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Cerebellar medulloblastoma: the importance of posterior fossa dose to survival and patterns of failure
036~3016/82/1 I1869-08$03.@0/0 Copyright 0 1982 Pergamon Press Ltd
Inr J Nodiarwn Oncology Ltiol Phys Vol. 8. pp 1869~ I876 Punted ,n the U S A All rights reserved
??Original Contribution CEREBELLAR MEDULLOBLASTOMA: THE IMPORTANCE OF POSTERIOR FOSSA DOSE TO SURVIVAL AND PATTERNS OF FAILURE CRAIG Mallinckrodt
L. SILVERMAN,
Institute
M.D.* AND JOSEPH
R.
SIMPSON,
of Radiology, Division of Radiation Oncology. Washington St. Louis. MO 63 I IO
M.D.,
PH.D.?
University School of Medicine,
Fifty patients with biopsy-proven cerebellar medulloblastoma were retrospectively analyzed for prognostic factors, survival and patterns of failure. Five- and ten-year actuarial survivals for the entire group were 51% and 42%. Survival and local control were significantly better for the 21 patients who received doses greater than 5000 rad to the posterior fossa (85 % and 80 % respectively) than for the remaining patients (38 % and 38 %, respectively). Significant prognostic factors included achievement of local control in the posterior fossa (p = .OOOl) and dose to the posterior fossa (p = .0005). Sex, age, duration of symptoms, extent of surgery and initial T-stage of disease were not significant. Posterior fossa was the predominant site of failure (71% of failures), but 10% of patients failed in the cerebrum and 12% outside the CNS. This experience confirms that survival rates of 70-80% are achievable with
current treatment policies but accurate and consistent dose delivery to the posterior fossa is essential. Medulloblastoma,
Radiotherapy, Dose to posterior fossa, Patterns of failure.
toma, 2) treatment with curative intent for primary disease (recurrent or metastatic cases were excluded from the analysis), 3) entire treatment received at our institution, 4) radiotherapy completed and 5) minimum followup of three years. The patients’ characteristics are summarized in Table I. Thirty-two patients were male and I8 were female. Twelve patients were older than I6 years. Thirty-eight patients (78%) were I6 years or younger; I4 patients were less than five years old; 24 patients were between five and I6 years. All patients presented with one or a combination of the classic cerebellar signs and symptoms of nausea, vomiting, headache, gait disturbance, ataxia or clumsiness. The duration of symptoms ranged from one day to two years. with the majority of patients presenting within two months of the onset of symptoms. In the earlier periods of the study ventriculography and pneumoencephalography were the diagnostic methods of choice, but after 1974, computed tomography (CT) scanning and angiography were the predominant radiographic tests. Forty-seven patients were retrospectively staged according to the system proposed by Harisiadis and
INTRODUCTION Medulloblastoma is an aggressive brain tumor that orginates in the cerebellum. It is the most frequent brain neoplasm in children and the most common neoplasm of the posterior fossa.’ The role of radiotherapy has been established since the initial observations by such investigators at Cutler et al., Lampe and Maclntyre, Paterson and Fart-, and Penheld and Feindel.‘“~‘x~2’~‘3They noted that while surgery alone, no matter how radical, provided few, if any, long term survivors,2,9 the addition of radiotherapy could lead to a significant prolongation of life in a proportion of patients. This report deals with 50 patients treated at our institution with megavoltage irradiation from 1954 to 1978, with an emphasis on the relationship of dose and volume to survival and patterns of failure. METHODS
AND
MATERIALS
We reviewed the records of all patients with cerebellar medulloblastoma or sarcoma treated at the Mallinckrodt Institute of Radiology. Division of Radiation Oncology between 1954 and 1978. Fifty patients fulfilled the following criteria: I) biopsy-proven cerebellar medulloblas-
*Recipient of American Cancer Society Clinical Fellowship 1981-82. tAmerican Cancer Society Junior Faculty Clinical Fellow Presented at the American Society of Therapeutic Radiologists 23rd Annual Scientific Meeting Miami Beach, Florida, October 12-16. 1981. Reprint requests to: Dr. Craig L. Silverman, University of Pittsburgh Health Center, Joint Radiation Oncology C:nter, 3601 5th Ave., Pittsburgh, PA I52 13.
A~knowlrd~emenrs~The authors wish to thank Dr. William Mill, Dr. Henry Schwartr and Dr. William Coxe for treating the patients, Sherry Breaux and Mary Ann Hederman for help with the statistical analysis, Elizabeth Byrd and Leslie MacConnell-Clubbs for the typing and illustrations. Accepted for publication IX June 1982.
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Table I. Patient characteristics for the entire group of 50 patients, stratified by dose and by local control (49 patients) Patient characteristics Posterior fossa Dose (rad) >5000 2 I patients T-Stage T, T, T, T, TX
is000 29 patients
5 10 4 I I
Local control 27 patients
Failures 22 patients
6 12 5 4 2
5 10 7 3 2
6 11 2 2
18 II
17 10
15 7
I
Sex
Males 14 Females 7 Dose (rad) Range 5,000-5,760 Median 5,380 Age (years) o-5 4 5-16 IO >I6 7 Duration of symptoms (months) Mean 4.1 Median 3
I ,400-4,9 IO 4,000 IO I4 5
I ,400-5,760 5,100 6 I4 7
5.2 3
2,800-5,400 4,200 7 IO 5
3.3 2
6.1 3
Note: Distribution by T Stage, sex, age and duration of symptoms are comparable.
Chang.” Eleven patients were T,, 22 were Tz, nine were T, and five were T,. Only three patients could not be staged retrospectively. Three patients presented with evidence of subarachnoid seeding at time of diagnosis and the remaining 47 patients had no gross evidence of seeding. and techniques of irradiation The majority of the patients were treated in the prone position on either a Cobalt 60 machine or a 4 MeV linear accelerator. In the earlier years of the study opposing lateral posterior fossa ports only were used, to moderate doses of 3000-3500 rad with or without intrathecal Aui9’. The spinal cord was rarely treated in the years prior to 1957. By the late 1950’s and early 1960’s whole brain radiation or larger posterior fossa ports that were obliqued 60 degrees posteriorly plus a posterior occipital boost were common, and the usual dose to the posterior fossa was increased to 3500-4000 rad. Most patients were treated in 24-27 fractions in 32-37 days. The spinal cord was routinely treated after 1957 to doses between 3000 and 3500 rad in either one or two direct posterior ports, which matched the whole brain ports with moving junctions in the cervical portion of the cord.26 Eighty percent of patients received the radiotherapy in 17-23 fractions in 28-35 days. After 1967 whole-brain lateral fields were used exclusively to a midparietal dose of 3800-4200 rad in 180 rad/day fractions. Because of the natural curvature of the skull, the posterior fossa received a 5-10s higher dose Dose
than, the midparietal region of the skull. A reduced posterior fossa field would then further boost the dose to 4500-5500 rad. Eight patients received intrathecal Au’~~. Doses were either 10 or 20 mCi evenly divided between a lumbar and a cisternal puncture. Actuarial survival was calculated by the Cutler-Ederer method” and the results compared by the Wilcoxon test.‘* RESULTS Five-year and ten-year actuarial survivals for the group as a whole were 51% and 42% respectively (Figure 1). Relapse-free survivals for the same time intervals were 46% and 42% respectively. Previously suggested prognostic factors such as sex and age were analyzed. Five-year actuarial survival for 32 males in the study was 5 1% versus 66.4% for the I8 female patients (p = 0.37). Five-year relapse-free survival was identical in both groups (p = 0.32). When the results were analyzed according to age, each age group of patients fared approximately the same; neither the older patients nor the very young patients fared worse than the 5 to 16 age group, though the numbers were small in each subgroup. An analysis of failure has demonstrated that 32 patients ultimately failed. Twenty-two patients (44%) initially recurred with a component of posterior fossa disease, I4 in the posterior fossa alone, six in the posterior fossa with concomitant spinal cord disease, one with
Cerebellar
medulloblastoma
??C. L.
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J. R.
SIMPSON
Table 2. Local control vs. dose to posterior
MEDULLOBLASTOMA
Dose to posterior fossa ~5.000 rad 4,500-5,000 4,000-4,500 14,000 rad
rad rad
fossa
Local control l6/20 3/9 l/5 7115
(80%) (33%) (20%) (47%) 1
I I /29 (38%)
Note: Difference between those receiving greater than 5,000 rad to the posterior fossa (16/20 = 80%) and those receiving less than 5,000 rad to the posterior fossa (I I /29 =38%) is significant (p = .Ol).
2 20 Y
01
1
I
I
I
I
I
I
I
I
J
1
2
3
4
5
6
7
6
9
10
YEARS
Fig. I. patients received and the to the IO-year
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Actuarial survival curves for the entire group of 50 (middle curve), the subgroup of 21 patients who greater than 5000 rad to the posterior fossa (top curve) subgroup of 29 patients who received less than 5000 rad posterior fossa. Differences between the 5-year and survival of the subgroups are significant (p = .OOOl).
wide-spread central nervous system disease and one in the cerebrum and posterior fossa (Figure 2). Posterior fossa recurrence was documented in 21/22 patients (in 7 patients by biopsy, in 7 by autopsy and in 7 by radiography). Nine patients failed outside the posterior fossa:
MEDULLOBLASTOMA Site of Initial Failure for Entire Group (50 patients)
three patients failed above the tentorium, five patients outside the CNS and one patient only in the spinal cord. (One patient failed in unknown sites and was deleted from the analysis of posterior fossa control in Tables 1, 2 and 3.) lntrathecal Au’~’ was used in eight patients, four patients in addition to spinal irradiation and four patients as the sole spinal cord treatment. Five of these eight patients failed in the posterior fossa (three alone, one with spinal cord disease and one with widespread CNS disease). One patient failed outside the CNS in the bones and nodes and one in the brain parenchyma. One patient remains disease free but developed a second primary at 280 months (a lymphoma). No complications such as cauda equina syndrome were observed despite long-term survival of 53, 54, 76, 144 and 280 months. Spinal
cord recurrences
There was a total of IO spinal cord failures (20%). All but one were associated with posterior fossa recurrence (Figure 2). In seven patients, spinal cord failure occurred simultaneously with a posterior fossa recurrence; two patients failed 32 and 36 months after the posterior fossa initially recurred and were successfully retreated with local radiotherapy. Times to failure after initial treatment for the seven patients were 1, 1, 2, 8, 24, 30 and 83 months. Five of seven failures had been within two years and six of seven failures within three years. Excluding the one patient who received no spinal irradiation, the average cord dose to the remaining six patients was 337 1 rad. In the two patients who subsequently failed, original doses to the spinal cord were 3750 rad and 3000 rad respecTable 3. Local control as a function of posterior dose and T stage T, ~5,000 rad (20 pts.) 4,500-5,000 ( 9 pts.) 4,000-4,500 ( 5 pts.) 54,000 ( I5 pts.) 49 pts.
Fig. 2. Patterns of initial failure for the 31 patients with documented failure. Note that 22/3l patients failed with a component of posterior fossa disease.
315 f/4 I */2* 5/ll
T? s/9* O/2 o/4* 2*/6* IO/21
T, 414 213 l/2 l/9
fossa
T,
Tx
O/l
l/l
l/l 2*/3 315
I*/2 213
*Individual Au’~” patients. Note: No difference is seen in local control by T stage alone.
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tively. Two of the patients had received intrathecal Au’~’ Only one patient failed in the spinal cord without posterior fossa disease. He received 2640 rad to the cord and failed 7 months after initial treatment. Cerebral
Recurrences
A total of five patients failed in the cerebrum. Two patients had concomitant posterior fossa disease but three patients (6%) failed only in the brain, one in bilateral frontal lobes and two associated with lateral ventricle disease (Figure 2). Times to failure were 8 and 32 months for the two patients with posterior fossa disease who had received 0 and 4080 rad whole-brain respectively. Whole brain doses were 3347, 3922, and 3500 rad in the other three patients who failed at 34, 54 and 168 months respectively. Extra-CNS
Metastases
Six patients failed outside the central nervous system in bones, nodes, and bone marrow. All occurred outside the central nervous system only (Figure 2), although one patient had had a prior posterior fossa recurrence 36 months previously that was successfully treated. Times to failure were 4, 6, IO, 15, 2 I and 94 months. No patient had had a ventriculoperitoneal shunt.
MEDULLOBLASTOMA (5000
Rad to Posterior Fossa (29 patients) Initial Sites of Failure
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Time to recurrence
In total, 32 patients (64%) eventually failed, 26 of 32 (82%) within three years; however, there were three ( IO%) very late recurrences at 83, 135 and 168 months. Nineteen of the 22 patients (86%) eventually failing in the posterior fossa did so within 36 months, and all but one patient within 60 months. When we analyzed all sites of failures as a whole, we obtained an identical rate of cumulative failure. The effect of dose to the posterior fossa on patterns of failure is seen in Figures 3A & 3B. Both the total number of treatment failures and the likelihood of spinal cord failure are reduced in the higher dose group with posterior fossa doses in excess of 5000 rad. Analysis of the doses of those patients failing in the posterior fossa demonstrated that the median posterior fossa dose was 4200 rad (ranging from 30 I8 to 5460 rad) compared to 5 100 rad (I 400 rad to 5760 rad) for those patients whose posterior fossa was controlled (Table I). A dose-response relationship was suggested. Sixteen of 20 (80%) tumors receiving doses greater than 5000 rad to the posterior fossa were controlled. Only I I of 29 (38%) patients receiving less than 5000 rad had local control (Table 2). An analysis of local control with respect to T-staging revealed that initial T-stage had no value in predicting
MEDULLOBLASTOMA )SOOO Rad to Posterior Fossa (2 1 patients) Initial Sites of Failure
Fig. 3A. Patterns of initial failure for the 29 patients who received less than 5000 rad to the posterior fossa. Note that IS/24 (75%) failed with a component of posterior fossa disease. Fig. 3B. Patterns of initial failure for the 21 patients who received greater than 5000 rad to the posterior fossa.
Cerebellar
medulloblastoma
0
local control or survival (Table 3). Local control for T, lesions was 46% (5/ 1 1); for Tz lesions, 48% (lo/21 ); for T, lesions, 78% (7/9); for T, lesions, 60% (3/5); and for T, lesions, 67% (2/3). In patients receiving greater than 5000 rad, local control for T, lesions was 3/5 (60%); for Tz, 8/9 (89%>); for T,, 4/4 ( 100%); for T,, O/ I ; and for T,, I/ 1 (100%). For less than 5000 rad, local control for T, was 2/6 (33%)); for T,, 2/ 12 (I 2%); for T,, 3/5 (60%); for T.,, 3/4 (75%); and for Tx, I /2 (50%). Five-year survival did not significantly differ for each T-stage (p = 0.24). Five-year actuarial survival was 85% for the 21 patients who received greater than 5000 rad to the posterior fossa and 36% actuarial survival (25% relapse free survival) for the 29 patients receiving less than 5000 rad to the posterior fossa (p = .OOOS) (Figure I). The five-year actuarial survival for those patients receiving greater than 4500 rad was only 69%, which was inferior to the survival of the patients who received greater than 5000 rad to the posterior fossa. Those patients achieving local control had an 80% fiveand ten-year actuarial survival vs 25% five-year and 7% ten-year survival for those patients failing in the posterior fossa (p = .OOOl ) (Figure 4). &j&V ofsurgery on local control We retrospectively determined the type of surgery for 47/50 patients. Two patients had biopsy only, 21 patients had total resection of tumor and 24 patients had a subtotal resection of tumor. The effect of type of resection and dose on local control is seen in Table 4. Local control for patients undergoing total resection was 13/21 (62%); subtotal resection, 12/23 (52%); and biopsy, I /2. In those receiving 5000 rad, local control for the total resection group was 7/9 and for the subtotal resection group, 9/ 1 I. Five-year actuarial survival was 51Y0 for the total resection group vs 57% for the subtotal resection group.
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MEDULLOSLASTOMA
0
I
I
I
I
I
I
I
1
I
J
1
2
3
4
5
6
7
6
9
IO
YEARS
Fig. 4. Actuarial survival for the 27 patients whose posterior fossa was controlled and for the 22 patients with documented posterior fossa failure. Difference is very significant (p = .OOOl).
covered the entire posterior fossa, which anatomically extends to the clinoid process and in the cephalad direction to the tent of the tentorium through which runs the straight sinus. For 73% of locally controlled (19/27) and 73% of uncontrolled patients (16/22), films were of sufficient quality to be reviewed. In patients whose disease was controlled in the posterior fossa, the whole-brain port was deemed adequate in 81 of 84 (96%). and the boost port in 20 of 34 (59%). Inadequacy occurred because of insufficient coverage of the tentorium or inadequate anterior margin. For those patients failing in the posterior fossa, the whole brain was adequately covered in only 60 of 76 (79%) films (the floor of the middle cranial fossa was often missed in an attempt to shield normal tissues), and only five of 3 I (16%) boost ports adequately covered the entire posterior fossa (Table 5). Retreatment
Accuraq)
oj’dose delivery Port films of each patient were reviewed to determine how accurately the prescribed dose had been delivered to the area at risk. Both whole-brain and boost ports were evaluated. The boost port was defined as adequate if it
Sixteen patients were retreated with chemotherapy, radiotherapy or a combination of both modalities after recurrence (Table 6). ten of these patients had failed in the posterior fossa alone, and three patients in the posterior fossa and spinal cord. Two additional patients had
Table 4. Local control as a function of dose and extent of operation c5.000
rad
to posterior Total resection (2 I patients) Subtotal resection (23 patients) Biopsy only (2 patients) Total
fossa
~5.000 rad to posterior fossa
6112
719
13/2l
3112
9/l I
12123 (52%) l/2 (50%)
l/2 IO/26
Note: No significant difference is seen in local control between total resection similar (5 I % vs. 57%). Again seen is the effect of dose.
(62%)
16120 (62%) and subtotal
resection
(52%). Survival was also
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whose neurological function deteriorated after surgery but who has had no subsequent decrease since irradiation. Three children are of markedly short stature, one with documented human growth hormone deficiency on replacement hormone, one with a normal hormone level and one whose endocrinological evaluation is pending. Intellectual function is presently being retrospectively analyzed with a wide range of psychometric tests and is the subject of a future publication. Preliminary results demonstrate a trend towards decreased IQ scores when compared to age-matched siblings.
Table 5. Local control as a function of portal adequacy
Local control (19 pts.) Local failure (I 6 pts.) Note: Controlled
Whole brain
Boost ports
8 i/84 (96%)
20/34 (59%)
60/76 (79%)
S/31 (16%)
patients
had more accurate
dose delivery.
failed only in the cerebrum and one had failed in the bones and lymph nodes. Two out of the 16 patients had no evidence of tumor at 49 and 86 months after retreatment; survival was extended 12 to 47 months in an additional five patients with a mean survival of 22 months and a median survival of I2 months for all 16 patients.
DISCUSSION The five- and ten-year survival rates for our entire group of patients of 5 I % and 42.4% compare well with the more recent reports in the literature (five-year: 33-73s;
Late efects of irradiation The late sequelae of the irradiation were analyzed. All but one patient appeared neurologically intact except for mild ataxia or tremor which did not impair normal function. The one severely disabled patient was a child
ten-year:
20_43,).'.3,4.6,8.'4.'6.'9
Favorable prognostic factors such as female sex,4 age greater than 164 (or greater than 5 years of age in one series’), and total surgical resection2’ have all been pro-
Table 6. Results of salvage in I6 patients Initial treatment Patient #
Whole brain
Cord
I
3,026
3,000
(rad) Posterior 3,026
fossa
Time to failure (mos.) 24
Site of failure
Posterior fossa/spinal cord
2*
3,490*
3
3,900
I3
Posterior
fossa
3,500*
4,000
58
Posterior
fossa fossa/spinal
4
4.1 I8
3,449
5,053
83
Posterior cord
5* 6
3,500 3,683
3,750
3,500 3,683
54 36
Cerebrum Posterior fossa
7*
3,000
3,000
27
Posterior
8 9
4,140 3,347
3,500 3,519
4,140 3,347
I1 I68
IO
4,080
3,000
5,096
24
Posterior
fossa
II
4,600
3,612
4,600
57
Posterior
fossa
I2
3,040
3,6 I I
4,640
30
13 I4 I5 16
3,960 4,000 4,080 4,080
3,520 3,900 4,590 3,500
4,202 4,585 5,049 4,986
34 4 27 20
Posterior fossa/spinal cord Posterior fossa Bones, nodes Posterior fossa Posterior fossa
fossa
Posterior fossa Brain-It. lat. vent.
Note: Two patients (#3, #I 5) were rendered *Au’~’ patients. VCR = Vincristine.
NED and 5 patients
had prolonged
retreated
Retreatment
Status after treatment
2,000 rad craniospinal XRT
Posterior fossa recurrence DWD 2
2,000 rad whole brain
months Posterior fossa recur-
4,450 rad whole brain +Au’~’ Steroids
rence DWD 5 months DNED 86 months
Posterior fossa recurrence DWD 10 months AWD 3,500 rad whole brain 3,582 rad whole brain Spinal cord recurrence DWD4months 3,600 rad posterior Posterior fossa recurfossa, 3,000 rad cord rence DWD 26 months 1,000 rad whole brain DWD 2 months Cranio-spinal XRT 2,000 rad MOPP chemotherapy Spinal cord seeding DWD I2 mos. 2,000 rad whole brain Posterior fossa recurrence DWD 31 months Cranio-spinal XRT DWD4months 1,050 rad Whole brain 2,000 rad DWD 5 months VCR + 3,000 rad DWD I7 months VCR NED 49 months Multiagent chemoDWD 12 months therapy survival of 12 months or more.
Cerebellar medulloblastoma 0 C. L.
posed. In our own study, although the numbers were small, five-year survival for the 12 patients greater than 16 years of age did not significantly differ from the five-year survival in younger children. Very young children, less than five years of age, also fared no worse. Our study suggests a trend, though not statistically significant, that females do better than males (p = 0.37). No improvement in survival or local control was demonstrated with respect to the extent of operation. It was the dose to the posterior fossa that appeared important as 80% of those patients receiving greater than 5000 rad to the posterior fossa were controlled regardless of the extent of resection. Our data, like the recent Toronto study,3 fail to show any prognostic value in the T-staging system that has been proposed, which conflicts with previous reports.7.‘3 Dose to the posterior fossa, independent of initial T-stage, determined local control and survival. Since posterior fossa recurrence is the predominant problem, occurring in up to 50% of all patients, and can account for 70% of failures,3.“,“.24 local control must be the paramount issue for radiotherapists. Our data show that the five- and ten-year actuarial survival rates for those achieving local control were 80%, versus 25% and 7% for those not locally controlled (p = .OOOl) (Figure 4). To increase the likelihood of achieving local control, certain authors advocate total excision or near total excision of the posterior fossa disease using an operating microscope, and have demonstrated better survival rates in selected patients.” However, the intrinsic radiosensitivity of this tumor may make extensive surgery unnecessary. We could show no difference in control or survival between total and subtotal resection and conclude that debulking of the tumor and relief of ventricular obstruction may be all that is needed. Our data confirm this intrinsic radiosensitivity, since 80% local control was achieved for those receiving at least 5000 rad to the posterior fossa regardless of the extent of resection; this dose would be expected to be adequate for only microscopic disease for epithelial tumors. Similar experiences have been reported by otherS.X.24.26
Equally as important as the dose prescribed is the accurate and consistent delivery of that prescribed dose to the volume at risk. The patients who were controlled had a more consistent delivery of the dose to the posterior fossa. Even though the boost ports in the later years were judged inadequate in approximately 40% of cases in the controlled patients, it is important to point out that the boost ports often only contributed an additional 500 rad, whereas the whole-brain port usually delivered the main bulk of the dose (4500 to 5000 rad) in those patients. Other authors have demonstrated the value of consistent set-up and frequent port films in increasing accuracy in other sites.‘” We found no advantage to intrathecal Au’~’ and no complications, despite long-term survival in 5/8 patients, although 4/8 patients had no spinal cord external irradia-
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tion and those receiving external beam irradiation had lower doses of AU’~~ (10 mCi). Failure in the brain was low (lo%), but accounted for 16% of all failures. Two of five patients had a concomitant posterior fossa failure and probable spread to the cerebrum secondarily from the posterior fossa. Three patients (6%) had cerebral failure only (two associated with lateral ventricle disease and one in the’subfrontal areas, bilaterally). Whole brain doses in these three patients were below 4000 rad but the failures occurred late, at 34, 54 and 168 months. This low failure rate corresponds to that of Berry et ~1.~We have not seen any failures in the brain in the 15 patients receiving greater than 4000 rad midparietal dose. We feel that 4000 rad is a well tolerated dose to the brain, even in younger children, and the low incidence of primary cerebral failure and the lack of failure above 4000 rad does not justify increasing the dose above that level. The patients who failed outside the central nervous system in our series, six of 50 (12%), exhibited a different clinical history. All patients had control of the posterior fossa, brain and spinal cord at the time of recurrence. These were usually early recurrences; all but one occurred within two years. Berry et al. have also noted this pattern of failure.3 Ventriculoperitoneal (VP) shunting has been implicated in the development of tumor outside the central nervous system,3,‘5 but none of our patients had had a VP shunt placed. Though other authors have noted metastases via the shunt tubing,15.” based on our experience, especially in light of the relatively short time to failure and lack of a ventriculoperitoneal shunt, we propose that extra-CNS metastases were already present at time of diagnosis. However, we were unable to detect prognostic factors to select out those patients at risk to fail outside the central nervous system. The use of chemotherapy and/or radiotherapy to salvage recurrences yields small but positive results. Of the 16 patients we treated (14 with follow-up information) two were free of disease at 49 and 86 months after retreatment, one was treated with Vincristine chemotherapy and the other with 4450 rad whole-brain irradiation and AU”’ (this patient had had no whole brain radiotherapy initially). Survival greater than one year was achieved in five other patients with a mean survival for all patients of 22 months and a median survival of 12 months, even when a dose of 4000-5000 rad whole brain or posterior fossa radiotherapy had been previously administered. However, with increasing primary treatment doses to the brain and posterior fossa, re-irradiation will be even more risky and chemotherapy may be the modality of choice in the future for recurrences. The role of adjuvant chemotherapy has not been established, but may be of value in those patients destined to fail outside the CNS or in those 20% of patients who will fail in the posterior fossa. In conclusion, two main factors to be stressed in the irradiation of medulloblastoma are the dose to the poste-
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rior fossa and the consistent delivery of that dose to the entire volume at risk. Use of whole-brain or whole craniospinal portals as advocated by Tokars et al.” to 4000 rad midparietal dose will reduce set-up error, and gener-
November 1982. Volume 8, Number 1I
ous posterior fossa boost fields to bring the dose to the fossa to a minimum of 5000 rad should increase local control. These procedures should translate into long-term survival rates of 70-80%.
REFERENCES I. Aron, B.S.: Medulloblastoma in children. Twenty-two years’ experience with radiation therapy. Am. J. Dis. Child. 121: 314~311,1911. 2. Bailey, P., Cushing, H.: Medulloblastoma cerebelli: A common type of midcerebellar glioma of childhood. Arch. Neurol. Psych. 14: 192-224, 1925. 3. Berry, M., Jenkin, R., Keen, C., Nair, B., Simpson, W.: Radiation treatment for medulloblastoma: A 2l-year review. J. Neurosurg. 55: 43-5 I, I98 I. 4. Bloom, H., Wallace, E., Henk, J.: The treatment and prognosis of medulloblastoma in children. A study of 82 verified cases. Am. J. Roentgenol. 105: 43-62, 1969. 5. Bouchard, J.: Radiation Therapy of Tumors and Diseases of the Central Nervous System. Philadelphia, Lea & Febiger, 1966. A 6. Brown, R., Gunderson, L., Plenk, H.: Medulloblastoma. review of the LDS hospital experience. Cancer 40: 55-60, 1917. 1. Chang, C., Housepian, E., Herbert, C., Jr.: An operative staging system and megavoltage radiotherapeutic technique for cerebellar medulloblastomas. Radiology 93: 1351-1359, 1969. 8. Cumberlin, R., Luk, K., Wara. W., Sheline, G., Wilson, C.: Medulloblastoma. Treatment results and effect on normal tissues. Cbncer 43: 1014-1020, 1919. 9. Cushing, H.: Experiences with cerebellar medulloblastoma: Critical review. Actu. Puthol. Microbial. &and. 7: l-86, 1930. 10. Cutler, E., Sosman, M., Vaughan, W.: The place of radiation in the treatment of cerebellar medulloblastoma: Report of 20 cases. Am. J. Roentgenol. 35: 429-453, 1936.
14.
15.
16.
Il.
18. 19.
20.
21. 22.
23.
24.
I I. Cutler,
S.J., Ederer, F.: Maximum utilization of the life table in analyzing survival. J. Chronic Dis. 8: 699-712. 1958. Wilcoxon test for comparing 12. Gehan, E.A.: A generalized arbitrarily singly censored samples. Biometrika 52: 203% 223, 1965. in children: A 13. Harisiadis, L., Chang, C.: Medulloblastoma
25.
26.
correlation between staging and results of treatment. Int. J. Rudiat. Oncol. Biol. Phys. 2: 833-841, 1911. Hirsch, J.F., Renier, D., Czeinichow, P., Benveniste, L., Pierre-Kahn, A.: Medulloblastoma in childhood. Survival and functional results. Actu. Neurochir. 48: I -I 5, 1919. Hoffman, H.J., Hendrick, E.B., Humphreys, R.P.: Metastases via ventriculoperitoneal shunt in patients with medulloblastoma. J. Neurosurg. 44: 562-566, 1976. Ingraham, F., Bailey, O., Barker, W.: Medulloblastoma cerebelli: Diagnosis, treatment, and survivals with a report of fifty-six cases. N. Engl. J. Med. 238: 17 I -I 74, 1948. Kessler, L.A., Dugan, P., Concannon, J.P.: Systemic metastasis of medulloblastoma promoted by shunting. Surg. Neural. 3: 147-l 52, 1915. Lampe, I., MacIntyre, R.S.: Medulloblastoma of the cerebellum. Arch. Neural. Psych. 62: 322-329, 1949. Landberg, T., Lindgren, M., Cavallin-Stahl, E.: Improvements in the radiotherapy of medulloblastoma (19461975). Cancer 45: 610p618, 1980. Marks, J.E.: The value of frequent treatment verification films in reducing localization error in the irradiation of complex fields. Cancer 37: 3755-6 I, 1976. Mealy, J., Hall, P.V.: Medulloblastoma in childrenSurvival and treatment. J. Neurosurg. 46: 56-64, 1971. Paterson, E., Farr, R.: Cerebellar medulloblastoma: Treatment by irradiation of the whole central nervous system. Actu Radiol. 39: 323-336, 1953. Penfield, W., Feindel, J.: Medulloblastoma of cerebellum with survival for seventeen years. Arch. Neurol. Psych. 57: 48 l-484, 1947. Smith, C.E., Long, D.M., Jones, T.K., Levitt, S.: Medulloblastoma: An analysis of time dose relationships and recurrence patterns. Cancer 32: 122-728, 1913. Tokars, R., Sutton, H., Griem, M.: Cerebellar medulloblastoma. Results of a new method of radiation treatment. Cancer 43: 129-l 36, 1919. Van Dyk, J., Jenkin, R.D.T., Leung, P.M.K.: Medulloblastoma: Treatment technique and radiation dosimetry. Int. J. Radiut. Oncol. Biol. Phys. 2: 993-1005, 1971.
Inr J Nodiarwn Oncology Ltiol Phys Vol. 8. pp 1869~ I876 Punted ,n the U S A All rights reserved
??Original Contribution CEREBELLAR MEDULLOBLASTOMA: THE IMPORTANCE OF POSTERIOR FOSSA DOSE TO SURVIVAL AND PATTERNS OF FAILURE CRAIG Mallinckrodt
L. SILVERMAN,
Institute
M.D.* AND JOSEPH
R.
SIMPSON,
of Radiology, Division of Radiation Oncology. Washington St. Louis. MO 63 I IO
M.D.,
PH.D.?
University School of Medicine,
Fifty patients with biopsy-proven cerebellar medulloblastoma were retrospectively analyzed for prognostic factors, survival and patterns of failure. Five- and ten-year actuarial survivals for the entire group were 51% and 42%. Survival and local control were significantly better for the 21 patients who received doses greater than 5000 rad to the posterior fossa (85 % and 80 % respectively) than for the remaining patients (38 % and 38 %, respectively). Significant prognostic factors included achievement of local control in the posterior fossa (p = .OOOl) and dose to the posterior fossa (p = .0005). Sex, age, duration of symptoms, extent of surgery and initial T-stage of disease were not significant. Posterior fossa was the predominant site of failure (71% of failures), but 10% of patients failed in the cerebrum and 12% outside the CNS. This experience confirms that survival rates of 70-80% are achievable with
current treatment policies but accurate and consistent dose delivery to the posterior fossa is essential. Medulloblastoma,
Radiotherapy, Dose to posterior fossa, Patterns of failure.
toma, 2) treatment with curative intent for primary disease (recurrent or metastatic cases were excluded from the analysis), 3) entire treatment received at our institution, 4) radiotherapy completed and 5) minimum followup of three years. The patients’ characteristics are summarized in Table I. Thirty-two patients were male and I8 were female. Twelve patients were older than I6 years. Thirty-eight patients (78%) were I6 years or younger; I4 patients were less than five years old; 24 patients were between five and I6 years. All patients presented with one or a combination of the classic cerebellar signs and symptoms of nausea, vomiting, headache, gait disturbance, ataxia or clumsiness. The duration of symptoms ranged from one day to two years. with the majority of patients presenting within two months of the onset of symptoms. In the earlier periods of the study ventriculography and pneumoencephalography were the diagnostic methods of choice, but after 1974, computed tomography (CT) scanning and angiography were the predominant radiographic tests. Forty-seven patients were retrospectively staged according to the system proposed by Harisiadis and
INTRODUCTION Medulloblastoma is an aggressive brain tumor that orginates in the cerebellum. It is the most frequent brain neoplasm in children and the most common neoplasm of the posterior fossa.’ The role of radiotherapy has been established since the initial observations by such investigators at Cutler et al., Lampe and Maclntyre, Paterson and Fart-, and Penheld and Feindel.‘“~‘x~2’~‘3They noted that while surgery alone, no matter how radical, provided few, if any, long term survivors,2,9 the addition of radiotherapy could lead to a significant prolongation of life in a proportion of patients. This report deals with 50 patients treated at our institution with megavoltage irradiation from 1954 to 1978, with an emphasis on the relationship of dose and volume to survival and patterns of failure. METHODS
AND
MATERIALS
We reviewed the records of all patients with cerebellar medulloblastoma or sarcoma treated at the Mallinckrodt Institute of Radiology. Division of Radiation Oncology between 1954 and 1978. Fifty patients fulfilled the following criteria: I) biopsy-proven cerebellar medulloblas-
*Recipient of American Cancer Society Clinical Fellowship 1981-82. tAmerican Cancer Society Junior Faculty Clinical Fellow Presented at the American Society of Therapeutic Radiologists 23rd Annual Scientific Meeting Miami Beach, Florida, October 12-16. 1981. Reprint requests to: Dr. Craig L. Silverman, University of Pittsburgh Health Center, Joint Radiation Oncology C:nter, 3601 5th Ave., Pittsburgh, PA I52 13.
A~knowlrd~emenrs~The authors wish to thank Dr. William Mill, Dr. Henry Schwartr and Dr. William Coxe for treating the patients, Sherry Breaux and Mary Ann Hederman for help with the statistical analysis, Elizabeth Byrd and Leslie MacConnell-Clubbs for the typing and illustrations. Accepted for publication IX June 1982.
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Table I. Patient characteristics for the entire group of 50 patients, stratified by dose and by local control (49 patients) Patient characteristics Posterior fossa Dose (rad) >5000 2 I patients T-Stage T, T, T, T, TX
is000 29 patients
5 10 4 I I
Local control 27 patients
Failures 22 patients
6 12 5 4 2
5 10 7 3 2
6 11 2 2
18 II
17 10
15 7
I
Sex
Males 14 Females 7 Dose (rad) Range 5,000-5,760 Median 5,380 Age (years) o-5 4 5-16 IO >I6 7 Duration of symptoms (months) Mean 4.1 Median 3
I ,400-4,9 IO 4,000 IO I4 5
I ,400-5,760 5,100 6 I4 7
5.2 3
2,800-5,400 4,200 7 IO 5
3.3 2
6.1 3
Note: Distribution by T Stage, sex, age and duration of symptoms are comparable.
Chang.” Eleven patients were T,, 22 were Tz, nine were T, and five were T,. Only three patients could not be staged retrospectively. Three patients presented with evidence of subarachnoid seeding at time of diagnosis and the remaining 47 patients had no gross evidence of seeding. and techniques of irradiation The majority of the patients were treated in the prone position on either a Cobalt 60 machine or a 4 MeV linear accelerator. In the earlier years of the study opposing lateral posterior fossa ports only were used, to moderate doses of 3000-3500 rad with or without intrathecal Aui9’. The spinal cord was rarely treated in the years prior to 1957. By the late 1950’s and early 1960’s whole brain radiation or larger posterior fossa ports that were obliqued 60 degrees posteriorly plus a posterior occipital boost were common, and the usual dose to the posterior fossa was increased to 3500-4000 rad. Most patients were treated in 24-27 fractions in 32-37 days. The spinal cord was routinely treated after 1957 to doses between 3000 and 3500 rad in either one or two direct posterior ports, which matched the whole brain ports with moving junctions in the cervical portion of the cord.26 Eighty percent of patients received the radiotherapy in 17-23 fractions in 28-35 days. After 1967 whole-brain lateral fields were used exclusively to a midparietal dose of 3800-4200 rad in 180 rad/day fractions. Because of the natural curvature of the skull, the posterior fossa received a 5-10s higher dose Dose
than, the midparietal region of the skull. A reduced posterior fossa field would then further boost the dose to 4500-5500 rad. Eight patients received intrathecal Au’~~. Doses were either 10 or 20 mCi evenly divided between a lumbar and a cisternal puncture. Actuarial survival was calculated by the Cutler-Ederer method” and the results compared by the Wilcoxon test.‘* RESULTS Five-year and ten-year actuarial survivals for the group as a whole were 51% and 42% respectively (Figure 1). Relapse-free survivals for the same time intervals were 46% and 42% respectively. Previously suggested prognostic factors such as sex and age were analyzed. Five-year actuarial survival for 32 males in the study was 5 1% versus 66.4% for the I8 female patients (p = 0.37). Five-year relapse-free survival was identical in both groups (p = 0.32). When the results were analyzed according to age, each age group of patients fared approximately the same; neither the older patients nor the very young patients fared worse than the 5 to 16 age group, though the numbers were small in each subgroup. An analysis of failure has demonstrated that 32 patients ultimately failed. Twenty-two patients (44%) initially recurred with a component of posterior fossa disease, I4 in the posterior fossa alone, six in the posterior fossa with concomitant spinal cord disease, one with
Cerebellar
medulloblastoma
??C. L.
SILVERMAN
AND
J. R.
SIMPSON
Table 2. Local control vs. dose to posterior
MEDULLOBLASTOMA
Dose to posterior fossa ~5.000 rad 4,500-5,000 4,000-4,500 14,000 rad
rad rad
fossa
Local control l6/20 3/9 l/5 7115
(80%) (33%) (20%) (47%) 1
I I /29 (38%)
Note: Difference between those receiving greater than 5,000 rad to the posterior fossa (16/20 = 80%) and those receiving less than 5,000 rad to the posterior fossa (I I /29 =38%) is significant (p = .Ol).
2 20 Y
01
1
I
I
I
I
I
I
I
I
J
1
2
3
4
5
6
7
6
9
10
YEARS
Fig. I. patients received and the to the IO-year
1871
Actuarial survival curves for the entire group of 50 (middle curve), the subgroup of 21 patients who greater than 5000 rad to the posterior fossa (top curve) subgroup of 29 patients who received less than 5000 rad posterior fossa. Differences between the 5-year and survival of the subgroups are significant (p = .OOOl).
wide-spread central nervous system disease and one in the cerebrum and posterior fossa (Figure 2). Posterior fossa recurrence was documented in 21/22 patients (in 7 patients by biopsy, in 7 by autopsy and in 7 by radiography). Nine patients failed outside the posterior fossa:
MEDULLOBLASTOMA Site of Initial Failure for Entire Group (50 patients)
three patients failed above the tentorium, five patients outside the CNS and one patient only in the spinal cord. (One patient failed in unknown sites and was deleted from the analysis of posterior fossa control in Tables 1, 2 and 3.) lntrathecal Au’~’ was used in eight patients, four patients in addition to spinal irradiation and four patients as the sole spinal cord treatment. Five of these eight patients failed in the posterior fossa (three alone, one with spinal cord disease and one with widespread CNS disease). One patient failed outside the CNS in the bones and nodes and one in the brain parenchyma. One patient remains disease free but developed a second primary at 280 months (a lymphoma). No complications such as cauda equina syndrome were observed despite long-term survival of 53, 54, 76, 144 and 280 months. Spinal
cord recurrences
There was a total of IO spinal cord failures (20%). All but one were associated with posterior fossa recurrence (Figure 2). In seven patients, spinal cord failure occurred simultaneously with a posterior fossa recurrence; two patients failed 32 and 36 months after the posterior fossa initially recurred and were successfully retreated with local radiotherapy. Times to failure after initial treatment for the seven patients were 1, 1, 2, 8, 24, 30 and 83 months. Five of seven failures had been within two years and six of seven failures within three years. Excluding the one patient who received no spinal irradiation, the average cord dose to the remaining six patients was 337 1 rad. In the two patients who subsequently failed, original doses to the spinal cord were 3750 rad and 3000 rad respecTable 3. Local control as a function of posterior dose and T stage T, ~5,000 rad (20 pts.) 4,500-5,000 ( 9 pts.) 4,000-4,500 ( 5 pts.) 54,000 ( I5 pts.) 49 pts.
Fig. 2. Patterns of initial failure for the 31 patients with documented failure. Note that 22/3l patients failed with a component of posterior fossa disease.
315 f/4 I */2* 5/ll
T? s/9* O/2 o/4* 2*/6* IO/21
T, 414 213 l/2 l/9
fossa
T,
Tx
O/l
l/l
l/l 2*/3 315
I*/2 213
*Individual Au’~” patients. Note: No difference is seen in local control by T stage alone.
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tively. Two of the patients had received intrathecal Au’~’ Only one patient failed in the spinal cord without posterior fossa disease. He received 2640 rad to the cord and failed 7 months after initial treatment. Cerebral
Recurrences
A total of five patients failed in the cerebrum. Two patients had concomitant posterior fossa disease but three patients (6%) failed only in the brain, one in bilateral frontal lobes and two associated with lateral ventricle disease (Figure 2). Times to failure were 8 and 32 months for the two patients with posterior fossa disease who had received 0 and 4080 rad whole-brain respectively. Whole brain doses were 3347, 3922, and 3500 rad in the other three patients who failed at 34, 54 and 168 months respectively. Extra-CNS
Metastases
Six patients failed outside the central nervous system in bones, nodes, and bone marrow. All occurred outside the central nervous system only (Figure 2), although one patient had had a prior posterior fossa recurrence 36 months previously that was successfully treated. Times to failure were 4, 6, IO, 15, 2 I and 94 months. No patient had had a ventriculoperitoneal shunt.
MEDULLOBLASTOMA (5000
Rad to Posterior Fossa (29 patients) Initial Sites of Failure
November
1982. Volume
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I
Time to recurrence
In total, 32 patients (64%) eventually failed, 26 of 32 (82%) within three years; however, there were three ( IO%) very late recurrences at 83, 135 and 168 months. Nineteen of the 22 patients (86%) eventually failing in the posterior fossa did so within 36 months, and all but one patient within 60 months. When we analyzed all sites of failures as a whole, we obtained an identical rate of cumulative failure. The effect of dose to the posterior fossa on patterns of failure is seen in Figures 3A & 3B. Both the total number of treatment failures and the likelihood of spinal cord failure are reduced in the higher dose group with posterior fossa doses in excess of 5000 rad. Analysis of the doses of those patients failing in the posterior fossa demonstrated that the median posterior fossa dose was 4200 rad (ranging from 30 I8 to 5460 rad) compared to 5 100 rad (I 400 rad to 5760 rad) for those patients whose posterior fossa was controlled (Table I). A dose-response relationship was suggested. Sixteen of 20 (80%) tumors receiving doses greater than 5000 rad to the posterior fossa were controlled. Only I I of 29 (38%) patients receiving less than 5000 rad had local control (Table 2). An analysis of local control with respect to T-staging revealed that initial T-stage had no value in predicting
MEDULLOBLASTOMA )SOOO Rad to Posterior Fossa (2 1 patients) Initial Sites of Failure
Fig. 3A. Patterns of initial failure for the 29 patients who received less than 5000 rad to the posterior fossa. Note that IS/24 (75%) failed with a component of posterior fossa disease. Fig. 3B. Patterns of initial failure for the 21 patients who received greater than 5000 rad to the posterior fossa.
Cerebellar
medulloblastoma
0
local control or survival (Table 3). Local control for T, lesions was 46% (5/ 1 1); for Tz lesions, 48% (lo/21 ); for T, lesions, 78% (7/9); for T, lesions, 60% (3/5); and for T, lesions, 67% (2/3). In patients receiving greater than 5000 rad, local control for T, lesions was 3/5 (60%); for Tz, 8/9 (89%>); for T,, 4/4 ( 100%); for T,, O/ I ; and for T,, I/ 1 (100%). For less than 5000 rad, local control for T, was 2/6 (33%)); for T,, 2/ 12 (I 2%); for T,, 3/5 (60%); for T.,, 3/4 (75%); and for Tx, I /2 (50%). Five-year survival did not significantly differ for each T-stage (p = 0.24). Five-year actuarial survival was 85% for the 21 patients who received greater than 5000 rad to the posterior fossa and 36% actuarial survival (25% relapse free survival) for the 29 patients receiving less than 5000 rad to the posterior fossa (p = .OOOS) (Figure I). The five-year actuarial survival for those patients receiving greater than 4500 rad was only 69%, which was inferior to the survival of the patients who received greater than 5000 rad to the posterior fossa. Those patients achieving local control had an 80% fiveand ten-year actuarial survival vs 25% five-year and 7% ten-year survival for those patients failing in the posterior fossa (p = .OOOl ) (Figure 4). &j&V ofsurgery on local control We retrospectively determined the type of surgery for 47/50 patients. Two patients had biopsy only, 21 patients had total resection of tumor and 24 patients had a subtotal resection of tumor. The effect of type of resection and dose on local control is seen in Table 4. Local control for patients undergoing total resection was 13/21 (62%); subtotal resection, 12/23 (52%); and biopsy, I /2. In those receiving 5000 rad, local control for the total resection group was 7/9 and for the subtotal resection group, 9/ 1 I. Five-year actuarial survival was 51Y0 for the total resection group vs 57% for the subtotal resection group.
C. L.
SIL.VERMAN
AND
J. R.
SIMPSON
1873
MEDULLOSLASTOMA
0
I
I
I
I
I
I
I
1
I
J
1
2
3
4
5
6
7
6
9
IO
YEARS
Fig. 4. Actuarial survival for the 27 patients whose posterior fossa was controlled and for the 22 patients with documented posterior fossa failure. Difference is very significant (p = .OOOl).
covered the entire posterior fossa, which anatomically extends to the clinoid process and in the cephalad direction to the tent of the tentorium through which runs the straight sinus. For 73% of locally controlled (19/27) and 73% of uncontrolled patients (16/22), films were of sufficient quality to be reviewed. In patients whose disease was controlled in the posterior fossa, the whole-brain port was deemed adequate in 81 of 84 (96%). and the boost port in 20 of 34 (59%). Inadequacy occurred because of insufficient coverage of the tentorium or inadequate anterior margin. For those patients failing in the posterior fossa, the whole brain was adequately covered in only 60 of 76 (79%) films (the floor of the middle cranial fossa was often missed in an attempt to shield normal tissues), and only five of 3 I (16%) boost ports adequately covered the entire posterior fossa (Table 5). Retreatment
Accuraq)
oj’dose delivery Port films of each patient were reviewed to determine how accurately the prescribed dose had been delivered to the area at risk. Both whole-brain and boost ports were evaluated. The boost port was defined as adequate if it
Sixteen patients were retreated with chemotherapy, radiotherapy or a combination of both modalities after recurrence (Table 6). ten of these patients had failed in the posterior fossa alone, and three patients in the posterior fossa and spinal cord. Two additional patients had
Table 4. Local control as a function of dose and extent of operation c5.000
rad
to posterior Total resection (2 I patients) Subtotal resection (23 patients) Biopsy only (2 patients) Total
fossa
~5.000 rad to posterior fossa
6112
719
13/2l
3112
9/l I
12123 (52%) l/2 (50%)
l/2 IO/26
Note: No significant difference is seen in local control between total resection similar (5 I % vs. 57%). Again seen is the effect of dose.
(62%)
16120 (62%) and subtotal
resection
(52%). Survival was also
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Radiation Oncology 0 Biology 0 Physics
November 1982. Volume 8, Number 11
whose neurological function deteriorated after surgery but who has had no subsequent decrease since irradiation. Three children are of markedly short stature, one with documented human growth hormone deficiency on replacement hormone, one with a normal hormone level and one whose endocrinological evaluation is pending. Intellectual function is presently being retrospectively analyzed with a wide range of psychometric tests and is the subject of a future publication. Preliminary results demonstrate a trend towards decreased IQ scores when compared to age-matched siblings.
Table 5. Local control as a function of portal adequacy
Local control (19 pts.) Local failure (I 6 pts.) Note: Controlled
Whole brain
Boost ports
8 i/84 (96%)
20/34 (59%)
60/76 (79%)
S/31 (16%)
patients
had more accurate
dose delivery.
failed only in the cerebrum and one had failed in the bones and lymph nodes. Two out of the 16 patients had no evidence of tumor at 49 and 86 months after retreatment; survival was extended 12 to 47 months in an additional five patients with a mean survival of 22 months and a median survival of I2 months for all 16 patients.
DISCUSSION The five- and ten-year survival rates for our entire group of patients of 5 I % and 42.4% compare well with the more recent reports in the literature (five-year: 33-73s;
Late efects of irradiation The late sequelae of the irradiation were analyzed. All but one patient appeared neurologically intact except for mild ataxia or tremor which did not impair normal function. The one severely disabled patient was a child
ten-year:
20_43,).'.3,4.6,8.'4.'6.'9
Favorable prognostic factors such as female sex,4 age greater than 164 (or greater than 5 years of age in one series’), and total surgical resection2’ have all been pro-
Table 6. Results of salvage in I6 patients Initial treatment Patient #
Whole brain
Cord
I
3,026
3,000
(rad) Posterior 3,026
fossa
Time to failure (mos.) 24
Site of failure
Posterior fossa/spinal cord
2*
3,490*
3
3,900
I3
Posterior
fossa
3,500*
4,000
58
Posterior
fossa fossa/spinal
4
4.1 I8
3,449
5,053
83
Posterior cord
5* 6
3,500 3,683
3,750
3,500 3,683
54 36
Cerebrum Posterior fossa
7*
3,000
3,000
27
Posterior
8 9
4,140 3,347
3,500 3,519
4,140 3,347
I1 I68
IO
4,080
3,000
5,096
24
Posterior
fossa
II
4,600
3,612
4,600
57
Posterior
fossa
I2
3,040
3,6 I I
4,640
30
13 I4 I5 16
3,960 4,000 4,080 4,080
3,520 3,900 4,590 3,500
4,202 4,585 5,049 4,986
34 4 27 20
Posterior fossa/spinal cord Posterior fossa Bones, nodes Posterior fossa Posterior fossa
fossa
Posterior fossa Brain-It. lat. vent.
Note: Two patients (#3, #I 5) were rendered *Au’~’ patients. VCR = Vincristine.
NED and 5 patients
had prolonged
retreated
Retreatment
Status after treatment
2,000 rad craniospinal XRT
Posterior fossa recurrence DWD 2
2,000 rad whole brain
months Posterior fossa recur-
4,450 rad whole brain +Au’~’ Steroids
rence DWD 5 months DNED 86 months
Posterior fossa recurrence DWD 10 months AWD 3,500 rad whole brain 3,582 rad whole brain Spinal cord recurrence DWD4months 3,600 rad posterior Posterior fossa recurfossa, 3,000 rad cord rence DWD 26 months 1,000 rad whole brain DWD 2 months Cranio-spinal XRT 2,000 rad MOPP chemotherapy Spinal cord seeding DWD I2 mos. 2,000 rad whole brain Posterior fossa recurrence DWD 31 months Cranio-spinal XRT DWD4months 1,050 rad Whole brain 2,000 rad DWD 5 months VCR + 3,000 rad DWD I7 months VCR NED 49 months Multiagent chemoDWD 12 months therapy survival of 12 months or more.
Cerebellar medulloblastoma 0 C. L.
posed. In our own study, although the numbers were small, five-year survival for the 12 patients greater than 16 years of age did not significantly differ from the five-year survival in younger children. Very young children, less than five years of age, also fared no worse. Our study suggests a trend, though not statistically significant, that females do better than males (p = 0.37). No improvement in survival or local control was demonstrated with respect to the extent of operation. It was the dose to the posterior fossa that appeared important as 80% of those patients receiving greater than 5000 rad to the posterior fossa were controlled regardless of the extent of resection. Our data, like the recent Toronto study,3 fail to show any prognostic value in the T-staging system that has been proposed, which conflicts with previous reports.7.‘3 Dose to the posterior fossa, independent of initial T-stage, determined local control and survival. Since posterior fossa recurrence is the predominant problem, occurring in up to 50% of all patients, and can account for 70% of failures,3.“,“.24 local control must be the paramount issue for radiotherapists. Our data show that the five- and ten-year actuarial survival rates for those achieving local control were 80%, versus 25% and 7% for those not locally controlled (p = .OOOl) (Figure 4). To increase the likelihood of achieving local control, certain authors advocate total excision or near total excision of the posterior fossa disease using an operating microscope, and have demonstrated better survival rates in selected patients.” However, the intrinsic radiosensitivity of this tumor may make extensive surgery unnecessary. We could show no difference in control or survival between total and subtotal resection and conclude that debulking of the tumor and relief of ventricular obstruction may be all that is needed. Our data confirm this intrinsic radiosensitivity, since 80% local control was achieved for those receiving at least 5000 rad to the posterior fossa regardless of the extent of resection; this dose would be expected to be adequate for only microscopic disease for epithelial tumors. Similar experiences have been reported by otherS.X.24.26
Equally as important as the dose prescribed is the accurate and consistent delivery of that prescribed dose to the volume at risk. The patients who were controlled had a more consistent delivery of the dose to the posterior fossa. Even though the boost ports in the later years were judged inadequate in approximately 40% of cases in the controlled patients, it is important to point out that the boost ports often only contributed an additional 500 rad, whereas the whole-brain port usually delivered the main bulk of the dose (4500 to 5000 rad) in those patients. Other authors have demonstrated the value of consistent set-up and frequent port films in increasing accuracy in other sites.‘” We found no advantage to intrathecal Au’~’ and no complications, despite long-term survival in 5/8 patients, although 4/8 patients had no spinal cord external irradia-
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tion and those receiving external beam irradiation had lower doses of AU’~~ (10 mCi). Failure in the brain was low (lo%), but accounted for 16% of all failures. Two of five patients had a concomitant posterior fossa failure and probable spread to the cerebrum secondarily from the posterior fossa. Three patients (6%) had cerebral failure only (two associated with lateral ventricle disease and one in the’subfrontal areas, bilaterally). Whole brain doses in these three patients were below 4000 rad but the failures occurred late, at 34, 54 and 168 months. This low failure rate corresponds to that of Berry et ~1.~We have not seen any failures in the brain in the 15 patients receiving greater than 4000 rad midparietal dose. We feel that 4000 rad is a well tolerated dose to the brain, even in younger children, and the low incidence of primary cerebral failure and the lack of failure above 4000 rad does not justify increasing the dose above that level. The patients who failed outside the central nervous system in our series, six of 50 (12%), exhibited a different clinical history. All patients had control of the posterior fossa, brain and spinal cord at the time of recurrence. These were usually early recurrences; all but one occurred within two years. Berry et al. have also noted this pattern of failure.3 Ventriculoperitoneal (VP) shunting has been implicated in the development of tumor outside the central nervous system,3,‘5 but none of our patients had had a VP shunt placed. Though other authors have noted metastases via the shunt tubing,15.” based on our experience, especially in light of the relatively short time to failure and lack of a ventriculoperitoneal shunt, we propose that extra-CNS metastases were already present at time of diagnosis. However, we were unable to detect prognostic factors to select out those patients at risk to fail outside the central nervous system. The use of chemotherapy and/or radiotherapy to salvage recurrences yields small but positive results. Of the 16 patients we treated (14 with follow-up information) two were free of disease at 49 and 86 months after retreatment, one was treated with Vincristine chemotherapy and the other with 4450 rad whole-brain irradiation and AU”’ (this patient had had no whole brain radiotherapy initially). Survival greater than one year was achieved in five other patients with a mean survival for all patients of 22 months and a median survival of 12 months, even when a dose of 4000-5000 rad whole brain or posterior fossa radiotherapy had been previously administered. However, with increasing primary treatment doses to the brain and posterior fossa, re-irradiation will be even more risky and chemotherapy may be the modality of choice in the future for recurrences. The role of adjuvant chemotherapy has not been established, but may be of value in those patients destined to fail outside the CNS or in those 20% of patients who will fail in the posterior fossa. In conclusion, two main factors to be stressed in the irradiation of medulloblastoma are the dose to the poste-
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rior fossa and the consistent delivery of that dose to the entire volume at risk. Use of whole-brain or whole craniospinal portals as advocated by Tokars et al.” to 4000 rad midparietal dose will reduce set-up error, and gener-
November 1982. Volume 8, Number 1I
ous posterior fossa boost fields to bring the dose to the fossa to a minimum of 5000 rad should increase local control. These procedures should translate into long-term survival rates of 70-80%.
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