Brief Summary
RATIONALE: Drugs used in chemotherapy work in different ways to stop tumor cells from dividing so they stop growing or die. Giving a chemotherapy drug before surgery may shrink the tumor so that it is no longer present by conventional imaging and tumor markers from serum and cerebrospinal fluid. Radiation therapy uses high-energy x-rays to damage tumor cells. Peripheral stem cell transplantation may allow the doctor to give higher doses of chemotherapy drugs and kill more tumor cells. Combining different types of therapy may kill more tumor cells.
PURPOSE: This Phase II trial is studying how well neoadjuvant chemotherapy with or without surgery and with or without high dose chemotherapy and peripheral stem cell transplantation, can increase response rates prior to radiation therapy and increase progression free and overall surviving patients with newly diagnosed intracranial germ cell tumors.
PURPOSE: This Phase II trial is studying how well neoadjuvant chemotherapy with or without surgery and with or without high dose chemotherapy and peripheral stem cell transplantation, can increase response rates prior to radiation therapy and increase progression free and overall surviving patients with newly diagnosed intracranial germ cell tumors.
Brief Title
Neoadjuvant Chemotherapy With or Without Second-Look Surgery Followed by Radiation Therapy With or Without Peripheral Stem Cell Transplantation in Treating Patients With Intracranial Germ Cell Tumors
Detailed Description
OBJECTIVES:
* Determine the response rate of patients with non-germinomatous germ cell tumors treated with neoadjuvant chemotherapy.
* Determine the progression-free survival and overall survival of patients treated with neoadjuvant chemotherapy with or without second-look surgery followed by radiotherapy with or without autologous peripheral blood stem cell transplantation (PBSCT).
* Determine whether additional complete responses can be achieved after high-dose thiotepa and etoposide with PBSCT in patients with persistently positive markers, histological evidence of residual malignant elements, or unresectable residual tumors after initial neoadjuvant chemotherapy.
* Determine patterns of recurrence in patients treated with this regimen.
* Correlate tumor marker response with radiographic and clinical measures of response, as well as findings at second-look surgery in patients with radiological evidence of residual disease.
OUTLINE:
* Induction chemotherapy:
* Courses 1, 3, and 5: Patients receive carboplatin IV over 1 hour on day 1 and etoposide IV over 1 hour on days 1-3. Beginning on day 4, patients receive filgrastim (G-CSF) IV or subcutaneously (SC) for 10 days or until blood counts recover. Courses are 3 weeks in duration.
* Courses 2, 4, and 6: Patients receive etoposide IV over 1 hour followed by ifosfamide IV over 1 hour on days 1-5. Beginning on day 6, patients receive G-CSF IV or SC for 10 days or until blood counts recover. Courses are 3 weeks in duration.
Patients undergo re-evaluation. Patients with a complete response (CR) go directly to radiotherapy. Approximately 3 weeks after completion of induction chemotherapy, all patients with less than a CR are encouraged to undergo second-look surgery.
After second-look surgery, patients with a CR or a partial response (PR) go directly to radiotherapy. Patients with less than a PR undergo consolidation chemotherapy with peripheral blood stem cell rescue (PBSC) followed by radiotherapy.
* Consolidation chemotherapy: Patients undergo PBSC collection. Patients receive G-CSF SC until PBSC collection is complete. Patients then receive thiotepa IV over 3 hours followed by etoposide IV over 3 hours on days -5 to -3. PBSCs are reinfused on day 0. Beginning on day 1 and continuing until blood counts recover, patients receive G-CSF SC daily.
* Radiotherapy: All patients receive radiotherapy once daily 5 days a week for 5-6 weeks beginning after recovery from induction chemotherapy or second-look surgery or within 9 weeks after PBSC reinfusion.
Patients are followed every 3 months for 1 year, every 4 months for 1 year, every 6 months for 1 year, and then annually thereafter.
PROJECTED ACCRUAL: A total of 80-100 patients will be accrued for this study within 36-42 months.
* Determine the response rate of patients with non-germinomatous germ cell tumors treated with neoadjuvant chemotherapy.
* Determine the progression-free survival and overall survival of patients treated with neoadjuvant chemotherapy with or without second-look surgery followed by radiotherapy with or without autologous peripheral blood stem cell transplantation (PBSCT).
* Determine whether additional complete responses can be achieved after high-dose thiotepa and etoposide with PBSCT in patients with persistently positive markers, histological evidence of residual malignant elements, or unresectable residual tumors after initial neoadjuvant chemotherapy.
* Determine patterns of recurrence in patients treated with this regimen.
* Correlate tumor marker response with radiographic and clinical measures of response, as well as findings at second-look surgery in patients with radiological evidence of residual disease.
OUTLINE:
* Induction chemotherapy:
* Courses 1, 3, and 5: Patients receive carboplatin IV over 1 hour on day 1 and etoposide IV over 1 hour on days 1-3. Beginning on day 4, patients receive filgrastim (G-CSF) IV or subcutaneously (SC) for 10 days or until blood counts recover. Courses are 3 weeks in duration.
* Courses 2, 4, and 6: Patients receive etoposide IV over 1 hour followed by ifosfamide IV over 1 hour on days 1-5. Beginning on day 6, patients receive G-CSF IV or SC for 10 days or until blood counts recover. Courses are 3 weeks in duration.
Patients undergo re-evaluation. Patients with a complete response (CR) go directly to radiotherapy. Approximately 3 weeks after completion of induction chemotherapy, all patients with less than a CR are encouraged to undergo second-look surgery.
After second-look surgery, patients with a CR or a partial response (PR) go directly to radiotherapy. Patients with less than a PR undergo consolidation chemotherapy with peripheral blood stem cell rescue (PBSC) followed by radiotherapy.
* Consolidation chemotherapy: Patients undergo PBSC collection. Patients receive G-CSF SC until PBSC collection is complete. Patients then receive thiotepa IV over 3 hours followed by etoposide IV over 3 hours on days -5 to -3. PBSCs are reinfused on day 0. Beginning on day 1 and continuing until blood counts recover, patients receive G-CSF SC daily.
* Radiotherapy: All patients receive radiotherapy once daily 5 days a week for 5-6 weeks beginning after recovery from induction chemotherapy or second-look surgery or within 9 weeks after PBSC reinfusion.
Patients are followed every 3 months for 1 year, every 4 months for 1 year, every 6 months for 1 year, and then annually thereafter.
PROJECTED ACCRUAL: A total of 80-100 patients will be accrued for this study within 36-42 months.
Categories
Completion Date
Completion Date Type
Actual
Conditions
Brain Tumor
Central Nervous System Tumors
Childhood Germ Cell Tumor
Eligibility Criteria
DISEASE CHARACTERISTICS:
* One of the following diagnoses:
* Histologically confirmed intracranial non-germinomatous germ cell tumor (NGGCT) of 1 of the following types:
* Endodermal sinus tumor (yolk sac tumor)
* Embryonal carcinoma
* Choriocarcinoma
* Immature teratoma and teratoma with malignant transformation
* Mixed germ cell tumor
* Histologically confirmed germinoma with elevation of serum/CSF beta human chorionic gonadotropin (HCG) levels greater than 50 mIU/mL or any serum/CSF alpha-fetoprotein (AFP) levels greater than 10 ng/ml or above institutional norm
* Histologically unconfirmed pineal and/or suprasellar tumors with serum/CSF beta HCG levels greater than 50 mIU/mL or AFP levels greater than 10 ng/ml or above institutional norm
* Patients with normal AFP and beta HCG \< 50 mIU/mL without histologic diagnosis of a NGGCT or patients with pure germinoma without elevation of tumor marker are ineligible
* Initial diagnosis within the past 31 days
PATIENT CHARACTERISTICS:
Age
* 3 to 24 at diagnosis
Performance status
* No minimum performance level
Life expectancy
* At least 8 weeks
Hematopoietic
* Absolute neutrophil count at least 1,000/mm\^3
* Platelet count at least 100,000/mm\^3 (transfusion independent)
* Hemoglobin at least 10.0 g/dL (transfusion allowed)
Hepatic
* Bilirubin no greater than 1.5 times upper limit of normal (ULN)
* ALT no greater than 2.5 times ULN
Renal
* Creatinine no greater than 1.5 times ULN OR
* Creatinine clearance or radioisotope glomerular filtration rate at least 70 mL/min
Pulmonary
* No assisted ventilation
Other
* Seizure disorders allowed
* No patients in status or coma
* Not pregnant or nursing
* Negative pregnancy test
* Fertile patient must use effective contraception
PRIOR CONCURRENT THERAPY:
Biologic therapy
* Not specified
Chemotherapy
* Not specified
Endocrine therapy
* Prior corticosteroids allowed
* Concurrent corticosteroids allowed
* Concurrent endocrine replacement therapy allowed (e.g., L-thyroxine, testosterone, estrogen, desmopressin acetate)
* No concurrent growth hormone therapy
Radiotherapy
* Not specified
Surgery
* More than 1 prior surgery allowed
Other
* No other prior therapy for malignancy
* One of the following diagnoses:
* Histologically confirmed intracranial non-germinomatous germ cell tumor (NGGCT) of 1 of the following types:
* Endodermal sinus tumor (yolk sac tumor)
* Embryonal carcinoma
* Choriocarcinoma
* Immature teratoma and teratoma with malignant transformation
* Mixed germ cell tumor
* Histologically confirmed germinoma with elevation of serum/CSF beta human chorionic gonadotropin (HCG) levels greater than 50 mIU/mL or any serum/CSF alpha-fetoprotein (AFP) levels greater than 10 ng/ml or above institutional norm
* Histologically unconfirmed pineal and/or suprasellar tumors with serum/CSF beta HCG levels greater than 50 mIU/mL or AFP levels greater than 10 ng/ml or above institutional norm
* Patients with normal AFP and beta HCG \< 50 mIU/mL without histologic diagnosis of a NGGCT or patients with pure germinoma without elevation of tumor marker are ineligible
* Initial diagnosis within the past 31 days
PATIENT CHARACTERISTICS:
Age
* 3 to 24 at diagnosis
Performance status
* No minimum performance level
Life expectancy
* At least 8 weeks
Hematopoietic
* Absolute neutrophil count at least 1,000/mm\^3
* Platelet count at least 100,000/mm\^3 (transfusion independent)
* Hemoglobin at least 10.0 g/dL (transfusion allowed)
Hepatic
* Bilirubin no greater than 1.5 times upper limit of normal (ULN)
* ALT no greater than 2.5 times ULN
Renal
* Creatinine no greater than 1.5 times ULN OR
* Creatinine clearance or radioisotope glomerular filtration rate at least 70 mL/min
Pulmonary
* No assisted ventilation
Other
* Seizure disorders allowed
* No patients in status or coma
* Not pregnant or nursing
* Negative pregnancy test
* Fertile patient must use effective contraception
PRIOR CONCURRENT THERAPY:
Biologic therapy
* Not specified
Chemotherapy
* Not specified
Endocrine therapy
* Prior corticosteroids allowed
* Concurrent corticosteroids allowed
* Concurrent endocrine replacement therapy allowed (e.g., L-thyroxine, testosterone, estrogen, desmopressin acetate)
* No concurrent growth hormone therapy
Radiotherapy
* Not specified
Surgery
* More than 1 prior surgery allowed
Other
* No other prior therapy for malignancy
Inclusion Criteria
DISEASE CHARACTERISTICS:
* One of the following diagnoses:
* Histologically confirmed intracranial non-germinomatous germ cell tumor (NGGCT) of 1 of the following types:
* Endodermal sinus tumor (yolk sac tumor)
* Embryonal carcinoma
* Choriocarcinoma
* Immature teratoma and teratoma with malignant transformation
* Mixed germ cell tumor
* Histologically confirmed germinoma with elevation of serum/CSF beta human chorionic gonadotropin (HCG) levels greater than 50 mIU/mL or any serum/CSF alpha-fetoprotein (AFP) levels greater than 10 ng/ml or above institutional norm
* Histologically unconfirmed pineal and/or suprasellar tumors with serum/CSF beta HCG levels greater than 50 mIU/mL or AFP levels greater than 10 ng/ml or above institutional norm
* Patients with normal AFP and beta HCG \< 50 mIU/mL without histologic diagnosis of a NGGCT or patients with pure germinoma without elevation of tumor marker are ineligible
* Initial diagnosis within the past 31 days
PATIENT CHARACTERISTICS:
Age
* 3 to 24 at diagnosis
Performance status
* No minimum performance level
Life expectancy
* At least 8 weeks
Hematopoietic
* Absolute neutrophil count at least 1,000/mm\^3
* Platelet count at least 100,000/mm\^3 (transfusion independent)
* Hemoglobin at least 10.0 g/dL (transfusion allowed)
Hepatic
* Bilirubin no greater than 1.5 times upper limit of normal (ULN)
* ALT no greater than 2.5 times ULN
Renal
* Creatinine no greater than 1.5 times ULN OR
* Creatinine clearance or radioisotope glomerular filtration rate at least 70 mL/min
Pulmonary
* No assisted ventilation
Other
* Seizure disorders allowed
* No patients in status or coma
* Not pregnant or nursing
* Negative pregnancy test
* Fertile patient must use effective contraception
PRIOR CONCURRENT THERAPY:
Biologic therapy
* Not specified
Chemotherapy
* Not specified
Endocrine therapy
* Prior corticosteroids allowed
* Concurrent corticosteroids allowed
* Concurrent endocrine replacement therapy allowed (e.g., L-thyroxine, testosterone, estrogen, desmopressin acetate)
* No concurrent growth hormone therapy
Radiotherapy
* Not specified
Surgery
* More than 1 prior surgery allowed
Other
* No other prior therapy for malignancy
* One of the following diagnoses:
* Histologically confirmed intracranial non-germinomatous germ cell tumor (NGGCT) of 1 of the following types:
* Endodermal sinus tumor (yolk sac tumor)
* Embryonal carcinoma
* Choriocarcinoma
* Immature teratoma and teratoma with malignant transformation
* Mixed germ cell tumor
* Histologically confirmed germinoma with elevation of serum/CSF beta human chorionic gonadotropin (HCG) levels greater than 50 mIU/mL or any serum/CSF alpha-fetoprotein (AFP) levels greater than 10 ng/ml or above institutional norm
* Histologically unconfirmed pineal and/or suprasellar tumors with serum/CSF beta HCG levels greater than 50 mIU/mL or AFP levels greater than 10 ng/ml or above institutional norm
* Patients with normal AFP and beta HCG \< 50 mIU/mL without histologic diagnosis of a NGGCT or patients with pure germinoma without elevation of tumor marker are ineligible
* Initial diagnosis within the past 31 days
PATIENT CHARACTERISTICS:
Age
* 3 to 24 at diagnosis
Performance status
* No minimum performance level
Life expectancy
* At least 8 weeks
Hematopoietic
* Absolute neutrophil count at least 1,000/mm\^3
* Platelet count at least 100,000/mm\^3 (transfusion independent)
* Hemoglobin at least 10.0 g/dL (transfusion allowed)
Hepatic
* Bilirubin no greater than 1.5 times upper limit of normal (ULN)
* ALT no greater than 2.5 times ULN
Renal
* Creatinine no greater than 1.5 times ULN OR
* Creatinine clearance or radioisotope glomerular filtration rate at least 70 mL/min
Pulmonary
* No assisted ventilation
Other
* Seizure disorders allowed
* No patients in status or coma
* Not pregnant or nursing
* Negative pregnancy test
* Fertile patient must use effective contraception
PRIOR CONCURRENT THERAPY:
Biologic therapy
* Not specified
Chemotherapy
* Not specified
Endocrine therapy
* Prior corticosteroids allowed
* Concurrent corticosteroids allowed
* Concurrent endocrine replacement therapy allowed (e.g., L-thyroxine, testosterone, estrogen, desmopressin acetate)
* No concurrent growth hormone therapy
Radiotherapy
* Not specified
Surgery
* More than 1 prior surgery allowed
Other
* No other prior therapy for malignancy
Gender
All
Gender Based
false
Keywords
childhood central nervous system germ cell tumor
childhood teratoma
recurrent childhood malignant germ cell tumor
childhood central nervous system choriocarcinoma
childhood central nervous system embryonal tumor
childhood central nervous system germinoma
childhood central nervous system mixed germ cell tumor
childhood central nervous system teratoma
childhood central nervous system yolk sac tumor
recurrent childhood central nervous system embryonal tumor
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Maximum Age
24 Years
Minimum Age
3 Years
NCT Id
NCT00047320
Org Class
Network
Org Full Name
Children's Oncology Group
Org Study Id
ACNS0122
Overall Status
Completed
Phases
Phase 2
Primary Completion Date
Primary Completion Date Type
Actual
Official Title
A Phase II Study To Assess The Ability Of Neoadjuvant Chemotherapy Plus/Minus Second Look Surgery To Eliminate All Measurable Disease Prior To Radiotherapy For NGGCT
Primary Outcomes
Outcome Description
A patient who achieves a complete or partial response, defined a reduction of at least 65% in tumor size after induction chemotherapy will be considered to have experienced response.
Outcome Measure
Response to Induction Chemotherapy
Outcome Time Frame
18 weeks
Secondary Ids
Secondary Id
CDR0000257664
Secondary Id
COG-ACNS0122
Secondary Outcomes
Outcome Description
Event-free Survival was defined as time from study entry to death from any cause, disease progression or recurrence, or second malignant neoplasm. Event-free survival was estimated by KM estimate.
Outcome Time Frame
At 3 years from study entry
Outcome Measure
The Probability of Event-free Survival (EFS)
Outcome Description
Progression-free Survival was defined as time from study entry to disease progression or recurrence. Deaths that are clearly unrelated to disease progression, and second neoplasms are censored in this analysis. Progression -free survival was estimated by KM estimate.
Outcome Time Frame
At 3 years from study entry
Outcome Measure
Progression-free Survival (PFS)
Outcome Description
Overall Survival was defined as time from study entry to death from any cause. Overall survival was estimated by KM estimate.
Outcome Time Frame
At 3 years from study entry
Outcome Measure
Overall Survival (OS)
Outcome Description
Toxic death, defined as death predominantly attributable to treatment-related causes.
Outcome Time Frame
During chemotherapy (up to 18 weeks)
Outcome Measure
Number of Patients Experiencing Toxic Death
Outcome Description
The number of patients who experienced non-hematological grade 4 toxicities anytime during chemotherapy.
Outcome Time Frame
During chemotherapy(up to 18 weeks)
Outcome Measure
Occurrence of Non-hematological Grade 4 Toxicity Occurrence of Nonhematological Grade 4 Toxicity
Start Date
Status Verified Date
First Post Date
First Post Date Type
Estimated
First Submit Date
First Submit QC Date
Std Ages
Child
Adult
Maximum Age Number (converted to Years and rounded down)
24
Minimum Age Number (converted to Years and rounded down)
3
Investigators
Investigator Type
Principal Investigator
Investigator Name
Jonathan Gill
Investigator Email
jgill@montefiore.org
Investigator Phone
718-741-2331
Categories Mesh Debug
Brain, Spine & Nerve Cancers --- BRAIN NEOPLASMS
Brain, Spine & Nerve Cancers --- CENTRAL NERVOUS SYSTEM NEOPLASMS
Brain, Spine & Nerve Cancers --- NERVOUS SYSTEM NEOPLASMS
Cancer --- NEOPLASMS BY SITE
Cancer --- NEOPLASMS
Alzheimer's --- BRAIN DISEASES
Brain, Spinal Cord & Nervous System --- BRAIN DISEASES
Brain, Spine & Nerve Cancers --- BRAIN DISEASES
Alzheimer's --- CENTRAL NERVOUS SYSTEM DISEASES
Brain, Spinal Cord & Nervous System --- CENTRAL NERVOUS SYSTEM DISEASES
Brain, Spine & Nerve Cancers --- CENTRAL NERVOUS SYSTEM DISEASES
Brain, Spinal Cord & Nervous System --- NERVOUS SYSTEM DISEASES
Brain, Spine & Nerve Cancers --- NERVOUS SYSTEM DISEASES
MeSH Terms
BRAIN NEOPLASMS
CENTRAL NERVOUS SYSTEM NEOPLASMS
TERATOMA
NERVOUS SYSTEM NEOPLASMS
NEOPLASMS BY SITE
NEOPLASMS
BRAIN DISEASES
CENTRAL NERVOUS SYSTEM DISEASES
NERVOUS SYSTEM DISEASES
NEOPLASMS, GERM CELL AND EMBRYONAL
NEOPLASMS BY HISTOLOGIC TYPE
CARBOPLATIN
ETOPOSIDE
ETOPOSIDE PHOSPHATE
IFOSFAMIDE
THIOTEPA
CHEMOTHERAPY, ADJUVANT
NEOADJUVANT THERAPY
PERIPHERAL BLOOD STEM CELL TRANSPLANTATION
RADIOTHERAPY
CRANIOSPINAL IRRADIATION
COORDINATION COMPLEXES
ORGANIC CHEMICALS
PODOPHYLLOTOXIN
TETRAHYDRONAPHTHALENES
NAPHTHALENES
POLYCYCLIC AROMATIC HYDROCARBONS
HYDROCARBONS, AROMATIC
HYDROCARBONS, CYCLIC
HYDROCARBONS
POLYCYCLIC COMPOUNDS
GLUCOSIDES
GLYCOSIDES
CARBOHYDRATES
CYCLOPHOSPHAMIDE
PHOSPHORAMIDE MUSTARDS
NITROGEN MUSTARD COMPOUNDS
MUSTARD COMPOUNDS
HYDROCARBONS, HALOGENATED
PHOSPHORAMIDES
ORGANOPHOSPHORUS COMPOUNDS
OXAZINES
HETEROCYCLIC COMPOUNDS, 1-RING
HETEROCYCLIC COMPOUNDS
TRIETHYLENEPHOSPHORAMIDE
AZIRIDINES
AZIRINES
COMBINED MODALITY THERAPY
THERAPEUTICS
DRUG THERAPY
HEMATOPOIETIC STEM CELL TRANSPLANTATION
STEM CELL TRANSPLANTATION
CELL TRANSPLANTATION
CELL- AND TISSUE-BASED THERAPY
BIOLOGICAL THERAPY
TRANSPLANTATION
SURGICAL PROCEDURES, OPERATIVE