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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

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

Status
Completed
Phases
Phase 2
Study type
Interventional
Source
ClinicalTrials.gov
Registry ID
NCT00047320
Enrollment
104
Registered
2003-01-27
Start date
2004-01-31
Completion date
2009-02-28
Last updated
2018-02-14

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Brain Tumor, Central Nervous System Tumors, Childhood Germ Cell Tumor

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

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.

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.

Interventions

DRUGcarboplatin

Given IV

DRUGetoposide

Given IV

DRUGifosfamide

Given IV

DRUGthiotepa

Given IV

PROCEDUREadjuvant therapy
PROCEDUREconventional surgery
PROCEDUREneoadjuvant therapy
PROCEDUREperipheral blood stem cell transplantation
RADIATIONradiation therapy

craniospinal irradiation

Sponsors

National Cancer Institute (NCI)
CollaboratorNIH
Children's Oncology Group
Lead SponsorNETWORK

Study design

Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE

Eligibility

Sex/Gender
ALL
Age
3 Years to 24 Years
Healthy volunteers
No

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

Design outcomes

Primary

MeasureTime frameDescription
Response to Induction Chemotherapy18 weeksA 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.

Secondary

MeasureTime frameDescription
The Probability of Event-free Survival (EFS)At 3 years from study entryEvent-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.
Progression-free Survival (PFS)At 3 years from study entryProgression-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.
Overall Survival (OS)At 3 years from study entryOverall Survival was defined as time from study entry to death from any cause. Overall survival was estimated by KM estimate.
Number of Patients Experiencing Toxic DeathDuring chemotherapy (up to 18 weeks)Toxic death, defined as death predominantly attributable to treatment-related causes.
Occurrence of Non-hematological Grade 4 Toxicity Occurrence of Nonhematological Grade 4 ToxicityDuring chemotherapy(up to 18 weeks)The number of patients who experienced non-hematological grade 4 toxicities anytime during chemotherapy.

Countries

Australia, Canada, New Zealand, Switzerland, United States

Participant flow

Participants by arm

ArmCount
Radiation Therapy (CR From Induction)
Patients will receive 6 cycles of Induction chemotherapy consisting of carboplatin and etoposide (Cycles 1, 3, and 5) alternating with ifosfamide and etoposide (Cycles 2, 4, and 6). The entire length of Induction is 18 weeks unless delay occurs due to myelosuppression or unanticipated toxicity. Each cycle of Induction will begin when ANC \> 750/L and platelets \> 75,000/L and when off filgrastim (G-CSF) for at least 48 hours. Following the Induction phase (weeks 0-18) those patient in CR will undergo radiation therapy. carboplatin: Given IV etoposide: Given IV ifosfamide: Given IV radiation therapy: craniospinal irradiation
104
Total104

Withdrawals & dropouts

PeriodReasonFG000
Overall StudyIneligible2
Overall StudyLack of Efficacy8
Overall StudyLost to Follow-up1
Overall StudyPhysician Decision8
Overall StudyWithdrawal by Subject9

Baseline characteristics

CharacteristicRadiation Therapy (CR From Induction)
Age, Continuous12 years
Ethnicity (NIH/OMB)
Hispanic or Latino
17 Participants
Ethnicity (NIH/OMB)
Not Hispanic or Latino
85 Participants
Ethnicity (NIH/OMB)
Unknown or Not Reported
2 Participants
Race (NIH/OMB)
American Indian or Alaska Native
1 Participants
Race (NIH/OMB)
Asian
8 Participants
Race (NIH/OMB)
Black or African American
9 Participants
Race (NIH/OMB)
More than one race
0 Participants
Race (NIH/OMB)
Native Hawaiian or Other Pacific Islander
2 Participants
Race (NIH/OMB)
Unknown or Not Reported
12 Participants
Race (NIH/OMB)
White
72 Participants
Region of Enrollment
Australia
5 participants
Region of Enrollment
Canada
10 participants
Region of Enrollment
New Zealand
1 participants
Region of Enrollment
United States
88 participants
Sex: Female, Male
Female
25 Participants
Sex: Female, Male
Male
79 Participants

Adverse events

Event typeEG000
affected / at risk
deaths
Total, all-cause mortality
— / —
other
Total, other adverse events
70 / 102
serious
Total, serious adverse events
8 / 102

Outcome results

Primary

Response to Induction Chemotherapy

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.

Time frame: 18 weeks

Population: Of the 102 eligible patients, 85 completed induction chemotherapy with sufficient data to assess response. Central review response assessment is used.

ArmMeasureGroupValue (COUNT_OF_PARTICIPANTS)
Radiation Therapy (CR From Induction)Response to Induction ChemotherapyResponder74 Participants
Radiation Therapy (CR From Induction)Response to Induction ChemotherapyNon-Responder11 Participants
Secondary

Number of Patients Experiencing Toxic Death

Toxic death, defined as death predominantly attributable to treatment-related causes.

Time frame: During chemotherapy (up to 18 weeks)

Population: A total of 102 eligible patients treated with induction chemotherapy were included.

ArmMeasureValue (COUNT_OF_PARTICIPANTS)
Radiation Therapy (CR From Induction)Number of Patients Experiencing Toxic Death0 Participants
Secondary

Occurrence of Non-hematological Grade 4 Toxicity Occurrence of Nonhematological Grade 4 Toxicity

The number of patients who experienced non-hematological grade 4 toxicities anytime during chemotherapy.

Time frame: During chemotherapy(up to 18 weeks)

Population: A total of 102 eligible patients treated with induction chemotherapy were included.

ArmMeasureValue (NUMBER)
Radiation Therapy (CR From Induction)Occurrence of Non-hematological Grade 4 Toxicity Occurrence of Nonhematological Grade 4 Toxicity22 participants
Secondary

Overall Survival (OS)

Overall Survival was defined as time from study entry to death from any cause. Overall survival was estimated by KM estimate.

Time frame: At 3 years from study entry

Population: Two ineligible patients were excluded. A total of 102 eligible patients were analyzed.

ArmMeasureValue (NUMBER)
Radiation Therapy (CR From Induction)Overall Survival (OS)0.927 Probability
Secondary

Progression-free Survival (PFS)

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.

Time frame: At 3 years from study entry

Population: Two ineligible patients were excluded. A total of 102 eligible patients were analyzed. one patient died without the disease progression reported. But the death was due to the disease. The death was counted as event when progression-free survival (PFS) was calculated. So EFS and PFS at 3 years were same.

ArmMeasureValue (NUMBER)
Radiation Therapy (CR From Induction)Progression-free Survival (PFS)0.837 Probability
Secondary

The Probability of Event-free Survival (EFS)

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.

Time frame: At 3 years from study entry

Population: Two ineligible patients were excluded. A total of 102 eligible patients were analyzed.

ArmMeasureValue (NUMBER)
Radiation Therapy (CR From Induction)The Probability of Event-free Survival (EFS)0.837 Probability

Source: ClinicalTrials.gov · Data processed: Feb 20, 2026