Phase III Randomized Trial of Post-Radiation Chemotherapy in Patients With Newly Diagnosed Ependymoma Ages 1 to 21 Years
试验速览
- 阶段
- 3 期
- 状态
- 进行中（未招募）
- 入组人数
- 479
- 试验地点
- 209
- 主要终点
- Event-free Survival (EFS) in Children Who Have Completely Resected Ependymoma or Achieved CR and Are Treated With Post-radiation Maintenance Chemotherapy or Post-radiation Observation Only
研究概览
简要总结
The primary aim of this randomized phase III trial was to study whether the addition of maintenance chemotherapy delivered after surgical resection and focal radiation would be better than surgery and focal radiation alone. The trial also studied if patients who received induction chemotherapy and then either achieved a complete response or went on to have a complete resection would also benefit from maintenance chemotherapy. Children ages 1-21 years with newly diagnosed intracranial ependymoma were included. There were 2 arms that were not randomized. One arm studied patients with Grade II tumors located in the supratentorial compartment that were completely resected. One arm studied patients with residual tumor and those patients all received maintenance chemotherapy after focal radiation. Chemotherapy drugs, such as vincristine sulfate, carboplatin, cyclophosphamide, etoposide, and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving more than one drug (combination chemotherapy) may kill more tumor cells. Radiation therapy uses high-energy x-rays to kill tumor cells. 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. Giving chemotherapy in combination with radiation therapy may kill more tumor cells and allow doctors to save the part of the body where the cancer started.
详细描述
PRIMARY OBJECTIVE:
I. To determine the event free survival (EFS) and overall survival (OS) of children with completely resected ependymoma treated with post-operative conformal radiation therapy (cRT) and then randomized to receive or not receive four cycles of post radiation maintenance chemotherapy (vincristine, cisplatin, etoposide and cyclophosphamide [VCEC]).
EXPLORATORY OBJECTIVES:
I. To estimate the EFS and OS of children with incompletely resected ependymoma who are unable to achieve a complete response (CR) by post-operative induction chemotherapy or by second surgery who will then be non-randomly assigned to cRT followed by four cycles of maintenance chemotherapy (VCEC).
II. To further evaluate the EFS and OS of children with supratentorial classic ependymoma who achieve a complete resection at first or second resection OR children who achieve a CR to short course induction chemotherapy following first surgery.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 12 Months 至 21 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients must be newly diagnosed with histologically confirmed intracranial ependymoma; patients with classic ependymoma (WHO II) or anaplastic ependymoma (WHO III) are eligible, as are various subtypes described as clear cell, papillary, cellular or a combination of the above
- •There is no minimum performance level; children with ependymoma may suffer neurologic sequelae as a result of their tumor or surgical measures taken to establish a diagnosis and resect the tumor; in the majority of cases, there is neurologic recovery; neurologic recovery is not likely to be impeded by protocol therapy
- •REGULATORY: All patients and/or their parents or legal guardians must sign a written informed consent
- •REGULATORY: All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met
排除标准
- •Patients with evidence of metastatic disease will be excluded; any evidence of non-contiguous spread beyond the primary site as determined by pre or post-operative magnetic resonance (MR) imaging of brain, pre or post-operative MR imaging of the spine, and post-operative cerebrospinal fluid (CSF) cytology obtained from the lumbar CSF space (the requirement for lumbar CSF examination may be waived if deemed to be medically contraindicated); CSF cytology from a ventriculostomy or permanent ventriculoperitoneal (VP) shunt that reveals the presence of tumor cells is indicative of metastatic disease
- •Patients with a diagnosis of spinal cord ependymoma, myxopapillary ependymoma, subependymoma, ependymoblastoma, or mixed glioma are NOT eligible
- •No prior treatment other than surgical intervention and corticosteroids; patients are allowed to have had more than one attempt at resection prior to enrollment
- •Pregnant female patients are not eligible for this study
- •Post-menarchal females may not participate unless a pregnancy test with a negative result has been obtained
- •Males and females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method
- •Lactating females may not participate unless they have agreed not to breastfeed a child while on this study
研究组 & 干预措施
Arm I (chemotherapy, observation)
Patients with classic histology(WHO Grade II) supratentorial ependymoma who have undergone microscopic gross total resection (GTR1) or achieved CR either after first or second resection or after post-operative induction chemotherapy are assigned to observation. For patients without GTR1, induction chemotherapy is comprised of vincristine intravenously (IV) over 1 minute on days 1 and 8 of cycles 1 and 2, carboplatin IV over 15-60 minutes on day 1 of cycles 1 and 2, and cyclophosphamide IV over 30-60 minutes on days 1-2 of cycle 1 only. Patients also receive etoposide IV over 60-120 minutes on days 1-3 of cycle 2 only. Cycle 1 continues for 3 weeks and cycle 2 continues for 4 weeks in the absence of disease progression or unacceptable toxicity.
干预措施: Carboplatin (Drug)
Arm I (chemotherapy, observation)
Patients with classic histology(WHO Grade II) supratentorial ependymoma who have undergone microscopic gross total resection (GTR1) or achieved CR either after first or second resection or after post-operative induction chemotherapy are assigned to observation. For patients without GTR1, induction chemotherapy is comprised of vincristine intravenously (IV) over 1 minute on days 1 and 8 of cycles 1 and 2, carboplatin IV over 15-60 minutes on day 1 of cycles 1 and 2, and cyclophosphamide IV over 30-60 minutes on days 1-2 of cycle 1 only. Patients also receive etoposide IV over 60-120 minutes on days 1-3 of cycle 2 only. Cycle 1 continues for 3 weeks and cycle 2 continues for 4 weeks in the absence of disease progression or unacceptable toxicity.
干预措施: Cyclophosphamide (Drug)
Arm I (chemotherapy, observation)
Patients with classic histology(WHO Grade II) supratentorial ependymoma who have undergone microscopic gross total resection (GTR1) or achieved CR either after first or second resection or after post-operative induction chemotherapy are assigned to observation. For patients without GTR1, induction chemotherapy is comprised of vincristine intravenously (IV) over 1 minute on days 1 and 8 of cycles 1 and 2, carboplatin IV over 15-60 minutes on day 1 of cycles 1 and 2, and cyclophosphamide IV over 30-60 minutes on days 1-2 of cycle 1 only. Patients also receive etoposide IV over 60-120 minutes on days 1-3 of cycle 2 only. Cycle 1 continues for 3 weeks and cycle 2 continues for 4 weeks in the absence of disease progression or unacceptable toxicity.
干预措施: Etoposide (Drug)
Arm I (chemotherapy, observation)
Patients with classic histology(WHO Grade II) supratentorial ependymoma who have undergone microscopic gross total resection (GTR1) or achieved CR either after first or second resection or after post-operative induction chemotherapy are assigned to observation. For patients without GTR1, induction chemotherapy is comprised of vincristine intravenously (IV) over 1 minute on days 1 and 8 of cycles 1 and 2, carboplatin IV over 15-60 minutes on day 1 of cycles 1 and 2, and cyclophosphamide IV over 30-60 minutes on days 1-2 of cycle 1 only. Patients also receive etoposide IV over 60-120 minutes on days 1-3 of cycle 2 only. Cycle 1 continues for 3 weeks and cycle 2 continues for 4 weeks in the absence of disease progression or unacceptable toxicity.
干预措施: Filgrastim (Biological)
Arm I (chemotherapy, observation)
Patients with classic histology(WHO Grade II) supratentorial ependymoma who have undergone microscopic gross total resection (GTR1) or achieved CR either after first or second resection or after post-operative induction chemotherapy are assigned to observation. For patients without GTR1, induction chemotherapy is comprised of vincristine intravenously (IV) over 1 minute on days 1 and 8 of cycles 1 and 2, carboplatin IV over 15-60 minutes on day 1 of cycles 1 and 2, and cyclophosphamide IV over 30-60 minutes on days 1-2 of cycle 1 only. Patients also receive etoposide IV over 60-120 minutes on days 1-3 of cycle 2 only. Cycle 1 continues for 3 weeks and cycle 2 continues for 4 weeks in the absence of disease progression or unacceptable toxicity.
干预措施: Laboratory Biomarker Analysis (Other)
Arm I (chemotherapy, observation)
Patients with classic histology(WHO Grade II) supratentorial ependymoma who have undergone microscopic gross total resection (GTR1) or achieved CR either after first or second resection or after post-operative induction chemotherapy are assigned to observation. For patients without GTR1, induction chemotherapy is comprised of vincristine intravenously (IV) over 1 minute on days 1 and 8 of cycles 1 and 2, carboplatin IV over 15-60 minutes on day 1 of cycles 1 and 2, and cyclophosphamide IV over 30-60 minutes on days 1-2 of cycle 1 only. Patients also receive etoposide IV over 60-120 minutes on days 1-3 of cycle 2 only. Cycle 1 continues for 3 weeks and cycle 2 continues for 4 weeks in the absence of disease progression or unacceptable toxicity.
干预措施: Mesna (Drug)
Arm I (chemotherapy, observation)
Patients with classic histology(WHO Grade II) supratentorial ependymoma who have undergone microscopic gross total resection (GTR1) or achieved CR either after first or second resection or after post-operative induction chemotherapy are assigned to observation. For patients without GTR1, induction chemotherapy is comprised of vincristine intravenously (IV) over 1 minute on days 1 and 8 of cycles 1 and 2, carboplatin IV over 15-60 minutes on day 1 of cycles 1 and 2, and cyclophosphamide IV over 30-60 minutes on days 1-2 of cycle 1 only. Patients also receive etoposide IV over 60-120 minutes on days 1-3 of cycle 2 only. Cycle 1 continues for 3 weeks and cycle 2 continues for 4 weeks in the absence of disease progression or unacceptable toxicity.
干预措施: Vincristine (Drug)
Arm II (radiotherapy, chemotherapy)
Patients with supratentorial ependymoma (Grade II without GTR1 or Grade III) or any infratentorial ependymoma who have undergone gross or near total resection (GTR or NTR) or achieved CR either after first or second resection or after post-operative induction chemotherapy are randomized to undergo conformal radiotherapy over 6-7 weeks followed by maintenance chemotherapy. Maintenance chemotherapy comprised of vincristine IV on days 1, 8, and 15 of cycles 1-3 only, etoposide IV over 60-120 minutes on days 1-3, cisplatin IV over 1-8 hours on day 1, and cyclophosphamide IV over 30-60 minutes on days 2-3. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients without GTR or NTR at enrollment require induction chemotherapy (see Arm I) and possibly second surgery before randomization.
干预措施: 3-Dimensional Conformal Radiation Therapy (Radiation)
Arm II (radiotherapy, chemotherapy)
Patients with supratentorial ependymoma (Grade II without GTR1 or Grade III) or any infratentorial ependymoma who have undergone gross or near total resection (GTR or NTR) or achieved CR either after first or second resection or after post-operative induction chemotherapy are randomized to undergo conformal radiotherapy over 6-7 weeks followed by maintenance chemotherapy. Maintenance chemotherapy comprised of vincristine IV on days 1, 8, and 15 of cycles 1-3 only, etoposide IV over 60-120 minutes on days 1-3, cisplatin IV over 1-8 hours on day 1, and cyclophosphamide IV over 30-60 minutes on days 2-3. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients without GTR or NTR at enrollment require induction chemotherapy (see Arm I) and possibly second surgery before randomization.
干预措施: Cisplatin (Drug)
Arm II (radiotherapy, chemotherapy)
Patients with supratentorial ependymoma (Grade II without GTR1 or Grade III) or any infratentorial ependymoma who have undergone gross or near total resection (GTR or NTR) or achieved CR either after first or second resection or after post-operative induction chemotherapy are randomized to undergo conformal radiotherapy over 6-7 weeks followed by maintenance chemotherapy. Maintenance chemotherapy comprised of vincristine IV on days 1, 8, and 15 of cycles 1-3 only, etoposide IV over 60-120 minutes on days 1-3, cisplatin IV over 1-8 hours on day 1, and cyclophosphamide IV over 30-60 minutes on days 2-3. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients without GTR or NTR at enrollment require induction chemotherapy (see Arm I) and possibly second surgery before randomization.
干预措施: Cyclophosphamide (Drug)
Arm II (radiotherapy, chemotherapy)
Patients with supratentorial ependymoma (Grade II without GTR1 or Grade III) or any infratentorial ependymoma who have undergone gross or near total resection (GTR or NTR) or achieved CR either after first or second resection or after post-operative induction chemotherapy are randomized to undergo conformal radiotherapy over 6-7 weeks followed by maintenance chemotherapy. Maintenance chemotherapy comprised of vincristine IV on days 1, 8, and 15 of cycles 1-3 only, etoposide IV over 60-120 minutes on days 1-3, cisplatin IV over 1-8 hours on day 1, and cyclophosphamide IV over 30-60 minutes on days 2-3. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients without GTR or NTR at enrollment require induction chemotherapy (see Arm I) and possibly second surgery before randomization.
干预措施: Etoposide (Drug)
Arm II (radiotherapy, chemotherapy)
Patients with supratentorial ependymoma (Grade II without GTR1 or Grade III) or any infratentorial ependymoma who have undergone gross or near total resection (GTR or NTR) or achieved CR either after first or second resection or after post-operative induction chemotherapy are randomized to undergo conformal radiotherapy over 6-7 weeks followed by maintenance chemotherapy. Maintenance chemotherapy comprised of vincristine IV on days 1, 8, and 15 of cycles 1-3 only, etoposide IV over 60-120 minutes on days 1-3, cisplatin IV over 1-8 hours on day 1, and cyclophosphamide IV over 30-60 minutes on days 2-3. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients without GTR or NTR at enrollment require induction chemotherapy (see Arm I) and possibly second surgery before randomization.
干预措施: Filgrastim (Biological)
Arm II (radiotherapy, chemotherapy)
Patients with supratentorial ependymoma (Grade II without GTR1 or Grade III) or any infratentorial ependymoma who have undergone gross or near total resection (GTR or NTR) or achieved CR either after first or second resection or after post-operative induction chemotherapy are randomized to undergo conformal radiotherapy over 6-7 weeks followed by maintenance chemotherapy. Maintenance chemotherapy comprised of vincristine IV on days 1, 8, and 15 of cycles 1-3 only, etoposide IV over 60-120 minutes on days 1-3, cisplatin IV over 1-8 hours on day 1, and cyclophosphamide IV over 30-60 minutes on days 2-3. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients without GTR or NTR at enrollment require induction chemotherapy (see Arm I) and possibly second surgery before randomization.
干预措施: Laboratory Biomarker Analysis (Other)
Arm II (radiotherapy, chemotherapy)
Patients with supratentorial ependymoma (Grade II without GTR1 or Grade III) or any infratentorial ependymoma who have undergone gross or near total resection (GTR or NTR) or achieved CR either after first or second resection or after post-operative induction chemotherapy are randomized to undergo conformal radiotherapy over 6-7 weeks followed by maintenance chemotherapy. Maintenance chemotherapy comprised of vincristine IV on days 1, 8, and 15 of cycles 1-3 only, etoposide IV over 60-120 minutes on days 1-3, cisplatin IV over 1-8 hours on day 1, and cyclophosphamide IV over 30-60 minutes on days 2-3. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients without GTR or NTR at enrollment require induction chemotherapy (see Arm I) and possibly second surgery before randomization.
干预措施: Mesna (Drug)
Arm II (radiotherapy, chemotherapy)
Patients with supratentorial ependymoma (Grade II without GTR1 or Grade III) or any infratentorial ependymoma who have undergone gross or near total resection (GTR or NTR) or achieved CR either after first or second resection or after post-operative induction chemotherapy are randomized to undergo conformal radiotherapy over 6-7 weeks followed by maintenance chemotherapy. Maintenance chemotherapy comprised of vincristine IV on days 1, 8, and 15 of cycles 1-3 only, etoposide IV over 60-120 minutes on days 1-3, cisplatin IV over 1-8 hours on day 1, and cyclophosphamide IV over 30-60 minutes on days 2-3. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients without GTR or NTR at enrollment require induction chemotherapy (see Arm I) and possibly second surgery before randomization.
干预措施: Vincristine (Drug)
Arm III (radiotherapy, observation)
Patients with supratentorial ependymoma (Grade II without GTR1 or ST Grade III) or any infratentorial ependymoma (Grade II or III) who have undergone gross or near total resection or achieved CR either after first or second resection or after post-operative induction chemotherapy are randomized to undergo conformal radiotherapy over 6-7 weeks and then undergo observation. Patients without GTR or NTR at enrollment require induction chemotherapy (see Arm I) and possibly second surgery before randomization.
干预措施: 3-Dimensional Conformal Radiation Therapy (Radiation)
Arm III (radiotherapy, observation)
Patients with supratentorial ependymoma (Grade II without GTR1 or ST Grade III) or any infratentorial ependymoma (Grade II or III) who have undergone gross or near total resection or achieved CR either after first or second resection or after post-operative induction chemotherapy are randomized to undergo conformal radiotherapy over 6-7 weeks and then undergo observation. Patients without GTR or NTR at enrollment require induction chemotherapy (see Arm I) and possibly second surgery before randomization.
干预措施: Clinical Observation (Other)
Arm III (radiotherapy, observation)
Patients with supratentorial ependymoma (Grade II without GTR1 or ST Grade III) or any infratentorial ependymoma (Grade II or III) who have undergone gross or near total resection or achieved CR either after first or second resection or after post-operative induction chemotherapy are randomized to undergo conformal radiotherapy over 6-7 weeks and then undergo observation. Patients without GTR or NTR at enrollment require induction chemotherapy (see Arm I) and possibly second surgery before randomization.
干预措施: Laboratory Biomarker Analysis (Other)
ARM IV (radiotherapy, chemotherapy)
Patients with subtotal resection after induction chemotherapy (see Arm I) and second surgery are nonrandomly assigned to Arm II treatment.
干预措施: 3-Dimensional Conformal Radiation Therapy (Radiation)
ARM IV (radiotherapy, chemotherapy)
Patients with subtotal resection after induction chemotherapy (see Arm I) and second surgery are nonrandomly assigned to Arm II treatment.
干预措施: Cisplatin (Drug)
ARM IV (radiotherapy, chemotherapy)
Patients with subtotal resection after induction chemotherapy (see Arm I) and second surgery are nonrandomly assigned to Arm II treatment.
干预措施: Cyclophosphamide (Drug)
ARM IV (radiotherapy, chemotherapy)
Patients with subtotal resection after induction chemotherapy (see Arm I) and second surgery are nonrandomly assigned to Arm II treatment.
干预措施: Etoposide (Drug)
ARM IV (radiotherapy, chemotherapy)
Patients with subtotal resection after induction chemotherapy (see Arm I) and second surgery are nonrandomly assigned to Arm II treatment.
干预措施: Filgrastim (Biological)
ARM IV (radiotherapy, chemotherapy)
Patients with subtotal resection after induction chemotherapy (see Arm I) and second surgery are nonrandomly assigned to Arm II treatment.
干预措施: Laboratory Biomarker Analysis (Other)
ARM IV (radiotherapy, chemotherapy)
Patients with subtotal resection after induction chemotherapy (see Arm I) and second surgery are nonrandomly assigned to Arm II treatment.
干预措施: Mesna (Drug)
ARM IV (radiotherapy, chemotherapy)
Patients with subtotal resection after induction chemotherapy (see Arm I) and second surgery are nonrandomly assigned to Arm II treatment.
干预措施: Vincristine (Drug)
结局指标
主要结局
Event-free Survival (EFS) in Children Who Have Completely Resected Ependymoma or Achieved CR and Are Treated With Post-radiation Maintenance Chemotherapy or Post-radiation Observation Only
时间窗: Up to 10 years after enrollment. 5-year estimates of EFS are presented
Kaplan-Meier estimates of EFS are calculated from randomization date to first occurrence of disease progression, disease recurrence, second malignant neoplasm, or death from any cause. The comparison between randomized arms (post-radiation maintenance chemotherapy versus post-radiation observation only) is conveyed by the hazard ratio and 90.46% stagewise adjusted Wald confidence interval.
Overall Survival (OS) in Children Who Have Completely Resected Ependymoma or Achieved CR and Are Treated With Post-radiation Maintenance Chemotherapy or Post-radiation Observation Only
时间窗: Up to 10 years after enrollment. 5-year estimates of OS are presented.
Kaplan-Meier estimates of OS are calculated from randomization date to death from any cause. The comparison between randomized arms (post-radiation maintenance chemotherapy versus post-radiation observation only) is conveyed by the hazard ratio and 90.46% stagewise adjusted Wald confidence interval.
次要结局
未报告次要终点