Journal of Neuro-Oncology 58: 77–85, 2002. © 2002 Kluwer Academic Publishers. Printed in the Netherlands.
Clinical Study
Postoperative radiation therapy for medulloblastoma – high recurrence rate in the subfrontal region Li-Min Sun1 , Shyh-An Yeh1 , Chong-Jong Wang1 , Eng-Yen Huang1 , Hui-Chun Chen1 , Hsuan-Chih Hsu1 and Steve P. Lee2 1 Department of Radiation Oncology, Chang Gung Memorial Hospital, Kaohsiung, Taiwan; 2 Department of Radiation Oncology, University of California, Los Angeles, CA, USA
Key words: craniospinal irradiation, medulloblastoma, prognostic factors, radiation therapy, subfrontal relapse Summary Purpose: To investigate the treatment results and analyze the prognostic factors for patients with medulloblastoma (MB) treated by surgery and postoperative radiation therapy (RT). Methods and Materials: Thirty-five patients of MB receiving surgery followed by RT from February 1986 to September 1999 were reviewed. Their median age was 12 years with a slight male predominance. Twenty-four (69%) patients had total resection of tumor. Most (86%) cases received craniospinal irradiation (CSI). Adequate dose (craniospinal dose ≥ 30 Gy and posterior fossa dose ≥ 50 Gy) was given in 26 (74%) patients. Results: The median survival duration was 48 months. The 5-year and 10-year overall survival rates were 63% and 40%, respectively. Univariate analysis revealed that stage, shunt surgery, RT dose, and protracted RT course were significant factors in predicting overall survival (OS), disease-free survival (DFS), and/or posterior fossa control (PFC). Multivariate analysis showed that RT dose affected OS and PFC independently, stage influenced OS and DFS, while protracted RT course impacted DFS. A total of 20 cases developed disease relapse. The median time to relapse was 18 months. The posterior fossa (10 cases) was the most common site of first failure, followed by the subfrontal lobe (7 cases), spine (6 cases), and other areas (4 cases). Conclusion: Our results were compatible with others, except that more subfrontal relapses were found. Surgical resection followed by standard dose and adequate margin of CSI are recommended as the mainstays of treatment.
Introduction Medulloblastoma (MB) is classically identified as a unique primitive neuroectodermal tumor (PNET) occurring in the posterior fossa [1]. It accounts for 20–30% of brain tumors in children. More than 80% of MBs are diagnosed in children during the first 15 years of life, and the peak incidence occurs between 5 and 10 years of age [2–4]. Subarachnoid dissemination is noted at diagnosis in 20–30%. Craniospinal irradiation (CSI), along with surgical resection, has been the mainstay of therapy since Cutler et al. [5] reported the earliest case of successful treatment with this technique. Careful radiation therapy (RT) technique includes adequate irradiation of the neuraxis, with special attention to the cribriform plate region and the termination of the thecal sac [6]. This study is
a retrospective analysis of postoperative RT for MB, with emphasis on treatment results (particularly the relapse patterns) and prognostic factors. Methods and materials Between February 1986 and September 1999, 35 consecutive patients (male: 21, female: 14) with pathological diagnosis of MB received postoperative RT with curative intent at Chang Gung Memorial Hospital, Kaohsiung, Taiwan. Their clinical and RT technical records were reviewed retrospectively. The age distribution was from 14 months to 31 years, and the median age was 12 years. Patient and disease characteristics are shown in Table 1. The extension of tumors was investigated by standard diagnostic tools
78 Table 1. Patient and disease characteristics (n = 35)a
Table 2. Treatment characteristics (n = 35)a
Characteristics
Characteristics
Sex Male Female Age 1 month Image findings Hydrocephalus No hydrocephalus Stage (Chang staging) T1,M0 T2,M0 T3b,M0 T4,M0 T3b,M1 T2,M3 T4,M3 a
Number of cases 21 (60%) 14 (40%) 21 (60%) 14 (40%) 26 (74%) 21 (60%) 21 (60%) 4 (11%) 19 (54%) 16 (46%) 34 (97%) 1 (3%) 4 (11%) 20 (57%) 3 (8%) 4 (11%) 1 (3%) 1 (3%) 2 (6%)
N/V: nausea/vomiting.
considered appropriate at the time of diagnosis, and all but one showed hydrocephalus on the imaging studies. According to the Chang staging system [7], one patient was at stage M1 and three patients were at stage M3. Treatment characteristics are presented in Table 2. All patients received postoperative megavoltage (Cobalt-60, 6 MV or 10 MV X-rays) RT. Seventeen patients had received shunt surgery within 30 days of surgery. The median time from tumor resection to the start of RT was 25 days (range: 14–78 days). The majority of patients received CSI. Considering the acute toxicities or long-term sequelae, some very young patients might receive systemic chemotherapy with smaller-field RT rather than CSI. For CSI, prone position with a custom-designed face-down mold was used if the patient could cooperate. Some pediatric patients needed general anesthesia or sedation during simulation and each treatment. For craniospinal field, we used abutting fields with moving junctions, and the collimator of lateral opposed cranial fields were rotated to match the divergence from posterior spinal field. The spinal field was separated into 2 posterior fields if one field could not cover the whole cerebrospinal fluid
OP Total resection Subtotal or partial resection Shunt within 30 days of OP Yes No OP–RT interval 1 month >1 month RT field CSI + PF boost WB + PF boost PF only RT dose Adequateb Inadequate RT interruption > 1 week Yes No
Number of cases 24 (69%) 11 (31%) 17 (49%) 18 (51%) 24 (69%) 11 (31%) 30 (86%) 1 (3%) 4 (11%) 26 (74%) 9 (26%) 15 (43%) 20 (57%)
a CSI: craniospinal irradiation, PF: posterior fossa, WB: whole brain. b PF dose 50 Gy, spine dose 30 Gy.
bearing areas. The lower margin of spine field was set at level S2 or S3. We used the moving gaps method for abutting spinal fields, and the gap size was calculated according to the depth of the dose prescription, which was 4 or 5 cm from the skin. These complicated techniques were used to prevent overdosage or underdosage at the junction areas. We did not angle the treatment couch to match the superior border of the spine field to the divergent beam of the lateral cranial field, since we believed that theoretically the discrepancy over the craniospinal junction induced by this factor is small. All patients received 1.7–2.0 Gy RT daily, 5 days per week. For patients receiving CSI, the craniospinal dose ranged from 25.2 Gy to 42 Gy (median, 36 Gy). The posterior fossa received a total dose of 34.2–59.6 Gy (median, 54 Gy). We defined the ‘adequate RT dose’ as the CSI dose of at least 30 Gy and the posterior fossa dose of at least 50 Gy. According to this definition, 26 (74%) patients received adequate RT dose. During CSI, complete blood count and differential count were checked weekly and medications for relief of increased intracranial pressure were given to most patients. Fifteen (43%) patients required a treatment interruption for more than one week as a result of severe hematologic toxicity. Besides RT, seven patients have also received adjuvant chemotherapy, but there were no strict criteria
79
Statistical analysis Overall survival was measured from the date of surgery, to the date of death from any cause or the date of last contact. Disease-free survival was measured from the date of surgery, to the date of disease recurrence, death, or last contact. Posterior fossa control was measured from the date of surgery, to the date of posterior fossa recurrence, or last contact. Actuarial probabilities of OS, DFS, and PFC were calculated using the Kaplan–Meier methods. The log-rank test was used for comparison between the different groups of variables (univariate analysis). All variables were put into a stepwise Cox regression model, in order to disclose any independent prognostic factor (multivariate analysis). Data processing and statistics were carried out on a personal computer using the software SPSS 10.0 for Windows. A p-value of less than 0.05 was considered statistically significant. Results Survival and PFC The median follow-up time was 60 months (range: 22–176 months). The median OS duration for all 35 patients was 48 months, and there were 43 months and 56 months for the DFS duration and PFC duration, respectively. The OS rates were 63% and 40% at 5 and 10 years, respectively. DFS rates were 48% and 39%, and PFC rates were 69% and 56%, at 5 and 10 years, respectively (Figure 1). The univariate analysis revealed that stage (T1M0 or T2M0 vs. others), shunt surgery within 30 days of initial operation, and RT dose affected OS significantly (Table 3, Figures 2–4). Early stage disease, without further shunt surgery after operation, and adequate RT dose were favorable prognostic factors for OS. Stage and protracted RT course significantly affected DFS on univariate analysis (Table 4). Patients with early stage or receiving continuous RT course had better outcome for DFS. For PFC, RT dose and protracted RT course could predict prognosis (Table 5). Patients with adequate RT dose or continuous RT course had higher PFC rate. On multivariate analysis, RT dose affected OS and PFC independently, stage influenced OS and DFS, while protracted RT course impacted DFS (Table 6).
1.0
Survival or Control Rate
for chemotherapy and the regimens used were not consistent.
.8 PFC
.6
OS
.4
DFS
.2 0.0 0
24
48
72
96
120
144
168
192
Months Figure 1. Kaplan–Meier plot. OS, DFS and PFC after postoperative radiotherapy Table 3. Univariate analysis of prognostic factors for OS Factors
Sex M F Age 1 month RT dose Adequate Inadequate RT interruption > 1 week (+) (−)
Survival rate (%) Number of cases
5-year 10-year p-value
21 14
65 58
38 39
21 14
50 85
44 28
24 11
77 36
55 12
24 11
65 58
46 19
17 18
43 81
32 46
24 11
62 64
36 48
26 9
71 37
53 0
0.8071
0.4177
0.0083
0.5062
0.0341
0.7074
0.0131
0.1473 15 20
60 65
21 47
Patterns of failure and salvage treatments A total of 20 patients had disease relapses. The median time to relapse was 18 months and 11 patients had
1.0
1.0
.8
.8
Overall Survival
Overall Survival
80
T1,2M0
.6
.4
0.2
Adequate RT dose
.6
Inadequate RT dose
.4
.2
Others
0.0
0.0 0
24
48
72
96
120
144
168
192
0
24
48
Months
96
120 144 168 192
Months
Figure 2. Kaplan–Meier plot of OS curves. A significant difference (p = 0.0083) was observed between patients with early stages (T1,2M0) and advanced stages (others).
Figure 4. Kaplan–Meier plot of OS curves. A significant difference (p = 0.0131) was observed between patients received adequate RT dose and patients without it. Table 4. Univariate analysis of prognostic factors for DFS
1.0
Factors
Overall Survival
72
.8
.6 Shunt (-)
.4
Shunt (+)
.2 0.0 0
24
48
72
96
120 144 168 192
Months Figure 3. Kaplan–Meier plot of OS curves. A significant difference (p = 0.0341) was observed between patients received shunt surgery within 30 days of initial operation and patients without it.
disease relapses within 2 years. At the time of diagnosis of disease relapse, the relapse patterns according to site of failure are shown in Table 7. The posterior fossa was the most common site of failure, followed by the subfrontal lobe and spine. Two patients had isolated bony metastasis, one was in the T- and L-spines with images diagnosis, and the other was in the femur with pathological confirmation. The subfrontal lobe relapse (Figure 5) as the only site of failure was noted in 4 (20%) patients, and as a component of failure in 7 (35%) patients. It was interesting to find the high recurrence rate in the subfrontal region because this area is located in the supratentorial region and far from tumor occurring site – the posterior fossa. According
Sex M F Age 1 month RT dose Adequate Inadequate RT interruption > 1 week (+) (−)
Survival rate (%) Number of cases
5-year
10-year
21 14
51 43
34 43
21 14
37 64
28 34
24 11
58 23
41 11
24 11
56 18
44 18
17 18
38 58
38 42
24 11
41 64
34 48
26 9
55 21
50 0
p-value 0.9302
0.2501
0.0263
0.3878
0.1697
0.2889
0.0751
0.0267 15 20
24 70
16 61
to our retrospective review of simulation films and comparison them with image findings, five of these seven patients had tumor relapses in the margin of treatment field (Figure 6), and which may be judged as marginal failures.
81 Salvage treatments with surgery, RT, and/or chemotherapy have been given to 12 patients. Nine of them died with disease and three were still alive till the date of last contact. Of these three patients, two have gained disease-free state and one was alive with disease. Eight patients did not receive salvage treatment because of poor general condition, dissemination of disease, or family refusal. All of them died of disease within 18 months of tumor relapse. Patients who received treatment had a median survival time Table 5. Univariate analysis of prognostic factors for PFC Factors
Control rate (%) Number of cases
Sex M F Age 1 month RT dose Adequate Inadequate RT interruption > 1 week (+) (−)
5-year 10-year p-value
71 65
48 65
21 14
70 69
70 34
24 11
70 70
61 35
24 11
82 24
65 24
17 18
76 69
76 50
24 11
70 64
58 48
0.4640
0.1391
0.7035
0.6134
Surgery Surgery remains one of the main modalities in the treatment of MB. The goals of surgery are to relieve obstructive hydrocephalus, obtain tissue for diagnosis, and achieve as complete a resection as possible. Albright et al. [11] have found that a 90% or greater resection of tumor is associated with improved
0.0018 80 28
73 0 0.0229
15 20
47 89
The treatment in MB, with modern techniques of neurosurgery, RT, and chemotherapy, has improved survival chance for patients over the past 30 years. Current estimates of 5- and 10-year survival rates for MB are 50–83% and 30–64%, respectively [8–10]. Our treatment outcome is comparable to these values.
Stage The most commonly used staging system for MB is the Chang staging system [7]. The M-stage in the Chang system has been shown to have a more consistent correlation with survival than T-stage [11,12]. Le et al. [13] found that localized disease within the posterior fossa is an important prognostic factor for posterior fossa control. The recent publication from Jenkin et al. [14] revealed that stage M0 + M1 was the most powerful favorable prognostic factor. Our study showed the similar findings, and those patients with advanced stage have poorer outcome for OS and DFS on both univariate and multivariate analyses.
0.5167
26 9
Discussion
Prognostic factors
0.9977 21 14
of 11 months from the time of diagnosis of their recurrence to death compared to 3 months for the eight patients who had no further treatment.
31 76
Table 6. Multivariate analysis of prognostic factors Factors
Sex Age Stage OP Shunt OP–RT RT dose Interruption
OS
DFS
PFC
p-value OR (95% CI)
p-value OR (95% CI)
p-value OR (95% CI)
0.3380 0.5041 0.0031 0.6649 0.0980 0.4043 0.0040 0.6251
0.8347 0.7651 0.22 (0.08–0.60) 0.0261 0.8462 0.1829 0.1918 4.54 (1.62–12.73) 0.2657 0.0280
OR: odds ratio, CI: confidence interval.
0.7577 0.9347 0.36 (0.15–0.89) 0.2582 0.3676 0.5872 0.1822 0.0055 0.35 (0.13–0.89) 0.1770
5.59 (1.66–18.81)
82 Table 7. Patterns of failure Site of failure
Only site of failure
Any component of failure
Posterior fossa Subfrontal lobe Spine Bone Other supratentorial area
6 (30%) 4 (20%) 3 (15%) 2 (10%) 0 (0%)
10 (50%) 7 (35%) 6 (30%) 2 (10%) 2 (10%)
Figure 6. Simulation film of one of the four patients with single subfrontal relapse showing that the margin of treatment field is relative tight over the subfrontal area.
Figure 5. Computed tomographic image showing a 4 cm globular mass with heterogeneous enhancement and peripheral edema over the left subfrontal area.
survival. Similar findings were reported by Raimondi and Tomita [15]. However, Sutton et al. [16] reported similar median survival times for patients with gross total resection and for those in whom a small amount of the tumor was left behind, this finding is similar to our data, which revealed that the extent of tumor removal (total resection vs. subtotal or partial resection) did not affect OS, DFS or PFC. RT Postoperative CSI has been shown to provide the single greatest improvement in the control of tumors. The most commonly used RT dose is 30–40 Gy to the spine, 40–50 Gy to the brain, with a boost to a total of 54 Gy to the posterior fossa [17]. Silverman and Simpson [18] found that posterior fossa dose was an important factor for local control. Their local failure rate
was 20% at the posterior fossa dose 50 Gy compared to 62% at posterior fossa dose ≥ 50 Gy. The study from Wolff et al. [2] demonstrated that posterior fossa dose higher than 50 Gy was a significant, single most important positive prognostic factor. In 1986, the Children’s Cancer Group and Pediatric Oncology Group initiated a prospective randomized trial comparing standard neuraxis RT dose (36 Gy) with reduced neuraxis RT dose (23.4 Gy) in patients with low-risk MB. A statistically significant increase was observed in the number of overall relapses as well as isolated neuraxis relapses in patients randomized to the lower-dose arm [19]. The final analysis of that trial concluded that reduced-dose neuraxis irradiation is associated with increased risk of early relapse, early isolated neuraxis relapse, and lower 5-year event-free survival and OS [20]. The results from our study are compatible with these findings, and show lower RT dose is indeed an independent adverse prognostic factor for OS and PFC on both univariate and multivariate analyses. Goldwein et al. [21] suggested that reduced neuraxis RT dose plus chemotherapy might offer another treatment choice for children under age of five with MB. Our patients did
83 not receive chemotherapy with strict criteria regularly, so it is difficult to compare the chemotherapy effect.
of MB. We did not have enough cases of very young patient to reflect to the impact of age.
Protracted RT course Some patients receiving CSI required a treatment interruption for more than 1 week to recover from hematologic toxicity, thus resulting in a protracted RT course. delCharco et al. [8] analyzed the time–dose relationship based on a 30-year review for MB, and found a statistically significant improvement in local control and freedom from relapse when the RT duration was less than 45 days, assuming adequate doses had been given to the posterior fossa. In our study, we found that a protracted RT course significantly influences DFS (univariate and multivariate analyses), and PFC (univariate analysis).
OP–RT interval Traditionally, CSI is started at about 3 weeks after surgery, to allow time for postoperative recovery and healing. Sometimes, it might be delayed for younger patients. Jenkin et al. [10] found that subtotally resected patients would have a poor prognosis if RT were delayed. When CSI was started within 21 days after surgery, the 5-year DFS was 57%, as opposed to 0% when RT was delayed (p = 0.04). This phenomenon was not shown in our study.
Cerebrospinal fluid diversion Mild-to-severe hydrocephalus exists in at least 80–90% of patients with moderate-to-large posterior fossa tumor [22]. All but one of our patients had marked hydrocephalus demonstrated on imaging studies. David et al. [23] reviewed 80 cases from a single institute, and found 17 patients required cerebrospinal fluid diversion procedures within 30 days of the operation. Those patients had a significantly shorter survival time. It is possible that the failure of hydrocephalus to respond to the removal of tumor correlates with disease severity, as reported by Lee et al. [24]. Seventeen patients in our study had received shunt surgery within 30 days of surgery, and there was a marginal significance (p = 0.0341) to show shorter OS in comparison with others, by univariate analysis. Age and sex The younger patients have always had a poorer prognosis than their older counterparts. [2,3,14,21,25]. There are two possible explanations. First, the disease is typically more extensive in these patients [26]. Second, a difference in treatment delivery (e.g. RT is frequently delayed or delivered at reduced doses) for younger patients may also account for the adverse outcome [21,25]. However, several studies [23,27] have found no difference in survival as related to age. Most studies [23,28] did not show sex to affect treatment outcome significantly, but other results showed female patients to have a better prognosis [2,29]. Our study did not reveal any significant difference of outcome for these two factors. The median age of our patients was 12 years, which is older than the average age of occurrence
Patterns of failure and subfrontal relapses In our series, the median time for disease relapse was 18 months. It was similar to the data of previous reports [8,23,30]. Leptomeningeal failure is a common component of failure and occurs in the leptomeninges of the posterior fossa, as well as the spine. The posterior fossa is still the most common site of isolated tumor failure [30–32]. However, relapses in the supratentorial region, especially in the cribriform plate-subfrontal area, are not rare. Cerebrospinal fluid flows in the subfrontal/cribriform plate region. When a skull is viewed from above, this region lies between the orbital roofs. When viewed laterally, one can readily see that the orbital roof is above the cribriform region. Thus, a lateral block for whole-brain irradiation field designed to spare the eyes may block out the cribriform plate region. This has the potential to provide a nidus for tumor relapse [33]. Miralbell et al. [32] reviewed RT technique and patterns of failure for 86 pediatric patients with MB, and found 12 patients had supratentorial failure, 5 of them in the subfrontal area. A correlation between adequacy of the whole-brain irradiation field coverage and supratentorial failure-free survival was observed. Several other authors have mentioned insufficient coverage of the cribriform plate as a reason for subfrontal recurrence [34–37]. Halperin [33] and Hardy et al. [37] suggested that patients lying in the prone during the operation on the posterior fossa and during each time of radiation procedure (simulation and treatment) could facilitate the migration of tumor cells to the cribriform plate (gravitational effect), hence might generate subsequent tumor recurrence. To avoid this phenomenon, Jereb et al. [38] suggested adding an anterior electron field boost to cover the possibility of miss the subfrontal region. This may not be necessary
84 if adequate lateral fields were used. The cribriform plate-subfrontal relapses were also seen in our study, and the frequency was even higher than previous reports. A total of 20 patients had disease relapses in our review, four of them failed in the subfrontal region as the only site of failure and seven failed in this region as a component of failure sites. These failures might be attributed to blocks that shielded the cribriform plate region, and five of these seven patients were judged as a marginal failure after reviewing of previous simulation films retrospectively. For the extra-central nervous system metastases, bone is the most common site [39]. Two of our patients developed bone metastasis, one was confirmed by pathological specimen and the other was diagnosed by images and bone scan examinations. In conclusion, our results were comparable to other studies of MB, except for more subfrontal relapses in our patients. Our findings agreed with the notion that surgical resection of tumor followed by an adequate dose of CSI is the mainstay of treatment. Also important is whole-brain irradiation field coverage with special attention to the cribriform plate-subfrontal region.
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Address for offprints: Li Min Sun, Department of Radiation Oncology, Chang Gung Memorial Hospital, 123, Ta-Pei Road, Niao Sung Hsiang, Kaohsiung Hsien, Taiwan; Tel.: 886-7-7317123, ext. 2600; Fax.: 886-7-7322813; E-mail:
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