Brain Tumor, Central Nervous System Tumor
Conditions
Keywords
childhood central nervous system germ cell tumor
Brief summary
RATIONALE: Radiation therapy uses high-energy x-rays to damage tumor cells. Drugs used in chemotherapy work in different ways to stop tumor cells from dividing so they stop growing or die. It is not yet known whether radiation therapy alone is as effective as chemotherapy plus radiation therapy in treating germ cell tumor. PURPOSE: This randomized phase III trial is studying radiation therapy alone to see how well it works compared to chemotherapy and radiation therapy in treating patients with newly diagnosed primary CNS germ cell tumor.
Detailed description
OBJECTIVES: Primary * Compare event-free survival and overall survival of patients with newly diagnosed primary CNS germ cell tumor treated with conventional radiotherapy alone (regimen A) vs chemotherapy followed by tumor response-based radiotherapy (regimen B). Secondary * Determine the complete response rate in patients treated with regimen B. * Determine the acute and subacute toxicity of regimen B in these patients. * Compare treatment-related morbidity, in terms of verbal learning and memory, executive functioning, and quality of life, in patients treated with these regimens. * Determine the prognostic value of baseline serum, lumbar, and intraventricular levels of human chorionic gonadotropin levels from patients treated with these regimens. * Determine the prognostic value of extent of disease (M+ vs modified M+ vs M0) on event-free survival and overall survival of patients treated with these regimens. OUTLINE: This is a randomized, multicenter study. Patients are stratified according to tumor location (pineal vs suprasellar vs pineal + suprasellar or other), and disease stage (disseminated vs occult multi-focal vs localized). Patients are randomized to 1 of 2 treatment regimens. All patients undergo an operative procedure (endoscopic biopsy, stereotactic biopsy, or open craniotomy) to confirm the diagnosis of pure germ cell germinoma followed by an intraoperative and perioperative staging evaluation. * Regimen A (radiotherapy only): Within 52 days of surgery, patients undergo standard-dose radiotherapy once daily on days 1-5 for approximately 5-6 weeks. * Regimen B (chemotherapy plus radiotherapy): * Courses 1 and 2: Patients receive carboplatin IV over 1 hour on days 1 and 2 and etoposide IV over 2 hours on days 1-3. Treatment repeats every 21 days for 2 courses. Patients achieving a complete response (CR) proceed to reduced-dose radiotherapy. Patients with minimal residual disease (MRD), a partial response (PR), or stable disease (SD) receive chemotherapy courses 3 and 4 as outlined below. Patients with progressive disease undergo a second surgical procedure for biopsy and are restaged. Patients with a confirmed diagnosis of germ cell tumor with no change in tumor markers and no new lesions after restaging proceed to chemotherapy courses 3 and 4. * Courses 3 and 4: Patients receive cisplatin IV over 6 hours on day 1, cyclophosphamide IV over 1 hour on days 2 and 3, and filgrastim (G-CSF) subcutaneously or IV beginning on day 4 and continuing until blood counts recover. Treatment repeats every 21 days for 2 courses. Patients achieving a CR or MRD proceed to reduced-dose radiotherapy. Patients with a PR, SD, or progressive disease are restaged. Patients with a confirmed diagnosis of germ cell tumor after restaging undergo standard radiotherapy as in regimen A. * Reduced-dose radiotherapy: Within 6 weeks of starting course 4, patients undergo lower-dose radiotherapy once daily on days 1-5 for 5 weeks. Treatment in both regimens continues in the absence of unacceptable toxicity or in the event that a non-germinomatous germ cell tumor is detected. Quality of life and neuropsychological function within the domains of intelligence, attention-concentration, memory, and executive functioning are assessed at 9, 30, and 60 months after diagnosis. Patients are followed every 4 months for 2 years, and then annually thereafter. PROJECTED ACCRUAL: A total of 225 patients (approximately 112 per treatment regimen) will be accrued for this study within 5 years.
Interventions
BIOLOGICALfilgrastim
Given by infusion or injection
DRUGcarboplatin
Given IV over 1 hour
DRUGcisplatin
Given IV over 6 hours
DRUGcyclophosphamide
Given IV over 1 hour
DRUGetoposide
Given IV over 2 hours
RADIATIONradiation therapy
Patients undergo radiotherapy 5 days a week
Sponsors
National Cancer Institute (NCI)
Children's Oncology Group
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
3 Years to 25 Years
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: * Histologically confirmed primary CNS pure germ cell tumor * Diagnosed within the past 31 days * Meets any 1 OR none (i.e., M0 \[localized disease\]) of the following staging criteria: * M+ (disseminated disease) * Leptomeningeal or intraventricular metastases visualized on MRI scans of the brain and spine * Clumps of tumor cells on lumbar cerebrospinal fluid (CSF) cytology * Visible tumor studding the walls of the lateral or third ventricles noted during endoscopy or surgery * Primary tumor arising within the parenchyma of the brain, brainstem, or spinal cord * Measurable multi-focal tumors arising in both the pineal and suprasellar regions (i.e., multiple midline tumors) * Infiltrative, intra-axial extension on brain MRI \> 1 cm beyond enhancing tumor * Modified M+ (occult multi-focal disease) * M0 at diagnosis with a localized pineal region tumor with signs and symptoms of diabetes insipidus without measurable disease in the suprasellar region * Lumbar CSF assay meeting criteria for the following marker profiles: * Serum and CSF beta human chorionic gonadotropin (β-HCG) ≤ 50 IU/dL * Serum alpha fetoprotein (AFP) ≤ 10 IU/L AND ≤ institutional norm * CSF AFP ≤ 2.0 IU/L AND ≤ institutional norm PATIENT CHARACTERISTICS: Age * 3 to 25 Performance status * Not specified Life expectancy * Not specified Hematopoietic * Absolute neutrophil count \> 1,000/mm\^3 * Platelet count \> 100,000/mm\^3 (transfusion independent) * Hemoglobin \> 10.0 g/dL (transfusion allowed) Hepatic * Bilirubin ≤ 1.5 times upper limit of normal (ULN) * aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \< 2.5 times ULN Renal * Creatinine adjusted according to age as follows\*: * No greater than 0.4 mg/dL (≤ 5 months) * No greater than 0.5 mg/dL (6 months -11 months) * No greater than 0.6 mg/dL (1 year-23 months) * No greater than 0.8 mg/dL (2 years-5 years) * No greater than 1.0 mg/dL (6 years-9 years) * No greater than 1.2 mg/dL (10 years-12 years) * No greater than 1.4 mg/dL (13 years and over \[female\]) * No greater than 1.5 mg/dL (13 years to 15 years \[male\]) * No greater than 1.7 mg/dL (16 years and over \[male\]) AND * Creatinine clearance OR radioisotope glomerular filtration rate \> 70 mL/min Other * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception * Euthyroid (with or without levothyroxine sodium therapy) as determined by normal T4 ± thyroid-stimulating hormone levels\* * Diabetes insipidus allowed provided patient is relatively stable on desmopressin acetate * Normal endogenous cortisol function\* * Adequate antidiuretic hormone reserves\* NOTE: \*Unless receiving replacement therapy PRIOR CONCURRENT THERAPY: Biologic therapy * Not specified Chemotherapy * Not specified Endocrine therapy * Concurrent replacement hormones allowed (e.g., corticosteroids, levothyroxine sodium, and desmopressin acetate) Radiotherapy * Not specified Surgery * Prior surgery for germ cell tumor allowed Other * No other prior therapy for germ cell tumor * Concurrent anticonvulsants allowed
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Event-free Survival | Study enrollment until date of earliest qualifying event (QE), date last known to be QE-free if the patient is followed for less than three years and is QE-free at the time of analysis, or 3 years if the patient is QE-free at 3 years | Data will be summarized as number of patients in the following categories at the time of data cutoff for analyses of 3-year EFS: 1)Experienced a qualifying event (QE) (see below);2)Event-free through 3 years of follow-up;3)Event-free until data cutoff (if less than 3 years of follow-up);4)Withdrew from study;5)Lost to follow-up. QEs: 1)disease progression, defined as increase \>= 40% in tumor volume or \>= 25% in tumor area of target lesions;2)development of new lesions;3)occurrence of a second malignant neoplasm, defined as a malignancy with different histological type from trial-qualifying diagnosis;4)death from any cause. Stat. analyses will be based on time from enrollment to the earliest of: 1)occurrence of any of the QEs;2)withdrawal from study or lost to follow-up;3)completion of three years of follow-up event-free;4)data cutoff for completion of the statistical analyses for the protocol's primary objective. NOTE: Reported data are through May 2009 (see Caveats section). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With a Response to Regimen B | 5 years from beginning of treatment | To assess the complete response rate to pre-radiotherapy chemotherapy (Reg B only). Response was determined after completing 2-4 cycles of chemotherapy on Reg B. Complete Response (CR) is defined as disappearance of all target lesions. |
| Toxicity and Safety as Assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 | From the beginning of treatment, assessed up to 5 years | The analysis of toxicity will focus on estimating the rates of key acute and subacute toxicity occurring during the first induction chemotherapy. The list of toxicities of interest include Anemia or Febrile Neutropenia; Nausea or Vomiting; Infections and Infestations; Neutrophil or White blood count decrease; and Hypokalemia or Hyponatremia |
| Quality of Life (QOL) and Neurocognitive Assessment (NP) | 2 years from beginning of treatment | The primary endpoints for QOL and NP assessments will be the global scale value from each of these instruments at the two-year time point. Analyses of subscales (if they exist) and of assessments at other times will be of secondary interest. It is assumed that scale values are standardized to a reference normal population. The scores range from 0 to 100 with higher score reflecting better QoL or neurocognitive assessment. |
Countries
Australia, Canada, Puerto Rico, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Regimen A (Radiotherapy Only) Within 52 days of surgery, patients will undergo standard-dose radiation therapy 5 days a week for approximately 5-6 weeks. | 11 |
| Regimen B (Chemotherapy Plus Radiotherapy) Courses 1 and 2: Patients receive carboplatin IV over 1 hour on days 1 and 2 and etoposide IV over 2 hours on days 1-3. Treatment repeats every 21 days for 2 courses.
Within 3 weeks of completing chemotherapy, patients with CR undergo low-dose radiation therapy 5 days a week for 5 weeks. Patients with MRD, a PR, or SD receive chemotherapy courses 3 and 4 as outlined below.
Courses 3 and 4: Patients receive cisplatin IV over 6 hours on day 1, cyclophosphamide IV over 1 hour on days 2 and 3, and filgrastim (G-CSF) SC or IV beginning on day 4 and continuing until blood counts recover.
Treatment repeats every 21 days for 2 courses. Patients achieving a CR or MRD proceed to reduced-dose radiotherapy. Patients with a PR, SD, or PD are restaged and may undergo standard radiation therapy as in regimen A.
Reduced-dose radiation therapy: Within 6 weeks of starting course 4, patients undergo lower-dose radiation therapy once daily on days 1-5 for 5 weeks | 13 |
| Total | 24 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Ineligible | 1 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Regimen A (Radiotherapy Only) | Regimen B (Chemotherapy Plus Radiotherapy) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 10 Participants | 13 Participants | 23 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants | 0 Participants | 1 Participants |
| Region of Enrollment Australia | 1 participants | 4 participants | 5 participants |
| Region of Enrollment Switzerland | 0 participants | 1 participants | 1 participants |
| Region of Enrollment United States | 10 participants | 8 participants | 18 participants |
| Sex: Female, Male Female | 4 Participants | 1 Participants | 5 Participants |
| Sex: Female, Male Male | 7 Participants | 12 Participants | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 4 / 10 | 11 / 12 |
| serious Total, serious adverse events | 0 / 10 | 0 / 12 |
Outcome results
Primary
Event-free Survival
Data will be summarized as number of patients in the following categories at the time of data cutoff for analyses of 3-year EFS: 1)Experienced a qualifying event (QE) (see below);2)Event-free through 3 years of follow-up;3)Event-free until data cutoff (if less than 3 years of follow-up);4)Withdrew from study;5)Lost to follow-up. QEs: 1)disease progression, defined as increase \>= 40% in tumor volume or \>= 25% in tumor area of target lesions;2)development of new lesions;3)occurrence of a second malignant neoplasm, defined as a malignancy with different histological type from trial-qualifying diagnosis;4)death from any cause. Stat. analyses will be based on time from enrollment to the earliest of: 1)occurrence of any of the QEs;2)withdrawal from study or lost to follow-up;3)completion of three years of follow-up event-free;4)data cutoff for completion of the statistical analyses for the protocol's primary objective. NOTE: Reported data are through May 2009 (see Caveats section).
Time frame: Study enrollment until date of earliest qualifying event (QE), date last known to be QE-free if the patient is followed for less than three years and is QE-free at the time of analysis, or 3 years if the patient is QE-free at 3 years
Population: By protocol design, all eligible patients were considered in the evaluation of primary study aim. Two (2) patients were considered ineligible. All other patients (10 enrolled to regimen A and 12 enrolled to regimen B) are included in the evaluation for the primary outcome measure.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Regimen A (Radiotherapy Only) | Event-free Survival | Event-free through 3 years of follow-up | 0 participants |
| Regimen A (Radiotherapy Only) | Event-free Survival | Withdrew from study prior to 3 years of follow-up | 0 participants |
| Regimen A (Radiotherapy Only) | Event-free Survival | Event-free at data cutoff (if < 3 years follow-up) | 9 participants |
| Regimen A (Radiotherapy Only) | Event-free Survival | Lost to follow-up prior to 3 years of follow-up | 0 participants |
| Regimen A (Radiotherapy Only) | Event-free Survival | Experienced a qualifying event | 1 participants |
| Regimen B (Chemotherapy Plus Radiotherapy) | Event-free Survival | Lost to follow-up prior to 3 years of follow-up | 0 participants |
| Regimen B (Chemotherapy Plus Radiotherapy) | Event-free Survival | Experienced a qualifying event | 1 participants |
| Regimen B (Chemotherapy Plus Radiotherapy) | Event-free Survival | Event-free through 3 years of follow-up | 0 participants |
| Regimen B (Chemotherapy Plus Radiotherapy) | Event-free Survival | Event-free at data cutoff (if < 3 years follow-up) | 11 participants |
| Regimen B (Chemotherapy Plus Radiotherapy) | Event-free Survival | Withdrew from study prior to 3 years of follow-up | 0 participants |
Secondary
Number of Participants With a Response to Regimen B
To assess the complete response rate to pre-radiotherapy chemotherapy (Reg B only). Response was determined after completing 2-4 cycles of chemotherapy on Reg B. Complete Response (CR) is defined as disappearance of all target lesions.
Time frame: 5 years from beginning of treatment
Population: Patients who were treated in Regimen B and had at least one response assessment are included in this analysis. One patient in Regimen B withdrew from the pre-Radiotherapy chemotherapy and did not have any response assessment were not included for the response analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Regimen A (Radiotherapy Only) | Number of Participants With a Response to Regimen B | 8 Participants |
Secondary
Quality of Life (QOL) and Neurocognitive Assessment (NP)
The primary endpoints for QOL and NP assessments will be the global scale value from each of these instruments at the two-year time point. Analyses of subscales (if they exist) and of assessments at other times will be of secondary interest. It is assumed that scale values are standardized to a reference normal population. The scores range from 0 to 100 with higher score reflecting better QoL or neurocognitive assessment.
Time frame: 2 years from beginning of treatment
Population: All eligible patients who also successfully completed therapy and were assessed for quality of life and neurocognitive outcome.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Regimen A (Radiotherapy Only) | Quality of Life (QOL) and Neurocognitive Assessment (NP) | Overall IQ Score | 98.60 Scores on a scale | Standard Deviation 17.95 |
| Regimen A (Radiotherapy Only) | Quality of Life (QOL) and Neurocognitive Assessment (NP) | Self Report Score-Internalizing Problems | 41.00 Scores on a scale | Standard Deviation 2.83 |
| Regimen A (Radiotherapy Only) | Quality of Life (QOL) and Neurocognitive Assessment (NP) | Self Report Score-Emotional Problems | 44.00 Scores on a scale | Standard Deviation 2.83 |
| Regimen A (Radiotherapy Only) | Quality of Life (QOL) and Neurocognitive Assessment (NP) | Self Report Score-Personal Adjustment Strengths | 51.50 Scores on a scale | Standard Deviation 2.12 |
| Regimen A (Radiotherapy Only) | Quality of Life (QOL) and Neurocognitive Assessment (NP) | Parent Report QoL Total Score | 88.04 Scores on a scale | Standard Deviation 6.15 |
| Regimen A (Radiotherapy Only) | Quality of Life (QOL) and Neurocognitive Assessment (NP) | Self Report QoL Total Score | 95.65 Scores on a scale | — |
| Regimen B (Chemotherapy Plus Radiotherapy) | Quality of Life (QOL) and Neurocognitive Assessment (NP) | Parent Report QoL Total Score | 79.35 Scores on a scale | Standard Deviation 6.15 |
| Regimen B (Chemotherapy Plus Radiotherapy) | Quality of Life (QOL) and Neurocognitive Assessment (NP) | Overall IQ Score | 92.43 Scores on a scale | Standard Deviation 6.27 |
| Regimen B (Chemotherapy Plus Radiotherapy) | Quality of Life (QOL) and Neurocognitive Assessment (NP) | Self Report Score-Personal Adjustment Strengths | 60.50 Scores on a scale | Standard Deviation 3.32 |
| Regimen B (Chemotherapy Plus Radiotherapy) | Quality of Life (QOL) and Neurocognitive Assessment (NP) | Self Report Score-Internalizing Problems | 42.50 Scores on a scale | Standard Deviation 5.51 |
| Regimen B (Chemotherapy Plus Radiotherapy) | Quality of Life (QOL) and Neurocognitive Assessment (NP) | Self Report QoL Total Score | 90.76 Scores on a scale | Standard Deviation 0.76 |
| Regimen B (Chemotherapy Plus Radiotherapy) | Quality of Life (QOL) and Neurocognitive Assessment (NP) | Self Report Score-Emotional Problems | 42.00 Scores on a scale | Standard Deviation 4.55 |
Secondary
Toxicity and Safety as Assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0
The analysis of toxicity will focus on estimating the rates of key acute and subacute toxicity occurring during the first induction chemotherapy. The list of toxicities of interest include Anemia or Febrile Neutropenia; Nausea or Vomiting; Infections and Infestations; Neutrophil or White blood count decrease; and Hypokalemia or Hyponatremia
Time frame: From the beginning of treatment, assessed up to 5 years
Population: Patients who received any pre-radiotherapy chemotherapy in Regimen B
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Regimen A (Radiotherapy Only) | Toxicity and Safety as Assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 | Anemia or Febrile Neutropenia | 2 Participants |
| Regimen A (Radiotherapy Only) | Toxicity and Safety as Assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 | Nausea or Vomiting | 2 Participants |
| Regimen A (Radiotherapy Only) | Toxicity and Safety as Assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 | Infections and Infestations | 2 Participants |
| Regimen A (Radiotherapy Only) | Toxicity and Safety as Assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 | Neutorphil or White blood count decrease | 7 Participants |
| Regimen A (Radiotherapy Only) | Toxicity and Safety as Assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 | Hypokalemia or Hyponatremia | 3 Participants |