Medulloblastoma: Recent advances and directions in diagnosis and management—Part II

MEDULLOBLASTOMA: RECENT ADVANCES AND DIRECTIONS IN DIAGNOSIS AND MANAGEMENT PART II, HONG WOO CHIN, M.D., PH.D. YOSH MARUYAMA, M.D. A. BYRON YOUNG, M.D.

0147-0272/84/06-001-051-$9.95 9 1984, Year Book Medical Publishers, Inc.

TABLE OF CONTENTS THERAPEUTIC MANAGEMENT. RESULTS .

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DIRECTIONS FOR FUTURE MANAGEMENT. .

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COMMENT

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is an Assistant Professor of Radiation Medicine at the University of Kentucky, College of Medicine. He received his M.D. and Ph.D. degrees from Seoul National University, Seoul, Korea. His postgraduate training in Radiation Oncology was completed at McGill University, Montreal. Dr. Chin's major area of research interest is malignant diseases of the CNS.

is Professor and Chairman of Radiation Medicine and Professor of Health Radiation Sciences at the University of Kentucky Medical Center. After graduating from the University of California at San Francisco Medical School he interned at the UCSF Hospital. He completed training in Radiology at Massachusetts General Hospital and Harvard Medical School, Boston, and was the recipient of the first James Picker Advanced Academic Fellowship, served at Stanford Medical School. A Fellow of the American College of Radiology, Dr. Maruyama has pioneered clinical research in the neutron therapy of neural, gynecologic, and other human tumors. He is the author of over 375 publications, including one book on tumor localization.

Professor and Chairman of the Division of Neurosurgery at the University of Kentucky, was born in 1939 in Richmond, Kentucky. He is a graduate of Transylvania University in Lexington and received his M.D. degree at the University of Kentucky in 1965. Dr. Young did his internship and neurosurgery residency at Vanderbilt University. Dr. Young's chief research interests are head injuries and brain tumors. A major contribution has been in the area of posttraumatic epilepsy prophylaxis. Current studies include the role of nutrition in head injury outcome and the metabolic accompaniments of head injury. In addition, a current clinical research project is the study of the treatment of glioblastomas with interstitial neutron therapy. His chief clinical interests are the treatment of brain tumors and cerebral vascular disease.

THERAPEUTIC MANAGEMENT The historical evolution of the combined therapeutic approaches in medulloblastoma began with the recognition t h a t n e u r o s u r g e r y alone could not cure brain tumors. The beneficial effects of radiation were recognized as early as the 1920s, when the experiences of Bailey et al. 1' 2, 37 indicated t h a t roentgen t h e r a p y could prolong survival and relieve the symptoms produced by tumor. In 1928 Beclere recommended roentgen t h e r a p y for brain tumors before surgical decompression, and for a time, irradiation of suspected b r a i n tumors was common practice in t h e United States. Cushing 29 also suggested t h a t r a d i o t h e r a p y was more reliable t h a n n e u r o s u r g e r y alone and recommended utilizing r a d i o t h e r a p y w h e n a skilled neurosurgeon was not available. However, early r o e n t g e n t h e r a p y was associated with some morbidity and m o r t a l i t y because the t u m o r reacted promptly to irradiation, resulting in brain swelling. Bailey and Cushing1, 37 proposed t h a t t h e best method of t r e a t m e n t was suboccipital decompression followed by roentgen-ray therapy. With subsequent improvement in surgical techniques, more successful t u m o r resection became possible. In 1930 Bailey 37 wrote, concerning cerebellar medulloblastomas, 4

Experience with surgical removal of these growths prior to 1925 had been very disappointing but was later more successful, and Bailey and Cushing were led to express themselves more hopefully concerning their prognosis. They said in 1926 that they had had "one or two apparently successful extirpations . . . so that under favorable circumstances, in spite of its desperate situation, a more radical attempt at extirpation than has commonly been made in the past may be justifiable." With imp r o vem e nt of surgical technique, Bailey and Cushing did not recommend roentgen t r e a t m e n t for patients in whom resection of medulloblastoma appeared to be complete. However, t h ey later realized t h a t the decision was not correct, as disease shortly recurred and rapidly progressed to death. Retrospectively, Bailey 37 said of t hei r efforts, "In fact they were so confident that a complete extirpation had been accomplished that no postoperative radiation was advised, undoubtedly an error in judgment in view of the subsequent clinical course. That roentgen therapy is able to prevent a local recurrence for long periods of time is proved, among others, by the following case . . . . " Following a complete analysis of the entire series of 81 medulloblastoma cases at the P e t e r Bent B r i g h a m Hospital in Boston, Cutler et al. ss came to the following conclusions: (1) roentgen t h e r a p y offers the only hope for the cure of medulloblastoma; (2) roentgen t h e r a p y m a y be given without decompression; and (3) irradiation m a y be used in selected cases of suspected medulloblastoma as a therapeutic test for differential diagnosis. Cutler et al. believed t h a t just as good results were achieved with ra di ot he r apy alone as with operation followed by irradiation. The characteristic clinical response of cerebellar medulloblastoma to radiation will confirm t he diagnosis almost as surely as a biopsy, ss Their conclusions were based on the following findings: (1) No m a t t e r how complete and radical the operation had been, there was almost invariably a recurrence of the signs and symptoms due to recurrence of the t um or in 3 - 6 months unless r a di ot he r apy was given after the operation. (2) The surgical m or t a l i t y was ext r e m el y high, about 25%, compared to less t h a n 2% following irradiation. (3) There were too few medical centers where good intracranial surgery was being done. Cutler et al. suggested t h a t a t h e r a p e u t i c trial with lowdose radiation would differentiate medulloblastoma from the rest of tumors in the posterior fossa. A presumptive diagnosis of medulloblastoma could be made in cases of rapid clinical improvement, and radiation t r e a t m e n t could be continued. Surgical extirpation was recommended if there was no response to the radiotherapy. Their recommendation did not gain wide acceptance among neurosurgeons or radiotherapists because the diagnosis could 5

never be made histologically and other less radiosensitive posterior" fossa tumors also might be treated inadvertently, becauses~ of very similar clinical presentation. In 1949, Pelrce et al. proposed a new technique of twist-drill brain biopsy for the histologic diagnosis of cerebellar tumors. They reported that experience with 16 cases had proved its usefulness for histologic diagnosis with no serious complications. It seemed to be an advance in the m a n a g e m e n t of cerebellar medulloblastomas, but further experiences were not encouraging. Twist-drill biopsy turned out not to be an innocuous procedure, and the mortality was as high as the operative mortality. THERAPEUTIC MANAGEMENT OF PRIMARY TUMOR

Neurosurgery When clinical findings suggest a posterior fossa tumor, CT scans with and without contrast enhancement should be obtained. Angiography is rarely indicated. Myelography or lumbar puncture should not be done when a posterior fossa tumor has been demonstrated, Whether preoperative shunting should be done to relieve hydrocephalus prior to suboccipital craniectomy remains controversial. Preoperative decompression, when necessary, is most often accomplished now with dexamethasone or external ventricular drainage. When hydrocephalus is present but not treated preoperatively with external drainage, a catheter is usually placed in the lateral ventricle in the operating room, just prior to posterior fossa craniotomy. The tissue diagnosis of medulloblastoma is established by operation. Although the goal of Surgery should be complete excision, this can be safely accomplished only in about one fourth of cases. Medulloblastoma originates in the cerebellar vermis in most cases. At operation the neoplasm is about equally found to be confined to the vermis, to extend into the brain stem from the vermis, or to invade a cerebellar hemisphere from the vermis. In less than 10% of cases the tumor originates in one cerebellar hemisphere. Mortality from surgery should be less than 5%. Major complications are usually caused by damage to the brain stem during tumor removal. Evoked potential monitoring during surgery m a y indicate to the surgeon when excessive traction is compromising vital brain stem functions. Park et al. 72 reported a significant improvement in survival in patients with more extensive removal of tumor, Mealey and Hall, 71 however, reported that completeness of excision was not significantly related to length of survival.

Radiation Therapy Because of the tumor's extreme radiosensitivity, radiation treatment has been used for medulloblastoma since the late 6

1920s. There has been a continuous improvement in equipment and techniques of radiotherapy, leading to an improved cure rate. BASIC PRINCIPLES.--Radiation therapy can be delivered using different methods--that is, external, interstitial, or intrathecal 9~ irradiation. Of these, external beam radiotherapy has been the main strategy of radiation treatment for brain tumors. The quality of radiation has increased remarkably with the development of megavoltage equipment. Megavoltage radiation delivers a sharper and more penetrating radiation. As beam energy increases, there is increasing tissue penetration without excessive skin irradiation; i.e., there is a skin-sparing effect. Figure 1 shows the different percentage de2th dose curves of kilovoltage x-ray versus megavoltage beam (~ as a function of depth. The depth dose of kilovoltage x-ray beams decreases quickly with increasing depth from the surface, and the surface dose is high. In addition, there is wide-angled side scattering of relatively low-energy photons. Because of these scattered x-rays, a significant dose is deposited in surrounding tissue outside the port. The radiation dose absorbed is maximal at the skin and decreases rapidly with depth. Due to a high radiation dose to the skin and low tumor dose in the target volume, high-dose ISODOSE DISTRIBUTION KVP

DEPTH cm Co- 60

Fig 1.--Comparison of isodose distribution between kilovoltage x-rays and 6~ x-rays. Kilovoltage x-ray beam shows wide scatter outside beam edge, and the percentage depth dose decreases rapidly. In 6~ beam, skin surface dose is relatively low and a maximum dose (100%) starts at a depth of 0.5 cm.

radiotherapy in the kilovoltage era was limited. Kilovoltage xray beams were used until the 1940s-1960s. On the other hand, high-energy photons (including ~~ have a dose buildup region below the skin surface, which provides a skin-sparing advantage. The beam edges are sharper, less scatter occurs outside the port, and the absorbed tumor dose is higher. The edges of the megavoltage beam are more sharply defined t h a n with kilovoltage irradiation. The depth dose of kilovoltage irradiation at 10 cm is only 32% of the skin dose, whereas it is about 56% with megavoltage radiation, that is, more than 20% higher. The major advantages of megavoltage radiation are the following: (1) greater penetrating power and tumor dose, (2) less absorption by bone, (3) skin-sparing effect, (4) sharper demarcation of the edges of radiation field, (5) fewer delayed side effects, (6) larger radiation portals possible, and (7) avoidance of junctional port overlap and "hot" spots. EVOLUTION OF RADIOTHERAPY MACHINES.--Roentgen discovered x-rays in 1895, and M. Curie isolated radium in 1898. Soon after these discoveries, x-rays were found to produce changes in tissues, both diseased and healthy, and a role in tumor therapy began to be investigated. In the early 1900s, x-rays were used for the t r e a t m e n t of malignant and even nonmalignant diseases. Radium bomb therapy was used for treatment, and multiple 11/4square inch portals were distributed over the head. The results were almost always poor until the early 1920s. In the 1920s1940s, 50-200-kVp x-ray machines were developed and used to treat tumors. In 1930s-1940s the mechanical rectifier was replaced by a constant potential generator. There was no way to measure the dose until the ionization chamber was devised and the "roentgen" unit was designated a measure of radiation dose. F u r t h e r progress in the 1940s led to million-volt x-ray machines. As a byproduct of World War II, the radionuclide 6~ became available for radiotherapy in the 1950s. The megavoltage x-ray machines or 6~ teletherapy units began to be used in clinical practice, and by the late 1950s and early 1960s most orthovoltage machines in major cancer centers were replaced by megavoltage x-ray or 6~ units. This introduced the era of megavoltage radiotherapy of medulloblastoma.

RADIOTHERAPY METHOD.--In modern practice, radiotherapy is delivered in a course of fractionated doses over a period of 6 - 8 weeks, usually 5 days a week. The daily tumor dose to the brain is 150-180 cGy, depending on the age of the patient, and is usually delivered through multiple irradiation ports to achieve a good tumor dose distribution. Accurate localization of tumor in placing t r e a t m e n t ports is essential to the success of irradiation therapy. Treatment planning and tumor dose calculation are aided by computerized techniques to determine the size and 8

number of irradiation ports. In general, smaller doses per fraction and greater fractionation of t r e a t m e n t is preferable for younger children in order to reduce late effects on brain and normal tissue. RADIATION EFFECTS ON NORMAL TISSUES.--Several common and uncommon radiation effects on normal tissues are described below.

Skin reactions.--The most frequent and easily visible radiation reactions appear in skin. Erythema, dry or moist desquamation, and even necrosis were seen in the orthovoltage era. With megavoltage radiotherapy, however, serious skin reactions are no longer seen. E r y t h e m a of mild or moderate degree frequently develops after a 3 - 4 - w e e k latent period. There m a y be macular or papular eruptions, rarely associated with any symptoms. With rapid or high radiation doses, moist desquamation may develop b u t is not frequent. The skin usually recovers completely within a few weeks after the conclusion of radiation treatment. Chronic and late reactions such as atrophy, ulceration, deep fibrosis, depigmentation, and telangiectasia were seen with orthovoltage therapy but are now rarely seen. Hair loss.--Another important reaction is epilation, which appears 3 - 6 weeks after the start of treatment. The hair usually begins to regrow during the second month after completion of irradiation. With excessive high-dose irradiation, epilation may be permanent. By use of the calvarial-scalp compensator, described by the University of Kentucky researchers, 91 the 2 0 % 30% overdose to the vertex of the cranium is no longer delivered, and hair depilation and regrowth are more uniform. Growth problems.--The adverse effects of irradiation on growing bones have been known for years. 92' 93 Many investigators have demonstrated that radiation causes retarded bone growth. The changes produced primarily depend on the total dose delivered, the size of the dose fraction, the overall period of treatment, and the age of the patient at treatment. Animal studies 94 on the effects of radiation indicated that (1) irradiation of the epiphyseal region may cause impaired osteogenesis and bone growth, (2) radiation to the metaphyseal area may cause poor modeling of calcified bone or cartilage, and (3) diaphyseal irradiation m a y result in altered periosteal growth. The major effect on the spine from radiation treatment in children with medulloblastoma is vertical growth impairment of the spinal column. As a rule of thumb, the younger the child and the higher the radiation dose, the greater the probability and extent of impaired spinal growth. Nausea and vomiting.--Mild nausea and vomiting m a y be 9

seen, but severe vomiting rarely occurs. If patients experience unusual vomiting, other possible causes of vomiting should be sought to rule out any serious or superimposed CNS or gastrointestinal problems.

Chronic otitis media and~or otitis externa.--Some patients m a y experience skin changes or other problems in the ear canals, especially with accumulated cerumen and skin infections. This is because the auditory canals are within the field of radiation. Sensory hearing loss.--Some acute decrease in hearing m a y result from edema of the internal auditory meatus. Recently concern has been expressed about late sensory hearing loss after irradiation. The literature suggests a probability of hearing loss of neural origin in younger children, especially after doses higher than 3,000 cGy to the auditory apparatus. The incidence of this problem is not known. Endocrine functions.--Effects of radiation on the endocrine glands are not seen acutely with therapeutic doses, but may be delayed in appearance. It is known that high doses of irradiation, 10,000-20,000 cGy, are needed to destroy pituitary function.95, 98 Delayed changes in endocrine functions, however, can occur and are now being investigated extensively. There are reports in the literature of depressed growth hormone levels in later life in patients who received pituitary irradiation in childhoodY' ~s Damage to the microvasculature is thought to develop in the pituitary gland many years after radiotherapy, and there is also some evidence of a decrease in number of acidophilic cells. Reports on this problem are not conclusive and may relate to the techniques of radiotherapy used, especially dose per fraction and total radiation dose. More definitive information m a y be forthcoming in the future. Myelosuppression.--Spinal irradiation affects hematopoietic function and results in temporary suppression of circulating blood cells. Sometimes fairly severe leukopenia and/or thrombocytopenia can develop, necessitating a temporary interruption of radiotherapy.99, loo However, it is usually not serious, and the blood cell counts and hematopoietic function recover to normal in most cases soon after completion of therapy. Mental retardation.--This subject is important but still not well-defined. Further study will be needed in the future. Late effects m a y accord with extent and size of the tumor, the extent of brain damage produced by the tumor, the age of the patient at the time of diagnosis and treatment, the manner in which radiation was delivered, and whether the tumor was controlled. Uncommon but possible adverse reactions.--Although the incidence is low, brain necrosis, transverse myelitis, and hypothy10

roidism can develop. Young children are more susceptible to irradiation and their organs are developing and growing, so they are at risk of developing many late effects.

Late malignancies.--Malignant tumor may arise in irradiated bone or organs such as thyroid. Leukemia, sarcoma, meningioma, and thyroid tumors are the more frequently encountered malignancies following irradiation. However, the risk of a late malignancy after radiation t r e a t m e n t is not well defined in the literature because other genetic or environmental factors as well as host susceptibility can contribute to the development of second malignancies. Furthermore, synchronous or subsequent multiple primary malignancies m a y not be necessarily related to radiation effects. In general, the incidence 1~176 of another malignancy in children who received radiotherapy for various primary tumors is estimated to be 0.5%-5%, but the exact role of irradiation in relation to the second malignancy is controversial. There is no dose-effect relationship of radiation predicted by the linear hypothesis. Hutchison 1~ has noted that at relatively high doses, radiation is either noncarcinogenic or follows a different quantitative relationship from that seen at low doses. Iacono et al. 1~ described one patient who developed benign multiple meningiomas 27 years after irradiation therapy for medulloblastoma. They collected an additional 37 reports of late meningioma that developed m a n y years after radiotherapy. Only three patients in the series had medulloblastoma as the primary tumor. The majority of meningiomas occurred after lowdose radiotherapy for benign conditions. RADIATION TECHNIQUES.--Of the brain tumors, medulloblastoma is the most sensitive to irradiation, and radiation therapy following brain surgery has long been standard treatment for medulloblastomas. Radiotherapy includes whole cranial and spinal irradiation because medulloblastoma has a strong tendency to spread throughout the leptomeninges within the brain and spinal axis. Since CNS irradiation technique for medulloblastoma was first described by Cutler et al. in 1936, ss there has been continuous improvement in equipment, technique, and the quality of radiation. In the late 1950s, high-energy, megavoltage machines became available for clinical use. Since then, orthovoltage machines used in the past have been replaced by megavoltage machines with better radiation beams. To help understand differences in survival using orthovoltage or megavoltage techniques for the treatment of medulloblastoma, we will review various technical changes in radiotherapy. In Cushing's series, 2' 29 the earliest patients treated in the 1920s received local roentgen therapy to the cerebellar region only. Failure was due to tumor spread to the spinal cord, and Cutler et al. ss decided to add prophylactic spinal axis irradiation to the 11

postoperative radiotherapy. Later, following autopsy studies, they described a similar tumor spread and extension into the third ventricle and into the subarachnoid fluid p a t h w a y over the surface of the brain. The radiation ports were successively increased with each new finding for a period of several years. The small localized ports of irradiation were extended to large, whole craniospinal ports. The radiotherapeutic technique of Cutler e t al. ss entailed the use of five separate p o r t s - - o n e posterior port for the cerebellum, bilateral opposed ports for the head, one port for the cervical and upper thoracic spine, and one port for the lower thoracic and lumbar spine. They used a 200-kV mechanically rectified machine, and the size of typical ports was 10 x 10 cm for the posterior cerebellar port, 15 x 15 cm for the lateral cranial ports, and 12 x 30 cm for the spinal ports. During the 1940s and 1950s, further improvements were made in radiotherapeutic techniques. In the 1950s Paterson and Farr described a technique in which one undivided volume of irradiation was delivered to the entire brain and spinal cord. ~5 They used an orthovoltage 250-kVp machine. The single undivided radiation port was used to avoid cold spots between separate irradiation fields, because autopsy findings in untreated patients had revealed extensive seeding of malignant cells to the brain and spinal cord from the primary tumor in the posterior fossa. To irradiate the craniospinal axis in its entirety, a single spade-shaped posterior field was used, extending from the top of the head to the level of the second sacral vertebra. The patient was placed in the prone position, and a supplemental anterior cranial port was added to the head for more homogeneous cranial irradiation. The minimal radiation dose was 3,500 rad delivered over 5-week periods, or 3,000 rad delivered over 3 weeks to the brain. The spinal cord received a radiation dose of 3,500 rad in 5 weeks. Although there was no cold spot between the cranial and spinal ports from the single large posterior port, the single port technique had the disadvantage of inhomogeneous dose distribution in the brain (Fig 2,A). Paterson and Farr thought that the dose to the cerebellar tumor should always be considerably higher than the minimum tumor dose prescribed. The radiotherapeutic approach in the 1960s was different from that used in 1950s. In reporting their experience with 82 verified cases of medulloblastomas, Bloom et al. 5~ said, "we have not, however, adhered to the principle of uniform dosage throughout the treated volume, which has been the practice in some centers." They used one posterior and two opposing bilateral fields for head irradiation. The m a x i m u m radiation dose to the posterior fossa was generally 4,500-5,000 tad delivered over 6 - 7 weeks, although there was much variation in actual radiation doses used. They aimed for m a x i m u m irradiation of the posterior fossa because almost all of their patients had evidence of persis12

Fig 2,--Historical review of radiation isodose curves. The curves are rough reproductions from the literature, and may not be exact. A, typical isodose curves produced by brain ports for orthovoltage radiotherapy of medulloblastoma, used in 1950s (after Paterson and Farr). Anteroposterior and posteroanterior opposing ports were used. B, isodose distribution in 1960s. Bloom and associates used two opposing lateral brain ports along with the third posterior port. The posterior fossa received higher tumor dose than the rest of the brain, C, the University of Kentucky technique (1970-1980s). Homogeneous maximum tumor dose was given to the posterior fossa, and the rest of the brain received 80%-85% of the posterior fossa tumor dose using 6~ machine. Bilateral opposing ports were used and completely covered the whole brain, including leptomeninges. D, Calvadal-scalp compensator was routinely used to deliver homogeneous radiation dose and to avoid hot spots on the vertex of the skull.

tent or recurrent tumor in the cerebellum and brain stem region following radical radiotherapy. The radiation doses to the rest of the brain varied considerably. Radiation dose to the middle part of the brain ranged between 3,500 and 4,000 rad, and the frontal region of the brain received only 2,500-3,000 rad. Bloom and associates were able to concentrate a higher tumor dose in the posterior fossa with somewhat improved isodose distributions in the cerebellum (Fig 2,B). In 1977 Van Dyk et al. described the current status of radiation technique for the treatment of medulloblastomaJ ~ A common technique is to divide the radiation ports into two or three segments. A parallel pair of two o ~ o s i n g lateral ports is usually used for whole brain irradiation. Co or 4-meV linear accelerator machines are commonly used and are most suitable for ther13

apy. The spinal cord is irradiated through one or two direct posterior ports, with a gap separating the spinal from the brain irradiation port. A radiation dose of 3,500-4,000 cGy is given to the CNS, and the primary tumor in the posterior fossa receives an additional boost of 1,500-2,000 cGy. Megavoltage beams of excessively high energy are less satisfactory for brain and spinal cord irradiation (e.g., 6 - 1 0 meV). RADIATION TREATMENT AT THE UNIVERSITY OF K E N T U C K Y . T h e system in use at the University of Kentucky has achieved

excellent curative results and is described here (Fig 2,C). The goal of modern radiotherapy is to deliver a tumoricidal dose to the tumor bed where microscopic or residual tumor cells exist and a prophylactic dose to the rest of the craniospinal axis. Whole craniospinal radiation treatment is instituted in two large separate portals of irradiation: lateral cranial ports to the whole brain and one long posterior port to the spinal axis. At the University of Kentucky Medical Center, the radiation to the whole brain is delivered through two parallel opposed bilateral ports using a 6~ or 4-meV teletherapy unit. The whole brain receives 3,500-4,500 cGy over 32-38 days, with a dose per fraction of 150-160 cGy, depending on patient age. At the same time, the spinal axis is treated using a single direct posterior field with a tumor dose of 3,000-3,500 cGy and a dose per fraction of 125-150 cGy over 5 - 6 weeks, again depending on patient age. The gap between the cranial and spinal fields is moved up and down, using short and long fields alternately to avoid hot and cold spots within the gapped area (Fig 3). Following whole brain irradiation, an additional boost dose of 1,000-2,000 cGy is added to the primary tumor bed in the posterior fossa. Total tumor dose to the posterior fossa should be 5,000-5,500 cGy delivered over 6 - 7 weeks and is determined by patient age and residual tumor burden. A uniform tumor dose within the cranial field is essential, and to accomplish this careful techniques are essential. We have used a calvarial-scalp compensator 91 which was developed at this institution (Figs 2,D and 3). If a compensator is not used, the dose at the vertex of the skull and the curved areas of the skull is about 25%-30% higher than at the midplane. If a very high-energy beam is used, a correct dose may not be delivered to the leptomeninges at the vertex of the skull. The field should be a large open field with the compensators in place and not blocked with lead except in critical areas, such as over the eyes of the bases of the skull. The field should include the frontal and temporal region. In some recent studies recurrence in these zones has been noted, probably from too small a field or excessive blocking. RADIATION TUMOR D O S E . - - A l t h o u g h r a d i o t h e r a p y h a s b e e n

used for t r e a t m e n t of medulloblastoma since the discoveries of ]4

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Fig 3.--Modern optimum megavoltage radiotherapeutic technique entailing the use of two lateral opposing cranial ports to the whole brain and a matching, single posterior port to the spinal axis, with a gap (/) between cranial and spinal ports. The gap is moved up and down, using short and long fields alternately. This is to avoid hot or cold spots within the gapped area. Calvarial-scalp O compensator is used as shown in the cranial port. (From Chin and Maruyama. 7 Reproduced by permission of Pergamon Press, Ltd.)

x-ray in late 19th century, the radiation dose necessary to control the primary tumor was not established until recently. Many textbooks recommend a wide range of radiation dose, such as 4,500, 5,000-5,500, or 5,000-6,000 cGy delivered over 6 - 7 weeks. Irradiation must be prescribed to a precise therapeutic dose--one with a high likelihood to cure the patient with medulloblastoma. It has recently been shown that there are remarkable differences in outcome and local control of tumor between radiation doses of 4,000 and 5,500 cGy. The dose chosen can lead to frequent success in tumor control or regular t r e a t m e n t failure in the primary site.

Low-dose radiotherapy.--In 1981 Lowery et al., 1~ from the Bowman-Gray School of Medicine, reported their experience with low-dose megavoltage irradiation of medulloblastoma. They used a 4-meV x-ray machine or 6~ teletherapy unit and a uniform dose of 4,500 cGy to the midplane of the whole brain over a 6-week period. No boost dose was given to the posterior fossa, and the spinal cord received 3,500 cGy. One exceptional patient received 4,800 cGy to the whole brain and 3,733 cGy to the spinal cord. The median follow-up period was 4 years 9 months, and there were only eight survivors (44%) from a total 18 patients at the last follow-up. Only half of 12 patients survived 3 years or longer (50% 3-year disease-free survival rate). The clinical failure and recurrence rate were close to 50%. Of 15

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nine proved recurrences, seven were intracranial (about 78%). There were five extracranial nervous system metastases (28%), and two patients had biopsy-proved bone metastases with no evidence of intracranial recurrence. In 1978, Nuchel and Andersen 1~ from Denmark reported 36% 3-year and 33% 5-year survival rates in 44 patients with medulloblastoma. With a few exceptions, they used a similar technique of 4,500 cGy whole brain irradiation delivered over 6 weeks and 3,000 cGy to the spine delivered over 4 - 5 weeks. The patients who received low-dose radiation t r e a t m e n t of less t h a n 4,500 cGy had at best a 33%-40% chance of tumor control at 5 years.

High-dose radiotherapy.--Beginning in the 1970s, encouraging survival results have appeared in the literature. A number of investigators have reported 70%-80% 5-year survival rates following high-dose radiotherapy. 3' 7-10, 107 In 1981, Chin and M a r u y a m a 7,~7 demonstrated a dose-response relationship in the radiotherapy of medulloblastoma based on a comprehensive analysis of their experience at the University of Kentucky. As shown in Figure 4, the overall 5-year survival rate in the entire group was 44%, comparable to figures reported in the older literature. The series included as well patients who had been treated by the inhomogeneous radiation techniques of earlier eras. Since 1970, however, medulloblastoma patients have been treated with a homogeneous dose technique of radiotherapy and receive high-dose radiotherapy (>5,000 cGy) using a uniform technique. The patients seen before 1970 received low-dose radiotherapy (<4,000 cGy) using a nonhomogeneous radiation technique. We referred to the former group as the high-dose radiation group, or optimum radiation group, and the latter as the low-dose radiation group, or suboptimum radiation group. A striking difference in survival was observed between these two groups (see Fig 4). The 5-year survival in the optimum group was roughly 80%, compared to around 20% in the suboptimum group. To confirm our findings of improved response with highdose radiotherapy, we reviewed 139 cases of medulloblastoma reported in the literature for which sufficient data were available to enable us to construct survival curves according to the radiation tumor dose used (i.e., high- versus low-dose radiotherapy). There were 105 patients in the high-dose group, and the 5year survival was around 80%, was almost identical to our data. The suboptimum or low-dose group was made up of 34 patients who received less t h a n 5,000 cGy. The survival curve continued to fall steeply, and its shape was very similar to the shape of the survival curve in our suboptimally treated patients. Optimum radiation tumor dose.--The most important target in radiotherapy is the tumor-bearing area in the posterior fossa. 16

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0 I 2 3 4 5 6 TIME AFTER TREATMENT (YEARS) Fig 4.--Survival curves according to radiation dose. An analysis at the University of Kentucky revealed differences in survival of patients treated by low- or high-dose radiotherapy. (Modified from Chin and Maruyama. 7 Reproduced by permission of Pergamon Press, Ltd.)

The tumor dose in this region should be high enough to sterilize the residual tumor burden. In the preliminary analysis of our data in the period 1964-1976, 7 patients were divided into two large categories of optimum (high-dose) or suboptimum (lowdose) radiotherapy. The survival statistics are shown in Figure 5 in relation to radiation tumor dose to the tumor bed in the posterior fossa. For a better understanding of the tumor dosesurvival relationship, each category was further subdivided, as shown in Figure 5. Of the 11 patients in the high-dose radiation groups (5,000-6,000 cGy), eight (72%) survived at least 5 years. Of the nine patients in the low-dose radiation groups, eight (89%) died within 5 years. Although the number of patients was small, a definite improvement in survival with larger radiation doses was noted. Survival rate in the suboptimum category was poor, and doses of radiotherapy less than 4,000 cGy were totally ineffective (0% 5-year survival rate). In the category of optimum radiotherapy, there were differences in survival between groups III and IV (75% vs. 83% 5-year survival). To explore the reproducibility of the radiation tumor dose-survival relationship, we carefully examined a different subset of medulloblastoma patients in an extended period up to 1981. 5s' 59 In this period 17

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ment in survival status with increment of radiation tumor dose to the primary tumor bed is apparent. Subgroups I and II received suboptimum radiation; subgroups III, IV, and V received optimum radiation. (Modified from Chin and Maruyama. 7 Reproduced by permission of Pergamon Press, Ltd.)

(1964-1981) we saw 23 children with medulloblastoma. The child patients 59 were divided into two large categories (categories A and B, or suboptimum and optimum radiotherapy), or four subgroups (A1, A2, B1, B2) according to the tumor dose in the same fashion as above. As shown in Figure 6, no long-term survivor (0% 5-year survival rate) was seen in patients given very low-dose radiotherapy, less t h a n 4,000 cGy (subgroup A1). Small increases in tumor dose made a difference in the survival status of the patients. When the tumor dose was increased to above 4,000 cGy but less than 5,000 cGy, roughly one third of patients survived (subgroup A2). With further increases in dosage, progressive improvement in survival was observed. In the optimum radiotherapy category, treatment results turned out to be entirely different from those of the suboptimum radiotherapy category. In subgroup B1, more than half of patients who received moderate tumor doses of 5,000-5,200 cGy were long-term survivors. The best results were obtained when the tumor dose was at least 5,400 cGy (subgroup B2). With this schedule we observed almost 100% 5-year cures if treatment was initiated at an early stage of disease.

Chemotherapy Trials with chemotherapy have resulted in favorable response in the treatment of certain childhood tumors, such as acute leu18

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3 4 5 6 7 8 9 I0 II 12 YEARS AFTER TREATMENT Fig 6.--Survival status of 23 children with medulloblastoma in different radiotherapeutic groups. Category A (low-dose, suboptimum radiotherapy): A1, tumor dose less than 4,000 cGy delivered over 4-5 weeks; A2, 4,000-4,900 cGy delivered over 4-6 weeks. Category B (high-dose, optimum radiotherapy): B1, 5,000-5,300 cGy of irradiation delivered over 5-7 weeks; B2, 5,400-5,500 cGy delivered over 6-71/2 weeks. (From Chin and Maruyama.s9 Reproduced by permission of Martinus Nijhoff, Publisher.) I

2

kemia, Hodgkin's disease, Wilms' tumor, and others. In view of such encouraging results in certain malignancies in children, there have been multiple trials of systemic chemotherapy for primary medulloblastoma by cooperative groups or single institutions. Overall results have shown no definite advantage of adjuvant chemotherapy for the treatment of medulloblastoma. For a better understanding of the results of current chemotherapy, published reports from the United States and Europe on adjuvant chemotherapy for the initial treatment of primary medulloblastoma are reviewed below. SOUTHWEST ONCOLOGY GROUP (SWOG) STUDY T R I A L - - T h e SWOG study 1~176 included patients with medulloblastoma as well as those with ependymoma and consisted of two therapeutic arms, radiotherapy alone and radiation plus chemotherapy. In this review only the experience with medulloblastoma will be considered for analysis. Of the 34 evaluable patients with medulloblastoma, 18 were randomly assigned to receive no further treatment (no chemotherapy) and 16 were assigned to receive chemotherapy following postoperative radiotherapy. Modern techniques of radiotherapy were used with megavoltage machines. Parallel opposing bilateral ports were used to deliver ra19

diation to the whole brain and the spinal port extended from the sacrum to the bottom of the C-2 vertebra. The t u m o r dose to the whole brain was 4,000 cGy at midplane (3,500 cGy for children less than 3 years old). An additional 1,000 cGy of boost irradiation was given to the posterior fossa (total dose of 4,500-5,000 cGy). The tumor dose to the spinal axis was 3,000 cGy in older children and 2,500 cGy in children less than 3 years old. The spinal port extended from the junctional area in the cervical region to the level of S-2 and was treated concurrently with lateral whole brain irradiation. Chemotherapeutic agents used were vincristine (2.0 mg/m2), hydrocortisone, and methotrexate, the latter two at the same dose of 15.0/m 2 intrathecally. The chemotherapy was initially started in the first week following completion of radiation therapy. All three drugs were given weekly for up to four doses, and then every 4 weeks for 12 doses. The total course took 52 weeks to complete. The SWOG study demonstrated no advantage to adjuvant chemotherapy (Fig 7). There were more severe toxic effects in children who received combination chemotherapy and radiotherapy, especially hematologic and some neurologic reactions.

Fig 7.--Survival in medulloblastoma patients treated with radiotherapy with or without chemotherapy in the Southwest Oncology Group Study. See text for details. (From van Eys et al. 1~176 Total Fail 1.0 ~ , ~ l!

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INTERNATIONAL SOCIETY OF PEDIATRIC ONCOLOGY (SIOP) STUDY: THE ITALIAN EXPERIENCE AS A SUBGROUP OF THE CHEMOTHERAPY AND RADIOTHERAPYARM.--From 1975 to 1980 33 con-

secutive patients were treated according to the chemotherapy arm of the SIOP protocol. High-dose radiotherapy was u s e d - - u p to 5,000-5,500 cGy to the primary tumor, 3,500-4,000 cGy to the whole brain, and 3,000-3,500 cGy to the spinal cord. Children less than 3 years of age were given tumor doses reduced by 1,000 cGy. No details as to radiation technique (e.g., ports and tumor dose fractions) are available. During the course of radiation treatment, IV vincristine (1.0 mg/m 2) was given weekly. Maintenance therapy was started 4 weeks after the completion of radiotherapy with weekly IV vincristine (1.5 mg/m 2) and oral CCNU (100 mg/m 2) every 4 weeks for up to eight courses over a period of 48 weeks. Because this trial represented a subgroup of the chemotherapy a r m in the SIOP protocol, there was no control group (radiotherapy alone) for comparison in the study. Most patients had less t h a n 5 years of follow-up. The mean actuarial survival was about 28 months. On short-term follow-up, there were already three local failures, five spinal failures, and two cases of extra-CNS metastases. The overall survival result was not better than that of other studies using radiation alone. CHILDREN'S CANCER STUDY GROUP (CCSG) AND RADIATION THERAPY ONCOLOGY GROUP (RTOG) JOINT S T U D Y . - - A prelimi-

nary report on t h e interim results of the joint CCSG and RTOG study l~ revealed that survival was similar in groups treated with combined chemotherapy-radiotherapy and radiotherapy only. Of the 144 patients entered in the study at the time of the report, only 32 had been studied for 2 years or longer. The calculated life t a b l e survival at 2 years was 67% for patients receiving radiation and chemotherapy and 72% for those treated with radiotherapy alone. Some 65% of patients treated with chemotherapy developed moderate to severe hematologic toxic effects, compared to 35% in the control group receiving radiation alone. Radiation therapy was interrupted in 35% of patients receiving chemotherapy versus 16% in the control group because of depressed peripheral blood cell counts. SWISS PEDIATRIC ONCOLOGY GROUP (SPOG) STUDY T R I A L - - I n the SPOG study, 11~ 20 children with medulloblastoma received adjuvant chemotherapy with procarbazine, vincristine, and prednisone after surgical resection and cerebrospinal radiotherapy. The survival results were compared with the preliminary results of the CCSG and SIOP studies. The SPOG study also failed to demonstrate superior survival results when chemotherapy was added to radiation. Postoperative radiotherapy was initiated 2 - 4 weeks after surgery. The radiation dose to the poste21

rior fossa was 5,000-6,500 cGy delivered over 7 - 8 weeks, 3,5004,500 cGy to the rest of the brain, and 3,000-3,500 cGy to the spinal cord delivered over 5 - 6 weeks. Chemotherapy was begun 2 months after the completion of radiotherapy. Each course of chemotherapy consisted of IV vincristine (1.5 mg/me), three doses given at weekly intervals; oral procarbazine (150 mg/m 2) for 14 days; and oral prednisone (40 mg/m 2) for 14 days. This chemotherapy schedule was repeated every 6 weeks for up to eight courses. Survival was similar in control patients in the CCSG and SIOP trials who were given radiotherapy alone. ITALIAN CHILD'S NEUROONCOLOGY GROUP (ICNG) STUDY.The ICNG study 111 was a randomized two-arm study limited to

medulloblastoma. Two different chemotherapeutic regimens were compared; there was no control group receiving radiation alone. Patients received either (1) surgery + radiotherapy + CCNU and vincristine, or (2) surgery + radiotherapy + CCNU, vincristine, and procarbazine. Radiation was given in dosages of 3,500-4,000 cGy to the whole craniospinal axis and 5,000-5,500 cGy to the posterior fossa delivered over 5 - 6 weeks. All patients received IV vincristine in a dosage of 1.0 mg/m 2 at weekly intervals throughout the course of radiotherapy. The rest of the chemotherapeutic regimen started 4 weeks after the conclusion of radiation treatment. The schedule of regimen I consisted of CCNU (120 mg/m 2 orally) on day 1 and vincristine (1.5 mg/m 2 IV) on days 1, 8, and 15. Regimen II included procarbazine (100 mg/m 2 orally) on days 8-21, in addition to regimen I drugs. Seventeen children with medulloblastoma were entered into the study in a 3-year period. Pezzotta et al. reported that all but one were alive at the time of reporting, although the median followup period was not clear. In contrast to other chemotherapy trials, there was only one case of severe leucothrombocytopenia. UNIVERSITY OF PADOVA EXPERIENCE.--Twenty-nine patients were randomly assigned to one of two chemotherapy groups: intrathecal methotrexate (trial M) or IV cyclophosphamide (trial C). All patients received 6~ radiotherapy after brain surgery. The whole craniospinal axis received radiation; 5,500 cGy was delivered to the primary tumor site, 4,000 cGy to the whole brain, and 3,500 cGy to spinal cord over a period of 6 - 7 weeks. The patients in trial C received induction therapy with IV vincristine (1.5 mg/m 2) and cyclophosphamide (600 mg/m2), and then maintenance therapy of alternate courses (every 2 weeks) of IV vincristine and cyclophosphamide (at the same dosages) for a total of 48 doses over a 1-year period. In trial M, IV vincristine (1.5 mg/m 2) and IT methotrexate (10 mg/m 2) were used for induction therapy; maintenance treatment was with intermittent courses of IV vincristine (every 2 weeks) and methotrexate for 1 year. Again, the same drugs and doses were used in mainte22

nance therapy. The results were not encouraging. The local recurrence rate was 69% in both trial C and trial M. Two patients in each group developed extensive dissemination as well as spinal cord metastases. Thus, chemotherapy preceding radiotherapy did not appear to increase tumor control frequency. USL OF PERUGIA EXPERIENCE.--In this study 113 low-dose radiotherapy was used; the whole brain received 2,500-3,000 cGy with an additional 1,500 cGy boost to the posterior fossa, and the spinal axis received 2,500 cGy. Chemotherapy was started within 4 weeks after the completion of radiotherapy. A single oral dose of CCNU (130 mg/m2), or the IV administration of BCNU (80 mg/m 2) for 3 days, was given every 8 weeks for 2 years. Seventeen patients were followed up for 12 months and longer. There were 12 recurrences (71%) in this group. Of the 12 patients who relapsed, seven had recurrence in the posterior fossa (58%). There were two patients with spinal dissemination and one with extra-CNS metastasis. The 3-year survival rate was 40% and the 5-year survival rate was 25%. Thus, inadequate and low-dose radiation with aggressive high-dose nitrosourea therapy did not improve tumor cure or local control or prevent distant spread of medulloblastoma. Various combinations of chemotherapeutic agents have been used in conjunction with radiotherapy. The most common drugs used were vincristine, methotrexate, steroids, and nitrosoureas. Cyclophosphamide and procarbazine were also used in some trials. At present, none of these combination chemotherapy programs has had positive effects on cure or control of medulloblastoma. The overall results have shown no definite advantage for the use of adjuvant chemotherapy following radiotherapy in the t r e a t m e n t of medulloblastoma. CHEMOTHERAPY TOXICITY.--Acute adverse effects of adjuvant chemotherapy have been considerable. 1~176 1os-11s In the SWOG experience, toxic effects were severe in children who received combination chemotherapy and radiotherapy. In two children (of 34 patients) toxic effects were lethal. Side effects found in the chemotherapy trials were leukothrombocytopenia, anemia, somnolence, peripheral neuropathy, headaches, constipation, paresthesias, and mucositis. The most common acute toxic reaction has been hematologic toxicity, and chemotherapy has had to be modified in almost all patients in the various series. Some investigators noted only mild leukothrombocytopenia t h a t did not require interruption of radiation therapy for blood or platelet transfusions. When a combination of CCNU and methotrexate was used, there was often a long-lasting thrombocytopenia, so t h a t the later doses of chemotherapy had to be omitted or reduced. Toxic effects of vincristine include loss of deep tendon reflexes, pares23

thesias, anesthesia, and leg pain. Toxic effects are usually not so severe as to require discontinuation of the drug. Procarbazine causes a moderate hematologic toxicity, especially during the first two cycles of therapy. RETREATMENT FOR RECURRENT MEDULLOBLASTOMAS Patients with recurrent medulloblastoma can be reirradiated and often show a good symptomatic improvement. The radiation technique and tumor dose can be variable and should be individualized. There was a report t h a t 2,000-3,000 cGy had been well tolerated. 114 Chemotherapy following recurrence of medulloblastoma m a y prolong the lives of patients. At present, it seems appropriate to say t h a t the prognosis of recurrent medulloblastoma is generally bleak, and r e t r e a t m e n t gives only a palliative benefit. This is because additional radiotherapy is limited due to the previous irradiation, and because there are few effective drugs. Recurrent medulloblastomas m a y sometimes be sensitive to multiagent chemotherapy, and remission induction can occur following successful retreatment, with longer survival of patients in some cases. Combination chemotherapy-radiotherapy could benefit some patients who develop recurrent or metastatic disease. There have been some encouraging reports on the retreatment of recurrent medulloblastomas using chemotherapy and irradiation. In 1978, the Southwest Collaborative Study 115 reported a 73.4% response rate of recurrent brain tumors to combination chemotherapy consisting of nitrogen mustard, vincristine, procarbazine, and prednisone (MOPP). There were ten patients with recurrent medulloblastoma in the series; three showed an unequivocal response, five showed a partial response, and two showed no response. The median duration of response i n responding patients was 6.5 months. According to the experience reported by Thomas et al., TM all eight patients with recurrent medulloblastoma responded to a combination chemotherapy regimen. They were treated with multiagent chemotherapy with vincristine, BCNU, dexamethasone, and intrathecal and intermediate-dose IV methotrexate. 114 Five patients also received low-dose local radiotherapy. Six patients showed complete responses and two showed partial responses. The median duration of response was 18.8 months. A study by Edwards et al. 51 indicated t h a t the best responses in the t r e a t m e n t of recurrent medulloblastoma had been obtained using a combination of a nitro~ sourea (CCNU), vincristine, and procarbazine. Of the 16 patients treated for recurrent medulloblastomas, ten showed a response. The median time to progression was 45 weeks. Levin et al. 118 reported a median survival of 2 years in 36 patients with recurrent medulloblastoma who had been treated with various 24

combination chemotherapy protocols. Intraventricular and intrathecal therapies included cytosine arabinoside (Ara-C), methotrexate, and thio-tepa given as single agents. Major systemic agents used alone or in combination included CCNU, procarbazine, vincristine, and hexitol epoxide. The patients also were reirradiated when there was definite tumor progression after all other therapies failed and/or because myelosuppression was so severe that further chemotherapy was not possible. The median period to first recurrence was 24 months, while the median survival was 56 months. This represents a gain of approximately 29 months from first recurrence as a result of chemotherapy and reirradiation. They reported that the quality of survival was good in m a n y patients, although most school-aged children lagged behind their peers in class level attained. According to Edwards et al. methotrexate seemed to be the most active agent, but two of five patients developed a transient encephalopathy, s2 They also found that currently available systemic chemotherapies could not eradicate malignant cells in the CSF or reduce elevated putrescine levels caused by cranial or spinal subarachnoid dissemination of medulloblastoma. 62 ' 116 An effective t r e a t m e n t was reirradiation of the craniospinal axis in conjunction with misonidazole. With this regimen, malignant cells in the CSF were cleared in three of four patients. 62 Their conclusion was that control of the primary tumor would be achieved only with development of effective chemotherapeuticagents, 62 RESULTS

Until the advent of megavoltage radiation therapy, t r e a t m e n t results were poor and it was widely belieYed that medulloblastoma was a hopeless disease. While radiation therapy in the past was inadequate and accomplished little beyond temporary arrest of tumor progression, modern megavoltage radiation is now able to overcome the physical limitation of radiation dose distribution of the poorly penetrating kilovoltage x-rays. The number of long-term disease-free survivors began to increase, and in the 1970s favorable reports of more than 70% 5-year survival appeared.~, 7, 9, 52, 70, 1or Table 1 shows the historical trends and changes in survival of patients with medulloblastoma. SURVIVAL

Historical Review In Bailey's and Cushing's series, 1 the estimated average survival of p a t i e n t s with medulloblastoma was about 12 months from onset of disease. After operation, only 6 - 9 months elapsed before recurrence. Table 1 shows the progressive changes and 25

TABLE

1 . - - P A S T AND PRESENT SURVIVAL RESULTS*

AVERAGE SURVIVAL FROM ONSET

1930 (Cushing et al.): (Bailey et al.):

8-9 mo. 12 mo. (surgery alone) 34 mo. (with postop, radiation)

3-YEAR SURVIVAL

1949 (Lampe et al.): 1953 (Paterson et al.):

28% 54%

5-YEAR SURVIVAL (KILOVOLTAGE)

1958 (Paterson): 1966 (Bouchard): 1969 (Bloom):

41% 21% 32%

5-YEAR SURVIVAL (MEGAVOLTAGE)

1970 (Hope-Stone): 75% 1979 (Hirsch et al.): 72% 1981 (Chin & Maruyama): 78% 1981 (Pichler et al.): 74% 1981 (Berry et al.): 74% 1982 (Duffner et al.): 74% *From Chin and Maruyama. 67 Reproduced by permission of Alan R. Liss, Inc. i m p r o v e m e n t in s u r v i v a l from t h e t i m e r o e n t g e n x-rays w e r e used by B a i l e y a n d C u s h i n g 2 to t h e era of o r t h o v o l t a g e irradiation, and to t h e e r a of m e g a v o l t a g e r a d i a t i o n t h e r a p y .

Survival Results with Modern Therapy The first r e p o r t s on t h e i m p o r t a n c e and dose d e p e n d e n c e of t u m o r control a p p e a r e d only r e c e n t l y . S e v e r a l y e a r s ago, we rep o r t e d on our e x p e r i e n c e at t h e U n i v e r s i t y of K e n t u c k y , w h i c h showed significantly i m p r o v e d s u r v i v a l at 5 y e a r s w h e n a n adeq u a t e a n d o p t i m u m dose of r a d i o t h e r a p y was g i v e n a f t e r surgical resection (see Fig 4). C o m p a r e d to t h e poor survival in pat i e n t s g i v e n low-dose r a d i o t h e r a p y , we found t h a t a n a p p r o x i m a t e l y 80% 5-year s u r v i v a l was possible if a h i g h t u m o r dose was d e l i v e r e d to the p r i m a r y t u m o r site in the posterior fossa. 7 A g r e a t n u m b e r of series r e p o r t e d in the l i t e r a t u r e showed s i m i l a r l y improved s u r v i v a l w i t h high-dose i r r a d i a tion.5, 7-1o, 52, 70 In addition, we found a r e l a t i o n s h i p b e t w e e n r a d i a t i o n t u m o r dose and s u r v i v a l (see Figs 3, P a r t I, and 5). C o m p a r a t i v e d a t a collected from t h e r e c e n t l i t e r a t u r e support a r a d i a t i o n d o s e d e p e n d e n t t u m o r control r e l a t i o n s h i p in m e d u l l o b l a s t o m a (see Figs 4 and 5, P a r t I). 47' 83, ~v T h e t r e a t m e n t r e s u l t s in r e l a t i o n to r a d i o t h e r a p e u t i c t e c h n i q u e s are shown in F i g u r e 5. The 5 - y e a r s u r v i v a l in p a t i e n t s w i t h m e d u l l o b l a s t o m a h a s improved from less t h a n 50% following low-dose r a d i o t h e r a p y to about 70% following high-dose m e g a v o l t a g e irradiation. It should be n o t e d t h a t all stages of disease w e r e included in t h e s e series, a n d t h e proportion of stages in each series was v a r i a b l e . D e p e n d i n g on 26

the proportion of early or advanced stage disease, there were differences in survival from series to series, although modern high-dose radiotherapy yielded roughly 70%-80% 5-year survival rates for all stages. Further detailed analysis of our data at the University of Kentucky revealed significant difference in survival rates in patients in the high-dose radiation group receiving 5,000-5,400 cGy of tumor dose delivered to the posterior fossa: there was an additional survival benefit with incremental tumor doses between 5,000 and 5,400 cGy (Fig 8). The treatment data of different radiotherapeutic groups were pooled to construct survival curves which showed a progressive improvement in survival with increment of total tumor dose. In Figure 8, A, different survival outcomes are shown according to radiation tumor doses. Curve A reflects survival in all 30 patients, who received widely varying tumor doses ranging from 3,700 cGy to 6,000 cGy. The 5-year survival rate was 45%, comparable to figures reported in the literature. Curve B represents the patients who received high-dose radiotherapy of at least 5,000 cGy of tumor dose delivered to the posterior fossa, with dose ranging from 5,000 to 6,000 cGy; the 5-year survival rate increased to 70%. With further increase of tumor dose, additional improvement in survival was again observed and the 5year survival rate increased to 79% (curve C). Figure 8, B, Fig &--Survival in patients with medulloblastoma of all stages treated at the University of Kentucky Medical Center. A, comparison of survival results in the highdose radiotherapy (curve B) group (---5,000 cGy) with survival in group as a whole (variable radiation doses (curve A) of 3,700-6,000 cGy). B, comparison of survival curves in four different radiation dose groups ->5400 cGy (curve C); 5000-5300 cGy (curve D); 4000-4900 cGy (curve E); -<4000 cGy (curve F). (Modified from Chin and Maruyama.67 Reproduced by permission of Alan R. Liss, Inc.)

MEDULLOBLASTOMA(DOSE/ RESPONSE RELATIONSHIP) I00

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shows survival in four subdivisions o f the radiation groups; group C received more than 5,400 cGy to the posterior fossa; group D, 5,000-5,300 cGy; group E, 4,000-4,900 cGy; and group F, less than 4,000 cGy. A close correlation was evident between radiation dose and survival: A progressive improvement in survival was seen with increments of radiation tumor doses in each group. The m a x i m u m survival was observed at a radiation dose of at least 5,400 cGy to the posterior fossa. Low-dose radiotherapy was not effective. Very low doses, less than 4,000 cGy, were totally ineffective and there were no 5-year survivors. From these survival curves, it is apparent that optimum radiotherapy should potentially be able to cure the disease in a majority of patients. Inadequate radiotherapy does not alter the natural course of medulloblastoma, as can be ascertained from Figure 8 (curves E and F). Of the number of prognostic factors influencing the outcome of medulloblastoma, the most important is the stage of disease at presentation. We noted two distinct presentations of medulloblastoma that also behaved differently in response to radiotherapy. 35 As shown in Figure 9,A, early stage medulloblastomas responded favorably to radiotherapy, and if adequate radiotherFig 9.--Survival in patients with medullobtastoma according to clinical stage and radiation tumor dose at the University of Kentucky Medical Center. A, low stage groups showed a direct relationship between survival of the patients and radiation tumor dose. B, high stage groups were not very responsive to radiotherapy, even with high-dose, optimum irradiation. (From Chin and Maruyama.~7 Reproduced by permission of Alan R. Liss, Inc.)

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apy was given, almost 100% 5-year survival was possible (curve C). In sharp contrast, the curves for advanced medulloblastoma (Fig 9,B) showed significantly poorer survival, even with highdose optimum radiotherapy. We observed no significant difference in survival of patients presenting with advanced stage disease whether treated with high- or low-dose radiotherapy. The curves c', d', and g' (Fig 9,B) fell steeply regardless of radiation dose. The results of radiotherapy in advanced stage disease were disappointing, and few patients survived 5 years. ANALYSIS OF CURRENT CHEMOTHERAPY Various studies of combination chemotherapy-radiotherapy have been carried out to determine whether this t r e a t m e n t plan is more effective than radiotherapy alone. The SWOG study l~176 used high-dose radiotherapy and chemotherapy. The t r e a t m e n t results showed no effect of adjuvant chemotherapy (Fig 7), and the report concluded that the survival rate among patients receiving radiotherapy only compared favorably with reports in the literature. The SIOP trial l~ reported results with combined chemotherapy-radiotherapy with a recurrence-free survival rate of 80% at 3 years. The majority of studies of adjuvant chemotherapy (CCSG, SPOG, University of Padova, University Hospital of Bern, 99 USL of Perugia) demonstrated that the survival rate with chemotherapy-radiotherapy was not superior to that with radiation alone. On the other hand, the incidence of adverse side effects with the combined modality was considerable and was reported to be twice as high as that following radiation alone.99, lo9 The addition of adjuvant chemotherapy to radiotherapy did not influence recurrence rate. There were 12 recurrences among 20 patients (60%) within 28 months in the Perugia series (low-dose radiotherapy and chemotherapy were used in the study). 113 Five (40%, or 25% of the total) patients developed spinal or bone metastases with or without local recurrence in the posterior fossa. In the SIOP series, l~ distant metastases in the spinal axis or extra-CNS occurred in all six recurrent cases (20%). According to Gerosa et al., 112 six of 29 patients (21%) developed spinal or extracranial metastases; four spinal and two bony metastases appeared within 5 years. A good palliative role for combined chemotherapy and reirradiation in the t r e a t m e n t of recurrent medulloblastoma was described earlier. TM 116 However, Mooney et al. 117 were not optimistic about the role of chemotherapy in recurrent medulloblastoma. Based on their own experience and a literature review, Mooney et al. 117 stated, "recurrent medulloblastoma sometimes responds to chemotherapy; the drugs most widely used a r e nitrosoureas, procarbazine, and vincristine, alone or in combination. Unfortunately, the re29

sponse rates are low and responses are not usually sustained even using these agents in combination. Information on responsiveness to other drugs is, therefore, urgently needed." While the treatment of all stages with chemotherapy appears unwarranted, effective multiagent chemotherapy identified from the treatment of recurrent tumors may have a role in the treatment of advanced stage medulloblastoma. This should be combined with high-dose optimum craniospinal irradiation, and systemic as well as intrathecal and intraventricular routes of drug administration should be used. The advanced stage is recognized by serial CT study for irreversible hydrocephalus, myelography, and bone marrow biopsy (see CT staging system proposed in Part I). FUNCTIONAL AND PERFORMANCE RESULTS

Optimum therapy for cerebellar medulloblastoma has led to long-term survival in patients with this extremely malignant tumor. As the number of young survivors has increased, attention has shifted to the long-term performance or sequelae following radiation, surgery, and chemotherapy. Because of the relatively few patients treated at each institution, few in-depth studies have been published on endocrine function, intellectual and physical development, and psychosocial behavior. Fragmentary and brief studies in the past were generally optimistic, although some recent reports are discouraging. In the series of patients treated at the University of Kentucky, Fig lO.--Personal data and survival in 11 long-term survivors at the University of Kentucky Medical Center. (From Chin and Maruyama. 119 Reproduced by permission.) AGE 8, SEX (yr./too.)

RADIATION DOSE

(posteriorfossa/spinalaxis)

LOW DOSE AI BI

I/6 M 510 F

HIGH DOSE 5/0 M C 8/0 F D 5/0 M UJ E or) 3/4 F
I

0

5129/3500 5400/3500 5200/3500 5000/3500 5000/3500 5500/3500 5400/3500

F

5400/3686

I0/0 F

5450/3500

7/0

J

K

4500/3000 4960/3500

I

I

5

I0

YEARS AFTER

3O

TREATMENT

there were 11 long-term survivors (Fig 10); nine had received high-dose radiotherapy and two had received low-dose radiation.lls, 119 The patients were divided into three age groups: younger t h a n 4 years old at t r e a t m e n t (group I); between 4 and 6 years old at t r e a t m e n t (group II); and of 7 years or older at treatment (group III). The following discussion on functional and performance results is based on this patient material.

Physical Status The most frequent abnormal finding in physical status has been short stature. Ataxia is a long-lasting sequela, but usually is very mild. In a series of patients treated by Broadbent et al., 12~ all the patients had some ataxia, from slight incoordination of fine movement to severe ataxia involving both upper and lower limbs. Nystagmus was seen in some patients, but no cataracts were noted. The youngest children, treated at the age of 1.1 years old, was considerably handicapped by ataxia and a probable visual field defect as well as hearing loss. This patient was treated with 250-kV orthovoltage radiation, and hearing loss was not due to radiation but to serous otitis. Danoff et al. 1~ found t h a t neurologic function appeared to be good to excellent in the majority of patients. In our series, no one was physically disabled (Table 2). The majority had short stature. All were able to walk and run; m a n y were able to swim and ride a bicycle. More t h a n h a l f enjoyed physical activities but did not participate in group activities. Esophoria was an abnormal neurologic finding in two patients. In these patients, esophoria was present before t r e a t m e n t and tended to improve slowly over a long period of time. Bouchard, 122 Hope-Stone, 1~ Bongartz et al.,5-and othersl2~, 124 found no significant physical effects in the majority of long-term survivors. Growth and Stature A short stature is a prominent and almost invariable sequela of radiation therapy. The retarded height has often been t h o u g h t to be due to growth hormone deficiency. However, several studies have demonstrated retardation of spinal growth as a result of growth-suppressive effects of radiation t r e a t m e n t on the spine. In 1950, Arkin et al. 12~ reported radiation-induced scoliosis in children treated for Wilms' tumor due to vertebral changes. Neuhauser et al. 126 found roentgenographic changes in the spinal column in 10 of 13 patients who received 2,000 rads, whereas none of 9 patients showed changes after less t h a n 1,000 rads. Vaeth et al. 1~7 reported an increasing degree of vertebral changes and scoliosis with an increase of radiation dose using orthovoltage irradiation. In the series of Probert et al., 93 16 of the 22 children showed retarded growth of the spine. Ten children had a sitting height (spinal length) more t h a n 2 SD from the normal mean for their age. All but one patient in our series 31

r~

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c~ 9

9 O

c~ c~

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32

had short stature (Fig 11), ns' 119 and the sitting heights were reduced. Sitting height is largely dependent on the length of the spinal column, which is shortened by radiation-induced suppression of bone growth. The upper segment to lower segment ratio (U/L ratio), or the ratio of the t r u n k to the extremities, is frequently used as an objective index to estimate the normal progress of skeletal growth. A typical example is shown in Figure 12. The patient, the youngest treated at the University of Kentucky, had received radiation therapy at the age of 18 months. He had a very short spinal column with an abnormal U/L ratio and short stature. Growth hormone therapy was not successful in stimulating growth. The majority of patients tested showed normal bone age for their chronological age. Short stature was most likely a sequela of the growth suppressive effects of radiation on vertebral bodies rather than a result of growth hormone deficiency. As N e u h a u s e r and associates 12~ suggested, the effects of irradiation on the vertebral column m a y be dose and age related, and perhaps the age at the time of irradiation is the most important factor. Children who received radiation t r e a t m e n t at the times of most active growth, that is, under the age of 6 and at the time of puberty, showed especially prominent spinal growth retardation. Endocrine Status In 1981 Broadbent et al. 12~reported long-term results of treatment in 8 children surviving medulloblastoma. They found surprisingly little evidence of endocrine disorders in their patients. Only one had an abnormal growth hormone response to exercise, and none showed clinical evidence of growth hormone deficiency. Our experience at the University of Kentucky 11s' 119 revealed similar results. All but two patients entered puberty; the two exceptions were still prepubertal. All eight patients who arrived at puberty developed normal secondary sex characteristics, and female patients had normal menstrual periods. One female patient, the oldest, has been married more than 2 years. Four of six long-term survivors who were seen more than 7 years after t r e a t m e n t underwent complete endocrine study that included thyroid function and plasma ACTH, cortisol, somatomedin, prolactin, and growth hormone stimulation tests. Two of them underwent more than two endocrinologic studies at l-year intervals. Growth hormone secretion responses to stimulation often were marginal, and one patient had suspicious hypothyroid status. Otherwise, all test results were within the normal range. Five of six patients tested had a normal bone age corresponding to the chronological age, and x-ray films showed normal development (see Table 2). This indicates that the patients had been secreting adequate amounts of hormones to meet physiologic stimuli and that their long bones were growing normally. None 33

.,....

oo,

N

g~N%

Fig 11.--Data on the physical development of ten survivors, boys (A) and girls (B). The majority of patients had short height. Most were in the fifth percentile in 34

iiiii~!iiiii~!i!!iii!il (EA

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N ~7 N '~4

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height; 95% of a control group should be taller than the children in this series. (From Chin and Maruyama, ~19 Reproduced by permission.) 35

Fig 12.--Short stature in a boy with abnormal U/L ratio. The boy received radiation treatment at the age of 18 months to the whole brain and spinal axis. Compared to his younger sister (left), an extremely short spine is apparent. Extremity growth appeared normal. of o u r p a t i e n t s h a d clinical e v i d e n c e of h o r m o n a l deficiency, a n d r e s u l t s of endocrinologic studies w e r e g r o s s l y w i t h i n n o r m a l limits. I n t e r p r e t a t i o n of r e s u l t s of t h e g r o w t h h o r m o n e s t i m u l a t i o n t e s t is difficult. T h e r e a d e r s will u n d e r s t a n d its c o m p l e x i t y b y t h e following e x a m p l e . In October 1972 a 5-year-old boy experienced the acute onset of ataxia and vomiting. Investigation at that time disclosed a posterior fossa tumor. He underwent posterior fossa craniotomy for a subtotal resection of a medulloblastoma at age 5 years 2 months. Postoperative radiotherapy followed, between November 1972 and J a n u a r y 1973, and he received 5,400 cGy to the posterior fossa and 3,500 cGy to the rest of the cranium and spine. About 5 years later, in December 1977, he was seen by a pediatrician because of short stature. He was quite concerned about his height because children were beginning to tease him at school. At that time, he was only 4 feet 2 inches tall at age 10 years 3 months. A complete history, physical examination, and endocrinologic study were performed. The results of endocrine tests (Table 3) were grossly within normal limits. In November 1979, hormonal tests were repeated at the age of 12. At that time he had Tanner stage III development and was 51.25 inches tall. He appeared to have a short trunk and relatively long legs. He showed signs of beginning puberty, with 36

TABLE

3.--SAMPLE LABORATORY TEST RESULTS*

JANUARY 1978

1. 0.5 gm arginine IV • 30 min, with no priming: Time (min) Serum hGH (ng/ml) Normal 0 2.2 1-5 60 13.7 >10 90 4.5 2. Serum cortisol, A.M. (with arginine testing): 57.4 ~g/dl (normal: 5 - 2 3 , h i g h e r with arginine testing) 3. Serum thyroxine: 10.1 ~g/dl (normal: 5-14) 4. Serum TSH: 9.6 ~U/ml (normal: 2 - 1 1 ) JUNE 1980

1. Arginine insulin tolerance test: Time Glucose hGH Cortisol 0 85 1 14 30 141 2.7 . . . 45 118 7.6 60 93 8.1 " -9" 90 55 2.7 13 120 105 2.1 23 2. S u m m a r y of results and recommendation by pediatric endocrinologist: A. Secreting adequate amounts of growth hormone; long bones are growing. B. Two levels of growth hormone were above 7 in response to arginine. C. No appropriate increase in growth hormone to hypoglycemic stimulation. D. Somatomedin level was clearly within normal limit, and the patient was receiving adequate amount of growth hormone stimulation. E. No documented endocrine abnormalities; felt not to qualify for growth hormone administration. BONE AGE

Date 10/72 12/77 11/79 6/80 12/80

Bone Age Chronological Age Medulloblastoma: Operated on and irradiated 6 yr 10 yr 3 mo. 10 yr 12 yr 2 mo. 12 yr 12 yr 9 mo. 13 yr 13 yr 3 mo.

GROWTH DATA

Date

Height

Surgery and radiotherapy 9/79 6/80

51 1/4 in. 53 1/2 in.

Growth hormone 2/81 9/81

55 1/4 in. 56 1/3 in.

*Presented at the 13th International Cancer Congress, 1982. F u r t h e r details will be published in CANCER, 1984.119 Reproduced by permission.

t h e r i g h t t e s t i s m e a s u r i n g 3.5 cm, t h e left t e s t i s 3 cm, a n d t h e p h a l l u s 9 cm when stretched. There was beginning pubic hair but no axillary h a i r . O n a n a r g i n i n e g r o w t h h o r m o n e s t i m u l a t i o n t e s t p r i m e d w i t h stilb e s t r o l , t h e b a s e l i n e g r o w t h h o r m o n e w a s 9.1, a n d a l l s u b s e q u e n t v a l , u e s w e r e less t h a n 7. T R H s t i m u l a t i o n t e s t s h o w e d a b a s e l i n e T S H of 0.6 w i t h a p e a k o f 42.6 a t 30 m i n u t e s . P r o l a c t i n r o s e f r o m a b a s e l i n e v a l u e of 8 to a p e a k a t 30 m i n u t e s of 26. B a s e l i n e T4 w a s 6.8 jxg/ml. T h e A.M. s e r u m c o r t i s o l l e v e l w a s 25 ~g/dl. F S H w a s 4 a n d L H w a s 5. S i n c e t h e d i a g n o s i s of b r a i n t u m o r ( m e d u l l o b l a s t o m a ) h i s g r o w t h veloc37

ity was roughly 1.6 inches per year. At conclusion of the evaluation, the subnormal arginine growth hormone stimulation response was the only abnormal test result noted. Because of subnormal growth hormone response to arginine stimulation, he was referred to another institution for a second opinion on a possible growth hormone therapy. The patient was 12 years 9 months when referred for reassessment. His hormonal status was carefully and completely reassessed. The arginine insulin tolerance test showed two values of growth hormone greater than 7. There was no appropriate increase in growth hormone to hypoglycemic stimulation 60 minutes following insulin injection via IV push. The somatomedin level was clearly within the normal range. This normal level of somatomedin suggested that the patient was receiving adequate amounts of growth hormone stimulation. Clinically, his eunuchoid U/L ratio suggested that the patient had been secreting adequate amounts of growth hormone. It also suggested that his short stature was related to damage inflicted on the spine when he received the radiation. The conclusion was that adequate amounts of growth hormone were secreted in response to normal physiologic stimuli and that his long bones were growing, as demonstrated on bone age study. He was not considered to qualify for growth hormone therapy. However, in accordance with his parents' wishes, he was started on growth hormone therapy in August 1980 on a trial basis, but there was no noticeable response to treatment. However, Hirsch et al. 9 reported a high incidence of growth hormone deficiency (65.5%) among 57 children. All patients were tr eated with radiation and chem ot he rapy for medulloblastoma. In 1976, Shalet et al. 12s suspected t h a t chemotherapeutic agents might sensitize nervous tissue to the effects of irradiation in th eir endocrinologic study of childhood brain t u m o r patients. In a subsequent report Shalet et al. 97 found t h a t 12 of 13 children grew very poorly in the first year after irradiation. One exceptional p at i e nt continued to grow in the 10th percentile and was the only p a t i ent who did not receive chemotherapy. On t he other hand, one pat i ent showed an increased growth velocity during the second y e a r of t r e a t m e n t while chemotherapy was continuing. Therefore, the cause of growth failure remained unclear. Shalet et al. concluded t h a t poor growth within 1 year of t r e a t m e n t of a br ai n t um or could not be assumed to indicate growth hormone deficiency. T he y stated t h a t in some children, growth hormone deficiency certainly contributed to the impaired growth rates seen several years after cranial radiation. T hey t r e a t e d six such children aged 3 - 1 0 years after x-ray therapy, with responses. In a review article, Shalet 9s noted t h a t children whose growth hormone secretion appeared to r e m a i n adequate over the first y e a r of study grew j us t as poorly as those in whom biochemical evidence of growth hormone deficiency appeared. T h er e was no difference in the m e a n bone age changes over the first 12 months of t r e a t m e n t between children with impaired growth hormone responses and those with normal growth hormone responses. 38

At present, the clinical significance of abnormal growth hormone response is unclear. A study by Shalet et al. revealed inadequate growth hormone response to hypoglycemic stimulation in 11 of 16 brain tumor patients who received postoperative radiotherapy and chemotherapy. If spinal irradiation cases were excluded, only two patients were below the third centile for standing height. There are still m a n y questions to be a n s w e r e d - - t h e incidence of growth hormone deficiency after treatment, the clinical significance of abnormal laboratory tests, the relationship between growth hormone and growth retardation, the correlation between growth hormone deficiency and/or growth retardation and radiation or chemoradiation. These interrelationships are complicated and need further objective studies. Several reports on children receiving radiotherapy alone noted a low incidence of hormonal abnormalities, and most growth retardation was attributed to a failure of spinal growth. Others, using combined chemotherapy and radiotherapy, have observed a relatively high incidence of endocrinologic abnormalities. Shalet suggested that the chemotherapeutic agents m a y sensitize tissues to radiation effects. Further careful studies in the future m a y solve these questions. Intellectual Status This subject is another matter of controversy. Because of the perceived rarity of long-term survival of medulloblastoma patients in the past, there were few studies regarding learning and intellectual development. According to Broadbent et al., 12~ five of eight long-term survivors were at normal schools or in continuous employment. Two of three handicapped patients were treated at the ages of 1.1 years and 1.7 years. None of five medulloblastoma patients described by Danoff et al. 121 were mentally defective. All five patients received craniospinal irradiation. In the series of patients treated by Bongartz and associates, 5 eight of 11 children were doing well at school; two were in the top third of their class and four were average in performance. Danoff et al. 121 found that brain tumor patients treated before age 3 years or with tumor extension to the hypothalamus had an increased incidence of mental retardation. No apparent correlation was found between the volume of brain irradiation and mental retardation. In the series of K u n et al., 124 24 patients with brain tumor (80%) showed no serious disabilities on routine medical and neurologic examinations. Two of 23 children (8.7%) evaluated had intellectual deficiency. Intellectual delays were seen in two of the nine children tested prior to irradiation, in one of nine (11%) who received posterior fossa irradiation, and in eight of 15 (53%) after supratentorial or whole cranial irradiation. Eleven patents had completed a formal assessment of academic achievement. Median achievement stan39

TABLE 4.--INTELLECTUAL DEVELOPMENTBY AGE AT TIME OF TREATMENT* AGE GROUP(YR)

Overall Reading Speaking Writing

0-4

5-7

8-15

Poor Poor Good Poor

Fair Fair Good Fair

Good Good Good Good

*Presented at the 13th International Cancer Congress, 1982. Further details will be published in Cancer, 1984.119 Reproduced by permission. Good: Average or better performance; grossly normal intellectual ability. Fair: Satisfactory and acceptable work; borderline but passing learning ability Poor: Unsatisfactory; needs special classes or tutor; behind average of class or in lower grade level than for chronologic age.

dard scores were within the normal range (> 90). Three patients were in the borderline or deficient ranges in all measures of mathematics, reading recognition, reading comprehension, and spelling. Ten patients were in learning disability programs. Data on school performance of ten long-term survivors from the University of Kentucky are shown on Table 4. In our experience children less than 4 years old (group I) had serious impairment in visual-motor perception. In patients aged 5 - 7 years (group II), learning ability was low normal b u t could be improved with special effort. The main problems were reading and writing, noted in the younger children. Older children (/> 8 years) (group III) had no serious problems in learning, reading, and writing abilities. Two patients had some difficulty in reading but gradually improved with effort. Three of four patients in this group performed average or better in school work. All of Hope-Stone's long-term survivors l~ were both physically and mentally fit and able. Bouchard 122 reported that nine of ten children followed more than 5 years from the onset of radiation treatment had grown and were living normally at 5-year followup. In the series reported by Bloom et al., ~~ 18 of 22 children (82%) surviving 5 - 1 7 years were leading active lives. Mental development is seriously disturbed in children with medulloblastoma who received both radiation and chemotherapy. In one study, only 12% of patients had normal IQs. 19 Suspected factors contributing to mental retardation are age at treatment (< 3 years), untreated panhypopituitarism, and tu40

mor involvement of the t h a l a m u s and/or hypothalamus. 121 Based on his study, LeBaron 129 stated t h a t "virtually all children treated for subcortical brain tumors experienced an initial dramatic decrease in general cognitive and motor function, but t h a t by nine months post-diagnosis the cognitive functioning of m a n y of these children had returned to a normal range." LeBaron also insisted t h a t "the assessment of children with medulloblastoma should be more subjective and individualized in a longitudinal investigation in addition to the formal psychometric approach. ''129

Psychoeducational Evaluation We have made psychoeducational evaluations using various tests; Stanford Binet Intelligence Test, Bender Gestalt for Young Children (BG) test, Goodenough Drawing Test (GDM), Peabody Picture Vocabulary Test (PPVT), Boehm Test of Basic Concepts, Wechsler Intelligence Scale for Children (WISC-R), Illinois Test of Psycholinguistic Abilities (ITPA), Wide Range Achievement Test (WRAT), and Slosson Drawing Coordination Test (SDCT). The results reflected similar findings: the younger the age of the patient at treatment, the poorer the learning ability. The most significant problem in the younger children was a weakness in visual perception. Two typical examples, from groups I and II, follow. The reports emphasize test results and intellectual development of the younger patients after high-dose radiation treatment. CASE 1 (GROUP I): A baby boy underwent brain surgery for removal of medulloblastoma at age 11/2 years. Two evaluations were made at about a 7-month interval. His first psychoeducational evaluation was made at age 6 years 8 months (first grade). He was able to express himself well, speaking in simple, compound, and complex sentences. He was very outgoing, initiating appropriate conversation. His overall functioning, as determined on the Stanfort-Binet test, appeared to be 11/2 years below his chronological age. He revealed a relative strength in verbal expression and fluency. He could accurately define and use vocabulary words at a level of a 6-year-old on the Stanford-Binet test. A relative weakness was apparent on visual-motor activities. His fine motor control and visual-motor integration were moderately to severely impaired. Other abilities that appeared near the 5-year developmental age included general comprehension, memory and concentration, spatial reasoning, nonverbal reasoning, and conceptual development. Ability to understand language and development of concepts were near a mental age of 5.

Psychologist's comments.--This evaluation revealed t h a t the child's overall intellectual functioning was approximately 11/2 years below his chronological age. This development was near the 5th percentile. His relative strength in verbal expression provided evidence of possible higher intellectual functioning. P r i m a r y weaknesses were noted in fine motor coordination, con41

ceptual development, and achievement. Other strengths included his desire for independence and his outgoing personality. The second test indicated an overall low average verbal intelligence with severe i m p a i r m e n t of visual-motor integration and auditory-visual association abilities. It was postulated t h a t previous damage in cerebellar s t r u c t u r e during infancy had probably affected these specific processes. Due to verbal strengths in the low average range, the psychologist felt he had potential above the educatable, m e nt a l l y handicapped range. CASE 2 (GROUPII): A young boy underwent brain surgery for the removal of a posterior fossa medulloblastoma at the age of 5 years and received postoperative radiation treatment; 5,400 cGy to the posterior fossa and 3,500 cGy to the rest of the brain and spinal cord. His first psychoeducation evaluation was made about 1 year after brain surgery, at age 6 years. At the time of evaluation he was attending first grade at a public school and was experiencing some learning difficulties in school. According to his mother, he did well as far as oral work was concerned but had difficulty putting letters or numbers onto paper. He was having difficulty reading words and putting letters together to spell words on paper. His mother noted that his vocabulary had increased since the beginning of the year, as had his ability to express himself orally. Formal testing indicated that the boy was functioning on the whole within the borderline range of normal intelligence, with a wide discrepancy between his verbal ability and perceptual-motor ability. His fullscale IQ on the WISC was 71, his verbal IQ was 80, and his performance IQ was 65. Like the child described in case 1 he was significantly stronger at verbal skills than perceptual-motor skills. There was a perceptual-motor deficit.

Comment.--This 6-year-old boy's overall intellectual ability seemed to be somewhere within the borderline to dull normal range of intelligence. Thus, one would expect hi m to be slower at lear n in g t h a n the average first grader. In addition, he clearly had a perceptual-motor deficit, which suggested a specific learning disability. He would probably experience significant difficulty in reading and writing, and perhaps would need to do a significant amount of his work orally. Since his weakness seemed to be in the visual channel r a t h e r t h a n the auditory channel, he was a child who would learn bet t er if given auditory clues t h a n if he had to depend on visual clues. The psychologist recommended keeping him in a second-grade class with parttime help from a l e a r ni ng disabilities teacher. Behavior and Psychological Status Behavioral or emotional problems were noted in 2 5 % - 4 3 % of children, v ar y i ng with series. Our patients did not have such problems. On the other hand, Hirsch et al. 9 reported t h a t emotional and behavioral trouble was noted in a r e m a r k a b l y high 42

proportion of patients (93%) who received radiation and chemotherapy. DIRECTIONS FOR FUTURE MANAGEMENT In the past decade, dramatic improvements in cure rates for medutloblastoma have been achieved, and medulloblastoma is no longer a hopeless disease. To be able to cure medulloblastoma, however, we must understand the disease, apply modern diagnostic techniques, and utilize maximum therapeutics. Advancements in diagnostic techniques, particularly CT and MR scans, have greatly improved our ability to detect and assess the extent of the disease at presentation. The investigations recommended in the routine workup and clinical staging of the medulloblastoma have been described. The studies are essential in ascertaining the disease status, in planning optimum therapy, and in predicting the outcome. The proposed CT staging system is simple, and easily applicable, and reproducible. In addition, the staging system should be useful for clinical practice in future studies because it is well correlated with outcome. Serial CT scanning, especially before and after brain surgery is an important a principal step in the staging workup. Myelography should be a valuable test in all children with medulloblastoma. Advanced (or systemic) disease is more frequently seen in very young children (< 5 years old) than in older children or adults. Modern brain surgery is more satisfactory in the initial management of medulloblastoma than in the past. Currently available microscopic techniques facilitate more radical removal of medulloblastoma. It is desirable to use coagulation rather than metal clips because the metal will interfere with CT or MR images on staging and follow-up scans. A principal function of brain surgery is to decrease the tumor ceil burden to as small as possible and allow optimal and careful postoperative radiotherapy. Medulloblastoma cannot be cured by surgery alone, and attempts at radical surgery are not recommended because of the risk of major complications. Low-dose radiotherapy has been ineffective in curing the disease, and the use of effective, high-dose irradiation is mandatory for the control of the primary tumor. At least 5,000-5,400 cGy of tumor dose will be needed. Further boost radiation dose may be crucial in dealing with residual tumor demonstrated on postoperative CT scans. Radiotherapeutic technique should be individualized, and the final tumor dose should be determined in accordance with residual tumor burden, the age of the patient, and the stage of disease. Current chemotherapy appears to play little role in the primary treatment of medulloblastoma. However, combined modality of multiagent chemotherapy and radiotherapy may be useful 43

for the treatment of recurrent medulloblastomas and is recommended for metastatic or disseminated medulloblastomas. With optimum radiation therapy, a 5-year cure is expected in about two thirds of all patients with medulloblastoma. Most patients with early stage medulloblastoma have an excellent chance of surviving the disease. Roughly one third of patients have advanced disease at presentation. Since the response rate to current radiotherapy in this subgroup is poor, the major concern now is exploration of new therapeutic approaches and protocols to improve the outcome of these p a t i e n t s - - t h a t is, combined modality chemotherapy and radiotherapy, and multi-daily fraction (MDF) radiotherapeutic techniques. The second concern is the quality of life of the patients, with development of proper rehabilitative programs in order to minimize long-term sequelae of treatment. We know almost nothing about long-term effects of successful therapy, and we need diligent investigations in the future. Data up to now appear encouraging, and the price for long-term survival m a y not be so expensive as some have feared. The primary concern in the long-term survivors appears to be learning problems. Young children who received radiation treatment, especially in conjunction with chemotherapy (e.g., methotrexate), are known to have an increased risk for the later development of learning problems, that is, cognitive defects, low IQ scores, and neuropsychological deficits. Very young children, less than 6 years old at treatment, appear more liable to such late sequelae. Yadin and associates 13~ studied the late effects of chemotherapy-radiotherapy on learning ability using a rat model of the immature brain. They found that 17-day-old rat pups demonstrated slow learning ability when treated with a combination of radiotherapy and methotrexate chemotherapy. The deficit was not evident when they received either chemotherapy or radiotherapy alone, nor was it observed in more mature 30-day-old rats receiving combined chemotherapy-radiotherapy. 13~ Yadin and associates 1 3 0 noted that ~,the nature of the problem seemed to be in the learning process of the task rather than in its retention. Once the task was appropriately mastered by rats given radiation and chemotherapy (methotrexate), they were able to perform as well as controls when tested 2 weeks later." Based on their personal observation, they also noted, "Parents have reported that some affected children could be made to learn by repeated exposure to the tasks and by special educational effort; and that once learned, the information was retained." Rehabilitation is a preventive and therapeutic program that focuses on recovering function or on preventing treatment sequelae. Evidence suggests that surviving children who received therapy in very early life developed learning difficulties, espe44

cially weakness in visual-motor integration and auditory-visual association abilities. They had slow learning ability but did not appear mentally retarded. They need additional effol~ and repetition to acquire new knowledge and require a longer time to master tasks. As Yadin and associates reported, they m a y be able to retain the knowledge once learned, and to apply it as well as a normal individual, i3~ These are very important findings. Clearly there is a need to develop active rehabilitative programs and special educational assistance for the children who survive a brain tumor and its therapy. COMMENT From our studies, we believe t h a t the view t h a t all brain tumors are fatal is an erroneous one. Our results show t h a t medulloblastomas are highly radioresponsive and potentially curable if adequate and proper postoperative radiotherapy is given. Adequate staging studies are important, as favorable results are seen with early stage disease, whereas poor results are seen with advanced stages. It is evident t h a t modern megavoltage radiotherapy has substantially increased the survival of patients with medulloblastoma. Survival rates have been consistently high since the adoption of optimum irradiation techniques. Many patients treated in early childhood have survived into their teens or young adult years with no subsequent symptoms or signs of tumor. Hynes TM stated t h a t "when remission of signs and symptoms persists for ten or more years, without the need of continued treatment, it is proper to describe such remission as apparent cure." In our series, all patients who have survived more t h a n 5 or 10 years have had no evidence of residual or recurrent disease. Although careful observations will be needed for at least 10 years or longer, analysis of the survival curves unambiguously indicates t h a t optimum radiation therapy not only significantly prolongs survival of patients with medulloblastoma, but is able to cure the disease in a substantial proportion of patients with early stage disease. For advanced cases, however, it seems unlikely t h a t substantial survival improvement can be achieved with radiotherapy alone. Thus, future research for advanced medulloblastoma therapy should be directed to a search for new approaches. We need to examine the efficacy of a variety of new treatment modalities, specifically multiagent chemotherapy combined with radiotherapy. Another focus in future studies should be the development of a practical staging system, which is very important in formulating therapeutic approach as well as in predicting prognosis. Finally, in dealing with this relatively uncommon tumor, large cancer centers of excellence in 45

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