Conformal Radiation Therapy for Pediatric Ependymoma, Chemotherapy for Incompletely Resected Ependymoma, and Observation for Completely Resected, Supratentorial Ependymoma

PURPOSE The Children’s Oncology Group trial ACNS0121 estimated event-free survival (EFS) and overall survival for children with intracranial ependymoma treated with surgery, radiation therapy, and—selectively—with chemotherapy. Treatment was administered according to tumor location, histologic grade, and extent of resection. The impacts of histologic grade, focal copy number gain on chromosome 1q, and DNA methylation profiles were studied for those undergoing surgery and immediate postoperative conformal radiation therapy (CRT). METHODS ACNS0121 included 356 newly diagnosed patients (ages 1 to 21 years). Patients with classic supratentorial ependymoma were observed after gross total resection (GTR). Those undergoing subtotal resection received chemotherapy, second surgery, and CRT. The remaining patients received immediate postoperative CRT after near-total resection or GTR. CRT was administered with a 1.0-cm clinical target volume margin. The cumulative total dose was 59.4 Gy, except for patients who underwent GTR and were younger than age 18 months (who received 54 Gy). Patients were enrolled between October 2003 and September 2007 and were observed for 5 years. Supratentorial tumors were evaluated for RELA fusion; infratentorial tumors, for chromosome 1q gain. Classification of posterior fossa groups A and B was made by methylation profiles. RESULTS The 5-year EFS rates were 61.4% (95% CI, 34.5% to 89.6%), 37.2% (95% CI, 24.8% to 49.6%), and 68.5% (95% CI, 62.8% to 74.2%) for observation, subtotal resection, and near-total resection/GTR groups given immediate postoperative CRT, respectively. The 5-year EFS rates differed significantly by tumor grade ( P = .0044) but not by age, location, RELA fusion status, or posterior fossa A/posterior fossa B grouping. EFS was higher for patients with infratentorial tumors without 1q gain than with 1q gain (82.8% [95% CI, 74.4% to 91.2%] v 47.4% [95% CI, 26.0% to 68.8%]; P = .0013). CONCLUSION The EFS for patients with ependymoma younger than 3 years of age who received immediate postoperative CRT and for older patients is similar. Irradiation should remain the mainstay of care for most subtypes.

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Molecular grouping and outcomes of young children with newly diagnosed ependymoma treated on the multi-institutional SJYC07 trial

Neuro-Oncology ◽

10.1093/neuonc/noz069 ◽

2019 ◽

Vol 21 (10) ◽

pp. 1319-1330 ◽

Cited By ~ 15

Author(s):

Santhosh A Upadhyaya ◽

Giles W Robinson ◽

Arzu Onar-Thomas ◽

Brent A Orr ◽

Catherine A Billups ◽

...

Keyword(s):

Young Children ◽

Progression Free Survival ◽

Subtotal Resection ◽

Newly Diagnosed ◽

Total Resection ◽

Conformal Radiation Therapy ◽

Significant Difference ◽

Molecular Grouping ◽

Supratentorial Ependymoma ◽

1Q Gain

Abstract Background This report documents the clinical characteristics, molecular grouping, and outcome of young children with ependymoma treated prospectively on a clinical trial. Methods Fifty-four children (aged ≤3 y) with newly diagnosed ependymoma were treated on the St Jude Young Children 07 (SJYC07) trial with maximal safe surgical resection, 4 cycles of systemic chemotherapy, consolidation therapy using focal conformal radiation therapy (RT) (5-mm clinical target volume), and 6 months of oral maintenance chemotherapy. Molecular groups were determined by tumor DNA methylation using Infinium Methylation EPIC BeadChip and profiled on the German Cancer Research Center/Molecular Neuropathology 2.0 classifier. Results One of the 54 study patients had metastases (cerebrospinal fluid positive) at diagnosis. Gross or near-total resection was achieved in 48 (89%) patients prior to RT. At a median follow-up of 4.4 years (range, 0.2–10.3 y), 4-year progression-free survival (PFS) was 75.1% ± 7.2%, and overall survival was 92.6% ± 4.4%. The molecular groups showed no significant difference in PFS (4-year estimates: posterior fossa ependymoma group A [PF-EPN-A; 42/54], 71.2% ± 8.3%; supratentorial ependymoma positive for v-rel avian reticuloendotheliosis viral oncogene homolog A [ST-EPN-RELA; 8/54], 83.3% ± 17.0%; and supratentorial ependymoma positive for Yes-associated protein [4/54], 100%, P = 0.22). Subtotal resection prior to RT was associated with an inferior PFS compared with gross or near-total resection (4-year PFS: 41.7% ± 22.5% vs 79.0% ± 7.1%, P = 0.024), as was PF-EPN-A group with 1q gain (P = 0.05). Histopathologic grading was not associated with outcomes (classic vs anaplastic; P = 0.89). Conclusions In this prospectively treated cohort of young children with ependymoma, ST-EPN-RELA tumors had a more favorable outcome than reported from retrospective data. Histologic grade did not impact outcome. PF-EPN-A with 1q gain and subtotal resection were associated with inferior outcomes.

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Ependymomas in infancy: underlying genetic alterations, histological features, and clinical outcome

Child s Nervous System ◽

10.1007/s00381-020-04655-x ◽

2020 ◽

Vol 36 (11) ◽

pp. 2693-2700

Author(s):

Stephanie T. Jünger ◽

Felipe Andreiuolo ◽

Martin Mynarek ◽

Evelyn Dörner ◽

Anja zur Mühlen ◽

...

Keyword(s):

Posterior Fossa ◽

Genetic Alterations ◽

Gross Total Resection ◽

Older Children ◽

Total Resection ◽

Who Grade ◽

Chromosome 1Q ◽

Stable Genome ◽

1Q Gain

Abstract Introduction Young age is an adverse prognostic factor in children with ependymomas. Treatment of these infants is challenging since beneficial therapeutic options are limited. As ependymomas are considered a biologically heterogeneous group, we aimed to characterize infant ependymomas with regard to their histological and genetic features. Materials and methods We analyzed 28 ependymomas occurring in children younger than 18 months at diagnosis enrolled into the HIT2000-E protocols with the aim to postpone irradiation until the age of 18 months if possible. All cases underwent neuropathological review, including immunohistochemical characterization. Genome-wide copy number alterations (CNA) were assessed by molecular inversion probe assays, and RELA and YAP1 fusions were detected by RT-PCR and sequencing. Results All infant ependymomas were anaplastic (WHO grade III). Twenty-one (75%) cases were located in the posterior fossa. Gross total resection was accomplished in 12 (57%) of these cases. All posterior fossa tumors showed loss of H3-K27me3 characteristic of PFA ependymomas. CNA analysis showed a stable genome in all cases with lack of chromosome 1q gain, an adverse prognostic marker in PFA ependymomas of older children. However, after a median follow-up of 5.4 years, 15 (71%) relapsed, and 9 (43%) died. Seven ependymomas (25%) occurred in the supratentorial region. Gross total resection could be achieved in only two of these cases. Four tumors carried C11orf95-RELA fusions, and two cases had typical YAP1-MAMLD1 fusions (one case was not analyzable). The RELA-fused cases did not display CDKN2A loss as an adverse indicator of prognosis in this disease entity. Although three infants (43%) with supratentorial ependymomas relapsed, all patients survived (median follow-up, 8.0 years). Conclusion Infant ependymomas seem to fall into three biological entities, with supratentorial tumors carrying RELA or YAP fusions and PFA posterior fossa ependymomas. The latter showed a poor outcome even though chromosome 1q gain was absent.

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Medulloblastoma in childhood: results of radical resection and low-dose neuraxis radiation therapy

Journal of Neurosurgery ◽

10.3171/jns.1986.64.2.0238 ◽

1986 ◽

Vol 64 (2) ◽

pp. 238-242 ◽

Cited By ~ 80

Author(s):

Tadanori Tomita ◽

David G. McLone

Keyword(s):

Radiation Therapy ◽

Radiation Dose ◽

Posterior Fossa ◽

Carbon Dioxide Laser ◽

Posterior Inferior Cerebellar Artery ◽

Radical Resection ◽

Subtotal Resection ◽

Total Resection ◽

Resection Group ◽

Cerebellar Peduncles

✓ This review concerns 22 children who were treated from 1980 through 1983 for medulloblastoma in the posterior fossa. Treatment included attempts at radical resection of the tumor and postoperative craniospinal radiation therapy, with 5000 to 5500 rads directed to the posterior fossa and 2500 rads to the remaining craniospinal axis. This lower radiation dose to the neuraxis was used to avoid late adverse effects upon the growing central nervous system of the children. Gross confirmation of total resection was obtained in 13 patients (the “total resection group”); however, nine patients had a subtotal resection leaving a small portion of the tumor extending into the cerebellar peduncles or the cerebellopontine angle, or else encasing the posterior inferior cerebellar artery (the “subtotal resection group”). Six patients in the total resection group demonstrated tumor extension into the cerebellar peduncles, which was removed by means of a surgical carbon dioxide laser without neurological sequelae. Biopsy of the arachnoid membrane from the cisterna magna and cytological examination of the cerebrospinal fluid (CSF) prior to manipulation of the tumor werecarried out in 12 patients. All but one showed dissemination of medulloblastoma cells. Myelography and CSF cytological study were undertaken 2 months after radiation therapy in 12 patients and were positive in two. There were no case mortalities in the total resection group during the 24- to 67-month follow-up period, whereas the 1-year survival rate in the “subtotal resection group” was only 44.4%. This study suggests that medulloblastoma can be controlled with a low radiation dose to the neuraxis, should a grossly confirmed total resection be achieved at craniotomy.

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A dosimetric comparison between 3D-conformal radiation therapy and intensity modulated radiation therapy plans in the treatment of posterior fossa boost in children with high risk medulloblastom

The Chinese-German Journal of Clinical Oncology ◽

10.1007/s10330-013-1211-1 ◽

2013 ◽

Vol 12 (11) ◽

pp. 540-545

Author(s):

I. Saad El Din ◽

H. Abd El AAl ◽

W. Makaar ◽

K. Mashhour ◽

D. El Beih ◽

...

Keyword(s):

Radiation Therapy ◽

High Risk ◽

Posterior Fossa ◽

Intensity Modulated Radiation Therapy ◽

Conformal Radiation Therapy ◽

Dosimetric Comparison ◽

Intensity Modulated ◽

3D Conformal Radiation Therapy

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Profound hearing loss following surgery in pediatric patients with posterior fossa low-grade glioma

Neuro-Oncology Practice ◽

10.1093/nop/npx025 ◽

2017 ◽

Vol 5 (2) ◽

pp. 96-103 ◽

Cited By ~ 1

Author(s):

Yahya Ghazwani ◽

Ibrahim Qaddoumi ◽

Johnnie K Bass ◽

Shengjie Wu ◽

Jason Chiang ◽

...

Keyword(s):

Hearing Loss ◽

Posterior Fossa ◽

Extent Of Resection ◽

Tumor Location ◽

Low Grade Glioma ◽

Gross Total Resection ◽

Subtotal Resection ◽

Low Grade ◽

Total Resection ◽

Profound Hearing Loss

Abstract Background Hearing loss may occur in patients with posterior fossa low-grade glioma who undergo surgery. Methods We retrospectively reviewed 217 patients with posterior fossa low-grade glioma, including 115 for whom results of hearing tests performed after surgery and before chemotherapy or radiation therapy were available. We explored the association of UHL with age at diagnosis, sex, race, tumor location, extent of resection, posterior fossa syndrome, ventriculoperitoneal shunt placement, and histology. Results Of the 115 patients, 15 (13.0%: 11 male, 6 black, 8 white, 1 multiracial; median age 7 years [range, 1.3–17.2 years]) had profound UHL after surgery alone or before receiving ototoxic therapy. Median age at tumor diagnosis was 6.8 years (range, 0.7–14.1 years), and median age at surgery was 6.8 years (range, 0.7–14.1 years). Patients with UHL had pathology characteristic of pilocytic astrocytoma (n = 10), ganglioglioma (n = 4), or low-grade astrocytoma (n = 1). Of these 15 patients, 4 underwent biopsy, 1 underwent gross total resection, 1 underwent near-total resection, and 9 underwent subtotal resection. UHL was more frequent in black patients than in white patients (OR 7.3, P = .007) and less frequent in patients who underwent gross total resection or near-total resection than in those who underwent subtotal resection (OR 0.11, P = .02). Conclusions Children undergoing surgery for posterior fossa low-grade glioma are at risk for UHL, which may be related to race or extent of resection. These patients should receive postoperative audiologic testing, as earlier intervention may improve outcomes.

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Radiation Therapy in the Treatment of Partially Resected Meningiomas

Neurosurgery ◽

10.1227/00006123-198704000-00003 ◽

1987 ◽

Vol 20 (4) ◽

pp. 525-528 ◽

Cited By ~ 219

Author(s):

Nicholas M. Barbaro ◽

Philip H. Gutin ◽

Charles B. Wilson ◽

Glenn E. Sheline ◽

Edwin B. Boldrey ◽

...

Keyword(s):

Radiation Therapy ◽

San Francisco ◽

Tumor Location ◽

Convincing Evidence ◽

Subtotal Resection ◽

Intracranial Meningioma ◽

Total Resection ◽

Female Ratio ◽

Time To Recurrence ◽

Male Female Ratio

Abstract To address the question of whether radiation therapy is beneficial in the management of partially resected meningiomas, we reviewed the records of all patients admitted to the University of California, San Francisco, between 1968 and 1978 who had a diagnosis of intracranial meningioma. The patients were divided into three groups: 51 patients had gross total resection and did not receive radiation therapy, 30 patients had subtotal resection and no radiation therapy, and 54 patients had subtotal resection followed by radiation therapy. The subtotal resection groups were similar in average age, male: female ratio, and tumor location, which allowed a valid comparison of the effects of irradiation. The recurrence rate in the total resection group was 4% (2 of 51 patients). Among patients in the subtotal resection groups, 60% of nonirradiated patients had a recurrence, compared with only 32% of the irradiated patients. The median time to recurrence was significantly longer in the irradiated group than in the nonirradiated group (125 vs. 66 months, P < 0.05). There was no complication related to irradiation. These results provide convincing evidence that radiation therapy is beneficial in the treatment of partially resected meningiomas.

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Long-Term Outcomes of Atypical Meningioma After Gross Total Resection (GTR) or Subtotal Resection (STR) With or Without Postoperative Radiation Therapy (PORT)

International Journal of Radiation Oncology*Biology*Physics ◽

10.1016/j.ijrobp.2016.06.081 ◽

2016 ◽

Vol 96 (2) ◽

pp. S28

Author(s):

M. Zhi ◽

M.R. Girvigian ◽

M.J. Miller ◽

J.C. Chen ◽

J. Rahimian ◽

...

Keyword(s):

Radiation Therapy ◽

Atypical Meningioma ◽

Gross Total Resection ◽

Subtotal Resection ◽

Postoperative Radiation ◽

Long Term Outcomes ◽

Total Resection ◽

Postoperative Radiation Therapy

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Is gross-total resection sufficient treatment for posterior fossa ependymomas?

Journal of Neurosurgery ◽

10.3171/jns.2005.102.4.0629 ◽

2005 ◽

Vol 102 (4) ◽

pp. 629-636 ◽

Cited By ~ 70

Author(s):

Leland Rogers ◽

Jeanette Pueschel ◽

Robert Spetzler ◽

William Shapiro ◽

Stephen Coons ◽

...

Keyword(s):

Radiation Therapy ◽

Posterior Fossa ◽

Local Control ◽

Median Duration ◽

Local Control Rate ◽

Gross Total Resection ◽

Total Resection ◽

Content Type ◽

Significant Difference ◽

Fine Print

Object. The goals of this study were to analyze outcomes in patients with posterior fossa ependymomas, determine whether gross-total resection (GTR) alone is appropriate treatment, and evaluate the role of radiation therapy. Methods. All patients with newly diagnosed intracranial ependymomas treated at Barrow Neurological Institute between 1983 and 2002 were identified. Those with supratentorial primary lesions, subependymomas, or neuraxis dissemination were excluded. Forty-five patients met the criteria for the study. Gross-total resection was accomplished in 32 patients (71%) and subtotal resection (STR) in 13 (29%). Radiation therapy was given to 25 patients: 13 following GTR and 12 after STR. The radiation fields were craniospinal followed by a posterior fossa boost in six patients and posterior fossa or local only in the remaining patients. With a median follow-up period of 66 months, the median duration of local control was 73.5 months with GTR alone, but has not yet been reached for patients with both GTR and radiotherapy (p = 0.020). The median duration of local control following STR and radiotherapy was 79.6 months. The 10-year actuarial local control rate was 100% for patients who underwent GTR and radiotherapy, 50% for those who underwent GTR alone, and 36% for those who underwent both STR and radiotherapy, representing significant differences between the GTR-plus-radiotherapy and GTR-alone cohorts (p = 0.018), and between the GTR-plus-radiotherapy and the STR-plus-radiotherapy group (p = 0.003). There was no significant difference in the 10-year actuarial local control rate between the GTR-alone and STR-plus-radiotherapy cohorts (p = 0.370). The 10-year overall survival was numerically superior in patients who underwent both GTR and radiotherapy: 83% compared with 67% in those who underwent GTR alone and 43% in those who underwent both STR and radiotherapy. These differences did not achieve statistical significance. Univariate analyses revealed that radiotherapy, tumor grade, and extent of resection were significant predictors of local control. Conclusions. Gross-total resection should be the intent of surgery when it can be accomplished with an acceptable degree of morbidity. Even after GTR has been confirmed with postoperative imaging, however, adjuvant radiotherapy significantly improves local control. The authors currently recommend the use of postoperative radiotherapy, regardless of whether the resection is gross total or subtotal.

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Induction Chemotherapy and Conformal Radiation Therapy for Very Young Children With Nonmetastatic Medulloblastoma: Children's Oncology Group Study P9934

Journal of Clinical Oncology ◽

10.1200/jco.2010.34.4341 ◽

2012 ◽

Vol 30 (26) ◽

pp. 3181-3186 ◽

Cited By ~ 55

Author(s):

David M. Ashley ◽

Thomas E. Merchant ◽

Douglas Strother ◽

Tianni Zhou ◽

Patricia Duffner ◽

...

Keyword(s):

Radiation Therapy ◽

Young Children ◽

Posterior Fossa ◽

Induction Chemotherapy ◽

Primary Site ◽

Postoperative Chemotherapy ◽

Oncology Group ◽

Event Free Survival ◽

Conformal Radiation Therapy ◽

Free Survival

Purpose P9934 was a prospective trial of systemic chemotherapy, second surgery, and conformal radiation therapy (CRT) limited to the posterior fossa and primary site for children between 8 months and 3 years old with nonmetastatic medulloblastoma. The study was open from June 2000 until June 2006. Patients and Methods After initial surgery, children received four cycles of induction chemotherapy, followed by age- and response-adjusted CRT to the posterior fossa (18 or 23.4 Gy) and tumor bed (cumulative 50.4 or 54 Gy) and maintenance chemotherapy. Neurodevelopmental outcomes were evaluated and event-free survival (EFS) results were directly compared with a previous study of multiagent chemotherapy without irradiation (Pediatric Oncology Group [POG] trial 9233). Results Seventy-four patients met eligibility requirements. The 4-year EFS and overall survival probabilities were 50% ± 6% and 69% ± 5.5%, respectively, which compared favorably to the results from POG 9233. Analysis showed that the desmoplastic/nodular subtype was a favorable factor in predicting survival. Our 4-year EFS rate was 58% ± 8% for patients with desmoplasia. Whereas seven of 10 patients who had disease progression before CRT had primary-site failure, 15 of 19 patients who progressed after CRT had distant-site failure. Neurodevelopmental assessments did not show a decline in cognitive or motor function after protocol-directed chemotherapy and CRT. Conclusion The addition of CRT to postoperative chemotherapy in young children with nonmetastatic medulloblastoma increased event-free survival compared with the use of postoperative chemotherapy alone. Future studies will use histopathologic typing (desmoplastic/nodular versus nondesmoplastic/nodular) to stratify patients for therapy by risk of relapse.

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