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Surveillance imaging in pediatric ependymoma

Pediatric Blood & Cancer, 2020
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Received: 1 June 2020 Revised: 13 July 2020 Accepted: 14 July 2020 DOI: 10.1002/pbc.28622 Pediatric Blood & Cancer The American Society of Pediatric Hematology/Oncology ONCOLOGY: RESEARCH ARTICLE Surveillance imaging in pediatric ependymoma Darren Klawinski 1, 2 Daniel J. Indelicato 3 Jobayer Hossain 4 Eric Sandler 1 1 Division of Pediatric Hematology/Oncology, Nemours Children’s Specialty Care and Wolfson Children’s Hospital, Jacksonville, Florida 2 Department of Pediatrics, University of Florida, Jacksonville, Florida 3 Department of Radiation Oncology, University of Florida, Jacksonville, Florida 4 Department of Statistics and Bioinformatics, A.I. DuPont Hospital for Children, Wilmington, Delaware Correspondence Darren Klawinski, Division of Pediatric Hema- tology/Oncology, Nemours Children’s Specialty Care and Wolfson Children’s Hospital, 807 Children’s Way, Jacksonville, FL 32207. Email: Darren.Klawinski@gmail.com The abstract for this manuscript was submitted for presentation at the 2020 American Society of Pediatric Hematology/Oncology conference in Fort Worth, TX, May 6–9 (canceled due to COVID-19) and was published in Pediatric Blood and Cancer. Abstract Background: Management of pediatric patients with ependymoma includes posttreat- ment surveillance imaging to identify asymptomatic recurrences. However, it is unclear whether early detection translates into improved survival. The objective was to deter- mine whether detection of ependymoma relapses on surveillance imaging translates into a survival benefit. Procedure: Patients with ependymoma aged <21 years at diagnosis treated in the Nemours’ Children’s Health System between January 2003 and October 2016 under- went chart review. Relapsed patients’ charts were assessed for details of initial ther- apy, surveillance imaging regimen, details of relapse including detection and therapy, and outcome. Median follow up of the entire cohort was 6.5 years from diagnosis and 3.5 years from relapse. Results: Ninety of 198 (45%) patients experienced relapse with 61 (68%) detected by surveillance imaging and 29 (32%) detected based on symptoms. Five-year OS in the surveillance group was 67% (confidence interval [CI] 55–82%, SE 0.1) versus 51% (CI 35–73%, SE 0.19) in the symptoms group (P = .073). From relapse, the 3-year OS in the surveillance group was 62% (CI 50–78%, SE 0.11) versus 55% (CI 39–76%, SE 0.17) in the symptoms group (P = .063) and the 3-year SPFS was 45% (CI 33–61%, SE 0.16) in the surveillance group versus 32% (CI 19–55%, SE 0.27) in the symptoms group (P = .028). Conclusion: Surveillance imaging may identify recurrences in patients when they are more amenable to salvage therapy, resulting in superior 3-year SPFS, but given lim- ited salvage options for children with recurrent ependymoma, the survival advantage of frequent surveillance imaging in asymptomatic patients remains ambiguous. KEYWORDS detection, ependymoma, prognosis, relapse, surveillance, survival 1 INTRODUCTION Ependymomas account for about 5% of pediatric central nervous sys- tem (CNS) tumors and are the second most common high-grade CNS tumor in children. 1 Despite aggressive treatment, it is associated with Abbreviations: CI, confidence interval; CNS, central nervous system; CT, computed tomography; MRI, magnetic resonance imaging; OS, overall survival; SPFS, second progression-free survival a high incidence of local tumor recurrence compared to other child- hood brain tumors with approximately one-third of patients experienc- ing relapse. 2-6 In the management of pediatric ependymoma, an essential com- ponent is serial follow-up imaging with magnetic resonance imaging (MRI) or computed tomography (CT) with the presumption that the early identification of asymptomatic recurrences leads to improve- ments in outcome. Surveillance protocols have been proposed based on the biological characteristics of a specific tumor and take into Pediatr Blood Cancer. 2020;e28622. © 2020 Wiley Periodicals LLC 1 of 8 wileyonlinelibrary.com/journal/pbc https://doi.org/10.1002/pbc.28622
2 of 8 KLAWINSKI ET AL. account the rate of tumor growth as well as incidence of local and metastatic recurrence. 7,8 While surveillance imaging may identify tumor recurrence before symptoms develop, it is less clear that early detection leads to improved outcomes and/or changes in treatment strategies. 3,7,8 Additionally, for many children, the practice of surveillance imag- ing is not without problems. Performing surveillance imaging has been associated with false positive results that not only add cost to both fam- ilies and the healthcare system but also lead to further imaging and unnecessary further therapy. False negative results may delay neces- sary treatment changes, add to costs, and compromise patient quality and length of life. 8,9 Both patients and families often experience signif- icant anxiety around the time of surveillance imaging. 8,10 Sedation or general anesthesia is often required, in particular for younger children, to obtain surveillance imaging. Wu and colleagues recently reviewed and discussed the relationship between general anesthetics and neu- rotoxicity and highlight how the developing brain may be particularly vulnerable to anesthesia leading to a risk for long-lasting impairments of cognitive function. 11 Advancements in pediatric neuroimaging have led to MRI replacing CT as studies have shown that MRI has improved image quality, bet- ter differentiation between normal brain and tumor using contrast, and has been better able to delineate the extent of tumor and metastases throughout the brain and spine. 8,12-14 While MRI has the advantages of being the better imaging modality for brain tumors and involves no ionizing radiation exposure, recent studies have shown that gadolin- ium contrast deposits in various parts of brain. The significance of this has not been determined, but it has the potential to result in long-term neurotoxicity. 15,16 For these reasons, obtaining a better understanding of the prognos- tic significance of surveillance imaging is necessary as clinicians weigh the positive and negative aspects for patients. While prior studies have been performed to assess the prognostic value of surveillance imag- ing in the detection of relapse in children with various brain tumors, including ependymoma, there is a relatively small amount of literature that includes little contemporary data addressing this question. 3,7,9 In addition, imaging techniques in previous studies included both CT and MRI and were more likely to be CT if the patient presented earlier in the study period and more likely to be MRI later in the study period. Both methods detected relapse, but the studies did not compare the two. 3,7 Based on this previous literature, it is hypothesized that fre- quent surveillance imaging will allow earlier detection of disease recur- rence, but will not confer an overall survival (OS) benefit. 2 METHODS 2.1 Study design and participants Under an Institutional Review Board approved protocol, patients with ependymoma who were treated in the Nemours Children’s Health System in Jacksonville, Delaware, Orlando, and Pensacola between January 2003 and October 2016 underwent chart review via the electronic medical record. Included patients were aged 21 years and under and were newly diagnosed with a primary ependymoma at least 2 years prior to the beginning of the study. They underwent and com- pleted treatment that consisted of surgical resection, radiation ther- apy, chemotherapy, or a combination thereof, with curative intent. At the end of treatment, they began a period of surveillance imaging with MRI to assess for disease recurrence. The schedule of surveil- lance imaging was based on the treating physician following the pat- tern of every 3–4 months for the first 3 years following treatment, every 6 months until 5 years off treatment, and yearly thereafter. Surveillance images included imaging of both the brain and the spine. However, spinal imaging was obtained less frequently for patients with primary disease in the brain, with an approximately 2:1 ratio of brain to spinal images. While all images for every patient were not avail- able, imaging was available immediately prior to and at the time of documented relapse on imaging. All patients had documented disease recurrence with MRI. The majority of patients were not enrolled on treatment clinical trials and received treatment based on the exper- tise of the treating physician. However, more than 90% of patients were enrolled on the University of Florida Proton Therapy Institute outcome tracking study. Diagnosis was based on institutional pathology for the majority of patients. Median follow up in the relapsed cohort was 6.5 years from diagnosis and 3.5 years from relapse. Patients with dis- ease progression prior to the end of treatment or who did not undergo initial treatment were excluded. All patients had relapse documented by MRI. 2.2 Study aims The study aims to assess the significance of current neuroimaging prac- tices as it relates to overall prognosis. It is hypothesized that frequent surveillance scanning will allow earlier detection of disease recurrence, but will not confer benefit to OS in these high-grade brain tumors. 2.3 Outcomes Charts of relapsed patients were further examined to assess details of initial therapy, surveillance imaging regimen, timing of relapse, means of detection, relapsed therapy, and outcome. The primary aim of the study was to assess correlation between method of relapse detection and survival. 2.4 Statistical analysis Survival analyses were computed for each group using the Kaplan- Meier method. Kaplan-Meier curves were constructed to show sur- vival over time. OS was determined as length of time of survival from diagnosis and second progression-free survival (SPFS) was determined as the length of time from relapse to disease progression. Ranges of OS and SPFS were observed and median survival times were computed
Received: 1 June 2020 Revised: 13 July 2020 Accepted: 14 July 2020 Pediatric Blood & Cancer DOI: 10.1002/pbc.28622 O N C O LO G Y: R E S E A R C H A RT I C L E The American Society of Pediatric Hematology/Oncology Surveillance imaging in pediatric ependymoma Darren Klawinski1,2 Daniel J. Indelicato3 Jobayer Hossain4 Eric Sandler1 1 Division of Pediatric Hematology/Oncology, Nemours Children’s Specialty Care and Wolfson Children’s Hospital, Jacksonville, Florida 2 Department of Pediatrics, University of Florida, Jacksonville, Florida 3 Department of Radiation Oncology, University of Florida, Jacksonville, Florida 4 Department of Statistics and Bioinformatics, A.I. DuPont Hospital for Children, Wilmington, Delaware Correspondence Darren Klawinski, Division of Pediatric Hematology/Oncology, Nemours Children’s Specialty Care and Wolfson Children’s Hospital, 807 Children’s Way, Jacksonville, FL 32207. Email: Darren.Klawinski@gmail.com The abstract for this manuscript was submitted for presentation at the 2020 American Society of Pediatric Hematology/Oncology conference in Fort Worth, TX, May 6–9 (canceled due to COVID-19) and was published in Pediatric Blood and Cancer. Abstract Background: Management of pediatric patients with ependymoma includes posttreatment surveillance imaging to identify asymptomatic recurrences. However, it is unclear whether early detection translates into improved survival. The objective was to determine whether detection of ependymoma relapses on surveillance imaging translates into a survival benefit. Procedure: Patients with ependymoma aged <21 years at diagnosis treated in the Nemours’ Children’s Health System between January 2003 and October 2016 underwent chart review. Relapsed patients’ charts were assessed for details of initial therapy, surveillance imaging regimen, details of relapse including detection and therapy, and outcome. Median follow up of the entire cohort was 6.5 years from diagnosis and 3.5 years from relapse. Results: Ninety of 198 (45%) patients experienced relapse with 61 (68%) detected by surveillance imaging and 29 (32%) detected based on symptoms. Five-year OS in the surveillance group was 67% (confidence interval [CI] 55–82%, SE 0.1) versus 51% (CI 35–73%, SE 0.19) in the symptoms group (P = .073). From relapse, the 3-year OS in the surveillance group was 62% (CI 50–78%, SE 0.11) versus 55% (CI 39–76%, SE 0.17) in the symptoms group (P = .063) and the 3-year SPFS was 45% (CI 33–61%, SE 0.16) in the surveillance group versus 32% (CI 19–55%, SE 0.27) in the symptoms group (P = .028). Conclusion: Surveillance imaging may identify recurrences in patients when they are more amenable to salvage therapy, resulting in superior 3-year SPFS, but given limited salvage options for children with recurrent ependymoma, the survival advantage of frequent surveillance imaging in asymptomatic patients remains ambiguous. KEYWORDS detection, ependymoma, prognosis, relapse, surveillance, survival 1 INTRODUCTION a high incidence of local tumor recurrence compared to other childhood brain tumors with approximately one-third of patients experienc- Ependymomas account for about 5% of pediatric central nervous system (CNS) tumors and are the second most common high-grade CNS tumor in children.1 Despite aggressive treatment, it is associated with ing relapse.2-6 In the management of pediatric ependymoma, an essential component is serial follow-up imaging with magnetic resonance imaging (MRI) or computed tomography (CT) with the presumption that the early identification of asymptomatic recurrences leads to improve- Abbreviations: CI, confidence interval; CNS, central nervous system; CT, computed tomography; MRI, magnetic resonance imaging; OS, overall survival; SPFS, second progression-free survival Pediatr Blood Cancer. 2020;e28622. https://doi.org/10.1002/pbc.28622 ments in outcome. Surveillance protocols have been proposed based on the biological characteristics of a specific tumor and take into wileyonlinelibrary.com/journal/pbc © 2020 Wiley Periodicals LLC 1 of 8 2 of 8 KLAWINSKI ET AL . account the rate of tumor growth as well as incidence of local and metastatic recurrence.7,8 electronic medical record. Included patients were aged 21 years and While surveillance imaging may identify under and were newly diagnosed with a primary ependymoma at least tumor recurrence before symptoms develop, it is less clear that early 2 years prior to the beginning of the study. They underwent and com- detection leads to improved outcomes and/or changes in treatment pleted treatment that consisted of surgical resection, radiation ther- strategies.3,7,8 apy, chemotherapy, or a combination thereof, with curative intent. At Additionally, for many children, the practice of surveillance imag- the end of treatment, they began a period of surveillance imaging ing is not without problems. Performing surveillance imaging has been with MRI to assess for disease recurrence. The schedule of surveil- associated with false positive results that not only add cost to both fam- lance imaging was based on the treating physician following the pat- ilies and the healthcare system but also lead to further imaging and tern of every 3–4 months for the first 3 years following treatment, unnecessary further therapy. False negative results may delay neces- every 6 months until 5 years off treatment, and yearly thereafter. sary treatment changes, add to costs, and compromise patient quality Surveillance images included imaging of both the brain and the spine. and length of life.8,9 Both patients and families often experience signif- However, spinal imaging was obtained less frequently for patients with icant anxiety around the time of surveillance imaging.8,10 Sedation or primary disease in the brain, with an approximately 2:1 ratio of brain general anesthesia is often required, in particular for younger children, to spinal images. While all images for every patient were not avail- to obtain surveillance imaging. Wu and colleagues recently reviewed able, imaging was available immediately prior to and at the time of and discussed the relationship between general anesthetics and neu- documented relapse on imaging. All patients had documented disease rotoxicity and highlight how the developing brain may be particularly recurrence with MRI. The majority of patients were not enrolled on vulnerable to anesthesia leading to a risk for long-lasting impairments treatment clinical trials and received treatment based on the exper- of cognitive function.11 tise of the treating physician. However, more than 90% of patients were Advancements in pediatric neuroimaging have led to MRI replacing enrolled on the University of Florida Proton Therapy Institute outcome CT as studies have shown that MRI has improved image quality, bet- tracking study. Diagnosis was based on institutional pathology for the ter differentiation between normal brain and tumor using contrast, and majority of patients. Median follow up in the relapsed cohort was has been better able to delineate the extent of tumor and metastases 6.5 years from diagnosis and 3.5 years from relapse. Patients with dis- throughout the brain and spine.8,12-14 While MRI has the advantages ease progression prior to the end of treatment or who did not undergo of being the better imaging modality for brain tumors and involves no initial treatment were excluded. All patients had relapse documented ionizing radiation exposure, recent studies have shown that gadolin- by MRI. ium contrast deposits in various parts of brain. The significance of this has not been determined, but it has the potential to result in long-term neurotoxicity.15,16 2.2 Study aims For these reasons, obtaining a better understanding of the prognostic significance of surveillance imaging is necessary as clinicians weigh The study aims to assess the significance of current neuroimaging prac- the positive and negative aspects for patients. While prior studies have tices as it relates to overall prognosis. It is hypothesized that frequent been performed to assess the prognostic value of surveillance imag- surveillance scanning will allow earlier detection of disease recurrence, ing in the detection of relapse in children with various brain tumors, but will not confer benefit to OS in these high-grade brain tumors. including ependymoma, there is a relatively small amount of literature that includes little contemporary data addressing this question.3,7,9 In addition, imaging techniques in previous studies included both CT and 2.3 Outcomes MRI and were more likely to be CT if the patient presented earlier in the study period and more likely to be MRI later in the study period. Charts of relapsed patients were further examined to assess details of Both methods detected relapse, but the studies did not compare the initial therapy, surveillance imaging regimen, timing of relapse, means two.3,7 Based on this previous literature, it is hypothesized that fre- of detection, relapsed therapy, and outcome. The primary aim of the quent surveillance imaging will allow earlier detection of disease recur- study was to assess correlation between method of relapse detection rence, but will not confer an overall survival (OS) benefit. and survival. 2 2.4 2.1 METHODS Study design and participants Statistical analysis Survival analyses were computed for each group using the KaplanMeier method. Kaplan-Meier curves were constructed to show sur- Under an Institutional Review Board approved protocol, patients with vival over time. OS was determined as length of time of survival from ependymoma who were treated in the Nemours Children’s Health diagnosis and second progression-free survival (SPFS) was determined System in Jacksonville, Delaware, Orlando, and Pensacola between as the length of time from relapse to disease progression. Ranges of January 2003 and October 2016 underwent chart review via the OS and SPFS were observed and median survival times were computed 3 of 8 KLAWINSKI ET AL . for each cohort. Characteristics of each cohort were compared using surveillance imaging, whereas in the surveillance group, all except one Z-tests of proportions as well as T-tests, where appropriate. Univari- patient were on a yearly schedule, however that patient was previ- ate and multivariate hazard ratios were calculated with Cox propor- ously lost to follow up and at re-presentation had a surveillance scan tional hazard model with relationship to SPFS, OS, and survival follow- at 14 months that showed disease recurrence. All four patients with ing recurrence. recurrence detected on surveillance are alive at median follow up from relapse of 20.5 months and four of five patients detected on symptoms are alive at median follow up of 26.5 months from recurrence. 2.5 Role of funding source Those funding the study had no role in the study design, data collection, 4 DISCUSSION data analysis, data interpretation, or writing of the report. DK and ES had full access to all the data in the study while JH and DI had access to Surveillance imaging is a practice performed in all pediatric brain part of the data in the study. DK and ES had final responsibility for the tumors and many other solid tumors to detect asymptomatic disease decision to submit for publication. recurrence with the hopes that early identification will lead to improvement in outcome with salvage therapy. In pediatric ependymoma, this question has not been definitively answered.3,7 In this study, the 3 RESULTS OS from initial diagnosis and from time of relapse was different for those with asymptomatic detection on surveillance than those with Ninety of 198 (45%) patients experienced disease progression. Of symptomatic detection, but this failed to show statistical significance. those patients, 61 (68%) were detected with surveillance imaging while However, there was a significantly better 3-year SPFS observed in 29 (32%) were detected based on symptoms. Characteristics of each asymptomatic patients with recurrences that were detected on MRI. cohort (Table 1) were compared. Median time to relapse in both groups In addition, univariate and multivariate analyses showed death was was 12 months from end of treatment. Median time since last negative almost twice as likely when recurrence was detected first by symptoms. image in both groups was 4 months. Five-year OS in the surveillance This difference seems largely due to our observation that patients group was 67% (confidence interval [CI] 55–82%, SE 0.1) versus 51% whose disease recurrence was found on surveillance imaging were (CI 35–73%, SE 0.19) in the symptoms group (P = .073) (Figure 1). The more likely to undergo salvage therapy than their symptomatic coun- 3-year survival from time of relapse in the surveillance group was 62% terparts, 58 of 61 (95%) when asymptomatic compared to 24 of 29 (CI 50–78%, SE 0.11) versus 55% (CI 39–76%, SE 0.17) in the symptoms (83%) when symptomatic. Additionally, we found that when relapse group (P = .063) (Figure 1). Following treatment of recurrence, the was detected, patients in the symptoms cohort were more likely to 3-year SPFS was 45% (CI 33–61%, SE 0.16) in the surveillance group have metastatic disease 12 of 29 (41%). Those with metastatic recur- versus 32% (CI 19 55%, SE 0.27) in the symptoms group (P = .028) rence, no matter which cohort, were also less likely to receive sal- (Figure 1). Hazard ratios were calculated for symptomatic detection vage chemotherapy. Symptomatic recurrences may have represented versus detection by surveillance imaging and in both univariate and a greater disease burden and were felt to be less amenable to ther- multivariate analysis were 1.83 (P = .078) and 1.93 (P = .06) for OS from apy. Likewise, beliefs by patients and their families as well as clinicians diagnosis, 1.86 (P = .069) and 1.88 (P = .067) for OS from relapse, and that symptomatic disease and/or metastatic disease was more signifi- 1.84 (P = .034) and 2.12 (P = .011) for SPFS (Table 2). cant and less amenable to salvage may have dictated a strictly palliative In all patients, 57 of 90 (63%) experienced a local recurrence. In approach to further management. the surveillance cohort, 40 of 61 (66%) experienced a local recurrence, While recurrent ependymoma was once considered fatal, there while 21 of 61 (34%) experienced a metastatic recurrence, whereas in are increasing options for salvage therapy including craniospinal re- the symptoms cohort, 17 of 29 (59%) were local recurrence and 12 irradiation (if focal irradiation performed as part of initial therapy), of 29 (41%) were metastatic recurrence. Univariate and multivariate chemotherapy, and combination therapy.2,5,17,18 Additionally, genomic hazard ratios for metastatic recurrence were 3.06 (P = .001) and 3.33 analysis in ependymoma has led to identification of numerous potential (P = .001) for OS from diagnosis, 3.38 (P = <.001) and 3.21 (P = .001) for targets that could be incorporated into salvage therapy.19 These and OS from recurrence, and 2.10 (P = .011) and 2.17 (P = .008) for SPFS. other salvage treatment approaches were not available or considered Following recurrence, 82 of 90 (91%) underwent salvage therapy: 58 at the time of previous studies addressing this topic. of 61 (95%) when detected by surveillance versus 24 of 29 (83%) when One challenge when comparing asymptomatic and symptomatic dis- detected by symptoms. In all patients, 55 of 57 (97%) with local recur- eases is lead-lead time bias; the bias that asymptomatic detection rence underwent salvage therapy and 27 of 33 (82%) with metastatic occurs earlier in a disease course leading to the appearance of longer recurrence underwent salvage therapy (P = .0181). survival relative to those who present later in the course and have Beyond 5 years from initial therapy, there were four of 61 (7%) symptomatic detection. In our study, it was found that the median time recurrences detected based on surveillance, while five of 29 (17%) in to relapse and the median time since last negative surveillance image the symptoms group occurred after 5 years (overall 10% occur after in both cohorts did not differ. This suggests that lead-time bias was 5 years). In the symptoms group, two patients were not getting yearly minimal in this study. It would therefore be reasonable to assume that 4 of 8 TA B L E 1 KLAWINSKI ET AL . Comparison of relapsed cohorts Symptoms (n = 29) Surveillance (n = 61) Age at diagnosis (mos) P value (95% CI) .0369 Range 8-226 5-168 Median 36 28 Gender .0489 Male (n = 58) 22 (76%) 36 (59%) Female (n = 32) 7 (24%) 25 (41%) Histology Grade I 0 (0%) 2 (3%) .1731 Grade II 9 (31%) 20 (33%) .8509 Grade III 20 (69%) 39 (64%) .6407 17 (59%) 47 (77%) .0945 Location at diagnosis Infratentorial Supratentorial 12 (41%) 12 (20%) .0483 Spine 0 (0%) 2 (3%) .1731 Brain 1 (3%) 0 .176 Spinal cord 0 1 (2%) .1342 Gross total 18 (62%) 42 (69%) .5225 Near total 3 (10%) 8 (13%) .6744 Subtotal resection 8 (28%) 11 (18%) .3089 Metastatic at diagnosis Resection Tx post resection Observation 4 (14%) 5 (8%) .4196 RT only 13 (45%) 25 (41%) .7244 Chemotherapy only 3 (10%) 19 (31%) .0108 RT + chemotherapy 9 (31%) 12 (20%) .2786 Time to relapse (mos) .1198 Range 0-120 0-78 Median 12 12 Last negative image to relapse detection (mos) .0908 Range 2-67 2-14 Median 4 4 Local 17 (59%) 40 (66%) Metastatic 12 (41%) 21 (34%) None 5 (17%) 3 (5%) .1161 Relapse .5293 Tx post relapse Surgery only 0 (0%) 2 (3%) .1731 Radiation only 1 (3%) 2 (3%) 1 Chemotherapy only 2 (7%) 2 (3%) .4505 RT + chemotherapy 1 (3%) 2 (3%) 1 Surgery + RT 9 (31.0%) 29 (48%) .1176 Surgery + chemotherapy 3 (10%) 7 (12%) .7767 Surgery + RT + chemotherapy 8 (28%) 14 (23%) .6197 Abbreviations: Mos, months; RT, radiation therapy; Tx, treatment. KLAWINSKI ET AL . 5 of 8 F I G U R E 1 Kaplan-Meier Curves for survival probability based on relapse detection by modality surveillance (solid) and symptoms (dashed). (A) Overall survival from diagnosis, (B) overall survival from relapse, and (C) second progression-free survival 6 of 8 KLAWINSKI ET AL . TA B L E 2 Hazard ratios Univariate analysis Second progression-free survival Overall survival from diagnosis Overall survival from relapse HR HR HR 95% CI P-value 95% CI P-value 95% CI P-value Age at diagnosis (mos) 0.99 0.98-1.01 .273 0.98 0.96-1.00 .02 0.99 0.97-1.01 .255 Male gender 1.47 0.81-2.65 .206 1.89 0.89-4.01 .1 1.86 0.87-3.96 .11 Symptomatic detection 1.84 1.05-3.24 .034 1.83 0.93-3.60 .078 1.86 0.95-3.62 .069 Grade III histology 1.06 0.59-1.88 .856 1.16 0.58-2.31 .684 1.30 0.64-2.67 .467 Supratentorial disease 0.55 0.28-1.08 .083 0.68 0.31-1.5 .341 0.63 0.28-1.39 .25 NTR 1.08 0.45-2.58 .863 1.75 0.70-4.40 .235 1.85 0.73-4.69 .192 STR 1.66 0.85-3.71 .136 2.11 1.00-4.45 .05 2.25 1.06-4.76 .035 Metastatic relapse 2.10 1.19-3.71 .011 3.06 1.55-6.05 .001 3.38 1.71-6.67 <.001 0.99 0.97-1.00 .071 0.97 0.95-0.99 .006 0.99 0.97-1.01 .147 Multivariate analysis Age at diagnosis (mos) Symptomatic detection 2.12 1.19-3.80 .011 1.93 0.97-3.83 .06 1.88 0.96-3.7 .067 Metastatic relapse 2.17 1.23-3.84 .008 3.33 1.66-6.67 .001 3.21 1.63-6.34 .001 Abbreviations: HR, hazard ratio; mos, months; NTR, near total resection; STR, subtotal resection. symptomatic recurrences were similar to asymptomatic recurrences, DATA AVAILABILITY STATEMENT but simply in a location that was more likely to result in symptoms. The data that support the findings of this study are available on request One limitation of this study was that molecular testing was not available for the majority of the patients and therefore those factors could from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. not be analyzed regarding prognosis and risk of relapse in relation to surveillance imaging. If a specific cohort defined molecularly showed CONFLICT OF INTEREST much poorer prognosis, a difference may or may not be seen in OS or The authors declare that there is no conflict of interest. SPFS between asymptomatic and symptomatic recurrences and further research is necessary to address this question. Data from this cohort show that recurrence detected on surveillance was associated with a higher probability of survival and more ORCID Darren Klawinski Daniel J. Indelicato https://orcid.org/0000-0003-4524-2743 https://orcid.org/0000-0001-5765-1873 often lead to salvage therapy and improved SPFS from relapse. It remains unclear if this leads to a significant difference in OS, but the associated benefits should be individualized to patients and families and weighed against any costs or risks. Based on the median time to relapse of 12 months from end of treatment and few experiencing relapse after 5 years, an appropriate surveillance imaging schedule would be more frequent imaging for the first 3 years off treatment, then spacing of imaging to every 6 months until 5 years off treatment, followed by yearly imaging afterward. These data therefore underscore current surveillance imaging recommendations. 5 CONCLUSION Given the current limited salvage options for children with recurrent ependymoma, the survival advantage of frequent surveillance imaging in asymptomatic patients remains ambiguous. Surveillance imaging may identify recurrences in patients when they are more amenable to salvage therapy, resulting in superior 3-year progression-free survival. However, further research with larger cohorts is necessary to fully define the role of surveillance imaging. REFERENCES 1. Ostrom QT, Gittleman H, Truitt G et al. CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2011–2015. Central Brain Tumor Registry of the United States (CBTRUS). Neuro Oncol. 2018;20(S4):1-86. 2. Indelicato DJ, Bradley JA, Rotondo RL, et al. Outcomes following proton therapy for pediatric ependymoma. Acta Oncol. 2018;57(5):644648. 3. Good CD, Wade AM, Hayward RD, et al. Surveillance neuroimaging in childhood intracranial ependymoma: how effective, how often, and for how long? J Neurosurg. 2001;94:27-32. 4. Merchant TE, Li C, Xiong X, Kun LE, Boop FA, Sanford RA. 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Neuromol Med. 2017;19:256-270. How to cite this article: Klawinski D, Indelicato DJ, Hossain J, Sandler E. Surveillance imaging in pediatric ependymoma. Pediatr Blood Cancer. 2020;e28622. https://doi.org/10.1002/pbc.28622