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Common Strategy for Adult and Pediatric Medulloblastoma: A Multicenter Series of 253 Adults
Int. J. Radiation Oncology Biol. Phys., Vol. 68, No. 2, pp. 433– 440, 2007 Copyright © 2007 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/07/$–see front matter
doi:10.1016/j.ijrobp.2006.12.030
CLINICAL INVESTIGATION
Brain
COMMON STRATEGY FOR ADULT AND PEDIATRIC MEDULLOBLASTOMA: A MULTICENTER SERIES OF 253 ADULTS LAETITIA PADOVANI, M.D.,* MARIE-PIERRE SUNYACH, M.D.,† DAVID PEROL, M.D.,‡ CEDRIC MERCIER, M.D., PH.D.,¶¶ CLAIRE ALAPETITE, M.D.,§ CHRISTINE HAIE-MEDER, M.D.,¶ SYLVETTE HOFFSTETTER, M.D.,储 XAVIER MURACCIOLE, M.D.,* CHRISTINE KERR, M.D.,# JEAN-PHILIPPE WAGNER, M.D.,** JEAN-LÉON LAGRANGE, M.D.,†† JEAN-PHILIPPE MAIRE, M.D.,‡‡ DIDIER COWEN, M.D. PH.D.,* DIDIER FRAPPAZ, M.D.,†§§ AND CHRISTIAN CARRIE, M.D.† Departments of *Radiation Oncology and ¶¶Medical Oncology, Hôpital de la Timone, Marseille, France; Departments of Radiation Oncology and ‡Biostatistics, Centre Léon Bérard, Lyon, France; §Department of Radiation Oncology, Institut Curie, Paris, France; ¶Department of Radiation Oncology, Institut Gustave Roussy, Villejuif, France; 储Department of Radiation Oncology, Centre Alexis Vautrin, Nancy, France; #Department of Radiation Oncology, Centre Val D’aurelle, Montpellier, France; **Department of Radiation Oncology, Clinique de l’Orangerie, Strasbourg, France; ††Department of Radiation Oncology, Hopital Henry Mondor, Créteil, France; ‡‡Department of Radiation Oncology, Hôpital Saint André, Bordeaux, France; and §§Department of Neuro-oncology, Centre Léon Bérard, Lyon, France †
Purpose: To assess prognostic factors for adults with medulloblastoma in a multicenter, retrospective study. Methods and Materials: Data were collected by file review or mail inquiry for 253 adults treated between 1975 to 2004. Radiologists or surgeons assessed disease characteristics, such as volume and extension. Patients were classified as having either high- or standard-risk disease. Prognostic factors were analyzed. Results: Median patient age was 29 years. Median follow-up was 7 years. Radiotherapy was delivered in 246 patients and radiochemotherapy in 142. Seventy-four patients relapsed. Respective 5- and 10-year overall survival rates were 72% and 55%. Univariate analysis showed that survival significantly correlated with metastasis, postsurgical performance status, brainstem involvement, involvement of the floor of the fourth ventricle (V4), and radiation dose to the spine and to the posterior cerebral fossa (PCF). By multivariate analysis, brainstem, V4 involvement, and dose to the PCF were negative prognostic factors. In the standard-risk subgroup there was no overall survival difference between patients treated with axial doses of >34 Gy and patients treated with craniospinal doses <34 Gy plus chemotherapy. Conclusion: We report the largest series of medulloblastoma in adults. Prognostic factors were similar to those observed in children. Results suggest that patients with standard-risk disease could be treated with radiochemotherapy, reducing doses to the craniospinal area, maintaining at least 50 Gy to the PCF. The role of chemotherapy for this group is still unclear. A randomized study should be performed to confirm these results, but because frequency is very low, such a study would be difficult. © 2007 Elsevier Inc. Radiotherapy, Medulloblastoma, Adults.
INTRODUCTION
in children and guide therapeutic strategies (3). In contrast, in adults, the majority of reported cases of medulloblastoma are single-institution, retrospective series including only a few patients (4, 5). Adult and pediatric medulloblastomas are radiologically distinct. Adult tumors usually involve the lateral cerebellar hemispheres, and pediatric tumors occur in the vermis. Histology also differs between adult and pediatric tumors. The aim of the present study was to identify prognostic
Medulloblastoma is a malignant neuroectodermal tumor uncommon in adults. Median age at diagnosis is 5 years (1). Medulloblastoma accounts for 30% of brain tumors of childhood but fewer than 3% of all primary neoplasms of the central nervous system (CNS) in adults (2). Most children treated for medulloblastoma are included in prospective studies. Clinical prognostic factors have been identified
L.P., M-P.S., D.F., and C.C. contributed equally to this work. Conflict of interest: none. Acknowledgment—The authors thank Rosalyn Vu for her valuable help with preparation of the manuscript in English. Received Sept 26, 2006, and in revised form Dec 6, 2006. Accepted for publication Dec 11, 2006.
Reprint requests to: Laetitia Padovani, M.D., Departement d’Oncologie Radiothérapie, Hopital La Timone, 264 Bd Saint-Pierre, 13385 Marseille, France. Tel: (⫹33) 4-9138-4334; Fax: (⫹33) 4-9138-5692; E-mail: [email protected] Presented at the Forty Seventh Annual Meeting of the American Society of Therapeutic Radiology and Oncology (ASTRO), October 16 –20, 2005, Denver, CO. 433
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Table 1. Patients characteristics Characteristic
No. of patients
Mean ⫾ SD or n (%)
160/88 251 230 219
30.9 ⫾ 9.5 45.3 ⫾ 18.4 62.4 ⫾ 63.1
Gender (male/female) Age at surgery (y) (18–58, median 29) Duration of radiation (d) (median, 44) Delay between surgery and radiotherapy (d) (median, 45) Histology type None Desmoplastic Classic Other Brainstem involvement Fourth ventricular (V4) floor involvement Medullary involvement Peduncular involvement Surgical residue Positive spinal fluid, postoperative Postoperative performance status 0 1 2 3 4 Chemotherapy Radiotherapy plus chemotherapy Brain radiation dose ⱖ30 Gy Spinal radiation dose ⱖ30 Gy Posterior fossa radiation dose ⱖ50 Gy
253
213 205 248 204 237 216 179
252 253 249 249 250
5 (1) 75 (30) 166 (66) 7 (3) 12 (6) 63 (31) 14 (6) 42 (21) 87 (37) 17 (8) 32 (18) 88 (49) 40 (22) 13 (7) 6 (3) 146 (58) 142 (56) 217 (87) 227 (91) 231 (92)
Abbreviation: SD ⫽ standard deviation.
factors in adult patients with medulloblastomas and evaluate the results of treatment combining reduced-dose radiotherapy with chemotherapy for patients with tumors classified as having standard risk for recurrence. METHODS AND MATERIALS Between 1975 and 1991, 156 patients were included in the initial database. Carrie et al. initiated the present study in 1991 (3), and data from 97 patients treated after 1991 have been added. The data were updated by mail inquiry or from patient files. Thus, between January 1975 and January 2004, 253 patients aged ⬎18 years with histologically proven medulloblastoma and treated in 1 of 13 French centers were enrolled in this retrospective study. The median age of patients at diagnosis was 29 years (range, 18 –58 years). Table 1 shows disease and patient characteristics. Extent of disease location (central or lateral) within the brainstem and infiltration of the peduncle were assessed by myelography or computed tomography (CT) and/or magnetic resonance imaging (MRI) of the CNS. Involvement of the cerebrospinal fluid (CSF) was assessed by spinal puncture. Results were reported solely according to available data. All patients underwent surgical removal of their tumors, except 2 who refused surgery. Surgery was considered complete when operative chart and postsurgical imaging indicated no residual tumor. Infiltration of the floor of the fourth ventricle (V4) was assessed by the surgeon intraoperatively. Postoperative performance status was recorded when possible using the Eastern Co-
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operative Oncology Group performance scale. Treatment was delivered by either a 60Co teletherapy machine or linear accelerator at fractions of 1.8 –2 Gy/d. Patients were irradiated with two opposed fields for the brain, with a boost to the posterior cerebral fossa (PCF); direct posterior fields were achieved with moving junctions for the spinal axis with either electron, photon, or mixed beam. Patients were classified as having either high or standard risk for recurrence of medulloblastoma. The high-risk group included patients with metastatic disease and/or CSF involvement and/or macroscopic tumor residue after surgery. The standard-risk group had none of these risk factors. Only patients with data available for all items were considered for analysis.
Descriptive statistics Overall survival was calculated from the date of surgery to either the date of death from any cause or to last follow-up for living patients (censored observation). Progression-free survival (PFS) was measured from surgery to disease progression or death or was censored at last follow-up. Survival estimates were calculated using the Kaplan-Meier method (6). Differences in survival estimates were assessed in univariate analysis by the log–rank test (7). Independent prognostic factors of overall survival were identified by multivariate regression analysis (Cox proportional hazards regression model) (8), using a backward procedure to eliminate non-influential variables. A significance level of 0.05 was used to select explanatory variables. Survival and disease-free survival were determined in the entire population and in the standard- and high-risk subgroups. Among standard-risk patients, we compared overall survival between patients treated with high-dose radiation (36 Gy) and with lower doses of radiation combined with chemotherapy.
RESULTS Among 238 patients (150 men, 88 women) for whom data were available, median age at diagnosis was 29 years (range, 18 –58 years). Total surgery was performed in 147 patients, and 87 presented with residual tumor after surgery, as determined by either the surgeon or early postoperative CT or MRI scans. For 3 patients, CT or MRI data were not found. The median delay between surgery and radiation was 45 days. All patients except 6 received radiotherapy. Four patients died of sepsis before irradiation. Of those 4, 2 had received previous chemotherapy: 1 who died immediately after surgery and 1 who died from disease progression despite the chemotherapy. The fifth patient did not receive the entire radiation dose because of hematologic toxicity, and did not receive previous chemotherapy. The last patient was irradiated only to the PCF with a dose of 45 Gy because the patient’s mental retardation precluded immobilization. These patients were included in the analysis. All others received craniospinal irradiation. The median duration of irradiation was 44 days. Median doses delivered were 35 Gy to the brain, 35 Gy to the spinal area, and 54 Gy to the PCF. One hundred forty-six patients received adjuvant chemotherapy. Because data were collected over a very long period and for patients treated at 13 different centers, delivery regimens were heterogeneous (9 –11). Median follow-up was 7 years, median overall survival, 13 years. At 5
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classified as having standard risk in 124 patients and high risk in 95. For 34 patients, data were unavailable for the three criteria (metastatic disease and/or CSF involvement and/or macroscopic tumor residue after surgery). Five-year overall survival was 65% in the population with high-risk medulloblastoma and 77% in those with standard-risk tumors. Survival between the two populations was significantly different (p ⫽ 0.0338). Metastasis (p ⫽ 0.046), postsurgical performance status (p ⬍ 0.0004), brainstem involvement (p ⫽ 0.013), V4 floor involvement (p ⫽ 0.0002), spinal radiation dose (p ⫽ 0.0054), and posterior fossa radiation dose (p ⬍ 0.0001) correlated significantly with survival. A trend for negative correlation was found for postsurgical residue (p ⫽ 0.08).
0,8
0,6
0,4
0,2
0,0 0
2
4
6
8
10
12
14
16
18
20
22
24
Years post surgery
Fig. 1. Overall survival.
years after surgery, the overall survival rate was 72% (95% confidence interval [CI], 66 –78%), and at 10 years, 55% (95% CI, 47– 63%) (Fig. 1). At 5 years after surgery, disease-free survival was 65% (95% CI, 59 –71%), and at 10 years, 55% (95% CI, 48 – 63%) (Fig. 2). At last follow-up, 151 patients were alive without cancer relapse; 7 were alive with disease, and deaths included 67 from disease, 9 from early treatment complications (1 postoperative respiratory disease, 1 acute pancreatitis, 1 Lyell syndrome due to medication to prevent Pneumocystis carinii pneumonia, 1 bacterial meningitis, 2 septic shock, 1 medullary aplasia, and 2 toxic infection; further data were not collected), 5 from radio-induced encephalitis, and 2 from secondary cancer (lung cancer and leukemia M5). Data were unavailable for 12 patients. Pattern of relapse Seventy-four patients experienced relapse, with a median delay after surgery of 2 years (range, 0.13– 6.75 years). The site of relapse was unknown for 6 patients but was most frequent in the posterior fossa (35 patients). In 25 of these, recurrence was limited to the PCF. The other 10 experienced multiple recurrence including the posterior fossa and the following: spine (1), extranervous metastases (2), spine and extranervous metastases (1), supratentorial region (5), and spine and supratentorial region (1). Recurrence was isolated supratentorially in 12. Eight presented with isolated recurrence in the spine. Nine patients presented with extranervous metastases in the CNS. Four presented with spinal relapse and extranervous metastases. Univariate analysis Results of analysis, including all variables in the univariate analysis, are reported in Table 2. Medulloblastoma was
Multivariate analysis In multivariate analysis, brainstem involvement, V4 floor involvement, and dose to the posterior fossa ⬍50 Gy were negative independent prognostic factors correlated with event-free survival (Table 3). Standard-risk group The last part of our analysis focused on patients classified as having standard-risk tumors. For this subgroup, factors associated with overall survival in univariate analysis are reported in Table 4. In multivariate analysis, radiation dose to the posterior fossa ⬍50 Gy and involvement of the V4 floor were significantly negatively associated with overall survival. Overall survival was not significantly different between patients treated with axial doses of ⱖ34 Gy and patients treated with craniospinal doses ⬍34 Gy in combination with chemotherapy (log–rank test, p ⫽ 0.7) (Fig. 3). All variables that reached a p value ⬍0.10 in the univariate analysis were included in a regression model, except
1,0
0,8
Progression free survival
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Overall survival
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0,6
0,4
0,2
0,0 0
2
4
6
8
10
12
14
16
18
Years post surgery
Fig. 2. Event-free survival.
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22
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Table 2. Univariate analysis Factor Gender Male Female Metastasis No Yes Histology type 0 (Group 0 compared with Group 1) 1 Classic (Group 2 compared with Group 1) 2 Desmoplastic 3 Other Brainstem involvement Yes No Fourth ventricular (V4) floor involvement Yes No Peduncular involvement Yes No Medullary involvement Yes No Lumbar puncture, postoperative Yes No Surgical residue Yes No Postoperative performance status ⱕ2 ⱖ3 Chemotherapy Yes No Brain radiation dose (Gy) ⱕ29 ⬎29 Spinal radiation dose (Gy) ⱕ29 ⬎29 Posterior fossa radiation dose (Gy) ⬍50 ⱖ50 Risk group Standard High Location Central Lateral Radiation duration (d) ⱕ45 ⬎45 Date of surgery Before 1990 After 1990 Abbreviation: NE ⫽ not evaluated.
No. of patients
5-y overall survival (%)
10-y overall survival (%)
160 88
72 73
54 57
188 26
75 57
60 37
4 164 74 7
38 70 78 71
38 50 69 36
12 197
56 75
23 62
61 140
61 81
37 68
40 161
60 77
49 60
13 231
50 73
NE 58
17 195
59 74
49 60
87 147
67 74
48 58
159 19
77 19
63 NE
143 105
71 73
58 53
31 215
65 74
55 55
22 224
48 75
30 58
15 229
32 76
21 59
124 95
77 65
62 49
119 85
70 77
51 67
137 89
68 74
56 53
139 110
72 72
54 57
p 0.62 0.046
0.26 0.20 NE 0.013 0.0002 0.121 0.004 0.28 0.08 ⬍0.0004 0.95 0.48 0.0054 ⬍0.0001 0.034 0.27 0.756 0.85
Prognostic factors for medulloblastoma
Table 3. Multivariate analysis Factors Brainstem involvement (⫹) Fourth ventricular (V4) floor involvement (⫹) Dose of radiotherapy to the posterior fossa ⬍50 Gy
Relative risk
95% confidence interval
p
2.7
1.2–5.9
0.017
2.2
1.3–3.7
0.002
2.7
1.3–5.8
0.009
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(13–15). The prognostic factors identified in this multicenter series were all similar to those observed in children. Histology differs somewhat between adults and children. More adult medulloblastomas are desmoplastic (25– 40%) (4, 12), and 30% in the present series were desmoplastic. In a series of children’s medulloblastomas, 15% were desmoplastic (16). The prognostic value for desmoplastic subtype is not established. Some investigators consider desmoplastic histology a favorable prognostic factor (17, 18), but others disagree (16, 19). In the present series, desmoplastic histology did not influence prognosis. Lower growth rate parameters have been described in adult medulloblastoma. For example, Giordana et al. (20) described a low rate of MDM2 amplification and p53 gene mutation in adult medulloblastomas. In univariate analysis, MDM2 and Tp 53 had poor outcome in adults. This may explain the late recurrence of adult medulloblastomas. In the present study, most relapses occurred 2–7 years after treatment, as described in the other series. Adult medulloblastomas occurred more often in the medial part of the PCF. In the present series, 44% of patients experienced a laterally located tumor, but tumor location
pre- and postsurgery performance status because of the high percentage of missing values (Table 5). DISCUSSION We report the largest series of adult medulloblastomas, with a median follow-up of 7 years. Five-year and 10-year survival rates were 72% and 55%. This is comparable to results reported in two other adult series (72% and 83%) (5, 12). Large series of children’s medulloblastomas have been reported, with 5-year survival rates of 65% and 70.7%
Table 4. Univariate analysis in the standard-risk group Factor Histoloy 1 Classical 2 Desmoplastic 3 Other Brainstem involvement Yes No Fourth ventricular (V4) floor involvement Yes No Peduncular involvement Yes No Postoperative performance status ⱕ2 ⬎3 Chemotherapy Yes No Spinal radiation dose (Gy) ⱕ29 ⬎29 Posterior cerebral fossa radiation dose (Gy) ⬍50 ⱖ50 Location Central Lateral Duration of radiation (d) ⱕ45 ⬎45 Date of surgery Before 1990 After 1990 Abbreviation: NE ⫽ not evaluated.
No. of patients
5-y overall survival (%)
10-y overall survival (%)
75 47 2
75 80 100
58 69 NE
2 108
100 80
NE 71
20 85
68 83
43 70
11 94
61 82
40 68
83 6
82 NE
68 NE
67 56
77 78
65 56
12 112
46 80
46 63
13 111
31 83
23 67
58 48
70 81
50 70
73 40
76 75
64 54
68 56
75 81
57 69
p 0.85
0.058 0.16 ⬍0.0001 0.79 0.043 ⬍0.0001 0.34 0.45 0.24
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1,0 ,9
Overall survival
,8 ,7 ,6 ,5 ,4 ,3 ,2 ,1 0,0
0
2
4
6 8 10 12 14 Years post surgery
16
18
20
Fig. 3. Overall survival according to subgroup. Solid line represents low radiation dose and chemotherapy; dashed line represents high radiation dose; dotted line represents other.
was not a prognostic factor, agreeing with results published by Park et al. (16) and Bloom and Bessell (19). In this study, the presence of surgical residue had borderline significance. In contrast, Chan’s group (12) reported a series of 32 adult medulloblastomas in which gross total resection was the most important prognostic factor. Hartsell et al. reported similar results (5). Similarly, in children, the presence of residue ⬎1.5 cm2 has prognostic value (21). Our retrospective study included patients treated between 1975 and 2002; the evaluation of surgical residue was probably better performed with MRI after 1990. The issue of locoregional invasion may be crucial: brainstem and V4 floor involvement were negatively correlated with survival in multivariate analysis in this study, with a high correlation between V4 floor involvement and surgical residue. These prognostic factors are similar to those identified in pediatric medulloblastoma series (3, 22). The true prognostic significance of the extent of surgical resection is still unclear. Similarly, postoperative performance status was found to be a significant prognostic factor only in univariate analysis, but was strongly correlated with the extension of disease and so not found to be an independent prognostic factor. One may wonder whether locoregional extension and the presence of residue may depend on intrinsic biologic factors that would render the tumor more invasive. Chemotherapy did not increase survival in either the whole population or in the patients designated as having standard or high risk in this series. One probable explanation is the heterogeneity of regimens in this multicenter study that included patients treated over a long period. Efficiency of chemotherapy has been well established in the pediatric population with metastases, but it is still controversial in the subgroup designated as being at standard risk for recurrence. For example, Taylor’s group (13) reported a series of primitive neuroectodermal tumors that compared three cycles of vincristine, etoposide, cyclophosphamide, and carboplatin followed by radiotherapy with radiotherapy
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alone. The 5-year PFS rate was 74.2% with combined therapy, compared with 59.8% in the group receiving radiotherapy alone; but no difference was observed regarding overall survival. Similarly, the eight drugs in 1 day used in most patients of the current series may not be the best protocol for treatment of medulloblastoma: Zelter’s group (21) randomized 203 patients to receive vincristine, lomustine, and prednisone or eight drugs in 1 day after standarddose radiotherapy. The 5-year PFS rate was 63% with the three-drug regimen, compared with 45% in the eight-in-1day regimen (p ⫽ 0006). In the present study, 124 patients were classified with standard-risk medulloblastoma. Their survival was significantly different from that of patients with high-risk tumors, with respective 10-year survival rates of 62% and 49% (p ⫽ 0.03). In this series, 6 patients did not receive radiotherapy, 4 because of chemotherapy toxicities. The toxicity of chemotherapy delaying or suppressing radiation in standardrisk tumors was described as negatively impacting prognosis by Kortman et al. (23). They reported a 3-year PFS rate of 65% in patients receiving postoperative high doses of chemotherapy (methotrexate, ifosfamide, etoposide, cisplatin, and cytarabine) delivered before radiotherapy, compared with 78% in patients receiving postirradiation chemotherapy (cisplatin, vincristine, and lomustine) (23). Results of the last French pediatric protocol purposed to suppress chemotherapy and to treat patients with standard risk with hyperfractionated radiation (24) showed a PFS rate of 81% at 3 years. This rate compared favorably to those published by Thomas et al. for the Children’s Cancer Group (25) with standard dose and by Kortman et al. for the HIT protocol (23). Moreover, preliminary results from the M-SFOP 98 evaluation of intelligence quotient (IQ) seemed to demonstrate no decrease of IQ in the 22 evaluated patients after 2 years, whereas during this same period in children treated with standard irradiation, cognitive impairment is usually already evident (24). The impact of the timing of chemotherapy in the treatment or the type of regimens is not clear; chemotherapy must not delay the start of radiation. Hyperfractionated treatment for adult standard-risk medulloblastoma should be evaluated with prospective investigations. In univariate analysis, radiotherapy dose delivered to the spinal axis and on the PCF are significant prognostic factors. In multivariate analysis only, radiation doses ⬍50 Gy to the posterior fossa are significant. These results suggest that dose to the PCF was superior at 50 Gy. Moreover, most relapses occurred in the PCF, as reported in major studies for adult
Table 5. Multivariate analysis in the standard-risk group Factor Fourth ventricular (V4) floor involvement (⫹) Posterior fossa radiation dose ⬍50 Gy
Relative 95% Confidence risk interval
p
2,4
1.1–5.2
0.035
3,6
1.5–8.4
0.004
Prognostic factors for medulloblastoma
medulloblastomas (4, 26 –28). The importance of dose delivered to the PCF is already established in children (29, 30). Only one prospective clinical trial has been reported for adult medulloblastoma. Between 1988 and 2002, 36 patients received 36 Gy to the craniospinal area and 54.8 Gy to the posterior fossa. Patients at high risk received neoadjuvant and maintenance chemotherapy. Five-year PFS was significantly better for patients at low risk (75%) than for those at high risk (61%). Patients with nonmetastatic medulloblastoma had better outcome (5-year PFS 75% vs. 45%; p ⫽ 0.01) (31). A usual dose of 36 Gy is established for the brain and spinal axis. Pediatric protocols try to evaluate the possibility of reducing craniospinal dose in patients at standard risk. Exclusive low-dose irradiation is not optimal according to the results of the Pediatric Oncology Group/Children’s Cancer Group (25). This study randomized 126 children to receive standard- or low-dose (23.4 Gy) craniospinal irradiation. The PFS rate was 67% in patients receiving the standard dose, compared with 52% in the low-dose group (p ⫽ 0.08). In a recent study by the French Society of Pediatric Oncology (32), 136 patients between the age of 3 and 18 years with standard-risk medulloblastoma received two courses of eight drugs in 1 day followed by two courses of etoposide plus carboplatin. Radiotherapy was administered with reduced dose to the craniospinal region. Overall and 5-year survival was 73.8%. The investigators concluded that reduced-dose craniospinal radiation therapy can be proposed in standard-risk medulloblastoma. For patients with standard-risk medulloblastoma in the present series, no significant difference in spinal or brain relapse was observed between the patients treated with 36 Gy to the craniospinal area and those treated with lower doses of radiotherapy and concomitant chemotherapy. In this favorable group, only 3 patients experienced spinal relapse with 36 Gy, and 2 with 30 Gy. Several studies showed a decline in IQ in children of different ages who received craniospinal radiation (33–35). A study purposed to evaluate the impact of therapy on neurocognitive outcome in children treated for CNS malignancies (36) showed a significant difference in IQ decline between children treated by craniospinal radiation and children treated without radiation (p ⫽ 0.005). In this study, decline of IQ in patients receiving cranial dose of ⱖ33 Gy was greater than in those receiving ⱕ24 Gy. Although IQ evaluation was impossible in the current retrospective study because of lack of data, these results suggest the neurocognitive impact in
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decreasing the craniospinal radiation dose in adult patients. Similar to the pediatric series, it seems possible to reduce the craniospinal dose in the favorable group of adult patients receiving chemotherapy by maintaining at least 50 Gy to the posterior fossa. However, the several limitations to this include the lack of quality control of dosimetry. This series is a retrospective study, and no quality control of treatment planning was performed, although several trials have suggested that the quality of radiation impacts outcome (13, 37, 38). In a series published by Carrie et al. (38), the number of major deviations in radiotherapy treatment correlated strongly with the risk of tumor relapse (67% 3-year relapse rate in the patient group with two major deviations, 78% in those with three major deviations). Treatment planning should be reviewed by a panel of experts to decrease the target deviations. Quality control would improve survival to an extent equivalent to that attributed to adjuvant chemotherapy. CONCLUSION Medulloblastoma is a malignant neuroectodermal tumor uncommon in adults. We present the largest multicenter series of adult medulloblastomas, from 253 patients aged ⬎18 years. The median overall survival at 5 and 10 years was comparable to survival reported in children (72% and 55%). Prognostic factors identified in this multicenter series were all similar to prognostic factors observed in childhood. As in pediatric series, the posterior fossa remains the major site of relapse. In patients with tumors at standard risk for recurrence, results suggested that treatment should consist of either lower-dose irradiation to the craniospinal area with at least 50 Gy to the posterior fossa plus chemotherapy, or hyperfractionated radiation without chemotherapy. Only a large, randomized study could ensure the role of chemotherapy, but because of the rarity of this disease, the results would remain uncertain. Moreover, the use of different techniques of irradiation, such as a hyperfractionated regimen, and the development of quality control should improve survival to an extent equivalent to that attributed to adjuvant chemotherapy. The irradiation techniques need strict control and should only be performed by centers that treat pediatric patients. As in pediatric trials, radiation treatment planning should be reviewed by a panel of consultant radiation oncologists to decrease the target deviations before the beginning of treatment.
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8. Cox DR. Regression models and life tables. J R Stat Soc Ser B 1972;34:187–202. 9. Chastagner P, Olive D, Philip T, et al. Efficacy of the “8 drugs in a day” protocol in brain tumors in children [French]. Arch Fr Pediatr 1988;45:249 –254. 10. Gentet JC, Doz F, Bouffet E, et al. Carboplatin and VP 16 in medulloblastoma: A phase II study of the French Society of Pediatric Oncology (SFOP). Med Pediatr Oncol 1994;23:422– 427. 11. Pendergrass TW, Milstein JM, Geyer JR, et al. Eight drugs one day chemotherapy for brain tumors: Experience in 107 children and rational for preradiation chemotherapy. J Clin Oncol 1987;5:1221–1231. 12. Chan AW, Tarbell NJ, Black PM, et al. Adult medulloblastoma: Prognostic factors and patterns of relapse. Neurosurgery 2000;47:623– 631. 13. Taylor RE, Bailey CC, Robinson KJ, et al. Impact of radiotherapy parameters on outcome in the International Society of Paediatric Oncology/United Kingdom Children’s Cancer Study Group PNET-3 study of preradiotherapy chemotherapy for M0-M1 medulloblastoma. Int J Radiat Oncol Biol Phys 2004; 58:1184 –1193. 14. Danjoux CE, Jenkin RD, McLaughlin J, et al. Childhood medulloblastoma in Ontario, 1977-1987: Population-based results. Med Pediatr Oncol 1996;26:1–9. 15. Packer RJ, Sutton LN, Goldwein JW, et al. Improved survival with the use of adjuvant chemotherapy in the treatment of medulloblastoma. J Neurosurg 1991;74:433– 440. 16. Park TS, Hoffman HJ, Hendrick EB, et al. Medulloblastoma: Clinical presentation and management. Experience at the Hospital for Sick Children, Toronto, 1950-1980. J Neurosurg 1983;58:543–552. 17. Kopelson G, Linggood RM, Kleinman GM. Medulloblastoma. The identification of prognostic subgroups and implications for multimodality management. Cancer 1983;51:312–319. 18. Sharma BS, Kak VK, Mittal RS, et al. Medulloblastoma in adults—Clinical observations and results of treatment. Indian J Cancer 1989;26:156 –163. 19. Bloom HJ, Bessell EM. Medulloblastoma in adults: A review of 47 patients treated between 1952 and 1981. Int J Radiat Oncol Biol Phys 1990;18:763–772. 20. Giordana MT, Duo D, Gasverde S, et al. MDM2 overexpression is associated with short survival in adults with medulloblastoma. Neurooncology 2002;4:115–122. 21. Zeltzer PM, Boyett JM, Finlay JL, et al. Metastasis stage, adjuvant treatment, and residual tumor are prognostic factors for medulloblastoma in children: Conclusions from the Children’s Cancer Group 921 randomized phase III study. J Clin Oncol 1999;17:832– 845. 22. Choux M, Lena G, Hassoun J. Prognosis and long-term follow-up in patients with medulloblastoma. Clin Neurosurg 1983;30:246 –277. 23. Kortmann RD, Kuhl J, Timmermann B, et al. Postoperative neoadjuvant chemotherapy before radiotherapy as compared to immediate radiotherapy followed by maintenance chemotherapy in the treatment of medulloblastoma in childhood: Results of the German prospective randomized trial HIT ’91. Int J Radiat Oncol Biol Phys 2000;46:269 –279.
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24. Carrie C, Muracciole X, Gomez F, et al. Conformal radiotherapy, reduced boost volume, hyperfractionated radiotherapy, and online quality in standard-risk medulloblastoma without chemotherapy: Results of the French M-SFOP 98 protocol. Int J Radiat Oncol Biol Phys 2005;1:711–716. 25. Thomas PR, Deutsch M, Kepner JL, et al. Low-stage medulloblastoma: Final analysis of trial comparing standard-dose with reduced-dose neuraxis irradiation. J Clin Oncol 2000;18: 3004 –3011. 26. Carrie C, Lasset C, Blay JY, et al. Medulloblastoma in adults: Survival and prognostic factors. Radiother Oncol 1993;29: 301–307. 27. Hughes EN, Shillito J, Sallan SE, et al. Medulloblastoma at the joint center for radiation therapy between 1968 and 1984. The influence of radiation dose on the patterns of failure and survival. Cancer 1988;61:1992–1998. 28. Kopelson G, Linggood RM, Kleinman GM. Medulloblastoma in adults: Improved survival with supervoltage radiation therapy. Cancer 1982;49:1334 –1337. 29. Chin HW, Maruyama Y. Prognostic factors in medulloblastoma. Am J Clin Oncol 1982;5:359 –369. 30. Silverman CL, Simpson JR. Cerebellar medulloblastoma: The importance of posterior fossa dose to survival and patterns of failure. Int J Radiat Oncol Biol Phys 1982;8:1869 –1876. 31. Brandes AA, Ermani M, Amista P, et al. The treatment of adults with medulloblastoma: A prospective study. Int J Radiat Oncol Biol Phys 2003;57:755–761. 32. Oyharcabal-Bourden V, Kalifa C, Gentet JC, et al. Standardrisk medulloblastoma treated by adjuvant chemotherapy followed by reduced-dose craniospinal radiation therapy: A French Society of Pediatric Oncology Study. J Clin Oncol 2005;23:4726 – 4734. 33. Grill J, Renaux VK, Bulteau C, et al. Long-term intellectual outcome in children with posterior fossa tumors according to radiation doses and volumes. Int J Radiat Oncol Biol Phys 1999;45:137–145. 34. Mulhern RK, Kepner JL, Thomas PR, et al. Neuropsychologic functioning of survivors of childhood medulloblastoma randomized to receive conventional or reduced-dose craniospinal irradiation: A Pediatric Oncology Group study. J Clin Oncol 1998;16:1723–1728. 35. Mulhern RK, Reddick WE, Palmer SL, et al. Neurocognitive deficits in medulloblastoma survivors and white matter loss. Ann Neurol 1999;46:834 – 841. 36. Fouladi M, Chintagumpala M, Laningham FH, et al. White matter lesions detected by magnetic resonance imaging after radiotherapy and high-dose chemotherapy in children with medulloblastoma or primitive neuroectodermal tumor. J Clin Oncol 2004;22:4551– 4560. 37. Carrie C, Alapetite C, Mere P, et al. Quality control of radiotherapeutic treatment of medulloblastoma in a multicentric study: The contribution of radiotherapy technique to tumour relapse. The French Medulloblastoma Group. Radiother Oncol 1992;24:77– 81. 38. Carrie C, Hoffstetter S, Gomez F, et al. Impact of targeting deviations on outcome in medulloblastoma: Study of the French Society of Pediatric Oncology (SFOP). Int J Radiat Oncol Biol Phys 1999;45:435– 439.
doi:10.1016/j.ijrobp.2006.12.030
CLINICAL INVESTIGATION
Brain
COMMON STRATEGY FOR ADULT AND PEDIATRIC MEDULLOBLASTOMA: A MULTICENTER SERIES OF 253 ADULTS LAETITIA PADOVANI, M.D.,* MARIE-PIERRE SUNYACH, M.D.,† DAVID PEROL, M.D.,‡ CEDRIC MERCIER, M.D., PH.D.,¶¶ CLAIRE ALAPETITE, M.D.,§ CHRISTINE HAIE-MEDER, M.D.,¶ SYLVETTE HOFFSTETTER, M.D.,储 XAVIER MURACCIOLE, M.D.,* CHRISTINE KERR, M.D.,# JEAN-PHILIPPE WAGNER, M.D.,** JEAN-LÉON LAGRANGE, M.D.,†† JEAN-PHILIPPE MAIRE, M.D.,‡‡ DIDIER COWEN, M.D. PH.D.,* DIDIER FRAPPAZ, M.D.,†§§ AND CHRISTIAN CARRIE, M.D.† Departments of *Radiation Oncology and ¶¶Medical Oncology, Hôpital de la Timone, Marseille, France; Departments of Radiation Oncology and ‡Biostatistics, Centre Léon Bérard, Lyon, France; §Department of Radiation Oncology, Institut Curie, Paris, France; ¶Department of Radiation Oncology, Institut Gustave Roussy, Villejuif, France; 储Department of Radiation Oncology, Centre Alexis Vautrin, Nancy, France; #Department of Radiation Oncology, Centre Val D’aurelle, Montpellier, France; **Department of Radiation Oncology, Clinique de l’Orangerie, Strasbourg, France; ††Department of Radiation Oncology, Hopital Henry Mondor, Créteil, France; ‡‡Department of Radiation Oncology, Hôpital Saint André, Bordeaux, France; and §§Department of Neuro-oncology, Centre Léon Bérard, Lyon, France †
Purpose: To assess prognostic factors for adults with medulloblastoma in a multicenter, retrospective study. Methods and Materials: Data were collected by file review or mail inquiry for 253 adults treated between 1975 to 2004. Radiologists or surgeons assessed disease characteristics, such as volume and extension. Patients were classified as having either high- or standard-risk disease. Prognostic factors were analyzed. Results: Median patient age was 29 years. Median follow-up was 7 years. Radiotherapy was delivered in 246 patients and radiochemotherapy in 142. Seventy-four patients relapsed. Respective 5- and 10-year overall survival rates were 72% and 55%. Univariate analysis showed that survival significantly correlated with metastasis, postsurgical performance status, brainstem involvement, involvement of the floor of the fourth ventricle (V4), and radiation dose to the spine and to the posterior cerebral fossa (PCF). By multivariate analysis, brainstem, V4 involvement, and dose to the PCF were negative prognostic factors. In the standard-risk subgroup there was no overall survival difference between patients treated with axial doses of >34 Gy and patients treated with craniospinal doses <34 Gy plus chemotherapy. Conclusion: We report the largest series of medulloblastoma in adults. Prognostic factors were similar to those observed in children. Results suggest that patients with standard-risk disease could be treated with radiochemotherapy, reducing doses to the craniospinal area, maintaining at least 50 Gy to the PCF. The role of chemotherapy for this group is still unclear. A randomized study should be performed to confirm these results, but because frequency is very low, such a study would be difficult. © 2007 Elsevier Inc. Radiotherapy, Medulloblastoma, Adults.
INTRODUCTION
in children and guide therapeutic strategies (3). In contrast, in adults, the majority of reported cases of medulloblastoma are single-institution, retrospective series including only a few patients (4, 5). Adult and pediatric medulloblastomas are radiologically distinct. Adult tumors usually involve the lateral cerebellar hemispheres, and pediatric tumors occur in the vermis. Histology also differs between adult and pediatric tumors. The aim of the present study was to identify prognostic
Medulloblastoma is a malignant neuroectodermal tumor uncommon in adults. Median age at diagnosis is 5 years (1). Medulloblastoma accounts for 30% of brain tumors of childhood but fewer than 3% of all primary neoplasms of the central nervous system (CNS) in adults (2). Most children treated for medulloblastoma are included in prospective studies. Clinical prognostic factors have been identified
L.P., M-P.S., D.F., and C.C. contributed equally to this work. Conflict of interest: none. Acknowledgment—The authors thank Rosalyn Vu for her valuable help with preparation of the manuscript in English. Received Sept 26, 2006, and in revised form Dec 6, 2006. Accepted for publication Dec 11, 2006.
Reprint requests to: Laetitia Padovani, M.D., Departement d’Oncologie Radiothérapie, Hopital La Timone, 264 Bd Saint-Pierre, 13385 Marseille, France. Tel: (⫹33) 4-9138-4334; Fax: (⫹33) 4-9138-5692; E-mail: [email protected] Presented at the Forty Seventh Annual Meeting of the American Society of Therapeutic Radiology and Oncology (ASTRO), October 16 –20, 2005, Denver, CO. 433
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Table 1. Patients characteristics Characteristic
No. of patients
Mean ⫾ SD or n (%)
160/88 251 230 219
30.9 ⫾ 9.5 45.3 ⫾ 18.4 62.4 ⫾ 63.1
Gender (male/female) Age at surgery (y) (18–58, median 29) Duration of radiation (d) (median, 44) Delay between surgery and radiotherapy (d) (median, 45) Histology type None Desmoplastic Classic Other Brainstem involvement Fourth ventricular (V4) floor involvement Medullary involvement Peduncular involvement Surgical residue Positive spinal fluid, postoperative Postoperative performance status 0 1 2 3 4 Chemotherapy Radiotherapy plus chemotherapy Brain radiation dose ⱖ30 Gy Spinal radiation dose ⱖ30 Gy Posterior fossa radiation dose ⱖ50 Gy
253
213 205 248 204 237 216 179
252 253 249 249 250
5 (1) 75 (30) 166 (66) 7 (3) 12 (6) 63 (31) 14 (6) 42 (21) 87 (37) 17 (8) 32 (18) 88 (49) 40 (22) 13 (7) 6 (3) 146 (58) 142 (56) 217 (87) 227 (91) 231 (92)
Abbreviation: SD ⫽ standard deviation.
factors in adult patients with medulloblastomas and evaluate the results of treatment combining reduced-dose radiotherapy with chemotherapy for patients with tumors classified as having standard risk for recurrence. METHODS AND MATERIALS Between 1975 and 1991, 156 patients were included in the initial database. Carrie et al. initiated the present study in 1991 (3), and data from 97 patients treated after 1991 have been added. The data were updated by mail inquiry or from patient files. Thus, between January 1975 and January 2004, 253 patients aged ⬎18 years with histologically proven medulloblastoma and treated in 1 of 13 French centers were enrolled in this retrospective study. The median age of patients at diagnosis was 29 years (range, 18 –58 years). Table 1 shows disease and patient characteristics. Extent of disease location (central or lateral) within the brainstem and infiltration of the peduncle were assessed by myelography or computed tomography (CT) and/or magnetic resonance imaging (MRI) of the CNS. Involvement of the cerebrospinal fluid (CSF) was assessed by spinal puncture. Results were reported solely according to available data. All patients underwent surgical removal of their tumors, except 2 who refused surgery. Surgery was considered complete when operative chart and postsurgical imaging indicated no residual tumor. Infiltration of the floor of the fourth ventricle (V4) was assessed by the surgeon intraoperatively. Postoperative performance status was recorded when possible using the Eastern Co-
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operative Oncology Group performance scale. Treatment was delivered by either a 60Co teletherapy machine or linear accelerator at fractions of 1.8 –2 Gy/d. Patients were irradiated with two opposed fields for the brain, with a boost to the posterior cerebral fossa (PCF); direct posterior fields were achieved with moving junctions for the spinal axis with either electron, photon, or mixed beam. Patients were classified as having either high or standard risk for recurrence of medulloblastoma. The high-risk group included patients with metastatic disease and/or CSF involvement and/or macroscopic tumor residue after surgery. The standard-risk group had none of these risk factors. Only patients with data available for all items were considered for analysis.
Descriptive statistics Overall survival was calculated from the date of surgery to either the date of death from any cause or to last follow-up for living patients (censored observation). Progression-free survival (PFS) was measured from surgery to disease progression or death or was censored at last follow-up. Survival estimates were calculated using the Kaplan-Meier method (6). Differences in survival estimates were assessed in univariate analysis by the log–rank test (7). Independent prognostic factors of overall survival were identified by multivariate regression analysis (Cox proportional hazards regression model) (8), using a backward procedure to eliminate non-influential variables. A significance level of 0.05 was used to select explanatory variables. Survival and disease-free survival were determined in the entire population and in the standard- and high-risk subgroups. Among standard-risk patients, we compared overall survival between patients treated with high-dose radiation (36 Gy) and with lower doses of radiation combined with chemotherapy.
RESULTS Among 238 patients (150 men, 88 women) for whom data were available, median age at diagnosis was 29 years (range, 18 –58 years). Total surgery was performed in 147 patients, and 87 presented with residual tumor after surgery, as determined by either the surgeon or early postoperative CT or MRI scans. For 3 patients, CT or MRI data were not found. The median delay between surgery and radiation was 45 days. All patients except 6 received radiotherapy. Four patients died of sepsis before irradiation. Of those 4, 2 had received previous chemotherapy: 1 who died immediately after surgery and 1 who died from disease progression despite the chemotherapy. The fifth patient did not receive the entire radiation dose because of hematologic toxicity, and did not receive previous chemotherapy. The last patient was irradiated only to the PCF with a dose of 45 Gy because the patient’s mental retardation precluded immobilization. These patients were included in the analysis. All others received craniospinal irradiation. The median duration of irradiation was 44 days. Median doses delivered were 35 Gy to the brain, 35 Gy to the spinal area, and 54 Gy to the PCF. One hundred forty-six patients received adjuvant chemotherapy. Because data were collected over a very long period and for patients treated at 13 different centers, delivery regimens were heterogeneous (9 –11). Median follow-up was 7 years, median overall survival, 13 years. At 5
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classified as having standard risk in 124 patients and high risk in 95. For 34 patients, data were unavailable for the three criteria (metastatic disease and/or CSF involvement and/or macroscopic tumor residue after surgery). Five-year overall survival was 65% in the population with high-risk medulloblastoma and 77% in those with standard-risk tumors. Survival between the two populations was significantly different (p ⫽ 0.0338). Metastasis (p ⫽ 0.046), postsurgical performance status (p ⬍ 0.0004), brainstem involvement (p ⫽ 0.013), V4 floor involvement (p ⫽ 0.0002), spinal radiation dose (p ⫽ 0.0054), and posterior fossa radiation dose (p ⬍ 0.0001) correlated significantly with survival. A trend for negative correlation was found for postsurgical residue (p ⫽ 0.08).
0,8
0,6
0,4
0,2
0,0 0
2
4
6
8
10
12
14
16
18
20
22
24
Years post surgery
Fig. 1. Overall survival.
years after surgery, the overall survival rate was 72% (95% confidence interval [CI], 66 –78%), and at 10 years, 55% (95% CI, 47– 63%) (Fig. 1). At 5 years after surgery, disease-free survival was 65% (95% CI, 59 –71%), and at 10 years, 55% (95% CI, 48 – 63%) (Fig. 2). At last follow-up, 151 patients were alive without cancer relapse; 7 were alive with disease, and deaths included 67 from disease, 9 from early treatment complications (1 postoperative respiratory disease, 1 acute pancreatitis, 1 Lyell syndrome due to medication to prevent Pneumocystis carinii pneumonia, 1 bacterial meningitis, 2 septic shock, 1 medullary aplasia, and 2 toxic infection; further data were not collected), 5 from radio-induced encephalitis, and 2 from secondary cancer (lung cancer and leukemia M5). Data were unavailable for 12 patients. Pattern of relapse Seventy-four patients experienced relapse, with a median delay after surgery of 2 years (range, 0.13– 6.75 years). The site of relapse was unknown for 6 patients but was most frequent in the posterior fossa (35 patients). In 25 of these, recurrence was limited to the PCF. The other 10 experienced multiple recurrence including the posterior fossa and the following: spine (1), extranervous metastases (2), spine and extranervous metastases (1), supratentorial region (5), and spine and supratentorial region (1). Recurrence was isolated supratentorially in 12. Eight presented with isolated recurrence in the spine. Nine patients presented with extranervous metastases in the CNS. Four presented with spinal relapse and extranervous metastases. Univariate analysis Results of analysis, including all variables in the univariate analysis, are reported in Table 2. Medulloblastoma was
Multivariate analysis In multivariate analysis, brainstem involvement, V4 floor involvement, and dose to the posterior fossa ⬍50 Gy were negative independent prognostic factors correlated with event-free survival (Table 3). Standard-risk group The last part of our analysis focused on patients classified as having standard-risk tumors. For this subgroup, factors associated with overall survival in univariate analysis are reported in Table 4. In multivariate analysis, radiation dose to the posterior fossa ⬍50 Gy and involvement of the V4 floor were significantly negatively associated with overall survival. Overall survival was not significantly different between patients treated with axial doses of ⱖ34 Gy and patients treated with craniospinal doses ⬍34 Gy in combination with chemotherapy (log–rank test, p ⫽ 0.7) (Fig. 3). All variables that reached a p value ⬍0.10 in the univariate analysis were included in a regression model, except
1,0
0,8
Progression free survival
1,0
Overall survival
●
0,6
0,4
0,2
0,0 0
2
4
6
8
10
12
14
16
18
Years post surgery
Fig. 2. Event-free survival.
20
22
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Table 2. Univariate analysis Factor Gender Male Female Metastasis No Yes Histology type 0 (Group 0 compared with Group 1) 1 Classic (Group 2 compared with Group 1) 2 Desmoplastic 3 Other Brainstem involvement Yes No Fourth ventricular (V4) floor involvement Yes No Peduncular involvement Yes No Medullary involvement Yes No Lumbar puncture, postoperative Yes No Surgical residue Yes No Postoperative performance status ⱕ2 ⱖ3 Chemotherapy Yes No Brain radiation dose (Gy) ⱕ29 ⬎29 Spinal radiation dose (Gy) ⱕ29 ⬎29 Posterior fossa radiation dose (Gy) ⬍50 ⱖ50 Risk group Standard High Location Central Lateral Radiation duration (d) ⱕ45 ⬎45 Date of surgery Before 1990 After 1990 Abbreviation: NE ⫽ not evaluated.
No. of patients
5-y overall survival (%)
10-y overall survival (%)
160 88
72 73
54 57
188 26
75 57
60 37
4 164 74 7
38 70 78 71
38 50 69 36
12 197
56 75
23 62
61 140
61 81
37 68
40 161
60 77
49 60
13 231
50 73
NE 58
17 195
59 74
49 60
87 147
67 74
48 58
159 19
77 19
63 NE
143 105
71 73
58 53
31 215
65 74
55 55
22 224
48 75
30 58
15 229
32 76
21 59
124 95
77 65
62 49
119 85
70 77
51 67
137 89
68 74
56 53
139 110
72 72
54 57
p 0.62 0.046
0.26 0.20 NE 0.013 0.0002 0.121 0.004 0.28 0.08 ⬍0.0004 0.95 0.48 0.0054 ⬍0.0001 0.034 0.27 0.756 0.85
Prognostic factors for medulloblastoma
Table 3. Multivariate analysis Factors Brainstem involvement (⫹) Fourth ventricular (V4) floor involvement (⫹) Dose of radiotherapy to the posterior fossa ⬍50 Gy
Relative risk
95% confidence interval
p
2.7
1.2–5.9
0.017
2.2
1.3–3.7
0.002
2.7
1.3–5.8
0.009
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(13–15). The prognostic factors identified in this multicenter series were all similar to those observed in children. Histology differs somewhat between adults and children. More adult medulloblastomas are desmoplastic (25– 40%) (4, 12), and 30% in the present series were desmoplastic. In a series of children’s medulloblastomas, 15% were desmoplastic (16). The prognostic value for desmoplastic subtype is not established. Some investigators consider desmoplastic histology a favorable prognostic factor (17, 18), but others disagree (16, 19). In the present series, desmoplastic histology did not influence prognosis. Lower growth rate parameters have been described in adult medulloblastoma. For example, Giordana et al. (20) described a low rate of MDM2 amplification and p53 gene mutation in adult medulloblastomas. In univariate analysis, MDM2 and Tp 53 had poor outcome in adults. This may explain the late recurrence of adult medulloblastomas. In the present study, most relapses occurred 2–7 years after treatment, as described in the other series. Adult medulloblastomas occurred more often in the medial part of the PCF. In the present series, 44% of patients experienced a laterally located tumor, but tumor location
pre- and postsurgery performance status because of the high percentage of missing values (Table 5). DISCUSSION We report the largest series of adult medulloblastomas, with a median follow-up of 7 years. Five-year and 10-year survival rates were 72% and 55%. This is comparable to results reported in two other adult series (72% and 83%) (5, 12). Large series of children’s medulloblastomas have been reported, with 5-year survival rates of 65% and 70.7%
Table 4. Univariate analysis in the standard-risk group Factor Histoloy 1 Classical 2 Desmoplastic 3 Other Brainstem involvement Yes No Fourth ventricular (V4) floor involvement Yes No Peduncular involvement Yes No Postoperative performance status ⱕ2 ⬎3 Chemotherapy Yes No Spinal radiation dose (Gy) ⱕ29 ⬎29 Posterior cerebral fossa radiation dose (Gy) ⬍50 ⱖ50 Location Central Lateral Duration of radiation (d) ⱕ45 ⬎45 Date of surgery Before 1990 After 1990 Abbreviation: NE ⫽ not evaluated.
No. of patients
5-y overall survival (%)
10-y overall survival (%)
75 47 2
75 80 100
58 69 NE
2 108
100 80
NE 71
20 85
68 83
43 70
11 94
61 82
40 68
83 6
82 NE
68 NE
67 56
77 78
65 56
12 112
46 80
46 63
13 111
31 83
23 67
58 48
70 81
50 70
73 40
76 75
64 54
68 56
75 81
57 69
p 0.85
0.058 0.16 ⬍0.0001 0.79 0.043 ⬍0.0001 0.34 0.45 0.24
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1,0 ,9
Overall survival
,8 ,7 ,6 ,5 ,4 ,3 ,2 ,1 0,0
0
2
4
6 8 10 12 14 Years post surgery
16
18
20
Fig. 3. Overall survival according to subgroup. Solid line represents low radiation dose and chemotherapy; dashed line represents high radiation dose; dotted line represents other.
was not a prognostic factor, agreeing with results published by Park et al. (16) and Bloom and Bessell (19). In this study, the presence of surgical residue had borderline significance. In contrast, Chan’s group (12) reported a series of 32 adult medulloblastomas in which gross total resection was the most important prognostic factor. Hartsell et al. reported similar results (5). Similarly, in children, the presence of residue ⬎1.5 cm2 has prognostic value (21). Our retrospective study included patients treated between 1975 and 2002; the evaluation of surgical residue was probably better performed with MRI after 1990. The issue of locoregional invasion may be crucial: brainstem and V4 floor involvement were negatively correlated with survival in multivariate analysis in this study, with a high correlation between V4 floor involvement and surgical residue. These prognostic factors are similar to those identified in pediatric medulloblastoma series (3, 22). The true prognostic significance of the extent of surgical resection is still unclear. Similarly, postoperative performance status was found to be a significant prognostic factor only in univariate analysis, but was strongly correlated with the extension of disease and so not found to be an independent prognostic factor. One may wonder whether locoregional extension and the presence of residue may depend on intrinsic biologic factors that would render the tumor more invasive. Chemotherapy did not increase survival in either the whole population or in the patients designated as having standard or high risk in this series. One probable explanation is the heterogeneity of regimens in this multicenter study that included patients treated over a long period. Efficiency of chemotherapy has been well established in the pediatric population with metastases, but it is still controversial in the subgroup designated as being at standard risk for recurrence. For example, Taylor’s group (13) reported a series of primitive neuroectodermal tumors that compared three cycles of vincristine, etoposide, cyclophosphamide, and carboplatin followed by radiotherapy with radiotherapy
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alone. The 5-year PFS rate was 74.2% with combined therapy, compared with 59.8% in the group receiving radiotherapy alone; but no difference was observed regarding overall survival. Similarly, the eight drugs in 1 day used in most patients of the current series may not be the best protocol for treatment of medulloblastoma: Zelter’s group (21) randomized 203 patients to receive vincristine, lomustine, and prednisone or eight drugs in 1 day after standarddose radiotherapy. The 5-year PFS rate was 63% with the three-drug regimen, compared with 45% in the eight-in-1day regimen (p ⫽ 0006). In the present study, 124 patients were classified with standard-risk medulloblastoma. Their survival was significantly different from that of patients with high-risk tumors, with respective 10-year survival rates of 62% and 49% (p ⫽ 0.03). In this series, 6 patients did not receive radiotherapy, 4 because of chemotherapy toxicities. The toxicity of chemotherapy delaying or suppressing radiation in standardrisk tumors was described as negatively impacting prognosis by Kortman et al. (23). They reported a 3-year PFS rate of 65% in patients receiving postoperative high doses of chemotherapy (methotrexate, ifosfamide, etoposide, cisplatin, and cytarabine) delivered before radiotherapy, compared with 78% in patients receiving postirradiation chemotherapy (cisplatin, vincristine, and lomustine) (23). Results of the last French pediatric protocol purposed to suppress chemotherapy and to treat patients with standard risk with hyperfractionated radiation (24) showed a PFS rate of 81% at 3 years. This rate compared favorably to those published by Thomas et al. for the Children’s Cancer Group (25) with standard dose and by Kortman et al. for the HIT protocol (23). Moreover, preliminary results from the M-SFOP 98 evaluation of intelligence quotient (IQ) seemed to demonstrate no decrease of IQ in the 22 evaluated patients after 2 years, whereas during this same period in children treated with standard irradiation, cognitive impairment is usually already evident (24). The impact of the timing of chemotherapy in the treatment or the type of regimens is not clear; chemotherapy must not delay the start of radiation. Hyperfractionated treatment for adult standard-risk medulloblastoma should be evaluated with prospective investigations. In univariate analysis, radiotherapy dose delivered to the spinal axis and on the PCF are significant prognostic factors. In multivariate analysis only, radiation doses ⬍50 Gy to the posterior fossa are significant. These results suggest that dose to the PCF was superior at 50 Gy. Moreover, most relapses occurred in the PCF, as reported in major studies for adult
Table 5. Multivariate analysis in the standard-risk group Factor Fourth ventricular (V4) floor involvement (⫹) Posterior fossa radiation dose ⬍50 Gy
Relative 95% Confidence risk interval
p
2,4
1.1–5.2
0.035
3,6
1.5–8.4
0.004
Prognostic factors for medulloblastoma
medulloblastomas (4, 26 –28). The importance of dose delivered to the PCF is already established in children (29, 30). Only one prospective clinical trial has been reported for adult medulloblastoma. Between 1988 and 2002, 36 patients received 36 Gy to the craniospinal area and 54.8 Gy to the posterior fossa. Patients at high risk received neoadjuvant and maintenance chemotherapy. Five-year PFS was significantly better for patients at low risk (75%) than for those at high risk (61%). Patients with nonmetastatic medulloblastoma had better outcome (5-year PFS 75% vs. 45%; p ⫽ 0.01) (31). A usual dose of 36 Gy is established for the brain and spinal axis. Pediatric protocols try to evaluate the possibility of reducing craniospinal dose in patients at standard risk. Exclusive low-dose irradiation is not optimal according to the results of the Pediatric Oncology Group/Children’s Cancer Group (25). This study randomized 126 children to receive standard- or low-dose (23.4 Gy) craniospinal irradiation. The PFS rate was 67% in patients receiving the standard dose, compared with 52% in the low-dose group (p ⫽ 0.08). In a recent study by the French Society of Pediatric Oncology (32), 136 patients between the age of 3 and 18 years with standard-risk medulloblastoma received two courses of eight drugs in 1 day followed by two courses of etoposide plus carboplatin. Radiotherapy was administered with reduced dose to the craniospinal region. Overall and 5-year survival was 73.8%. The investigators concluded that reduced-dose craniospinal radiation therapy can be proposed in standard-risk medulloblastoma. For patients with standard-risk medulloblastoma in the present series, no significant difference in spinal or brain relapse was observed between the patients treated with 36 Gy to the craniospinal area and those treated with lower doses of radiotherapy and concomitant chemotherapy. In this favorable group, only 3 patients experienced spinal relapse with 36 Gy, and 2 with 30 Gy. Several studies showed a decline in IQ in children of different ages who received craniospinal radiation (33–35). A study purposed to evaluate the impact of therapy on neurocognitive outcome in children treated for CNS malignancies (36) showed a significant difference in IQ decline between children treated by craniospinal radiation and children treated without radiation (p ⫽ 0.005). In this study, decline of IQ in patients receiving cranial dose of ⱖ33 Gy was greater than in those receiving ⱕ24 Gy. Although IQ evaluation was impossible in the current retrospective study because of lack of data, these results suggest the neurocognitive impact in
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decreasing the craniospinal radiation dose in adult patients. Similar to the pediatric series, it seems possible to reduce the craniospinal dose in the favorable group of adult patients receiving chemotherapy by maintaining at least 50 Gy to the posterior fossa. However, the several limitations to this include the lack of quality control of dosimetry. This series is a retrospective study, and no quality control of treatment planning was performed, although several trials have suggested that the quality of radiation impacts outcome (13, 37, 38). In a series published by Carrie et al. (38), the number of major deviations in radiotherapy treatment correlated strongly with the risk of tumor relapse (67% 3-year relapse rate in the patient group with two major deviations, 78% in those with three major deviations). Treatment planning should be reviewed by a panel of experts to decrease the target deviations. Quality control would improve survival to an extent equivalent to that attributed to adjuvant chemotherapy. CONCLUSION Medulloblastoma is a malignant neuroectodermal tumor uncommon in adults. We present the largest multicenter series of adult medulloblastomas, from 253 patients aged ⬎18 years. The median overall survival at 5 and 10 years was comparable to survival reported in children (72% and 55%). Prognostic factors identified in this multicenter series were all similar to prognostic factors observed in childhood. As in pediatric series, the posterior fossa remains the major site of relapse. In patients with tumors at standard risk for recurrence, results suggested that treatment should consist of either lower-dose irradiation to the craniospinal area with at least 50 Gy to the posterior fossa plus chemotherapy, or hyperfractionated radiation without chemotherapy. Only a large, randomized study could ensure the role of chemotherapy, but because of the rarity of this disease, the results would remain uncertain. Moreover, the use of different techniques of irradiation, such as a hyperfractionated regimen, and the development of quality control should improve survival to an extent equivalent to that attributed to adjuvant chemotherapy. The irradiation techniques need strict control and should only be performed by centers that treat pediatric patients. As in pediatric trials, radiation treatment planning should be reviewed by a panel of consultant radiation oncologists to decrease the target deviations before the beginning of treatment.
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