Brain Tumor, Central Nervous System Tumor
Conditions
Keywords
childhood supratentorial ependymoma, newly diagnosed childhood ependymoma, childhood infratentorial ependymoma
Brief summary
RATIONALE: Specialized radiation therapy that delivers a high dose of radiation directly to the tumor may kill more tumor cells and cause less damage to normal tissue. Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Giving chemotherapy before surgery may shrink the tumor so that it can be removed during surgery. PURPOSE: Phase II trial to determine the effectiveness of specialized radiation therapy either alone or after chemotherapy and second surgery in treating children who have undergone surgery for localized ependymoma.
Detailed description
OBJECTIVES: * Determine the local control and pattern of failure in children with completely resected, differentiated, supratentorial localized ependymoma after initial surgical resection alone. * Determine the rate of complete resection with second surgery after chemotherapy in patients with initially incompletely resected localized ependymoma. * Determine the local control and pattern of failure in patients treated with conformal radiotherapy. * Determine the influence of histologic grade on the time to progression in patients after treatment with conformal radiotherapy. OUTLINE: This is a multicenter study. Patients are stratified according to extent of prior surgical resection. * Group 1 (patients with supratentorial differentiated ependymoma who have undergone gross total resection and have no visible residual tumor): Patients undergo observation. * Group 2 (patients with supratentorial anaplastic ependymoma or infratentorial anaplastic or differentiated ependymoma who have undergone gross total resection or near total resection): Patients undergo conformal radiotherapy to the brain once daily 5 days a week for 6-6½ weeks. * Group 3 (patients with tumor of any histology or location who have undergone subtotal resection): Patients receive an initial course of chemotherapy comprising vincristine IV on days 1 and 8, carboplatin IV over 1 hour on day 1, and cyclophosphamide IV over 1 hour on days 1 and 2. Patients also receive filgrastim (G-CSF) subcutaneously or IV beginning on day 3 and continuing until blood counts recover. Patients then receive a second course of chemotherapy comprising vincristine IV on days 1 and 8, carboplatin IV over 1 hour on day 1, and oral etoposide on days 1-21. After completion of chemotherapy, patients are evaluated for second surgery. Patients who have unresectable disease undergo conformal radiotherapy. Patients who have resectable disease undergo second surgery followed by conformal radiotherapy. Patients are followed every 4 months for 3 years, every 6 months for 2 years, and then annually thereafter. PROJECTED ACCRUAL: A total of 250-350 patients will be accrued for this study within 5 years.
Interventions
BIOLOGICALfilgrastim
Given IV or SC (5mcg/kg/day) start on Day 3 and continue until ANC \>1500/μl given subcutaneously or intravenously.
DRUGcarboplatin
Given IV (375 mg/m2/day) Day 1 given as an IV infusion over one hour. For patients with BSA \<0.45m2 the dose is 12.5 mg/kg/day.
DRUGcyclophosphamide
Given IV (1000mg/m2/day) Day 1 and 2 given as an IV infusion over one hour following carboplatin administration. For patients with BSA\<0.45m2 the dose is 33mg/kg/day on Day 1 and 2.
DRUGetoposide
Given orally (50 mg/m2/day) orally once daily on Days 1 through 21. For patients with BSA \< 0.45 m2, the dosage is 1.7 mg/kg/day on Days 1 through 21.
DRUGvincristine sulfate
Given IV or orally (1.5mg/m2/day) (maximum dose 2 mg) Day 1 and 8 given as IV bolus. For patients with BSA\<0.45m2 the dose is 0.05mg/kg.
RADIATIONradiation therapy
Given once daily 5 days a week for 6-6½ weeks
DRUGMesna
Mesna (200mg/m2/dose) Day 1 and 2. For patients with BSA\<0.45m2 the dose is (7mg/kg/dose). Combine mesna (200mg/m2) with cyclophosphamide and administer intravenously over one hour followed by mesna (200mg/m2) in 375 cc/m2 D5-1/2NS and run intravenously over 3 hours at 125cc/m2/hr. After 3 hour mesna, administer mesna (200 mg/m2/dose) IV over 15 minutes at hour 5.
PROCEDUREtherapeutic conventional surgery
Sponsors
National Cancer Institute (NCI)
Children's Oncology Group
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Years to 21 Years
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: * Histologically confirmed intracranial ependymoma * Differentiated ependymoma or anaplastic ependymoma * No primary spinal cord ependymoma, myxopapillary ependymoma, subependymoma, ependymoblastoma, or mixed glioma * No evidence of noncontiguous spread beyond primary site * Initial surgical resection within the past 56 days PATIENT CHARACTERISTICS: Age: * 1 to 21 Performance status: * No restrictions Life expectancy: * At least 2 months Hematopoietic: * Not specified Hepatic: * Not specified Renal: * Not specified Other: * Able to undergo MRI * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception PRIOR CONCURRENT THERAPY: Biologic therapy: * Not specified Chemotherapy: * No prior chemotherapy Endocrine therapy: * Prior or concurrent corticosteroids allowed Radiotherapy: * No prior radiotherapy Surgery: * See Disease Characteristics * More than 1 prior surgery allowed Other: * No other prior treatment for ependymoma
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Event-free Survival | Up to 5 years after completion of study treatment | Event-free survival is calculated from the date of study enrollment to the date of disease progression, disease relapse, occurrence of second neoplasm, or death from any cause. The product-limit (Kaplan-Meier) estimate is for estimation of Event -free survival (EFS) probability at 5 years. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | Up to 5 years after completion of study treatment | Overall survival (OS) is measured from the date of study enrollment to the date to death. The product-limit (Kaplan-Meier) estimate is for estimation of OS probability at 5 years. |
| Rate of Gross-total or Near-total Resection and Second Surgery After Chemotherapy | At the time of second surgery | The Rate Of Gross-Total or Near-Total Resection With Second Surgery After Chemotherapy Treatment. |
| Event-free Survival (EFS) | At 5 years since the time of radiation therapy. | EFS between centrally reviewed differentiated ependymoma and anaplastic ependymoma for the patients who had sub-total resection initially. The event-free survival (EFS) defined as the date of disease progression, disease relapse, occurrence of a second neoplasm, or death from any cause, measured from the start date of radiation therapy. The product-limit (Kaplan-Meier) estimate is for estimation of EFS probability. |
| Local Control and Patterns of Failure | Up to 5 years after completion of study treatment | Documented and analyzed qualitatively and quantitatively. |
Countries
Australia, Canada, Netherlands, New Zealand, Switzerland, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| GTR1 Differentiated Histology Supratentorial (Group 1) Patients undergo observation. | 13 |
| Radiation (Group 2) Supratentorial Anaplastic Ependymoma (GTR1, GTR2, NTR) and Anaplastic or Differentiated Infratentorial Ependymoma (GTR1, GTR2, NTR) and Supratentorial Differentiated Ependymoma(GTR2, NTR). Patients undergo conformal radiation therapy to the brain once daily 5 days a week for 6-6½ weeks.
radiation therapy: Given once daily 5 days a week for 6-6½ weeks | 287 |
| Sub-Total Resection Any Histology or Location (STR) (Group 3) Patients receive initial course of chemotherapy comprising vincristine sulfate IV on days 1 and 8, carboplatin IV over 1 hour on day 1, and cyclophosphamide IV over 1 hour on days 1 and 2. Patients also receive filgrastim (G-CSF) subcutaneously or IV beginning on day 3 and continuing until blood counts recover. Patients then receive a second course of chemotherapy comprising vincristine sulfate IV on days 1 and 8, carboplatin IV over 1 hour on day 1, and oral etoposide on days 1-21. After completion of chemotherapy, patients are evaluated for second therapeutic conventional surgery. Patients who have unresectable disease undergo conformal radiation therapy. Patients who have resectable disease undergo second surgery followed by conformal radiotherapy.
filgrastim: Given IV or SC (5mcg/kg/day) start on Day 3 and continue until ANC \>1500/μl given subcutaneously or intravenously.
carboplatin: Given IV (375 mg/m2/day) Day 1 given as an IV infusion over one hour. For patient | 78 |
| Total | 378 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Entry into another COG therapeutic study | 0 | 5 | 2 |
| Overall Study | Ineligible for study | 2 | 6 | 14 |
| Overall Study | Lost to Follow-up | 0 | 41 | 9 |
| Overall Study | Neuraxis dissemination during/after ther | 0 | 2 | 5 |
| Overall Study | Withdrawal by Subject | 0 | 14 | 7 |
Baseline characteristics
| Characteristic | Total | GTR1 Differentiated Histology Supratentorial (Group 1) | Radiation (Group 2) | Sub-Total Resection Any Histology or Location (STR) (Group 3) |
|---|---|---|---|---|
| Age, Categorical <=18 years | 370 Participants | 13 Participants | 281 Participants | 76 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 8 Participants | 0 Participants | 6 Participants | 2 Participants |
| Age, Continuous | 5.60 years | 10.78 years | 5.58 years | 5.18 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 52 Participants | 0 Participants | 36 Participants | 16 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 311 Participants | 10 Participants | 242 Participants | 59 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 15 Participants | 3 Participants | 9 Participants | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 21 Participants | 0 Participants | 15 Participants | 6 Participants |
| Race (NIH/OMB) Black or African American | 39 Participants | 1 Participants | 34 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 3 Participants | 0 Participants | 3 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 2 Participants | 0 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 22 Participants | 3 Participants | 14 Participants | 5 Participants |
| Race (NIH/OMB) White | 290 Participants | 9 Participants | 219 Participants | 62 Participants |
| Region of Enrollment Australia | 15 participants | 0 participants | 10 participants | 5 participants |
| Region of Enrollment Canada | 37 participants | 1 participants | 28 participants | 8 participants |
| Region of Enrollment Netherlands | 9 participants | 0 participants | 6 participants | 3 participants |
| Region of Enrollment United States | 317 participants | 12 participants | 243 participants | 62 participants |
| Sex: Female, Male Female | 159 Participants | 7 Participants | 114 Participants | 38 Participants |
| Sex: Female, Male Male | 219 Participants | 6 Participants | 173 Participants | 40 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 52 / 281 | 27 / 64 |
| serious Total, serious adverse events | 38 / 281 | 55 / 64 |
Outcome results
Primary
Event-free Survival
Event-free survival is calculated from the date of study enrollment to the date of disease progression, disease relapse, occurrence of second neoplasm, or death from any cause. The product-limit (Kaplan-Meier) estimate is for estimation of Event -free survival (EFS) probability at 5 years.
Time frame: Up to 5 years after completion of study treatment
Population: The product-limit (Kaplan-Meier) estimate is for estimation of event-free survival probability at 5 years. All eligible patients in the study were included.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| GTR1 Differentiated Histology Supratentorial (Group 1) | Event-free Survival | 0.614 Probability of EFS at 5 years |
| Radiation (Group 2) | Event-free Survival | 0.685 Probability of EFS at 5 years |
| Sub-Total Resection Any Histology or Location (STR) (Group 3) | Event-free Survival | 0.372 Probability of EFS at 5 years |
Secondary
Event-free Survival (EFS)
EFS between centrally reviewed differentiated ependymoma and anaplastic ependymoma for the patients who had sub-total resection initially. The event-free survival (EFS) defined as the date of disease progression, disease relapse, occurrence of a second neoplasm, or death from any cause, measured from the start date of radiation therapy. The product-limit (Kaplan-Meier) estimate is for estimation of EFS probability.
Time frame: At 5 years since the time of radiation therapy.
Population: Of 64 eligible patients who had initial subtotal resection, 5 patients were off-therapy prior to radiation therapy, and 4 patients had a disease progression prior to radiation therapy. There were 55 eligible patients included in the analysis. The product-limit (Kaplan-Meier) estimate is for estimation of EFS probability.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| GTR1 Differentiated Histology Supratentorial (Group 1) | Event-free Survival (EFS) | 0.424 Probability of EFS at 5 years |
| Radiation (Group 2) | Event-free Survival (EFS) | 0.298 Probability of EFS at 5 years |
Secondary
Event-free Survival (EFS)
EFS between centrally reviewed differentiated ependymoma and anaplastic ependymoma for the patients who were treated with radiation therapy only. The event-free survival (EFS) defined as the time to disease progression, disease relapse, occurrence of a second neoplasm, or death from any cause, measured from the start of radiation therapy. The product-limit (Kaplan-Meier) estimate is for estimation of EFS probability at 5 years.
Time frame: At 5 years since the time of radiation therapy
Population: Supratentorial Anaplastic Ependymoma (GTR1, GTR2, NTR) and Anaplastic or Differentiated Infratentorial Ependymoma (GTR1, GTR2, NTR) and Supratentorial Differentiated Ependymoma(GTR2, NTR). Patients undergo conformal radiation therapy to the brain once daily 5 days a week for 6-6½ weeks.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| GTR1 Differentiated Histology Supratentorial (Group 1) | Event-free Survival (EFS) | 0.746 Probability of EFS at 5 years |
| Radiation (Group 2) | Event-free Survival (EFS) | 0.607 Probability of EFS at 5 years |
Secondary
Local Control and Patterns of Failure
Documented and analyzed qualitatively and quantitatively.
Time frame: Up to 5 years after completion of study treatment
Population: All eligible patients in the study were included.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| GTR1 Differentiated Histology Supratentorial (Group 1) | Local Control and Patterns of Failure | Local control | 6 Participant |
| GTR1 Differentiated Histology Supratentorial (Group 1) | Local Control and Patterns of Failure | Pattern of failure local | 4 Participant |
| GTR1 Differentiated Histology Supratentorial (Group 1) | Local Control and Patterns of Failure | Pattern of failure Metastatic | 0 Participant |
| GTR1 Differentiated Histology Supratentorial (Group 1) | Local Control and Patterns of Failure | Pattern of failure local & metastatic | 1 Participant |
| Radiation (Group 2) | Local Control and Patterns of Failure | Pattern of failure local & metastatic | 7 Participant |
| Radiation (Group 2) | Local Control and Patterns of Failure | Local control | 217 Participant |
| Radiation (Group 2) | Local Control and Patterns of Failure | Pattern of failure Metastatic | 26 Participant |
| Radiation (Group 2) | Local Control and Patterns of Failure | Pattern of failure local | 57 Participant |
| Sub-Total Resection Any Histology or Location (STR) (Group 3) | Local Control and Patterns of Failure | Pattern of failure local & metastatic | 4 Participant |
| Sub-Total Resection Any Histology or Location (STR) (Group 3) | Local Control and Patterns of Failure | Pattern of failure local | 31 Participant |
| Sub-Total Resection Any Histology or Location (STR) (Group 3) | Local Control and Patterns of Failure | Pattern of failure Metastatic | 5 Participant |
| Sub-Total Resection Any Histology or Location (STR) (Group 3) | Local Control and Patterns of Failure | Local control | 29 Participant |
Secondary
Overall Survival
Overall survival (OS) is measured from the date of study enrollment to the date to death. The product-limit (Kaplan-Meier) estimate is for estimation of OS probability at 5 years.
Time frame: Up to 5 years after completion of study treatment
Population: All eligible patients in the study were included. The product-limit (Kaplan-Meier) estimate is for estimation of OS probability.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| GTR1 Differentiated Histology Supratentorial (Group 1) | Overall Survival | 1 Probability of OS at 5 years |
| Radiation (Group 2) | Overall Survival | 0.862 Probability of OS at 5 years |
| Sub-Total Resection Any Histology or Location (STR) (Group 3) | Overall Survival | 0.702 Probability of OS at 5 years |
Secondary
Rate of Gross-total or Near-total Resection and Second Surgery After Chemotherapy
The Rate Of Gross-Total or Near-Total Resection With Second Surgery After Chemotherapy Treatment.
Time frame: At the time of second surgery
Population: Of 64 eligible patients in this group, 25 patients after chemotherapy had the second surgery. Of 25 patients with second surgery after chemotherapy, 19 had a Gross-Total or Near-Total resection. 19/25=76%.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| GTR1 Differentiated Histology Supratentorial (Group 1) | Rate of Gross-total or Near-total Resection and Second Surgery After Chemotherapy | 76 percentage of participants |