Med Oncol. & Tumor Pharmacother. Vol 9 No. 4 pp. 159-I 64, 1992
THE MANAGEMENT
073643118/90 $3.00 + .00
O F P E D I A T R I C B R A I N T U M O R S IN A T E R T I A R Y C E N T E R
M. M A N D E L , A. TOREN,* G. FINDLER, 2 Y. N E U M A N N , G. K E N D E , M. F A I B E L , 1 R, T A D M O R , 1 9 H. BRENNER, 3 A. SAHAR," B. RA2MOT, I. B E N - B A S S A T and G. R E C H A V I Institutes of Hematology, 1Radiology and Departments of 2Neurosurgery and 3Oncology, The Chaim Sheba Medical Center, Tei-Hashomer and Sackler Faculty of Medicine, Tel-Aviv University, Israel
(First submitted 25 September 1992: accepted after revision 4 December ]992)
Between January 1982 and January 1990, I20 newly diagnosed pediatric patients were treated at The Chaim Sheba Medical Center. Sixty three (52.5%) tumors arose in the posterior fossa and 57 (47.5%) appeared supratentoriaUy. A wide variety of histologic subtypes was seen, each requiring tumor-specific treatment. The modern imaging techniques - CT and MRI - offered better planning of operation, treatment and follow up. All children with highly malignant tumors were treated with combination chemotherapy besides the ~conventional radiotherapy'. Since 1987 the "eight in one day" protocol has been used extensively pre- and post-irradiation. Five-year survival, varied significantly according to tumor type, location and stage. The average delay from presentation of symptoms to diagnosis was 6 months. A multidisciplinaryapproach has been used in the treatment, rehabilitation and follow-up of these children. In this study, the results of treatment are presented and the role of chemotherapy is discussed~
Key words: Astrocytnma, Brain stem glioma, Ependymoma, Medulloblastoma.
histology and site of tumor and, therefore, the modalities of treatment, We report here the results of treatment in our center.
INTRODUCTION Brain tumors are the second most prevalent among childhood malignancies] The tumors arise from varying locations within the brain. More than 50% of the tumors are located in the posterior fossa, mainly cerebellar astrocytoma and medulloblastoma (MB)/primitive neuroectoderreal tumor (PNET). ~ Progress in their management has lagged behind that achieved in most other common types of childhood cancer. This is mainly because of the rare occurrence of even the more common distinct tumor entities such as MB and high grade cereberal astrocytoma, and because of the varying sites and aggressiveness of the tumors. All these made it difficult for meaningful therapeutic trials to be conducted. The standard approach to the management of childhood brain tumors has been either surgery alone or surgery followed by radiation therapy. However, based on encouraging results from CCSG and SIOP studies, 2'3 combination chemotherapy protocols have recently been introduced for the treatment of highly malignant brain tumors. From 1982 to 1990, 120 children with newly diagnosed brain tumors were treated at the Chaim Sheba Medical Center. The children differed in their clinical presentation,
M A T E R I A L AND METHODS The hospital and radiation therapy records of 120 consecutive infants and adolescents aged 4 months to 18 years (median 8 years) with brain tumors who were seen and evaluated in the Department of Pediatric Hemato-oncology at the Chaim Sheba Medical Center between January 1, 1982 and January 1990 were reviewed. This provided a minimum of 18 months from the time of diagnosis to the time of analysis. The median follow-up time was 4 1/2 years (range 18 mond~s to 8 years). No patients were excluded from the analysis. Seventy of the 120 patients were boys and 50 were girls. The diagnosis of brain tumors was made by clinical presentation, neuro-imaging techniques (CT and MRI) and laboratory tests for tumor markers. Since 1987, spinal MRI with Gadolinium is done routinely m tumors which have a tendency to metastise to the spinal cord, nmnely medulloblastoma and ependymoblastoma. The surgical approach is depicted in Table 1. Ventriculoperitoneal (VP) shunts were inserted in 35 children in whom tumor resection did not decompress the
* To whom correspondenceshould be addressed: Instituteuf Hematology. The Chaim Sheba Medical Center, Tel-Hashomer52 621. Israel
159
160 M Mandel et al. Table 1. Surgical Approaches
Table 2. Clinical Presentation
No biopsy
18%
Increased intra-cranial pressure
Biopsy Incomplete resection Complete resection
19% 39% 24%
Headaches Vomiting Cerebellar signs
80% 72% 41%
VP shunt alone
4%
VP shunt after or with other procedures
24%
Nerve paralysis Pyramidal signs
38% 31%
Visual abnormalities
46%
Growth and developmental delay Seizures Academic performance - decline
8% 18% 7%
Personality changes
10%
ventricles during the initial procedure. In some, this was the sole surgical manoeuvre. Routine pre-operative VP shunts were avoided in the hope of reducing the incidence of systemic metastases. After operation, further management was according to the histologic subtype and anatomy of the tumor. Tumors of low grade malignancy such as grade I or II astrocytoma, choroid plexus papilloma, and craniopharyngioma were treated surgically only. The highly malignant tumors, such as meduLloblastoma, high grade astrocytoma, and ependymoblastoma, were treated with irradiation and adjuvant chemotherapy. Radiation therapy was given to 75 patients; cranio-spinal radiation for medullobastoma, high grade ependymoma and ependymoblastoma as follows: whole brain 35-45 Gy, posterior fossa 50-55 Gy, spinal axis 25-35 Gy. High grade astrocytoma in the brain stem, thalamus and cerebrum were treated with 50--60 Gy to the tumor bed. Children under 3 years of age were given a reduced dose of approximately 5 Gy. Chemotherapy was given to 65 patients; between 1982-1987, high grade astrocytoma received the CCSG protocol 943 which included lomustine, vincristine and prednisone, while those with medulloblastoma and ependymoma received the SlOP II protocol which included vincristine, methotrexate, intrathecal methotrexate, carmustine and dexamethasone. Since 1987, we used uniformly the "eight in one day" protocol4 as follows: two courses within 10 days after surgery, followed by conventional radiotherapy and by 6 courses with a 3--6 weeks interval. The "eight in one day" course included: methyl prednisone 300mg/m 2, vincristine 1.5mg/in 2, lomustine 75mffm 2, p r o c a r b a z i n e 7 5 m g / m 2, h y d r o x y u r e a 1,500mg/m z, cis-platinum 60mg/m 2, cytosine arabinoside 300mg/m 2 and cyclophosphamide 300mg/m 2. Two patients with germinoma received the "BEP'S protocol which included Neomycin, etoposide and cis-platinum.
All patients had a blood count, creatinine clearance test and an audiologic exainination before each cycle of chemotherapy. The dosage of chemotherapy was modified when there was evidence of i~ematological, renal or audiologic toxicity. A C T scan with contrast dye rejection or
MRI with gadolinium were performed every 3 months in the first year and every 6 months in the second. RESULTS Clinical Characteristics and Survival
Fifty three percent of the tumors were in the subtentorial and 47% in the supratentorial area. The various subtypes are shown in Fig. 1. Interestingly 13 of the cerebellar astrocytomas were of low grade histology, while 10 of the 15 cerebral astrocytomas were of high grade malignancy. Nine of 10 optic gliomas were of low grade malignancy. The most prevalent presenting symptoms were as shown in Table 2, headaches, vomiting without nausea and cerebellar signs. The average delay from presentation of symptoms to diagnosis was 6 months. Seven of the patients suffered from hereditary disorders: Neurofibromatosis (3), tuberous sclerosis (2), albinism (1), Kleinfelter syndrome (1). Genotypic studies performed on 35% of the tumors found no myc or erb amplification. In contrast, preliminary results showed a p53 mutation in some cases of medulloblastoma, e Life table actuarial survival curves were calculated from the date of diagnosis by the Kaplan-Meyer method for file entire group and for the major sub-groups. Tile 2 and 5 years actuarial survival rates for the 120 patients were 58% and 47%, respectively (Fig. 2). Of interest is the fact that the 5 year survival for cerebellar astrocytoma was 90%, while for cerebral astrocytoma it was only 20%. The 2- and 5-year actuarial survival rates for medulloblastoma were 63% and 45%, respectively. Those who survived 5 years can be considered a.s cured, as none of them relapsed afterwards. The worst results were for brain stem gliomas - none of the patient survived for inore than 38 months (Fig. 3). There
The Management of Pediatric Brain Tumors 161
Fig. 1. A pie diagram depicting the prevalence of CNS tumors in the study group.
was no statistically significant difference between the survival in the highly malignant tumors and the various chemotherapeutic protocols used (data not shown). Radiation Toxicity: Short term toxicity (headaches and vomiting) were managed by dexamethasone. Leukoencephalopathy was diagnosed in only 4 patients. Chemotherapy: Transient drops in the blood counts were common requiring transfusion of 50 packed cells for 31 patients and of 24 platelets for 15 patients. On the whole, only 3 patients had neutropenic sepsis. Bone marrow function recovered in all patients before the next treatment. A loss of 20 dB in the high frequency hearing range was noticed in all patients with brain stem glioma and in 5 patients treated by the "eight in one day" protocol. Renal toxicity was transient and mild. Other late effects: Three patients required growth hormone replacement therapy and one became hypothyroidic. No one showed signs of delayed puberty. The results of formal intellectual tests are now under evaluation. No secondary malignant tumors were diagnosed. DISCUSSION The basic distribution of the various histological subtypes in our group are similar to that documented in the literature.' However, among the cerebral astrocytomas
there was a higher proportion of high grade malignancy in our group. The presenting signs and symptoms and the time delay in diagnosis, are similar to those described m other series. This suggests that a higher awareness of the general practitioner might bring some of these tumors to the oncologist's attention at a much earlier stage. The low grade histology tumors deserve an entirely different approach to that given to the high grade histology tumors. In the low grade histology tumors it has been proven that neither irradiation nor chemotherapy are of any benefit and the prognosis depends mainly on a radical resection of the tumor7. This is not the case for the high grade malignancy tumors, where the efficacy of irradiation and chemotherapy are doubtless. Based on this approach m the tow grade tumors, attempts have been made tbr a complete resection of the tumor and Iollow up only with good results (for example 14 of 15 children with cerebellar astrocytoma who were treated surgically only, are still alive at a median follow-up 5 years) Only one died from Staphylococcal-meningitis and one suffered from local recurrence which was successfully reoperated. As for the highly malignant tumors, apart from surgery and irradiation, all the children received adjuvant chemotherapy. The benefit of the latter modality has been established tot Ivltl/PNE'I', is doubtful for high grade 1
9
.
.
7
162 Mo M a n d e l et al.
PROPORTION SURVIVING
0.8 0.6 I
f--I
"'-'130
X
tt
E]
~
0.4 0.2 0
1 0
I
I
I
I
I
I
I
10
20
30
40 MONTHS
60
60
70
Fig. 2. Actuarial survival for the whole group of pediatric brain tumors, treated at The Chaim Sheba Medical Center between 1982-1990.
astrocytoma and is probably ineffective for brain stem glioma. 8 For the last 20 years, the most beneficial chemotherapy regimen to be used has been studied by many investigators. This started by the studies evaluating the role of adjuvant chemotherapy in medulloblastoma conducted by the CCSG and SIOP between 1976-1981. ,-.3These trials demonstrated that children with advanced metastatic MB showed a striking increase in event-free survival (46% vs. 0%; p = 0.006) following the addition of lomustine, vincristine, with or without prednisone, to standard radiotherapy. In contrast to these studies which showed only a modest increase in survival using adjuvant chemotherapy, some groups have lately published very high survival rates. Mclntosh et al. 9 reported on impressive survival of 81% at 6 years in a group of 21 patients with posterior fossa MB/PNET after treatment with radiotherapy and adjuvant chemotherapy using cyclophosphzunide and vincristine. The report by Packer et al. ~oof adjuvant chemotherapy in children with medulloblastoma, "also supports the benefit of this modality. They had a very small failure rate (1 of 26 patients) in children treated with lomustincisplatin-vincristine in addition to radiotherapy. The 'Jet' protocol which combines carboplatin and etoposide showed response in 50% of patients with recurrent MB or
high grade astrocytoma. ~ The report by Sposto et a l ) z indicates the benefit of chemotherapy in the treatment of children with high grade gliomas, demonstrating a 5-year event-free survival of 46% for children treated with radiotherapy plus lomustin-vincristine-prednisone vs. 18% for children treated with radiotherapy alone. Since most children with high grade gliomas are likely to die of recurrent disease, adjuvant chemotherapy may have only postponed the time-to-relapse in most of them. The "eight in one day" protocol4 which we used in our patients has already shown encouraging results for MB and high grade astrocytoma) ~It is now being evaluated in two CCSG trials for high grade astrocytoma, and for standard risk MB in which it is compared with vincristine, lomustin prednisone. One issue under study is the special group of children under 3 years of age. The aim of this study is to find a proper chemotherapeutic regimen to be used in order to delay the radiotherapy until the child is older and is less likely to suffer the profound neurotoxicity accompamying irradiation of the immature CNS) 4 Drugs under evaluation are cyclophosphaanide, vinoistine, cisplatinmn-etoposide, or MOPP combined with methotrexate.~3-~7 Another issue is re-evaluation of the role of the nitrosoureas (lomustin and cannustin) in view of the high percentage of lung fibrosis which follows their usage.~9
The Management o f Pediatric Brain Tumors 163
propotion s u r v i v i n g
0.8 0.6 0.4
0.2 0
i
0
>f
"+
THE MANAGEMENT
073643118/90 $3.00 + .00
O F P E D I A T R I C B R A I N T U M O R S IN A T E R T I A R Y C E N T E R
M. M A N D E L , A. TOREN,* G. FINDLER, 2 Y. N E U M A N N , G. K E N D E , M. F A I B E L , 1 R, T A D M O R , 1 9 H. BRENNER, 3 A. SAHAR," B. RA2MOT, I. B E N - B A S S A T and G. R E C H A V I Institutes of Hematology, 1Radiology and Departments of 2Neurosurgery and 3Oncology, The Chaim Sheba Medical Center, Tei-Hashomer and Sackler Faculty of Medicine, Tel-Aviv University, Israel
(First submitted 25 September 1992: accepted after revision 4 December ]992)
Between January 1982 and January 1990, I20 newly diagnosed pediatric patients were treated at The Chaim Sheba Medical Center. Sixty three (52.5%) tumors arose in the posterior fossa and 57 (47.5%) appeared supratentoriaUy. A wide variety of histologic subtypes was seen, each requiring tumor-specific treatment. The modern imaging techniques - CT and MRI - offered better planning of operation, treatment and follow up. All children with highly malignant tumors were treated with combination chemotherapy besides the ~conventional radiotherapy'. Since 1987 the "eight in one day" protocol has been used extensively pre- and post-irradiation. Five-year survival, varied significantly according to tumor type, location and stage. The average delay from presentation of symptoms to diagnosis was 6 months. A multidisciplinaryapproach has been used in the treatment, rehabilitation and follow-up of these children. In this study, the results of treatment are presented and the role of chemotherapy is discussed~
Key words: Astrocytnma, Brain stem glioma, Ependymoma, Medulloblastoma.
histology and site of tumor and, therefore, the modalities of treatment, We report here the results of treatment in our center.
INTRODUCTION Brain tumors are the second most prevalent among childhood malignancies] The tumors arise from varying locations within the brain. More than 50% of the tumors are located in the posterior fossa, mainly cerebellar astrocytoma and medulloblastoma (MB)/primitive neuroectoderreal tumor (PNET). ~ Progress in their management has lagged behind that achieved in most other common types of childhood cancer. This is mainly because of the rare occurrence of even the more common distinct tumor entities such as MB and high grade cereberal astrocytoma, and because of the varying sites and aggressiveness of the tumors. All these made it difficult for meaningful therapeutic trials to be conducted. The standard approach to the management of childhood brain tumors has been either surgery alone or surgery followed by radiation therapy. However, based on encouraging results from CCSG and SIOP studies, 2'3 combination chemotherapy protocols have recently been introduced for the treatment of highly malignant brain tumors. From 1982 to 1990, 120 children with newly diagnosed brain tumors were treated at the Chaim Sheba Medical Center. The children differed in their clinical presentation,
M A T E R I A L AND METHODS The hospital and radiation therapy records of 120 consecutive infants and adolescents aged 4 months to 18 years (median 8 years) with brain tumors who were seen and evaluated in the Department of Pediatric Hemato-oncology at the Chaim Sheba Medical Center between January 1, 1982 and January 1990 were reviewed. This provided a minimum of 18 months from the time of diagnosis to the time of analysis. The median follow-up time was 4 1/2 years (range 18 mond~s to 8 years). No patients were excluded from the analysis. Seventy of the 120 patients were boys and 50 were girls. The diagnosis of brain tumors was made by clinical presentation, neuro-imaging techniques (CT and MRI) and laboratory tests for tumor markers. Since 1987, spinal MRI with Gadolinium is done routinely m tumors which have a tendency to metastise to the spinal cord, nmnely medulloblastoma and ependymoblastoma. The surgical approach is depicted in Table 1. Ventriculoperitoneal (VP) shunts were inserted in 35 children in whom tumor resection did not decompress the
* To whom correspondenceshould be addressed: Instituteuf Hematology. The Chaim Sheba Medical Center, Tel-Hashomer52 621. Israel
159
160 M Mandel et al. Table 1. Surgical Approaches
Table 2. Clinical Presentation
No biopsy
18%
Increased intra-cranial pressure
Biopsy Incomplete resection Complete resection
19% 39% 24%
Headaches Vomiting Cerebellar signs
80% 72% 41%
VP shunt alone
4%
VP shunt after or with other procedures
24%
Nerve paralysis Pyramidal signs
38% 31%
Visual abnormalities
46%
Growth and developmental delay Seizures Academic performance - decline
8% 18% 7%
Personality changes
10%
ventricles during the initial procedure. In some, this was the sole surgical manoeuvre. Routine pre-operative VP shunts were avoided in the hope of reducing the incidence of systemic metastases. After operation, further management was according to the histologic subtype and anatomy of the tumor. Tumors of low grade malignancy such as grade I or II astrocytoma, choroid plexus papilloma, and craniopharyngioma were treated surgically only. The highly malignant tumors, such as meduLloblastoma, high grade astrocytoma, and ependymoblastoma, were treated with irradiation and adjuvant chemotherapy. Radiation therapy was given to 75 patients; cranio-spinal radiation for medullobastoma, high grade ependymoma and ependymoblastoma as follows: whole brain 35-45 Gy, posterior fossa 50-55 Gy, spinal axis 25-35 Gy. High grade astrocytoma in the brain stem, thalamus and cerebrum were treated with 50--60 Gy to the tumor bed. Children under 3 years of age were given a reduced dose of approximately 5 Gy. Chemotherapy was given to 65 patients; between 1982-1987, high grade astrocytoma received the CCSG protocol 943 which included lomustine, vincristine and prednisone, while those with medulloblastoma and ependymoma received the SlOP II protocol which included vincristine, methotrexate, intrathecal methotrexate, carmustine and dexamethasone. Since 1987, we used uniformly the "eight in one day" protocol4 as follows: two courses within 10 days after surgery, followed by conventional radiotherapy and by 6 courses with a 3--6 weeks interval. The "eight in one day" course included: methyl prednisone 300mg/m 2, vincristine 1.5mg/in 2, lomustine 75mffm 2, p r o c a r b a z i n e 7 5 m g / m 2, h y d r o x y u r e a 1,500mg/m z, cis-platinum 60mg/m 2, cytosine arabinoside 300mg/m 2 and cyclophosphamide 300mg/m 2. Two patients with germinoma received the "BEP'S protocol which included Neomycin, etoposide and cis-platinum.
All patients had a blood count, creatinine clearance test and an audiologic exainination before each cycle of chemotherapy. The dosage of chemotherapy was modified when there was evidence of i~ematological, renal or audiologic toxicity. A C T scan with contrast dye rejection or
MRI with gadolinium were performed every 3 months in the first year and every 6 months in the second. RESULTS Clinical Characteristics and Survival
Fifty three percent of the tumors were in the subtentorial and 47% in the supratentorial area. The various subtypes are shown in Fig. 1. Interestingly 13 of the cerebellar astrocytomas were of low grade histology, while 10 of the 15 cerebral astrocytomas were of high grade malignancy. Nine of 10 optic gliomas were of low grade malignancy. The most prevalent presenting symptoms were as shown in Table 2, headaches, vomiting without nausea and cerebellar signs. The average delay from presentation of symptoms to diagnosis was 6 months. Seven of the patients suffered from hereditary disorders: Neurofibromatosis (3), tuberous sclerosis (2), albinism (1), Kleinfelter syndrome (1). Genotypic studies performed on 35% of the tumors found no myc or erb amplification. In contrast, preliminary results showed a p53 mutation in some cases of medulloblastoma, e Life table actuarial survival curves were calculated from the date of diagnosis by the Kaplan-Meyer method for file entire group and for the major sub-groups. Tile 2 and 5 years actuarial survival rates for the 120 patients were 58% and 47%, respectively (Fig. 2). Of interest is the fact that the 5 year survival for cerebellar astrocytoma was 90%, while for cerebral astrocytoma it was only 20%. The 2- and 5-year actuarial survival rates for medulloblastoma were 63% and 45%, respectively. Those who survived 5 years can be considered a.s cured, as none of them relapsed afterwards. The worst results were for brain stem gliomas - none of the patient survived for inore than 38 months (Fig. 3). There
The Management of Pediatric Brain Tumors 161
Fig. 1. A pie diagram depicting the prevalence of CNS tumors in the study group.
was no statistically significant difference between the survival in the highly malignant tumors and the various chemotherapeutic protocols used (data not shown). Radiation Toxicity: Short term toxicity (headaches and vomiting) were managed by dexamethasone. Leukoencephalopathy was diagnosed in only 4 patients. Chemotherapy: Transient drops in the blood counts were common requiring transfusion of 50 packed cells for 31 patients and of 24 platelets for 15 patients. On the whole, only 3 patients had neutropenic sepsis. Bone marrow function recovered in all patients before the next treatment. A loss of 20 dB in the high frequency hearing range was noticed in all patients with brain stem glioma and in 5 patients treated by the "eight in one day" protocol. Renal toxicity was transient and mild. Other late effects: Three patients required growth hormone replacement therapy and one became hypothyroidic. No one showed signs of delayed puberty. The results of formal intellectual tests are now under evaluation. No secondary malignant tumors were diagnosed. DISCUSSION The basic distribution of the various histological subtypes in our group are similar to that documented in the literature.' However, among the cerebral astrocytomas
there was a higher proportion of high grade malignancy in our group. The presenting signs and symptoms and the time delay in diagnosis, are similar to those described m other series. This suggests that a higher awareness of the general practitioner might bring some of these tumors to the oncologist's attention at a much earlier stage. The low grade histology tumors deserve an entirely different approach to that given to the high grade histology tumors. In the low grade histology tumors it has been proven that neither irradiation nor chemotherapy are of any benefit and the prognosis depends mainly on a radical resection of the tumor7. This is not the case for the high grade malignancy tumors, where the efficacy of irradiation and chemotherapy are doubtless. Based on this approach m the tow grade tumors, attempts have been made tbr a complete resection of the tumor and Iollow up only with good results (for example 14 of 15 children with cerebellar astrocytoma who were treated surgically only, are still alive at a median follow-up 5 years) Only one died from Staphylococcal-meningitis and one suffered from local recurrence which was successfully reoperated. As for the highly malignant tumors, apart from surgery and irradiation, all the children received adjuvant chemotherapy. The benefit of the latter modality has been established tot Ivltl/PNE'I', is doubtful for high grade 1
9
.
.
7
162 Mo M a n d e l et al.
PROPORTION SURVIVING
0.8 0.6 I
f--I
"'-'130
X
tt
E]
~
0.4 0.2 0
1 0
I
I
I
I
I
I
I
10
20
30
40 MONTHS
60
60
70
Fig. 2. Actuarial survival for the whole group of pediatric brain tumors, treated at The Chaim Sheba Medical Center between 1982-1990.
astrocytoma and is probably ineffective for brain stem glioma. 8 For the last 20 years, the most beneficial chemotherapy regimen to be used has been studied by many investigators. This started by the studies evaluating the role of adjuvant chemotherapy in medulloblastoma conducted by the CCSG and SIOP between 1976-1981. ,-.3These trials demonstrated that children with advanced metastatic MB showed a striking increase in event-free survival (46% vs. 0%; p = 0.006) following the addition of lomustine, vincristine, with or without prednisone, to standard radiotherapy. In contrast to these studies which showed only a modest increase in survival using adjuvant chemotherapy, some groups have lately published very high survival rates. Mclntosh et al. 9 reported on impressive survival of 81% at 6 years in a group of 21 patients with posterior fossa MB/PNET after treatment with radiotherapy and adjuvant chemotherapy using cyclophosphzunide and vincristine. The report by Packer et al. ~oof adjuvant chemotherapy in children with medulloblastoma, "also supports the benefit of this modality. They had a very small failure rate (1 of 26 patients) in children treated with lomustincisplatin-vincristine in addition to radiotherapy. The 'Jet' protocol which combines carboplatin and etoposide showed response in 50% of patients with recurrent MB or
high grade astrocytoma. ~ The report by Sposto et a l ) z indicates the benefit of chemotherapy in the treatment of children with high grade gliomas, demonstrating a 5-year event-free survival of 46% for children treated with radiotherapy plus lomustin-vincristine-prednisone vs. 18% for children treated with radiotherapy alone. Since most children with high grade gliomas are likely to die of recurrent disease, adjuvant chemotherapy may have only postponed the time-to-relapse in most of them. The "eight in one day" protocol4 which we used in our patients has already shown encouraging results for MB and high grade astrocytoma) ~It is now being evaluated in two CCSG trials for high grade astrocytoma, and for standard risk MB in which it is compared with vincristine, lomustin prednisone. One issue under study is the special group of children under 3 years of age. The aim of this study is to find a proper chemotherapeutic regimen to be used in order to delay the radiotherapy until the child is older and is less likely to suffer the profound neurotoxicity accompamying irradiation of the immature CNS) 4 Drugs under evaluation are cyclophosphaanide, vinoistine, cisplatinmn-etoposide, or MOPP combined with methotrexate.~3-~7 Another issue is re-evaluation of the role of the nitrosoureas (lomustin and cannustin) in view of the high percentage of lung fibrosis which follows their usage.~9
The Management o f Pediatric Brain Tumors 163
propotion s u r v i v i n g
0.8 0.6 0.4
0.2 0
i
0
>f
"+
