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Medulloblastoma: Staging and treatment outcome
Inr. J. Radiatm Oncology Biol. P/y., Vol. 14, pp. 1103-I Printed in the U.S.A. All rights reserved.
107 Copyright
0360-3016/H $3.00 + .oO 0 1988 Pergamon Press plc
0 Original Contribution MEDULLOBLASTOMA:
STAGING MELVIN
Department
AND
DEUTSCH,
TREATMENT
OUTCOME
M.D.
of Radiation Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA
Fifty-two newly diagnosed patients with medulloblastoma were prospectively staged with myelography. Fifty also had at least one CSF cytology study. Twenty-four patients (46%) had evidence of dissemination beyond the posterior fossa at diagnosis. Patients under age 5 years were more likely to have dissemination at diagnosis than older patients (61% vs 38%). The 5-year disease-free survival for 45 patients diagnosed at least 1 year ago and treated with craniospinal irradiation was 62.6%. Overall 5-year survival for this group was 76.7%. Patients without evidence of dissemination at diagnosis had a 5-year disease-free survival of 73.3% compared to 49.1% for patients with Ml3 disease. Eighteen patients relapsed, 16 within 3 years of diagnosis. Eight patients had recurrent tumor in the posterior fossa, eight in the supratentorial compartment, seven in the cord, and five had systemic metastasis. Patients with initial cord involvement were more likely to develop systemic metastasis (4/12) than patients without initial cord involvement (l/33). Medulloblastoma, Myelography, CSF cytology, Staging, Spinal cord.
This report concerns a series of newly diagnosed medulloblastoma patients who have been evaluated with myelography and in most cases CSF cytology to assess incidence and extent of dissemination at diagnosis, patterns of relapse, and survival as related to dissemination (M-stage) at diagnosis. All patients were prospectively staged according to a modification of the M-stage criteria of Chang et ~1.~(Table 1) The M-l stage of Chang et al. does not specify the site from which CSF is taken for analysis. In my modification, malignant cells in the CSF constitute M-l stage only if the CSF is from the lateral ventricles or spinal subarachnoid space. The significance of malignant cells in the CSF from the fourth ventricle taken at the time of surgery on the primary tumor is unknown and is not considered M-l stage. For a patient to be considered M-2, there had to be tumor dissemination to the supratentorial region. Contiguous extension of the primary through the tentorial notch did not constitute M2 stage. In this modification, nodular seeding in the cerebellar subarachnoid by itself did not constitute M-2 disease. The T-stage classification was not used in this group of patients because of the difficulty in assigning a T stage retrospectively.
INTRODUCTION
Over the past 40 years there has been a dramatic improvement in the survival rates for patients with medulloblastoma. Based on the popularly held view that the posterior fossa is the most frequent site of therapeutic failure, radiation oncologists have emphasized the importance of administering at least 5,000 rad to the posterior fossa. Several reviews have attempted to show a correlation between high dose to the posterior fossa and improved survival. For certain subsets of newly diagnosed medulloblastoma patients receiving at least 5,000 rad to the posterior fossa, 5-year survival rates over 75% have been reported.3.5,7,13,‘5,17,18 There is continuing controversy concerning the optimum dose of radiation for irradiation of the craniospinal axis. Prior to the routine use of computerized tomography (CT), myelography, and cerebral spinal fluid (CSF) cytology studies, less than 20% of newly diagnosed patients with medulloblastoma were reported to have dis semination beyond the posterior fossa.‘y3Preliminary data from the Children’s Cancer Group (CCG) Medulloblastoma Study indicate that dissemination at diagnosis confers a poor prognosis.’ However, there are very few reported series containing large numbers of newly diagnosed medulloblastoma patients who have been thoroughly evaluated with myelography and CSF cytology prior to therapy.
METHODS
AND
MATERIALS
Since June 1974, 52 newly diagnosed medulloblastoma patients evaluated in the Department of Radiation On-
Reprint requests to: Melvin Deutsch, M.D., Department of Radiation Oncology, Presbyterian University Hospital, 230 Lothrop Street, Pittsburgh, PA 152 13.
Accepted for publication
1103
5 January 1988.
1104
I. J. Radiation Oncology 0 Biology 0 Physics
Table 1. M-Stage classification M-O:
No evidence of tumor beyond posterior fossa, CSF negative
M- 1:
Tumor cells in CSF from lateral ventricles or spinal tap. No tumor beyond posterior fossa
M-2:
Tumor in the supratentorial
M-3:
Tumor involving sninal cord
region
cology at the University of Pittsburgh Health Center have had myelography prior to therapy. A myelogram was usually performed within 2 weeks following posterior fossa surgery. It is now our standard practice to follow myelography with CT of the spine while the contrast material is still present. One patient with a normal conventional myelogram had multiple small nodules demonstrated by the post-myelogram CT. Fifty patients had cytology studies on at least one CSF sample taken from a shunt or spinal puncture site. The two patients without CSF cytology studies did not have other evidence of dissemination and thus were considered to be stage M-O. Three additional patients, all adults, diagnosed in this time interval refused myelography and did not have CSF cytology studies. Twenty-four (46%) of 52 staged patients had evidence of dissemination at diagnosis (Table 2). Eleven (61%) of 18 patients under age 5 years had evidence of dissemination at diagnosis as opposed to 13 (38%) of 34 patients over age 5 years. Males were more likely than females to have dissemination at diagnosis (52.5% vs 37.3%). In 23 patients (22 pre-op and 1 post-op), cytology studies were done on CSF from the lateral ventricle. Four patients (3 pre-op and 1 post-op) had malignant cells present in the CSF from the lateral ventricle and all had other evidence of dissemination. Three had cord involvement on myelography and a fourth had malignant cells in CSF from a spinal puncture site, although the myelogram was negative. A fifth patient had atypical cells in CSF from the lateral ventricle and cord involvement on myelography. Four patients had cytology studies on CSF taken from a lumbar puncture site prior to posterior fossa surgery. Three had malignant cells. One patient with malignant cells in the CSF had dissemination to the supratentorial brain and spinal cord. The other three patients, two with malignant cells and one without, did not have other evidence of dissemination. Forty-one patients had cytology
June 1988, Volume 14, Number 6
studies on CSF from a spinal puncture site postoperatively, usually at the time of myelography which was usually between 1 and 2 weeks after surgery. In eleven patients, CSF contained malignant cells. Seven of these latter patients also had spinal cord involvement. Of the seven patients with M-l disease, four had malignant cells in CSF from a spinal puncture site postoperatively, two had malignant cells in the CSF from the spinal puncture site preoperatively, and one had malignant cells in fluid from the shunt preoperatively and also from a spinal puncture site postoperatively. Three patients had M-2 staged disease. One had diffuse supratentorial involvement and the other two each had a suprasellar mass as the only site of dissemination beyond the posterior fossa. None of these three patients had spinal cord involvement or malignant cells in CSF from the spinal puncture site. Two additional patients with spinal cord involvement (M-3) also had supratentorial involvement at diagnosis. One had diffuse involvement and the other had a suprasellar metastatic lesion. Thus, three of five patients with supratentorial involvement at diagnosis had tumor in the suprasellar region (Fig. 1). Fourteen patients had spinal cord involvement at diagnosis (M-3). Three patients with spinal cord involvement did not have malignant cells in CSF from either the shunt or a spinal puncture site. Three other M-3 patients had CSF cytology studies only on fluid from the shunt: one contained malignant cells, one had atypical cells and in one, CSF was negative for malignant cells. One patient had negative cytology studies on fluid from the spinal site postoperatively but the shunt CSF preoperatively con-
Table 2. Stage versus age and sex
55 years >5 years Males Females Total
M-O
M-l
M-2
M-3
Total
7 (39%) 21 (62%) 16 (48%) 12 (63%) 28 (54%)
2 5 4 3 7
1 2 3 0 3
8 6 10 4 14
18 34 33 19 52
Fig. 1. Suprasellar metastatic lesion (M-2) at diagnosis.
1105
Medulloblastoma staging 0 M. DEUTSCH
tained malignant cells. The other seven M-3 patients had malignant cells in CSF from the spinal site. Forty-six patients were diagnosed over 1 year ago. One child, an infant with M-O disease, is being treated with chemotherapy after a gross total resection of the primary to delay radiotherapy. The 45 irradiated patients diagnosed greater than 1 year ago, form the basis for the treatment outcome analysis. The M-stage for these 45 patients is given in Table 3. All 45 patients were treated with craniospinal irradiation. All except seven patients received a posterior fossa dose 25,000 rad (5000-5600). Three patients received 4,940-4,980 rad and four infants, age 5-28 months, received 4,234-4,600 rad to the posterior fossa. Thirty-nine of 45 patients were treated with 23,000 rad to the spinal cord. Two received 2,880 rad and four other patients received 1,920-2,340 rad. Four of the six patients receiving ~3,000 rad to the spinal cord were under age 5 years. Two of these patients received a boost to involved portions of the spinal cord. Only four patients received ~3,000 rad (1,920-2,880) to the supratentorial brain. Fifteen patients also received adjuvant chemotherapy. Most received CCNU, Vincristine, and Prednisone as part of a CCG protocol. Two patients received the eight drugs in 1 day regimen described by Bleyer et al4 Ten of the 15 patients receiving adjuvant chemotherapy had evidence of dissemination at diagnosis (M 1-M3). RESULTS
The 5-year disease-free survival (Life Table) for the entire group of forty-five patients is 62.6%. Overall survival is 76.7% at 5 years. Patients without evidence of dissemination at diagnosis (M-O) had a 5-year disease-free survival of 73.3% compared to 49.1% for patients with M lM3 disease. Overall survival for the two groups was 86.5 and 53.7%, respectively. The 5-year disease-free survival rates for patients under age 5 years and over age 5 were 60.7%, and 62.6% respectively. Interestingly, all five patients under age 5 years with M-O stage medulloblastoma are alive and well. For females, 5-year disease-free survival was 73.5% versus 56.8% for males. In 18 patients tumor persisted or recurred following radiotherapy. (Table 4) Fifteen patients have died. In 16 patients, recurrent tumor was detected within three years of diagnosis. Two patients, (Table 5, #17, 18) both with an initial M-3 stage disease, relapsed at 64 and 73 months respectively. Sites of relapse are shown in Tables 4 and 5. Table 3. Patients staged rl year ago Stage
Number
M-O M-l M-2 M-3 Total
24 6 3 12 45
Number relapsed 6 3 : 18
Table 4. Sites of relapse Site
18 patients
Posterior fossa Supratentorium Spinal cord CSF Systemic Bone Bone marrow Ascites
8 8 7 6 5 3 1 1
An attempt was made to restage all patients with intracranial relapse with myelography and CSF cytology.
However, six patients with intracranial recurrence did not have myelography performed at relapse since their overall status was poor, there were no clinical signs of cord involvement, and further therapy was not being contemplated. One of these patients (Table 5 # 13) had recurrence diagnosed by CSF cytology. The patient expired before further diagnostic tests were performed. Two patients with just bone involvement at relapse and no evidence of central nervous system disease did not have myelography. Thus, the true incidence of relapse in the cord was probably higher than reported. Systemic relapse occurred in 5 patients. Three patients had a pre-operative ventricularperitoneal shunt. Two did not have any shunts. Three patients had concomitant relapse in the central nervous system. Two had bone involvement without evidence of central nervous system involvement and both died of systemic metastasis without ever manifesting tumor in the central nervous system. There was no definite correlation between the dose administered and relapse at a particular site. The eight relapses in the posterior fossa occurred in patients who had Table 5. Stage and sites of relapse Patient
Stage
Sites of relapse - Dose received
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
M-O M-O M-O M-O M-O M-O M-l M-l M-l M-2 M-3 M-3 M-3 M-3 M-3 M-3 M-3 M-3
PF 5450, ST 3450 ST 3387, SC 2340, CSF Bone ST 3450 SC 3000, CSF PF 5250 ST 3000, SC 3000 PF 5080, CSF ST 3450 PF 4950, ST 4950 PF 4980, ST 3226, CSF, BM PF 5380 CSF SC 3450 + boost, bone, PF 5450 ST 3450, SC 3450 + boost Bone SC 2040 + boost, CSF, ascites PF 5250, SC 3450 + boost
PF = Posterior fossa; ST = Supratentorium; cord, BM = bone marrow.
SC = Spinal
1106
I. J. Radiation Oncology 0 Biology 0 Physics
received 4,950-5,450 rad. Five had received r5,250 rad. Relapses in the supratentorial region occurred after doses of 3,226-4,950 rad. The patient receiving 4,950 rad had M-2 disease which persisted during radiotherapy. Three of the four patients with M-3 disease who subsequently relapsed in the cord, had received 3,450 rad to the entire cord plus an additional 900- 1,000 rad to areas of involvement. The fourth patient, a 5-month old infant, received 2,040 rad to the entire cord with a 1,500 rad boost to involved areas. One patient with Stage M-O disease, relapsed in the cord after receiving 2,340 rad. (Table 5) Three patients, (Table 5 #5, 6, 18) are alive without evidence of disease 53, 95, and 79 months, respectively from diagnosis of relapse. All were retreated with craniospinal irradiation and chemotherapy. Patients #6 and 18 also received Misonidazole concurrently with radiotherapy. None of these three patients had received adjuvant chemotherapy after the initial diagnosis. Because of the small numbers of patients, it is difficult to arrive at any conclusion concerning the value of adjuvant chemotherapy. Of patients with Ml-M3 disease initially, relapses occurred in six of 10 patients receiving chemotherapy and six of 11 patients who did not have chemotherapy. One of five patients with M-O disease who received chemotherapy relapsed. Of the three adult patients diagnosed during the same time interval, but not staged, one is alive and well at 10 years from diagnosis and two died at 9 and 20 months, respectively from diagnosis. DISCUSSION The incidence of dissemination at diagnosis for all staged patients was 46% (24/52). This is much higher than the estimates given for dissemination at diagnosis in most other reported series. In a large series of 122 patients reported by Berry et aL3 only 16% had evidence of dissemination at diagnosis. In the Children’s Cancer Group Study about 17% of the patients had evidence of dissemination at diagnosis.’ However, very few patients in both series were adequately staged with myelography and CSF cytology studies. Therefore, the incidence of M l-M3 stage very likely was underestimated. Allen and Epstein reported 8 of 25 (32%) medulloblastoma patients with dissemination at diagnosis.* Metastatic involvement of the supratentorial brain at diagnosis was seen in only five patients (9.6%) in this series. Two of these patients also had cord involvement and were thus considered to be Stage M-3. Note that, three of the five patients with supratentorial metastasis at diagnosis had a solitary lesion in the suprasellar region indicating the importance of studying this area thoroughly with CT or magnetic resonance imaging (Fig. 1). Most reports on medulloblastoma have stressed that the posterior fossa is the most common site of recurrent tumor.3*‘6*1EIn this series, tumor in the posterior fossa was present in 44% (8/ 18) of patients who relapsed. Before the advent of computerized tomography (CT) recurrence
June 1988, Volume 14, Number 6
in the supratentorial brain was rarely diagnosed. McFarland et al. in 1968 reviewed of the literature on medulloblastoma and reported that only 6% of cases with recurrence beyond the posterior fossa had supratentorial involvement.‘6 For this reason, they even questioned the necessity of irradiating the supratentorial brain in newly diagnosed medulloblastoma patients. In this series, relapse in the supratentorium was as common as posterior fossa relapse. The eight patients with supratentorial relapse comprised 44% of therapeutic failures. In three patients, recurrence appeared in the anterior cranial fossa just above the cribriform plate region. Relapse in this site has been noted by others and may be attributable to partial shielding of the cribriform plate area by blocks used to protect the orbits.‘2,14 The spinal cord was the site of relapse in seven patients, but only one patient had an isolated spinal cord relapse. Myelography is suggested for all patients with intracranial tumor at relapse. However, in this reported series, several patients did not have myelography at the time of relapse because of their rapidly deteriorating condition. Thus, it is possible that the true incidence of spinal cord involvement at relapse is higher than reported in this series. As would be expected, patients with initial spinal cord involvement at diagnosis were most at risk for experiencing relapse in the spinal cord. Systemic relapse occurred in four of 12 patients with M-3 disease. Only one of 33 patients without spinal cord involvement initially, developed systemic metastasis. The high incidence of bone involvement at relapse suggests that bone marrow and/or a bone scan should be included in the staging of newly diagnosed medulloblastoma patients, especially those with M-3 disease. Several reports have suggested that younger patients with medulloblastoma have a poorer prognosis than older patients. 3,5This may be related to the higher incidence of dissemination at diagnosis in the younger patients. Eleven of 18 staged patients under age 5 years had dissemination at diagnosis. In the series of 25 medulloblastoma patients reported by Allan and Epstein, seven of eight patients with dissemination were under age 5 years.* In their series, the mean age for patients with dissemination was 3.9 years versus 10.8 years for patients without dissemination. Stage for stage, patients under age 5 did not do any worse than older patients. In fact, all of the M-O patients under age 5 are alive and well compared to 13 of 19 older patients with M-O disease. This report confirms previous data from this institution which demonstrated a high incidence of dissemination beyond the posterior fossa in newly diagnosed medulloblastoma patients. Data from this report supports the prognostic value of staging for evidence of dissemination in newly diagnosed medulloblastoma patients.8-’ ’ Staging identifies a subset of medulloblastoma patients which should be considered for additional therapy: either higher doses of radiation to sites of dissemination and/or adjuvant chemotherapy.
Medulloblastoma staging ??M. DEUTSCH
1107
REFERENCES 1. Allen, J.C., Bloom, J., Ertel, I., Evans, A., Hammond, D., Jones, H., Levin, V., Jenkin, D., Sposto, R., Wara, W.: Brain tumors in children: Current cooperative and institutional chemotherapy trials in newly diagnosed and recurrent disease. Semin. Oncol. 13: 110-122, 1986. 2. Allen, J.C., Epstein, F.: Medulloblastoma and other primary malignant neuroectodermal tumors of the CNS. The effect of patients’ age and extent of disease on prognosis. J. Neurosurg. 57: 446-45 1, 1982. 3. Berry, M.P., Jenkin, R.D.T., Keen,C.W., Nair, B.D., Simpson, W.J.: Radiation treatment for medulloblastoma. A 2 lyear review. J. Neurosurg. 55: 43-5 1, 198 1. 4. Bleyer, W., Millstein, J., Balias, F., Pendergrass, T., Chard, R., Hartman, J.: 8 drugs in 1 day chemotherapy for brain tumors: A new approach and rationale for preradiation chemotherapy (Abst.). Med. Pediat. Oncol. 11: 213, 1983. 5. Brand, W.N., Schneider, P.A., Tokars, R.P.: Long term results of a pilot study of low dose cranial-spinal irradiation for cerebellar medulloblastoma. Int. J. Radiat. Oncol. Biol. Phys. 13: 1641-1645, 1987. 6. Chang, C.H., Housepian, E.M., Herbert, Jr., C.: An operative staging system and a megavoltage radiotherapeutic technique for cerebellar medulloblastoma. Radiofogy 93: 135 l1359, 1969. 7. Chin, H.W., Maruyama, Y.: Results of radiation treatment of cerebellar medulloblastoma. Int. J Radiat. Oncol. Biol. Phys. 7: 737-742, 1981. 8. Deutsch, M.: Myelography and cytology for staging very young children with medulloblastoma. Am. J. Clin. Oncol. (CCr) 6: 657-660, 1983. 9. Deutsch, M.: The impact of myelography on the treatment
10.
11. 12.
13.
14. 15.
16. 17.
18.
results for medulloblastoma. Int. J. Radiat. Oncol. Biol. Phys. 10: 999-1003, 1984. Deutsch, M., Reigel, D.H.: Myelography and cytology in the treatment of medulloblastoma. Znt. J. Radiat. Oncol. Biol. Phys. 7: 721-725, 1981. Deutsch, M., Scotti, L.N., Hardman, D.R., Reigel, D.H., Scarff, T.B.: Myelography in patients with medulloblastoma. Radiology 117: 467-468, 1975. Hardy, D.G., Hope-Stone, H.F., McKenzie, G.G., Scholtz, C.I.: Recurrence of medulloblastoma after homogeneous field radiotherapy. J. Neurosurg. 49: 434-440, 1978. Harisiadis, L., Chang, C.H.: Medulloblastoma in children: A correlation between staging and results of treatment. Znt. J. Radiat. Oncol. Biol. Phys. 2: 833-841, 1977. Jereb, B., Reid, A., Ahuja, R.K.: Patterns of failure in patients with medulloblastoma. Cancer 50: 2941-2947, 1982. Kopelson, G., Linggood, R.M., Kleinman, G.M.: Medulloblastoma. The identification of prognostic subgroups and implications for multimodality management. Cancer 51: 312-319, 1983. McFarland, D.R., Horwitz, H., Saenger, E.L., Bahr, G.K.: Medulloblastoma-A review of prognosis and survival. Br. J. Radiol. 42: 198-214, 1969. Norris, D.G., Bruce, D.A., Byrd, R.L., Schut, L., Littman, P., Bilaniuk, L.T., Zimmerman, R.A., Capp, R.: Improved relapse-free survival in medulloblastoma utilizing modem techniques. Neurosurgery 9: 66 l-664, 198 1. Silverman, CL., Simpson, J.R.: Cerebellar medulloblastoma: The importance of posterior fossa dose to survival and patterns of failure. Int. J. Radiat. Oncol. Biol. Phys. 8: 1869-1876, 1982.
107 Copyright
0360-3016/H $3.00 + .oO 0 1988 Pergamon Press plc
0 Original Contribution MEDULLOBLASTOMA:
STAGING MELVIN
Department
AND
DEUTSCH,
TREATMENT
OUTCOME
M.D.
of Radiation Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA
Fifty-two newly diagnosed patients with medulloblastoma were prospectively staged with myelography. Fifty also had at least one CSF cytology study. Twenty-four patients (46%) had evidence of dissemination beyond the posterior fossa at diagnosis. Patients under age 5 years were more likely to have dissemination at diagnosis than older patients (61% vs 38%). The 5-year disease-free survival for 45 patients diagnosed at least 1 year ago and treated with craniospinal irradiation was 62.6%. Overall 5-year survival for this group was 76.7%. Patients without evidence of dissemination at diagnosis had a 5-year disease-free survival of 73.3% compared to 49.1% for patients with Ml3 disease. Eighteen patients relapsed, 16 within 3 years of diagnosis. Eight patients had recurrent tumor in the posterior fossa, eight in the supratentorial compartment, seven in the cord, and five had systemic metastasis. Patients with initial cord involvement were more likely to develop systemic metastasis (4/12) than patients without initial cord involvement (l/33). Medulloblastoma, Myelography, CSF cytology, Staging, Spinal cord.
This report concerns a series of newly diagnosed medulloblastoma patients who have been evaluated with myelography and in most cases CSF cytology to assess incidence and extent of dissemination at diagnosis, patterns of relapse, and survival as related to dissemination (M-stage) at diagnosis. All patients were prospectively staged according to a modification of the M-stage criteria of Chang et ~1.~(Table 1) The M-l stage of Chang et al. does not specify the site from which CSF is taken for analysis. In my modification, malignant cells in the CSF constitute M-l stage only if the CSF is from the lateral ventricles or spinal subarachnoid space. The significance of malignant cells in the CSF from the fourth ventricle taken at the time of surgery on the primary tumor is unknown and is not considered M-l stage. For a patient to be considered M-2, there had to be tumor dissemination to the supratentorial region. Contiguous extension of the primary through the tentorial notch did not constitute M2 stage. In this modification, nodular seeding in the cerebellar subarachnoid by itself did not constitute M-2 disease. The T-stage classification was not used in this group of patients because of the difficulty in assigning a T stage retrospectively.
INTRODUCTION
Over the past 40 years there has been a dramatic improvement in the survival rates for patients with medulloblastoma. Based on the popularly held view that the posterior fossa is the most frequent site of therapeutic failure, radiation oncologists have emphasized the importance of administering at least 5,000 rad to the posterior fossa. Several reviews have attempted to show a correlation between high dose to the posterior fossa and improved survival. For certain subsets of newly diagnosed medulloblastoma patients receiving at least 5,000 rad to the posterior fossa, 5-year survival rates over 75% have been reported.3.5,7,13,‘5,17,18 There is continuing controversy concerning the optimum dose of radiation for irradiation of the craniospinal axis. Prior to the routine use of computerized tomography (CT), myelography, and cerebral spinal fluid (CSF) cytology studies, less than 20% of newly diagnosed patients with medulloblastoma were reported to have dis semination beyond the posterior fossa.‘y3Preliminary data from the Children’s Cancer Group (CCG) Medulloblastoma Study indicate that dissemination at diagnosis confers a poor prognosis.’ However, there are very few reported series containing large numbers of newly diagnosed medulloblastoma patients who have been thoroughly evaluated with myelography and CSF cytology prior to therapy.
METHODS
AND
MATERIALS
Since June 1974, 52 newly diagnosed medulloblastoma patients evaluated in the Department of Radiation On-
Reprint requests to: Melvin Deutsch, M.D., Department of Radiation Oncology, Presbyterian University Hospital, 230 Lothrop Street, Pittsburgh, PA 152 13.
Accepted for publication
1103
5 January 1988.
1104
I. J. Radiation Oncology 0 Biology 0 Physics
Table 1. M-Stage classification M-O:
No evidence of tumor beyond posterior fossa, CSF negative
M- 1:
Tumor cells in CSF from lateral ventricles or spinal tap. No tumor beyond posterior fossa
M-2:
Tumor in the supratentorial
M-3:
Tumor involving sninal cord
region
cology at the University of Pittsburgh Health Center have had myelography prior to therapy. A myelogram was usually performed within 2 weeks following posterior fossa surgery. It is now our standard practice to follow myelography with CT of the spine while the contrast material is still present. One patient with a normal conventional myelogram had multiple small nodules demonstrated by the post-myelogram CT. Fifty patients had cytology studies on at least one CSF sample taken from a shunt or spinal puncture site. The two patients without CSF cytology studies did not have other evidence of dissemination and thus were considered to be stage M-O. Three additional patients, all adults, diagnosed in this time interval refused myelography and did not have CSF cytology studies. Twenty-four (46%) of 52 staged patients had evidence of dissemination at diagnosis (Table 2). Eleven (61%) of 18 patients under age 5 years had evidence of dissemination at diagnosis as opposed to 13 (38%) of 34 patients over age 5 years. Males were more likely than females to have dissemination at diagnosis (52.5% vs 37.3%). In 23 patients (22 pre-op and 1 post-op), cytology studies were done on CSF from the lateral ventricle. Four patients (3 pre-op and 1 post-op) had malignant cells present in the CSF from the lateral ventricle and all had other evidence of dissemination. Three had cord involvement on myelography and a fourth had malignant cells in CSF from a spinal puncture site, although the myelogram was negative. A fifth patient had atypical cells in CSF from the lateral ventricle and cord involvement on myelography. Four patients had cytology studies on CSF taken from a lumbar puncture site prior to posterior fossa surgery. Three had malignant cells. One patient with malignant cells in the CSF had dissemination to the supratentorial brain and spinal cord. The other three patients, two with malignant cells and one without, did not have other evidence of dissemination. Forty-one patients had cytology
June 1988, Volume 14, Number 6
studies on CSF from a spinal puncture site postoperatively, usually at the time of myelography which was usually between 1 and 2 weeks after surgery. In eleven patients, CSF contained malignant cells. Seven of these latter patients also had spinal cord involvement. Of the seven patients with M-l disease, four had malignant cells in CSF from a spinal puncture site postoperatively, two had malignant cells in the CSF from the spinal puncture site preoperatively, and one had malignant cells in fluid from the shunt preoperatively and also from a spinal puncture site postoperatively. Three patients had M-2 staged disease. One had diffuse supratentorial involvement and the other two each had a suprasellar mass as the only site of dissemination beyond the posterior fossa. None of these three patients had spinal cord involvement or malignant cells in CSF from the spinal puncture site. Two additional patients with spinal cord involvement (M-3) also had supratentorial involvement at diagnosis. One had diffuse involvement and the other had a suprasellar metastatic lesion. Thus, three of five patients with supratentorial involvement at diagnosis had tumor in the suprasellar region (Fig. 1). Fourteen patients had spinal cord involvement at diagnosis (M-3). Three patients with spinal cord involvement did not have malignant cells in CSF from either the shunt or a spinal puncture site. Three other M-3 patients had CSF cytology studies only on fluid from the shunt: one contained malignant cells, one had atypical cells and in one, CSF was negative for malignant cells. One patient had negative cytology studies on fluid from the spinal site postoperatively but the shunt CSF preoperatively con-
Table 2. Stage versus age and sex
55 years >5 years Males Females Total
M-O
M-l
M-2
M-3
Total
7 (39%) 21 (62%) 16 (48%) 12 (63%) 28 (54%)
2 5 4 3 7
1 2 3 0 3
8 6 10 4 14
18 34 33 19 52
Fig. 1. Suprasellar metastatic lesion (M-2) at diagnosis.
1105
Medulloblastoma staging 0 M. DEUTSCH
tained malignant cells. The other seven M-3 patients had malignant cells in CSF from the spinal site. Forty-six patients were diagnosed over 1 year ago. One child, an infant with M-O disease, is being treated with chemotherapy after a gross total resection of the primary to delay radiotherapy. The 45 irradiated patients diagnosed greater than 1 year ago, form the basis for the treatment outcome analysis. The M-stage for these 45 patients is given in Table 3. All 45 patients were treated with craniospinal irradiation. All except seven patients received a posterior fossa dose 25,000 rad (5000-5600). Three patients received 4,940-4,980 rad and four infants, age 5-28 months, received 4,234-4,600 rad to the posterior fossa. Thirty-nine of 45 patients were treated with 23,000 rad to the spinal cord. Two received 2,880 rad and four other patients received 1,920-2,340 rad. Four of the six patients receiving ~3,000 rad to the spinal cord were under age 5 years. Two of these patients received a boost to involved portions of the spinal cord. Only four patients received ~3,000 rad (1,920-2,880) to the supratentorial brain. Fifteen patients also received adjuvant chemotherapy. Most received CCNU, Vincristine, and Prednisone as part of a CCG protocol. Two patients received the eight drugs in 1 day regimen described by Bleyer et al4 Ten of the 15 patients receiving adjuvant chemotherapy had evidence of dissemination at diagnosis (M 1-M3). RESULTS
The 5-year disease-free survival (Life Table) for the entire group of forty-five patients is 62.6%. Overall survival is 76.7% at 5 years. Patients without evidence of dissemination at diagnosis (M-O) had a 5-year disease-free survival of 73.3% compared to 49.1% for patients with M lM3 disease. Overall survival for the two groups was 86.5 and 53.7%, respectively. The 5-year disease-free survival rates for patients under age 5 years and over age 5 were 60.7%, and 62.6% respectively. Interestingly, all five patients under age 5 years with M-O stage medulloblastoma are alive and well. For females, 5-year disease-free survival was 73.5% versus 56.8% for males. In 18 patients tumor persisted or recurred following radiotherapy. (Table 4) Fifteen patients have died. In 16 patients, recurrent tumor was detected within three years of diagnosis. Two patients, (Table 5, #17, 18) both with an initial M-3 stage disease, relapsed at 64 and 73 months respectively. Sites of relapse are shown in Tables 4 and 5. Table 3. Patients staged rl year ago Stage
Number
M-O M-l M-2 M-3 Total
24 6 3 12 45
Number relapsed 6 3 : 18
Table 4. Sites of relapse Site
18 patients
Posterior fossa Supratentorium Spinal cord CSF Systemic Bone Bone marrow Ascites
8 8 7 6 5 3 1 1
An attempt was made to restage all patients with intracranial relapse with myelography and CSF cytology.
However, six patients with intracranial recurrence did not have myelography performed at relapse since their overall status was poor, there were no clinical signs of cord involvement, and further therapy was not being contemplated. One of these patients (Table 5 # 13) had recurrence diagnosed by CSF cytology. The patient expired before further diagnostic tests were performed. Two patients with just bone involvement at relapse and no evidence of central nervous system disease did not have myelography. Thus, the true incidence of relapse in the cord was probably higher than reported. Systemic relapse occurred in 5 patients. Three patients had a pre-operative ventricularperitoneal shunt. Two did not have any shunts. Three patients had concomitant relapse in the central nervous system. Two had bone involvement without evidence of central nervous system involvement and both died of systemic metastasis without ever manifesting tumor in the central nervous system. There was no definite correlation between the dose administered and relapse at a particular site. The eight relapses in the posterior fossa occurred in patients who had Table 5. Stage and sites of relapse Patient
Stage
Sites of relapse - Dose received
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
M-O M-O M-O M-O M-O M-O M-l M-l M-l M-2 M-3 M-3 M-3 M-3 M-3 M-3 M-3 M-3
PF 5450, ST 3450 ST 3387, SC 2340, CSF Bone ST 3450 SC 3000, CSF PF 5250 ST 3000, SC 3000 PF 5080, CSF ST 3450 PF 4950, ST 4950 PF 4980, ST 3226, CSF, BM PF 5380 CSF SC 3450 + boost, bone, PF 5450 ST 3450, SC 3450 + boost Bone SC 2040 + boost, CSF, ascites PF 5250, SC 3450 + boost
PF = Posterior fossa; ST = Supratentorium; cord, BM = bone marrow.
SC = Spinal
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received 4,950-5,450 rad. Five had received r5,250 rad. Relapses in the supratentorial region occurred after doses of 3,226-4,950 rad. The patient receiving 4,950 rad had M-2 disease which persisted during radiotherapy. Three of the four patients with M-3 disease who subsequently relapsed in the cord, had received 3,450 rad to the entire cord plus an additional 900- 1,000 rad to areas of involvement. The fourth patient, a 5-month old infant, received 2,040 rad to the entire cord with a 1,500 rad boost to involved areas. One patient with Stage M-O disease, relapsed in the cord after receiving 2,340 rad. (Table 5) Three patients, (Table 5 #5, 6, 18) are alive without evidence of disease 53, 95, and 79 months, respectively from diagnosis of relapse. All were retreated with craniospinal irradiation and chemotherapy. Patients #6 and 18 also received Misonidazole concurrently with radiotherapy. None of these three patients had received adjuvant chemotherapy after the initial diagnosis. Because of the small numbers of patients, it is difficult to arrive at any conclusion concerning the value of adjuvant chemotherapy. Of patients with Ml-M3 disease initially, relapses occurred in six of 10 patients receiving chemotherapy and six of 11 patients who did not have chemotherapy. One of five patients with M-O disease who received chemotherapy relapsed. Of the three adult patients diagnosed during the same time interval, but not staged, one is alive and well at 10 years from diagnosis and two died at 9 and 20 months, respectively from diagnosis. DISCUSSION The incidence of dissemination at diagnosis for all staged patients was 46% (24/52). This is much higher than the estimates given for dissemination at diagnosis in most other reported series. In a large series of 122 patients reported by Berry et aL3 only 16% had evidence of dissemination at diagnosis. In the Children’s Cancer Group Study about 17% of the patients had evidence of dissemination at diagnosis.’ However, very few patients in both series were adequately staged with myelography and CSF cytology studies. Therefore, the incidence of M l-M3 stage very likely was underestimated. Allen and Epstein reported 8 of 25 (32%) medulloblastoma patients with dissemination at diagnosis.* Metastatic involvement of the supratentorial brain at diagnosis was seen in only five patients (9.6%) in this series. Two of these patients also had cord involvement and were thus considered to be Stage M-3. Note that, three of the five patients with supratentorial metastasis at diagnosis had a solitary lesion in the suprasellar region indicating the importance of studying this area thoroughly with CT or magnetic resonance imaging (Fig. 1). Most reports on medulloblastoma have stressed that the posterior fossa is the most common site of recurrent tumor.3*‘6*1EIn this series, tumor in the posterior fossa was present in 44% (8/ 18) of patients who relapsed. Before the advent of computerized tomography (CT) recurrence
June 1988, Volume 14, Number 6
in the supratentorial brain was rarely diagnosed. McFarland et al. in 1968 reviewed of the literature on medulloblastoma and reported that only 6% of cases with recurrence beyond the posterior fossa had supratentorial involvement.‘6 For this reason, they even questioned the necessity of irradiating the supratentorial brain in newly diagnosed medulloblastoma patients. In this series, relapse in the supratentorium was as common as posterior fossa relapse. The eight patients with supratentorial relapse comprised 44% of therapeutic failures. In three patients, recurrence appeared in the anterior cranial fossa just above the cribriform plate region. Relapse in this site has been noted by others and may be attributable to partial shielding of the cribriform plate area by blocks used to protect the orbits.‘2,14 The spinal cord was the site of relapse in seven patients, but only one patient had an isolated spinal cord relapse. Myelography is suggested for all patients with intracranial tumor at relapse. However, in this reported series, several patients did not have myelography at the time of relapse because of their rapidly deteriorating condition. Thus, it is possible that the true incidence of spinal cord involvement at relapse is higher than reported in this series. As would be expected, patients with initial spinal cord involvement at diagnosis were most at risk for experiencing relapse in the spinal cord. Systemic relapse occurred in four of 12 patients with M-3 disease. Only one of 33 patients without spinal cord involvement initially, developed systemic metastasis. The high incidence of bone involvement at relapse suggests that bone marrow and/or a bone scan should be included in the staging of newly diagnosed medulloblastoma patients, especially those with M-3 disease. Several reports have suggested that younger patients with medulloblastoma have a poorer prognosis than older patients. 3,5This may be related to the higher incidence of dissemination at diagnosis in the younger patients. Eleven of 18 staged patients under age 5 years had dissemination at diagnosis. In the series of 25 medulloblastoma patients reported by Allan and Epstein, seven of eight patients with dissemination were under age 5 years.* In their series, the mean age for patients with dissemination was 3.9 years versus 10.8 years for patients without dissemination. Stage for stage, patients under age 5 did not do any worse than older patients. In fact, all of the M-O patients under age 5 are alive and well compared to 13 of 19 older patients with M-O disease. This report confirms previous data from this institution which demonstrated a high incidence of dissemination beyond the posterior fossa in newly diagnosed medulloblastoma patients. Data from this report supports the prognostic value of staging for evidence of dissemination in newly diagnosed medulloblastoma patients.8-’ ’ Staging identifies a subset of medulloblastoma patients which should be considered for additional therapy: either higher doses of radiation to sites of dissemination and/or adjuvant chemotherapy.
Medulloblastoma staging ??M. DEUTSCH
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