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

The Children's Oncology Group ACNS0121 Trial

Merchant et al.
Journal of Clinical Oncology, 2019

Introduction

• Ependymoma accounts for 8-10% of pediatric brain tumors
• Survival historically disappointing: 5-year EFS 23-45%
• Typically treated with maximal surgical resection
• Controversy around radiation in young children (< 3 years)
• Previous approaches:
  • Young children: surgery + chemotherapy, delay RT
  • Older children: immediate post-operative RT
• Recurrences primarily local (80%), but 20% distant failures

Study Objectives

• Estimate local control and pattern of failure in completely resected, classic supratentorial ependymoma after surgery alone
• Estimate rate of complete resection with second surgery after chemotherapy
• Estimate local control and pattern of failure using 3D conformal RT with 1-cm CTV margin
• Determine influence of histologic grade on time to progression after CRT
• Determine effect of focal copy number gains/losses and genomic profiling on outcome

Study Design

• Phase 3 trial of Children's Oncology Group
• Enrolled 378 patients (356 eligible) from Oct 2003 to Sept 2007
• Age 1-21 years with newly diagnosed intracranial ependymoma
• Treatment stratified by extent of resection, tumor location, and histology
• First cooperative group trial to use immediate postoperative RT in children < 3 years old
• Median follow-up: 7.89 years (range 0.09-11.0 years)

Treatment Schema

[Insert trial schema image here - Fig 1 from the paper]

• Stratum 1: GTR1, differentiated, supratentorial → observation only
• Stratum 2: STR, any grade, any location → chemotherapy → second surgery → CRT
• Stratum 3: NTR/GTR2, any grade, any location → immediate CRT
• Stratum 4: GTR1, anaplastic supratentorial or any grade infratentorial → immediate CRT

Patient Characteristics

• Median age: 5.6 years (range 1.01-21.01)
• 28.6% were ≤ 3 years old
• 57.9% male, 42.1% female
• Diagnosis:
  • Classic ependymoma: 215 (60.4%)
  • Anaplastic ependymoma: 141 (39.6%)
• Tumor location:
  • Infratentorial: 258 (72.5%)
  • Supratentorial: 96 (27.0%)
  • Transtentorial: 2 (0.5%)

Treatment Methods

Surgery:

• GTR1: No visible residual under microscope or on MRI
• GTR2: Microscopic residual, no visible on MRI
• NTR: Residual ≤ 0.5 cm on MRI
• STR: Residual > 0.5 cm on MRI

Conformal Radiation Therapy:

• CTV margin: 1.0 cm anatomically defined
• Dose: 59.4 Gy (1.8 Gy/fraction)
• Patients < 18 months with GTR: 54 Gy
• Photons or passive scattering protons allowed

Chemotherapy (Stratum 2):

• 2 cycles (7 weeks): vincristine, carboplatin, cyclophosphamide, etoposide
• Second surgery if feasible

Primary Outcomes by Stratum

[Insert Fig 2C/D from the paper - Primary EFS/OS outcomes by stratum]

Stratum5-year EFS5-year OSS1: GTR1, classic, supratentorial (observation)61.4% (33.2-89.6%)100%S2: STR (chemo → surgery → RT)37.2% (24.8-49.5%)70.2% (58.2-82.2%)S3: NTR/GTR2 (immediate RT)67.3% (58.5-76.1%)83.3% (76.2-90.4%)S4: GTR1 anaplastic or infratentorial (immediate RT)69.5% (62.1-76.9%)88.3% (83.0-93.6%)Combined strata 3+4 (all immediate RT)68.5% (62.8-74.2%)86.2% (81.9-90.6%)

Outcomes by Tumor Grade and Age

[Insert Fig 3 from paper - EFS by histologic subtype]

• Histology: For patients with immediate CRT (strata 3+4):
  • Classic ependymoma: 5-year EFS 74.6% (67.5-81.7%)
  • Anaplastic ependymoma: 5-year EFS 60.7% (51.5-69.9%)
  • Significant difference (p=.0044)
• Age: For patients with immediate CRT (strata 3+4):
  • Age < 3 years: 5-year EFS 62.9% (51.9-73.9%)
  • Age ≥ 3 years: 5-year EFS 70.5% (63.8-77.2%)
  • Not significantly different (p=.2295)

Molecular Markers and Outcomes

RELA Fusion (Supratentorial Tumors):

• Present in 30/39 (77%) of supratentorial tumors
• No significant difference in EFS, OS, or pattern of failure by RELA status

1q Gain (Infratentorial Tumors):

• Present in 24/121 (20%) of infratentorial tumors
• For patients with immediate CRT (strata 3+4):
  • Without 1q gain: 5-year EFS 82.8% (74.4-91.2%)
  • With 1q gain: 5-year EFS 47.4% (26.0-68.8%)
  • Significant difference (p=.0013)
• Significant association with both local and distant failure patterns

PFA/PFB Subgroups:

• No significant differences in outcome by PFA/PFB subgrouping alone
• Combined effect of PFA + 1q gain was significant:
  • PFA without 1q gain: 5-year EFS 81.5% (71.5-91.5%)
  • PFA with 1q gain: 5-year EFS 35.7% (12.8-58.6%)
  • Significant difference (p=.0005)

Secondary Outcomes

Patterns of Failure:

• Stratum 1 (observation): 36.4% local, 9.1% local + distant
• Stratum 2 (STR): 45.8% local, 6.8% local + distant, 8.5% distant
• Stratum 3 (NTR): 22.9% local, 2.5% local + distant, 11.0% distant
• Stratum 4 (GTR): 18.4% local, 2.5% local + distant, 8.0% distant

Second Surgery (Stratum 2):

• 39% of patients underwent second surgery after chemotherapy
• 56% achieved GTR
• 5-year EFS with second surgery: 50.5% (30.3-70.7%)
• 5-year EFS without second surgery: 28.5% (14.2-42.8%)
• Trend toward benefit but not statistically significant (p=.1163)

Second Malignancies:

• 7 patients developed second malignancies
• 10-year cumulative incidence: 3.43% (0.4-6.5%)

Conclusions

• Children < 3 years treated with immediate postoperative CRT had similar outcomes to older children
• Immediate CRT after maximal resection provides good local control (68.5% 5-year EFS for NTR/GTR)
• Tumor grade significantly impacts outcome after CRT
• 1q gain is a strong prognostic marker for inferior outcome in infratentorial tumors
• RELA fusion status did not predict outcome in supratentorial tumors with CRT
• Observation after GTR for classic supratentorial ependymoma may be reasonable in selected patients
• Irradiation should remain the mainstay of care for most subtypes

Strengths and Limitations

Strengths:

• Large, multi-institutional prospective study
• Long follow-up period (median 7.89 years)
• First cooperative group trial to use immediate RT in children < 3 years
• Systematic evaluation of defined target volumes with 1-cm CTV margin
• Comprehensive molecular analysis

Limitations:

• Non-randomized design
• Small sample size for some strata (especially stratum 1)
• Digital treatment planning data not uniformly collected
• Limited evaluation of late effects (neurocognitive, endocrine, etc.)
• Limited data on quality of life outcomes

Connection to ACNS0831

• ACNS0831 builds on ACNS0121 findings
• Continued observation-only approach for completely resected, classic supratentorial ependymoma
• Continued use of immediate post-operative radiation in young children
• Added randomization to maintenance chemotherapy vs. observation after CRT
• Main question: Will maintenance chemotherapy after CRT improve outcomes?
• Addresses remaining question of whether adjuvant chemotherapy benefits patients with adequate local control
• Also continues to collect molecular data and long-term outcome data

Discussion Points

1. How does this change our approach to very young children (< 3 years) with ependymoma?
2. Is observation-only appropriate for completely resected classic supratentorial ependymoma?
3. How should molecular markers (1q gain, PFA/PFB grouping) influence treatment decisions?
4. Should all patients receive immediate CRT, or are there subgroups where chemotherapy before or after RT is beneficial?
5. How should we integrate these findings with the current ACNS0831 trial design?