Im. J. Rdimon Oncoiogv Rid. Phys.. Vol. 7. pp. 731-741 036cr30l6/8l/06073~WsO2.00/0

Printed in the U.S.A. All rights rcLcrvc& Copyright Q 1981 Pcrgm~~~ Press Ltd.

0 Original Contribution

RESULTS OF RADIATION TR$ATMENT OF CEREBELLAR MEDULLOBLASTOMA*

HONG W. CHIN, M.D., PH.D. AND YOSH MARUYAMA, M.D. Radiation Medicine, University of Kentucky, Lexington, KY

A review of 20 patients with meduUoblastoma who were treated with radiitioa treatmeat at the University of Keatucky Mediii Center is preseated. The age range was 1,5 to 31 years; oaly five patieats were older thau 16 years of age. A mlationship between radiitioa dose aad survival *as obtaiaed. A 5-year dbease-free sumival of 80% was obtained witk a radiition dose of 5000 rad aad more wiqemas only 15% of patieats survived five years with a radiitioa dose of less tkan 5000. Treatment failures were n#iaiy a result of local recurreace. This occurred ia 78 ?6 of patieats’wko were treated with radiation dosage of &ES than !WO rad. Tbe development of hydrocephalus appeared to he because of advanced disease aad no 5-ye# survivors were noted in five patients who uadenveat systemic sbuntiag procedure. A review of published data aJso supports a d oseacpcndent 5-year survival. Effective radiatioa treatmeat methods, along witk doses to 5OfKb5$00 rad, appear to lead to loag term survival, frequent tamor cure aad high perfommnce o&come.

Medullobiasbam, Radiation therapy, Dose-response.

Medulloblastoma is considered one of the most common tumors of the central nervous system in children.23 It accounts for more than 20% of all intracranial neoplasms in childFen under 15 years of age.20 Although medullo- blastoma is highly radiosensitive and responds promptly to radiotherapy,2 there has been considerable variation in the survival rates among many published re- ports. s.9~1’~‘2.‘6~1’~19 Such variation is not surprising since the patients were treated with many modes of therapy and with widely varying radiation dosage. With the introduction of aggressive radiotherapy, there has been accumulating evidence for improved results9*2’*22 from therapy. Both cures as well as prolonged survival of patients with this tumor were observed in bur experience. This study reports a retrospective analysis of experience at the University of Kentucky Medical Center between 1964 and 1976, focusing on the survival data of this group of patients with medulloblastoma.

METHODS AND MATERIALS Patient characteristics

Between 1964 and 1976,20 patients with medulloblas- toma were referred to and treated at the University of Kentucky Medical Center. Following cranial surgery all patients were treated with a megavoltage Cobalt-60 machine. The age and sex distribution is shown in Figure 1. All patients are from the Kentucky and the adjacent

Appalachian region. The age range was 1.5 to 31 years with a median of 8 years. There were 5 patients older than 16 years of age. The sex distribution showed a male predominance (12 male and 8 female). All patients underwent a craniotomy with removal of as much tumor as possible. No patients had biopsy only without tumor resection. Histologic diagnosis of medulloblastoma was confirmed by the same neuropathologist. No patients in this series received adjuvant chemotherapy in the treat- ment of the primary tumor.

Radiation technique Patients were treated relatively uniformly and received

similar and relatively high doses of radiation. The radia- tion treatment technique used parallel opposed bilateral ports to whole brain and upper cervical cord followed by boost irradiation to the posterior fossa with reduced lateral opposing fields (Fig. 2). Spinal cord irradiation was delivered to the whole spinal axis with matching posterior fields, with the gap moved up and down, using short and long fields alternately, to avoid hot or cold spots within the gapped area.

For the whole brain irradiation, the daily dose used was between 150 and 180 rad with 5 fractions per week up to 35004500 rad over the period of 32 and 38 days. An additional boost dose of 1000-I 500 rad was delivered to the posteriQr fossa, using a daily dose of 160-200 rad.

*At the University of Kentucky Medical Center. Reprint requests to: H. W. Chin, M.D., Radiation Medicine,

University of Kentucky Medical Center, 800 Rose St., Lexing- ton, KY 40536.

Accepted for publication 6 February 198 1.

738 Radiation Oncology 0 Biology 0 Physics

0 Male

m Female

r;_ z 1=6- h- k 4-

El 3-

s2-

Z’I-

O-5 6-10 II-15 16-20 21-25 2g30 31-35

AGE ( YEARS)

Fig. 1. Age and sex distribution.

The daily dose, as well as total tumor dose, varied depending on the age of the patients. A total tumor dose of 5500 rad over 6-7 week period was delivered to the posterior fossa. For children under the age of 5 years, 5000 rad was delivered in 6-7 weeks. The youngest

Fig. 2. Calvarial scalp compensator” and cephalad portion of crania-spinal axis fields. An aluminum compensator was presented at the 1976 ASTR meeting by Schroader, K. and Maruyama, Y. as a scientific exhibit.

June 198 1, Volume 7. Number 6

patient in the high dose group was 3 years and 4 months. The group, which received 5000 rad or more, is termed the “high dose group.”

Between 3000 and 3500 rad of total tumor dose was delivered to the whole spinal axis over the period of 5-6 weeks. Higher doses were used for the older children and adults. Dose per fraction was 150-160 rad with 5 treat- ments per week. Concurrent irradiation to cranioaxial fields is a standard practice in this institution. A calvar-

ial-scalp compensator (Fig. 2) was developed at the University of Kentucky Medical Center to allow uniform radiation dose to be delivered and to minimize high dose effects.” By using this compensator one can avoid a 30% overdose to the vertex and obtain a homogeneous distri- bution of radiation dose within the cranial cavity. The latter treatment policy of uniform dosage radiation ther- apy was adopted in the early 1970’s; dosage before 1970 was usually less than 5000 rad.

In this analysis, patients are divided into two major groups: those who received a uniform and high dose radiation treatment (i.e. 5000 rad and more), and those who received relatively low-dose treatment (less than 5000 rad). The present series consists of 20 patients; six of whom were treated before 1970. Eleven patients completed treatment of 5000 rad or more. Three did not complete their planned radiation treatment because of their poor cooperation, although they did not have poor performance status. For example, one patient, a 21 year old female, was very reluctant to have treatments. She was inconsistent in coming for treatment and there were many interruptions of her radiation treatment. She refused to return for further treatment half way through her planned treatment course.

RESULTS Survival

Figure 3 shows three survival curves grouped by radia- tion dose. Survival calculations were made using Cutler and Ederer’s life table method.’ The overall 5-year survival rate in entire group was 44%; it was 80% in the high dose 5000-5500 rad dose group. The survival rate was 15% in the low dose group, (less than 5000 rad).

Dose and survival To better analyze the role of radiotherapy, survival

data are illustrated in Figure 4 in relation to treatment dose to the posterior fossa tumor. Of the 10 patients who received between 5000 and 5500 rad, 7 are alive and well. Two patients died within 5 years and an additional patient succumbed at 6 years following treatment. Of these 10 patients, -I-were treated more than 5 years ago.

Nine patients received less than 5000 rad. All but one died within 5 years after treatment. None of the patients in the radiation group who received less than 4000 rad survived more than 5 years. One patient treated with 6000 rad to the posterior fossa did not live more than 1 year. This patient had extensive. advanced disease and

Radiation of cerebellar medulloblastoma @ H. W. CHIN AND Y. MAHUYAMA 139

\

C5000 rod I I I

o-.-o-

I 1 I I I I I I

0 I2 3 4 5 6 TIME AFTER TREATMENT (YEARS)

Fig. 3. Survival curves according to radiation doses.

had to undergo a systemic shunting procedure at the initial surgery. In this case, radiation therapy was not effective in controlling the tumor or the advanced disease.

Age, sex and survival. In the high dose group, 2 out of 4 adult patients expired within 5 years. In children, all patients except one of 7 patients of the high dose group are alive and well. Seven of 8 patients who received

ALIVE DEAD -CHILDHOOD 0 .

ADULT 0 I

t I

%

I I I

I !

s <5000; . . I I

I I - 0 I

z a ~4000 :, c ?? t I

I I I $ ,a, 1 , , , , , I , 0 I2 3 4 5 6 7 8 9 1011

STATUS AFTER TREATMENT (YEARS) Fig. 4. Distribution of survival status and irradiation dose.

radiation treatment to doses less than 5000 rad expired within 5 years after treatment. According to the present analysis, age was not a significant factor in survival. However, female patients had a better survival. None of five female patients, including one adult, died with a minimum follow-up period of 4 years, if they received 2 5000 rad of radiation treatment (Fig. 3).

Trearment failure Hydrocephalus and shunting procedure. Five patients

underwent ventriculoperitoneal (VP) or ventricuioatriai (VA) shunts for hydrocephaius. Ail were short-term survivors. Once hydrocephaius developed, radiation treatment seemed to be less effective. Two patients had an initial shunting procedure and three needed systemic shunting procedures after initial craniotomy because of recurrent or progressive disease with clinical evidence of hydrocephaius.

Radiation dose and recurrences. Table 1 shows the relationship between radiation dose received, recurrence and survival. Almost ail of the patients who died devei- oped clinical evidence of tumor recurrence. Of nine patients who received less than 5000 rad to the posterior fossa, seven developed recurrent intracranial disease and ail seven died soon after developing the recurrence. Only one patient in this low dose group survived more than 5 years and never experienced recurrence of the disease. There were only two intracranial recurrences in the patients who received between 5000 and 5500 rad to the primary tumor.

Sizes ofrecurrences. The most common site of clinical recurrence in these patients was intracranial and in the posterior fossa. Of 11 patients who recurred, seven devel- oped posterior fossa recurrence with or without extension into the adjacent intracranial structures. Two had recur- rent disease in the posterior fossa as well as metastatic spread throughout the spinal subarachnoid space. The low dose group which received less than 5000 rad comprised 78% of the local and regional recurrences (7 out of 9 recurrent patients) (Table 2).

Both loco-regional recurrences were seen in the low dose radiation group that received less than 4000 rad (Table 2). One patient developed recurrence in the cervi- cal spine as well as the posterior fossa. This progressed to multiple spinal metastases confirmed by myelography 6

Table 1. Local recurrences in the first S-year follow-up period: radiation dose, survival, and recurrences

Radiation dose (rad)

5,500 5,000

t5,ooo t4.500

Recurrences

All Expired patients patients

116 l/l 114 l/l 213 212 516 5/6

740 Radiation Oncology ??Biology 0 Physics June 198 I, Volume 7, Number 6

Table 2. Sites of clinical recurrences

Radiation dosage (rad)

Local recurrences

(intracranial)

Loco-regional recurrences

(intracranial and spinal) Spinal

recurrences Extra-cranial recurrences

5,500 I 0 0 0 s.ooo I 0 0 I

<s,oOO 2 0 0 0 <4.000 3 2 0 1

months later. Another patient developed recurrent disease in the dorsal spine. Brain scan in this case revealed evidence of recurrent disease in the posterior fossa as well.

Distant metastases. Extra-axial dissemination of medulloblastoma is a rare problem. In this series we observed two such patients (10%) who developed bony metastases after primary subtotal excision of a cerebellar medulloblastoma and radiotherapy. Both of them had ventriculo-peritoneal shunts. One patient responded to chemotherapy with cyclophosphamide, vincristine and prednisone. However, ultimately resistance developed with progressive intra-abdominal soft tissue masses and peripheral lymphadenopathy. Details of one case were reported elsewhere.”

Performance status All patients who are presently alive have returned to

normal function. Follow-up investigation has revealed no evidence of recurrent disease. They are active and enjoy- ing useful lives. No one was seriously disabled with regard to neurological, psychological and endocrinologi- cal sequelae. Current Karnofsky performance status was rated greater than 90% in all patients who are alive. All but one patient were children when they received radia- tion treatment. Of these children, six of eight under 16 years old have survived more than 5 years since their treatment. The only apparent and common long-term complication was a mild to moderate degree of short stature. The younger the age of patients at the time of

therapy, the more considerable was the degree of short stature.

DISCUSSION In the past several decades the treatment of patients

with medulloblastoma has undergone considerable evolu- tion with advances in the methods of postoperative radio- therapy following craniotomy. Complete removal of the primary tumor is rarely possible; without postoperative radiation treatment the average life expectancy of the patient is less than one year.6 The survival of patients has been further increased by extending the irradiation field from treatment to the posterior fossa only to whole central nervous system (CNS), including the entire brain and spinal cord.” Even with complete radiation including the entire neuraxis, there is considerable variation in the survival rate according to the treatment technique and radiation dose used (Table 3). Radiation dose has been the most variable factor of the several factors influencing the survival of patients with medulloblastoma in the practice of radiotherapy from the various centers. In the literature, many of the published series include a variety of widely different doses of radiation. Radiation doses used for the treatment of medulloblastoma in each series varied from as low as 2500 to as high as 6000 rad. Five year survival rates varied from 27% to 77%. As shown in Figure 4, our experience with radiotherapy of medullo- blastoma shows a distinct dose-dependence for tumor control. Our patients were treated uniformly using a homogeneous and adequate tumor dose. The poor survi-

Table 3. 5-year survival from literature

Authors & year

Number of

patients

S-year survival

(%) Radiation dose

(rad)

Paterson and Farr (I 953)” 22 Mc,Farland er al. ( 1 969)16 26 Bloom et 01. ( 1969)’ 68 Kramer ( 1969)” 6 Jenkin (1969)” 30 Aron (I 969)’ 15 Hope-Stone (I 970)” 13 Smith et al. (1973)” *

Sheline ( 1977)” 8 Hirsch er al. ( 1 979)9 44

27 3,000-6,000 38 2,500 air-5,OOOR maximum dose 32 4,500-5,000 50 5,000 21 3,000-3,500 35 2,500-4,000 77 3,500-4,000 54 Complete CNS irradiation 30 Partial CNS irradiation 63 5.500 71 5,000

*Not stated.

Radiation of cerebeilar medulloblastoma 0 H. W. CHIN AND Y. MARUYAMA 741

CUMBERLIN et 01 L5000 PRESENT SERIES WOO-5500

SMITH et al 4500-5500

WISH et al 5000

MC FARLAND et al 3600- 5000

CUMBERLIN et 01 <4500

PATERSON 8 FARR 4000

MCFARLAND et 01 ~3800

JENKIN 3000-3500

m HIGH DOSE

0 VARIED DOSE

20 40 60 60 too

PERCENT SURVIVAL*

Fig. 5. Correlation between radiation dosage and survival rates from literature. *Cutler’s life table method.

vor rate occurred with doses less than 5000 rad and especially less than 4000 rad. The high dose and homoge- neous dose method instituted here in 1970 has led to a distinctly better outcome from therapy compared to that used before.

Because there was a progressive improvement in the 5-year survival rate with increasing radiation dose in this study, the authors have examined several papers for the relationship between radiation dose and survival. Suffi- ciently detailed data allowed the calculation of the survival rates in the various series treated with different dosages. Figure 5 gives information on the survival rates of patients treated with high or low doses of radiation. The survival rates have increased with the use of whole CNS irradiation, and with tumor doses of more than 5000 rad to the primary site, when compared with the use of local irradiation and/or doses of less than 5000 rad. With radiation dose of 5000 rad and more, 80% of our patients were free of disease and had long term cures. From experiences at this institution and that of otherss*‘9 we now advocate the use of radiation treatment to a tumor dose of 5000-5500 rad over 6-7 weeks to the primary tumor and 3000-3500 rad in 5-6 weeks to the spinal axis.

Treatment failures were mainly because of local recur- rence,18.*’ which occurred in 90% of the cases in this series. The incidence of local recurrence was closely related with radiation dose; almost 80% of the recur- rences were in the group treated with less than 5000 rad.

Recurrences in the high-dose group (25000 rad) were associated with advanced disease or extracranial metas- tases.

Extra-neural metastases of medulloblastoma are rare but at least 60 cases have been reported in the English literature. The most common site of metastasis is in the skeletal system.* Trials of chemotherapy for recurrent medulloblastoma’4*24 have been reported and our experi- ence and that of others suggests chemotherapeutic agents are useful in palliation.‘0*‘4 Recurrent tumor can some- times be controlled for fairly long periods by the use of chemotherapeutic treatment.” However, adjuvant chemotherapy would have been necessary in only 10% or less of the patients in this series.

Chang er aL4 have proposed an operative staging system but it has not been widely used in practice. In our experience, there has been a close relationship between clinical manifestations of hydrocephalus and stage of the disease. All of five patients who had clinical hydrocepha- lus did not survive more than two years and were less responsive to treatment. If hydrocephalus is present, it suggests a poorer prognosis or a more advanced stage of disease. This is a group where adjuvant therapy may be indicated and of some value.

With improvement in survival rates and frequent cure of medulloblastoma by improved radiotherapy, we must consider the delayed consequences of therapy in relation to long-term quality of life and the risk of late sequellae of treatment. Although all of the patients who survived in this series are active, leading normal lives and are not grossly handicapped, further evaluation is needed regard- ing occult and late effect of pituitary and gonadal func- tion, immune reaction, delayed malignancies, etc. It is recommended that all children should be under close observation, including endocrine evaluation, so that treat- ment be instituted at appropriate times. The frequent long term cure of patients with this tumor that are now being achieved suggests that every effort to control delayed complications and late side effects of radiother- apy are warranted. One method that we now use routinely in brain tumor treatment is the aluminum calvarial-scalp compensator first described from this institution.15 It is used to deliver uniform tumor dose and to avoid overdose of the vertex, which is the usual result of uncompensated lateral opposed cranial ports. With careful methods and high radiation doses of 25000 rad, medulloblastoma has proven to be a highly curable tumor at this institution.

REFERENCES I. Aron, B.S.: Twenty years’ experience with radiation ther-

apy of medulloblastoma. Am. J. Roentgenof. 105: 37-42, 1969.

2. Bailey, P., Cushing, H.: Medulloblastoma cerebefli. Arch. Neural. Psychiat. 14: 192-224, 1925.

3. Bloom, H.J.G., Wallace, E.N.K., Henk, J.M.: The treat- ment and prognosis of medulloblastoma in children: A

study of 82 varified cases. Am. J. Roentgen01 105: 43-62, 1969.

4. Chang, C.H., Hovsepian. E.M., Hervert, C. Jr.: An opera- tive staging system and a megavoltage radiotherapeutic technic for cerebellar medulloblastomas. Radiology 93: 1351-1359, 1969.

5. Cumberlin, R., Luk, K.H., Wara, W.M., Sheline, G.E..

742 Radiation Oncology 0 Biology ??Physics June 198 1, Volume 7, Number 6

Wilson, C.B.: Medulloblastoma: Treatment results and effect on normal tissues. Cancer 43: 1014-1020, 1979.

6. Cushing, H.: Experiences with the cerebellar medulloblas- tomas. Acta Path. Microbial. Stand. 7: l-86, 1930.

7. Cutler, S.J., Ederer, F.: Maximum utilization of the life table method in analyzing survival. J. Chr. Dis. 8: 699-715, 1958:

8. Das, S., Dalby, J.E.: Distant metastases from medulloblas- toma. Acta Radiof. Ther. Phys. Biol. 16: 117-123. 1977.

9. Hirsch, J.F., Renier, D., Czernichow, P., Benveniste, L., Pierre-Kahn, A.: Medulloblastoma in childhood. Survival and functional results. Acta Neurochir. 48: I-1 5, 1979.

IO. Ho, E.P., Lieber, A., Deland, F.H., Maruyama, Y.: Gener- alized osteoblastic bony metastases from medulloblastoma. Oncology 33: 253-256, 1976.

I I. Hope-Stone, H.F.: Results of treatment of medulloblasto- mas. J. Neurosurg. 32: 83-88, 1970.

12. Jenkin, R.D.T.: Medulloblastoma in childhood: Radiation therapy. Canad. Med. Assoc. J. 100: 51-53, 1969.

13. Kramer, S.: Radiation therapy in the management of brain tumors in children. Ann. N. Y. Acad. Sci. 271-584, 1969.

14. Lassman, L.P., Pearce, G.W., Banna, M., Jones, R.D.: Vincristine sulphate in the treatment of skeletal metastases from cerebellar medulloblastoma. J. Neurosurg. 30~ 42-49, 1969.

15. Maruyama, Y., Wu, P., Arsdale, E.V.. Utley, J., Huilla, J.,

Wrede, D.E.: Calvariai-scalp compensator for radiothera- py. Radiology 117: 218-220, 1975.

16. McFarland, D.R., Horwitz, H., Saenger, E.L., Bahr, G.K.: Medulloblastoma: A review of prognosis and survival. Br. J. Radiol. 42: 198-214, 1969.

17. Mealey. J.J., Hall, P.V.: Medulloblastoma in children: Survival and treatment. J. Neurosurg. 42: 56-64, 1977.

18. Paterson, E., Farr, R.F.: Cerebellar medulloblastoma: Treatment by irradiation of the whole central nervous system. Acta Radiol. 39: 323-336, 1953.

19. Raimondi, A.J., Tomita, T.: Medulloblastoma in child- hood. Acta Neurochir. 50: 127-l 38, 1979.

20. Sheline, G.E.: Radiation therapy of brain tumors. Cancer 39: 873-881. 1977.

21. Smith, C.E., Long, D.M., Jones, T.K., Jr., Levitt, S.H.: Medulloblastoma: An analysis of time-dose relationships and recurrence patterns. Cancer 32: 722-728, 1973.

22. Tokars, R.P., Sutton, H.G., Griem, M.L.: Cerebellar meduiloblastoma: Results of a new method of radiation treatment. Cancer 43: 129-l 36, 1979.

23. Van Eys, J.: Malignant tumors of the central nervous system. In Clinical Pediatric Oncology. 2nd edition, W.W. Sutow. T.J. Vietti, D.J. Fernback, (Eds.). St. Louis, The C.V. Mosby Co. 1977. pp. 487-505.

24. Ward, HWC.: CCNU in the treatment of recurrent medul- loblastoma. Brit. Med. J. 1: 642, 1974.