J Neurosurg Pediatrics 13: Sunil KuKreja, M.S., Sudheer ambekar, M.d., anthony hunkyun Sin, M.d., and anil nanda, M.d., M.P.h.

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1 J Neurosurg Pediatrics 13: , 2014 AANS, 2014 Cumulative survival analysis of patients with spinal myxopapillary ependymomas in the first 2 decades of life A systematic review Sunil Kukreja, M.S., Sudheer Ambekar, M.D., Anthony Hunkyun Sin, M.D., and Anil Nanda, M.D., M.P.H. Department of Neurosurgery, Louisiana State University Health Sciences Center Shreveport, Shreveport, Louisiana Object. Reports of myxopapillary ependymomas (MPEs) of the spinal cord in pediatric patients are scarce. In the literature, various authors have shared their experiences with small groups of patients, which makes it difficult to create a consensus regarding the treatment approach for spinal MPEs in young patients. The aim of this study was to perform a survival analysis of patients in the first 2 decades of life whose cases were selected from the published studies, and to examine the influence of various factors on outcomes. Methods. A comprehensive search of studies published in English was performed on PubMed. Patients whose age was 20 years were included for integrative analysis. Information about age, treatment characteristics, critical events (progression, recurrence, and death), time to critical events, and follow-up duration was recorded. The degree of association of the various factors with the survival outcome was calculated by using Kaplan-Meier estimator and Cox proportional hazard model techniques. Results. A total of 95 patients were included in the analysis. The overall rate of recurrence (RR) was 34.7% (n = 33), with a median time to recurrence of 36 months (range months). Progression-free survival (PFS) and overall survival rates at 5 years were 73.7% and 98.9%, respectively. Addition of radiotherapy (RT) following resection significantly improved PFS (log-rank test, p = 0.008). In patients who underwent subtotal resection (STR), administering RT (STR + RT) improved outcome with the lowest failure rates (10.3%), superior to patients who underwent gross-total resection (GTR) alone (RR 43.1%; log-rank test, p < 0.001). Addition of RT to patients who underwent GTR was not beneficial (log-rank test, p = 0.628). In patients who had disseminated tumor at presentation, adjuvant RT controlled the disease effectively. High-dose RT ( 50 Gy) did not change PFS (log-rank test, p = 0.710). Conclusions. Routine inclusion of RT in the treatment protocol for spinal MPEs in young patients should be considered. Complete resection is always the goal of tumor resection. However, when complete resection does not seem to be possible in complex lesions, RT should be used as an adjunct to avoid aggressive resection and to minimize inadvertent injury to the surrounding neural tissues. High-dose RT ( 50 Gy) did not provide additional survival benefits, although this association needs to be evaluated by prospective studies. ( Key Words myxopapillary ependymoma spine survival oncology integrative analysis pediatric Abbreviations used in this paper: AWD = alive with disease; DOC = died of other causes; DOD = died of disease; EOR = extent of resection; GTR = gross-total resection; HR = hazard ratio; MPE = myxopapillary ependymoma; NED = no evidence of disease; OS = overall survival; PFS = progression-free survival; RR = recurrence rate; RT = radiotherapy; STR = subtotal resection. Myxopapillary ependymoma (MPE) is a rare histological subgroup of ependymoma, which typically originate from the conus medullaris, cauda equina, and filum terminale. This variant was first recognized by Kernohan in 1932 as a distinct entity due to its characteristic microscopic appearance. Myxopapillary ependymomas represent only 13% of all spinal ependymal tumors, and are even rarer in the pediatric age group. 7,10,11 According to the WHO classification system, MPEs are classified in Grade I because of their slow, indolent growth pattern and long-term survival. 18 Despite their benign histopathological features, MPEs have a tendency to recur and to disseminate along the craniospinal axis, features that are more pronounced in the pediatric age group. 1,2,4,7 In a recent systematic analysis, Feldman et al. 15 reported that the recurrence rates were significantly higher in the pediatric age group as compared with adults (40.5% vs 23.4%, p = 0.02). This article contains some figures that are displayed in color on line but in black-and-white in the print edition. 400 J Neurosurg: Pediatrics / Volume 13 / April 2014

2 Management of spinal myxopapillary ependymoma in children Various factors are described that influence the outcome in pediatric patients with spinal MPEs, of which complete resection of the tumor is considered to be an important outcome predictor. 7 On the other hand, there are reports that have recorded higher rates of recurrence even if gross-total resection (GTR) could be achieved. 1,4,31 The role of adjuvant radiotherapy (RT) in the management of spinal cord MPEs is not well defined. 4,6 However, the most recent clinical studies have strongly supported the role of adjuvant RT in achieving local tumor control and improving disease-free survival in pediatric patients. 1,4 The aim of our study was to perform a comprehensive review of the literature and to analyze the cumulative survival outcomes in patients with spinal MPEs in the first 2 decades of life. We also wanted to evaluate the influence of various factors on progression-free survival (PFS) and overall survival (OS) by using Kaplan-Meier estimator and Cox proportional hazard model techniques. Methods Search Strategy A comprehensive review of the literature was performed independently by 2 reviewers using a systematic search string. The potential articles for inclusion were extracted by inserting the key term Myxopapillary ependymoma on PubMed, which generated 5172 articles published between 1960 and MeSH terms like intramedullary spinal cord and cauda equina tumors were included in the search string to avoid exclusion of any relevant publications. Initial screening excluded 4698 articles on the basis of titles, and 476 publications were chosen for abstract reading. The potential articles were then selected for reading full text (n = 267). After perusing the full content of these articles, 20 publications were selected for final inclusion in this systematic review (Table 1). 1,2,4,5,7,8,10,12 14,16,17,19 23,26,31,32 Inclusion and Exclusion Criteria Articles containing individual patient information about age, treatment characteristics (extent of resection [EOR] with or without adjuvant RT), critical events (progression, recurrence, and death), time to critical events, and follow-up duration were included for the cumulative survival analysis. Case reports were excluded; however, an isolated patient from the case series whose age was 20 years was considered for inclusion. 32 In articles that described the outcomes in all age groups, patients in the first 2 decades of life were selected for the analysis. 1,2,7,13,17,19 21,26,32 Patients presenting with a history of previous surgery were not considered for inclusion. 7 Publications with integrated patient data and studies performed in the same institution were excluded. 6,28 Articles in languages other than English were not selected for analysis. Data Extraction Information on demographic features, clinical presentation, location of tumor, EOR, use of adjuvant treatment, dose of RT, recurrence or progression of disease, pattern of failure, mortality rates, time to recurrence or J Neurosurg: Pediatrics / Volume 13 / April 2014 death, follow-up duration, and status at the time of analysis was extracted. The primary treatment had 3 subgroups: surgery alone, surgery with adjuvant RT (surgery + RT), and biopsy. To assess the impact of EOR with or without RT on survival, treatment was further subcategorized into 5 groups: GTR, GTR + RT, subtotal resection (STR), STR + RT, and biopsy. The patients in whom information was provided regarding the dose of RT were subdivided into 2 subgroups: dose < 50 Gy and dose 50 Gy. 29 Status of the patients was divided into 4 groups: no evidence of disease (NED), alive with disease (AWD), died of disease (DOD), and died of other causes (DOC). The status described as stable disease was included in the AWD group. Statistical Analysis Categorical and continuous variables were analyzed using the chi-square and Kruskal-Wallis tests, respectively. Survival outcomes (PFS and OS) were evaluated with the Kaplan-Meier estimator and results were compared with the log-rank test. Univariate and multivariate analysis was performed using the Cox regression hazard model, which also calculated the hazard ratio (HR) and the 95% CI. Univariate analysis was performed by inserting the variables like age, sex, EOR, surgery with or without RT, and RT dose to explore the influence of these factors on survival. Backward stepwise model selection was used to adjust the confounding variables in multivariate analysis. Analyses were performed using SPSS software (v21; IBM, Inc.). A p value less than 0.05 was considered statistically significant. Results Ninety-five patients (age 20 years) were included in the cumulative survival analysis (Table 2). Back pain was the most common presenting symptom (84%), followed by radicular pain (52.1%), extremity weakness (36.2%), bowel/bladder involvement (23.1%), and sensory involvement (20.2%). Fourteen patients had craniospinal dissemination of tumor at the time of presentation. Except in 3 patients (cervical spine), tumors were located in lower spinal segments. At the mean follow-up of months (range months), 97.9% were alive (2 patients died; 1 DOD, 1 DOC). The overall rate of recurrence was 34.7% (n = 33), and the most common site of failure was local (69.7%). The median time to recurrence was 36 months (range months). The PFS and OS rates at 5 years were 73.7% and 98.9%, respectively (Fig. 1). The influence of outcome predictors was analyzed and survival results were described for each variable (Table 3). Survival Outcomes Categorized by Demographic Features The mean age at presentation was 13.3 years (range 1 20 years). Univariate analysis did not reveal an effect of the overall age on PFS (HR 1.05, 95% CI , p = 0.253). The male-to-female ratio was 2.2:1 (p < 0.05). Sex of the patients did not influence PFS (HR 0.56, 95% CI , p = 0.195). The impact of age and sex on PFS was not significant even in multivariate analysis (age: HR 1.09, 95% CI , p = 0.093; sex: HR 0.44, 95% CI , p = 0.068). 401

3 S. Kukreja et al. TABLE 1: Literature review of 20 articles on spinal MPEs in the first 2 decades of life* Authors & Year No. of Pts Symptoms EOR Adjuvant RT Recurrence Site of Recurrence Death Mean FU (mos) Status Chan et al., bp, 3 rp, 3 ew, 1 si, 1 bb, 2 diss 3 STR, 4 GTR 2 STR 2 GTR 1 dist, 1 loc/dist NED, 1 AWD Clover et al., NR 3 STR 3 STR 1 STR + RT 1 loc NED, 1 AWD Gagliardi et al., bp, 2 rp, 2 ew, 2 si, 2 bb 2 STR, 2 GTR 1 STR 1 STR 1 loc NED Ross et al., NR 1 STR, 4 GTR 1 STR, 3 GTR NED Nagib & O Fallon, bp, 3 rp 3 GTR 0 1 GTR 1 loc NED Yoshii et al., bp, 1 rp, 1 ew 1 GTR NED Chinn et al., bp, 3 rp, 3 ew, 1 si, 2 diss 1 STR, 2 GTR 1 STR, 1 GTR 1 GTR 1 loc/dist AWD Merchant et al., diss 4 STR 4 STR NED, 1 AWD, 1 DOC Kocak et al., bp 2 STR, 1 GTR 2 STR, 1 GTR 1 STR + RT, 1 GTR + RT 1 loc, 1 loc/dist NED, 1 AWD, 1 DOD Fassett et al., bp, 2 rp, 2 ew, 1 si, 1 bb, 4 diss 2 STR, 3 GTR 2 STR, 2 GTR 1 GTR + RT 1 dist NED, 1 AWD Akyurek et al., bp, 4 rp, 3 ew, 4 si, 2 bb 3 GTR, 1 biopsy 1 GTR 1 GTR + RT, 2 GTR, 1 biopsy 3 loc, 1 loc/dist NED, 1 AWD Lukashova-v.Zangen et 2 NR 1 STR, 1 GTR NED al., 2007 Han et al., bp, 1 rp, 1 ew, 1 si, 1 bb 2 GTR 0 2 GTR 2 loc 0 55 NR Meneses et al., ew 3 GTR NED Bagley et al., bp, 7 rp, 3 ew, 2 si, 3 bb 1 STR, 6 GTR 0 1 STR, 2 GTR 2 loc, 1 loc/dist NED, 2 AWD Al-Halabi et al., bp, 3 ew, 3 bb, 2 diss 3 STR, 4 GTR 3 STR, 1 GTR 1 STR + RT, 2 GTR 1 loc, 2 loc/dist NED, 6 AWD Benesch et al., NR 2 STR, 3 GTR, 1 1 biopsy 2 STR, 2 GTR 4 loc NED, 5 AWD biopsy Amsbaugh et al., NR 5 STR, 1 GTR 5 STR, 1 GTR NED Stephen et al., bp, 1 diss 2 STR, 6 GTR 2 STR, 1 GTR 4 GTR 4 loc NED, 4 AWD Agbahiwe et al., bp, 10 rp, 2 ew, 2 si, 3 4 STR, 8 GTR 3 STR, 2 GTR 1 STR, 2 GTR, 1 GTR + RT 3 loc, 1 dist NED, 2 AWD bb total bp, 36 rp, 25 ew, 14 si, 16 bb, 14 diss 36 STR, 57 GTR, 2 biopsy 43 5 STR, 3 STR + RT, 20 GTR, 4 GTR + RT, 1 biopsy 23 loc, 3 dist, 7 loc/dist NED, 28 AWD, 1 DOD, 1 DOC * Articles in which inclusion criteria were met, in which systematic analysis was performed. bb = bowel/bladder involvement; bp = back pain; diss = dissemination at presentation; dist = distant; ew = extremity weakness; FU = follow-up; loc = local; NR = not recorded; pts = patients; rp = radicular pain; si = sensory involvement. Seven patients who had previously undergone surgery were excluded from this analysis. 402 J Neurosurg: Pediatrics / Volume 13 / April 2014

4 Management of spinal myxopapillary ependymoma in children TABLE 2: Cumulative demographic, clinical, and treatment characteristics in 95 patients with spinal MPEs Variable No. of Pts (%) Available Data (%) age in yrs 95 (100) mean ± SD 13.3 ± 4.0 range 1 20 sex* 83 (87.4) M 57 (68.7) F 26 (31.3) location 89 (93.7) cervical 3 (3.4) thoracolumbar 17 (19.1) lumbosacral 68 (76.4) thoracolumbosacral 1 (1.1) symptoms 69 (72.6) bp 58 (84) rp 36 (52.1) ew 25 (36.2) si 14 (20.2) bb 16 (23.1) CNS diss 14 (14.7) 95 (100) primary treatment 95 (100) surgery alone 51 (53.7) surgery + RT 42 (44.2) biopsy 2 (2.1) EOR w/ or w/o RT 95 (100) GTR 44 (46.3) GTR + RT 13 (13.7) STR 7 (7.4) STR + RT 29 (30.5) biopsy 2 (2.1) * Statistically significant (p < 0.05). One patient with biopsy was given adjuvant RT. Survival Outcomes Categorized by Surgery With or Without RT Surgery alone was performed in 51 patients, whereas RT was used as an adjunct in 42 patients. Biopsy was performed in 2 patients, 1 of whom was given RT. Addition of RT following resection significantly improved PFS (HR 0.34, 95% CI , p = 0.043). The effect could be demonstrated on survival curve (Fig. 2 left, log-rank test, p = 0.008). The positive impact of adjuvant RT on PFS was also confirmed on multivariate analysis (HR 0.27, 95% CI , p = 0.006). Cases with information on the dose of RT administered to the tumor bed (37 of 41 patients) were selected for further analysis. The mean dose of RT was 47.7 ± 6.9 Gy (range Gy). An RT dose 50 Gy did not prolong PFS (HR 0.74, 95% CI , p = 0.711), which was also seen on the Kaplan-Meier curve (Fig. 2 right, log-rank test, p = 0.710). Except in one case, all the patients who presented with craniospinal dissemination were given adjuvant RT (n = 13), and tumor recurred in only 2 of these patients (1 local, 1 distant). J Neurosurg: Pediatrics / Volume 13 / April 2014 Survival Outcomes Categorized by EOR With or Without RT GTR was achieved in 57 patients, followed by STR in 36, and biopsy in 2 patients. The EOR regardless of RT status did not affect PFS (HR 0.69, 95% CI ; p = 0.341). A similar finding could be discovered on building a Kaplan-Meier curve (Fig. 3A, log-rank test, p = 0.335). Analysis was performed considering the RT status of the patients (biopsy excluded). Of 42 patients who were given RT, 29 patients were from the STR group (p < 0.05). The rate of recurrence was lowest in the STR + RT group (10.3%) as compared with GTR and STR (43.1% and 85.7%, respectively). Addition of RT in patients who underwent STR improved their PFS significantly compared with GTR alone (HR 0.24, 95% CI , p = 0.006). The prognosis was worst in those patients who underwent STR without adjuvant RT (HR 3.41, 95% CI ). Similar findings were seen on the survival plot (Fig. 3B, log-rank test, p < 0.001). In patients who underwent GTR, administering RT did not provide a survival benefit (Fig. 3C, log-rank test, p = 0.628). Patients in the STR + RT group had a survival advantage even in multivariate analysis (HR 0.24, 95% CI , p = 0.011). Patients in the STR + RT group achieved the highest rate of NED status (72.4%), as compared with the GTR, GTR + RT, and STR groups (68.1%, 61.5%, and 42.8%, respectively; Fig. 4). Discussion Age has a potential influence on disease-free survival in patients with spinal MPEs. The clinical course of the tumor has been observed to be more aggressive in younger patients. 2,3,7,8,25,31 In the largest series, presented by Pica et al., 25 but excluded from this study because it was not a pediatric series, the authors demonstrated lower PFS (88% vs 52%) in younger age groups (36 years). Similar findings were observed by Akyurek et al. 2 in patients < 35 years of age (p = 0.002). Bagley et al. 7 also reported a high rate of local recurrence in children (64%, vs 32% in adults). Patients in the pediatric group also have a higher incidence of disseminated disease at presentation. 4,6,12,14 This can be explained by an insidious onset of associated clinical symptoms, or this may be purely due to aggressive behavior of tumor in young patients. 4 As a result of this observation, pre- or postoperative screening for metastatic disease with CSF cytology and complete CNS imaging has been advocated as routine protocol in patients with MPEs. 12,14 Results describing the factors affecting the prognosis of spinal MPEs in pediatric patients are ambiguous. Bagley et al. 6 emphasized the role of aggressive complete resection in the excellent outcomes. In contrast to this, recent observations have supported the role of adjuvant RT for effective tumor control, regardless of the EOR achieved. 1,4,22 Due to the rare occurrence of MPEs in pediatric patients, conclusions by individual authors are usually based on small samples. The aim of our study was to perform a cumulative analysis of patients with spinal MPEs in the first 2 decades of life and to examine the role of various factors influencing the survival outcomes, 403

5 S. Kukreja et al. Fig. 1. Kaplan-Meier chart showing PFS (left) and OS (right) in 95 patients with spinal myxopapillary ependymoma in the first 2 decades of life. Cum = cumulative. so that the results could be demonstrated with greater statistical power. Complete resection of the tumor provides a long-term PFS in adult patients with spinal MPEs. 9,15,30 Similar observations have also been recorded in pediatric patients. 6 TABLE 3: Univariate analysis for PFS* Variable HR (95% CI) p Value age in yrs 1.05 ( ) sex M 1 F 0.56 ( ) primary treatment surgery alone 1 surgery + RT 0.34 ( ) EOR GTR 1 STR 0.69 ( ) EOR w/ or w/o RT GTR 1 GTR + RT 0.77 ( ) STR 3.41 ( ) STR + RT 0.24 ( ) RT dose <50 Gy 1 50 Gy 0.74 ( ) * A 1 designates the reference category. Variables that are significantly associated with the risk of progression. Primary treatment and EOR with or without RT reached the level of significance (p < 0.05). Independent of RT status. Analysis performed in patients with data available on RT dose (37 of 41 patients). Bagley et al. believed that due to its indefinite role and side effects, adjuvant RT was not required if there was radiological evidence of total resection, and suggested repeated excision if the tumor recurred locally. However, they have also shown a significant rate of postoperative complications (29% [4 of 14]), along with mild spinal deformities in 3 patients. Merchant et al. 22 reported 100% tumor control with STR combined with RT, and they recommended less radical resection to obtain a favorable clinical outcome. In their review, Fassett et al. 14 reported recurrence in 4 of 11 patients (2 local and 2 distant), who were treated with complete resection alone, and none of the patients treated with SRT + RT developed recurrence. Al-Halabi et al. 4 supported this finding in their study of 7 patients, and recorded high rates of treatment failure following GTR alone. They recommended routine use of RT to improve outcomes irrespective of EOR achieved. In their review, Feldman et al. 15 observed distinct outcomes in pediatric patients as compared with adults. They documented higher rates of recurrence in children (40.5% vs 23.4%, p = 0.02) and reported that in the patients who underwent GTR without RT, failure rates were higher among children as compared with adults (65% vs 7.6%, p < 0.001); however, the results were not significantly different between the two age categories when patients in the STR + RT group were compared (p = 0.20). In our analysis the overall rate of recurrence was 34.7%, with a PFS of 73.7% at 5 years. As compared with surgery alone, patients who were also given adjuvant RT had improved survival (log-rank test, p = 0.008). Irrespective of RT status of the patients, results were not different among GTR and STR groups. However, observations demonstrated on a Kaplan-Meier curve (Fig. 3B) revealed better survival in the STR group (although it did not reach statistical significance; log-rank test, p = 0.335), which may be due to the influence of RT, because more patients received RT in the STR group (p < 0.05). With 404 J Neurosurg: Pediatrics / Volume 13 / April 2014

6 Management of spinal myxopapillary ependymoma in children Fig. 2. Kaplan-Meier analysis of PFS by adjuvant RT. Left: Overall PFS was significantly affected by addition of RT to the surgery as compared with surgery alone (log-rank test, p = 0.008). Right: An RT dose 50 Gy did not affect the survival outcomes (log-rank test, p = 0.710). respect to RT status, we found that patients in the STR + RT group had significantly improved survival with low failure rates (recurrence rate [RR] 10.3%). Patients in the STR group had poor disease-free survival (RR 85.7%), and outcome results in patients who underwent GTR only were inferior as compared with patients in the STR + RT group (RR 43.1%). The addition of RT in patients who underwent GTR did not change PFS (log-rank test, p = 0.628). This finding may be due to various factors. In our opinion the most important reason for this observation is the small number of patients in the GTR + RT group (n = 13), which weakens statistical power and implications of the results. Another factor that may be responsible for this finding is an underlying selection bias; 5 of 14 patients who presented with craniospinal dissemination were from the GTR + RT group. However, only 1 of these 5 patients had distant recurrence, and the impact of 1 recurrence on the overall PFS in such a small group of patients cannot be denied. Second, some authors who have performed GTR + RT have not described or evaluated radiological features of the tumor in their reports, which may underestimate the exact numbers of aggressive lesions in this group. 1,5,19 Inclusion of this information becomes essential, especially when 3 of the 4 recurrences in the GTR + RT group were distant. The effect of selection bias gains more importance because the only patient who died of disease had undergone GTR + RT. Conversely, we may also interpret that GTR + RT is effective in controlling aggressive lesions, because 4 of 5 patients with disseminated disease at presentation responded well to the treatment. However, the small number of patients in this group Fig. 3. Kaplan-Meier analysis of PFS by EOR. A: Irrespective of RT status of patients, there was no significant difference in survival between those with GTR and STR (p = 0.335). B: Patients who underwent STR + RT had better disease-free survival as compared with GTR and STR alone (log-rank test, p < 0.001). C: Adjuvant RT did not affect survival in patients who underwent complete resection of the tumor (log-rank test, p = 0.628). J Neurosurg: Pediatrics / Volume 13 / April

7 S. Kukreja et al. already discussed, the inferior results in the GTR + RT group were probably due to selection bias, because patients with more aggressive tumors received adjunct RT following the complete resection of their lesions. The small numbers of patients in the GTR + RT, STR, and biopsy groups also limits the clinical implications of the results. Exclusion of studies with integrated data and in languages other than English further weakens the strength of the results. Because of insufficient information we did not evaluate the functional outcomes of patients, which need to be addressed because high rates of complications are described if radical resection is attempted. 6,27 Due to inconsistent reports in the included literature, we have not evaluated the influence of radiological presentation of the lesions on the clinical outcomes, which adds to the limitation of our analysis; especially because in some literature on adult patients, the status of encapsulation on MRI has been found to be an important guide to resectability and eventually to survival outcomes. 24,27,30 Fig. 4. Bar graph showing overall status at the time of analysis. The patients in the STR + RT group achieved high rates of NED status in comparison with STR and GTR alone. Two patients died; one in STR + RT (DOD) and the other in the GTR + RT group (DOC). and/or selection bias probably makes this interpretation statistically not applicable. We believe that this issue should be addressed in a separate clinical study in which there are sufficiently large numbers of patients and also that efforts should be made to avoid possible selection bias. We also note that even in those patients who had disseminated tumor at presentation (n = 14), adjuvant RT (n = 13) controlled the disease effectively (2 recurrences). Based on our analysis, we support the findings of previous studies, which documented longer disease-free outcomes in young patients with addition of RT. 1,4,14,15,22 Pica et al. 25 showed that the results were not statistically different with GTR or STR; however, high-dose RT (> 50.4 Gy) significantly improved disease control. The effect of radiation dose on survival has also been demonstrated by Schild et al., 29 and they reported total disease-free control (log-rank test, p = 0.08) in patients who received a dose > 50 Gy, although the results were based on only 12 patients. Chan et al. 10 also found the influence of RT dose (30 50 Gy) to prevent progression of the tumor. Agbahiwe et al. 1 also observed effective tumor control with a mean RT dose of 50.4 Gy. Conversely, in our analysis of studies of patients in the first 2 decades of life, we did not find any significant advantage of highdose RT ( 50 Gy) on survival (log-rank test, p = 0.710). Limitations of Our Study Studies of spinal MPEs in young patients are few, which makes our cumulative survival analysis an important contribution to aid in setting essential therapeutic guidelines. There are also several limitations of this systematic review. Selection bias is inevitable because all the included studies were retrospective. As we have Conclusions Based on results obtained in our analysis, adjuvant RT seems to play a very important role in improving recurrence-free survival in patients with spinal MPEs in the first 2 decades of life. Complete removal of tumor is always the goal of an operating surgeon. However, on the basis of our analysis it seems that residual tumor is very well controlled by adjuvant RT, and in view of protecting the normal neural tissue, an aggressive attempt at microscopic eradication of tumor is avoidable. We did not find a positive influence of RT dose 50 Gy on survival, although we believe a definitive association can be examined by performing well-designed randomized controlled trials. Inclusion of RT in the treatment protocol is necessary if the patient has craniospinal dissemination at presentation. Disclosure The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper. Author contributions to the study and manuscript preparation include the following. Conception and design: Kukreja. Acquisition of data: Kukreja. Analysis and interpretation of data: Kukreja. Drafting the article: Kukreja, Ambekar. Critically revising the article: all authors. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Nanda. Statistical analysis: Kukreja. Administrative/technical/material support: Nanda, Sin. Study supervision: Nanda, Sin. References 1. Agbahiwe HC, Wharam M, Batra S, Cohen K, Terezakis SA: Management of pediatric myxopapillary ependymoma: the role of adjuvant radiation. Int J Radiat Oncol Biol Phys 85: , Akyurek S, Chang EL, Yu TK, Little D, Allen PK, McCutcheon I, et al: Spinal myxopapillary ependymoma outcomes in patients treated with surgery and radiotherapy at M.D. Anderson Cancer Center. J Neurooncol 80: , Al-Habib A, Al-Radi OO, Shannon P, Al-Ahmadi H, Petrenko Y, Fehlings MG: Myxopapillary ependymoma: correlation of 406 J Neurosurg: Pediatrics / Volume 13 / April 2014

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J Spinal Disord 12: , 1999 Manuscript submitted October 9, Accepted January 13, Please include this information when citing this paper: published online February 14, 2014; DOI: / PEDS Address correspondence to: Anil Nanda, M.D., M.P.H., Department of Neurosurgery, Louisiana State Health Sciences Center Shreveport, P.O. Box 33932, 1501 Kings Highway, Shreveport, LA ananda@lsuhsc.edu. J Neurosurg: Pediatrics / Volume 13 / April