterior fossa
22 Right middle fossa and left Scan, ventriculogram, biopsy 3500 rads C N S and 1500 rads
posterior fossa posterior fossa
29 Left temporal area Scan 3500 rads C N S and 1000 rads
posterior fossa
Hypothalamus (and spinal) Scan Above plus 3300 rads CNS
40 Lateral ventricles Pneumoencephalograni, biopsy 3500 rads C N S and 1500 rads
posterior fossa
No. 3 MEDULLOBLASTOMASmith et al.-
TABLE
7. Intracranial Status of Spinal Recurrences
Intracranial condition a t time
Patient Dose to Spine of spinal recurrences
3 2780 rads
4 None
6 None
15 None
19 4300 rads
23 2980 rads
29 3500 rads
10 mCi Au'9*
31 2200 rads C-cord
1660 rads T-cord
740 rads L-cord
vivors a t 38 and 92 months, and both are
without evidence of active disease. There was
some selection of patients who were consid-
ered for reirradiation because the more
acutely ill patients and ones with a very rapid
downhill course did not receive further irra-
diation. Nevertheless, almost all of the pa-
ients definitely had an improvement in their
survival quality after reirradiation and proba-
bly had their survival prolonged.
Spinal recurrences occur earlier than intra-
cranial recurrences and the average survival
after reirradiation is 6 months. Although this
is much less than the survival after the intra-
cranial reirradiation attempts, the spinal re-
currences tended to appear with widespread
CNS disease and, therefore, would be expected
to have a shorter survival (Table 7). Clinical
symptoms often responded to the spinal reir-
radiation and improved the quality of sur-
vival, but in general, a spinal recurrence
tended to imply a poor prognosis as noted by
Smith.7
Most of the reirradiation of patients with
spinal recurrences was directed only toward
the spine. Since patients with spinal recur-
rences usually had associated intracranial dis-
ease, these fields would not have included the
entire extent of the disease. T w o patients did
have their reirradiation directed toward the
entire CNS with doses of 3300 and 3400 rads,
but they died in 14 and 10 months, respec-
tively.
CONCINSIONS
We have drawn the following conclusions
about the treatment of medulloblastoma from
the material presented. First, the entire CNS
727
Eventual intracranial condition
Uncontrolled Uncontrolled
Controlled Uncontrolled
Controlled Controlled
Uncontrolled Uncontrolled
Uncontrolled Uncontrolled
Controlled Uncontrolled
Uncontrolled Uncontrolled
Controlled Uncontrolled
must be initially irradiated. Second, the fre-
quency of anterior intracranial recurrences
may be decreased by delivering a dose of 5000
rads to the entire brain. Third, the spinal
cord should receive 3500 rads by external
beam therapy. This dose would seem to be
sufficient to control any microscopic spinal
cord seeding and avoids the complications of
intrathecal radiogold. Fourth, reirradiation of
intracranial and spinal recurrences gives good
symptomatic palliation and may occasionally
yield a long-term survivor. Finally, i t should
be reemphasized that diagnostic studies, per-
haps including biopsy, should be used for re-
currence localization. Conceivably, some of
the patients presenting with signs and symp-
toms of recurrent increased intracranial pres-
sure may have anatomic and functional
changes produced by previous therapy causing
the symptoms. Also, more accurate delinea-
tion of the recurrence would allow more ac-
curate beam positioning.
I t should be mentioned again that these
conclusions have been derived from data on
only a small number of patients, some of
whom have been followed for only a short pe-
riod of time. Further follow-up of patients
treated with o u r present therapeutic regimen
will be necessary to test the validity of the
conclusions drawn from this analysis.
SUMMARY
Forty-three cases of medulloblastoma were
analyzed for dose-survival relationships and
recurrence patterns. Patient survival is im-
proved when the entire CNS is irradiated ini-
tially. We believe the entire brain should re-
ceive 4500 to 5500 rads to control the primary
728 CANCER
September 1973
posterior fossa lesion as well as any extensions
or early metastases anterior to the posterior
fossa. The spinal cord should receive a mini-
mum of 3000 rads external beam and prefera-
bly this should be increased to greater than
3500 rads if only external beam therapy is
used. Intrathecal radioactive gold does not a p
pear to improve survival and does cause a
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1. Bloom, H. J. G.: T h e treatment and prognosis of
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105:43-62, 1969.
2. Cutler, E. D., Sosman, M. C.. and Vaughn. W.
W.:T h e Place of Radiation in the Treatment of Cere-
bellar Medulloblastomas. Report of Twenty Cases. A m .
J . Rentgenol. 35:429-450, 1936.
3. D’Angio, G . J., French. L.. Stadlan. E.. and Kief-
fer. S. A.: Intrathecal Radioisotopes for the Treatment
of I3rain Tumors. C h .Neurosurg. 15:288-300, 1968.
4. Jenkin, R. D. T.: Medulloblastoma in Childhood:
Vol. 32
high incidence of cauda equina syndrome as it
was employed in the patients in this study.
Reirradiation of intracranial recurrences offers
good palliation and occasional long-term con-
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indicative of widespread disease and reirradia-
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Radiation Therapy. Can. Med. Assoc. J . 100:51-53,
1969.
5. Kieffer, S. A., D’Angio, G. J., and Nowak, T. J.:
Laboratory Studies of Intrathecal Radiogold with a
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.inatomic Studies of the Distribution and Effects of In-
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