Childhood Embryonal Tumor, Childhood Extracranial Germ Cell Tumor, Childhood Extragonadal Germ Cell Tumor, Childhood Malignant Ovarian Germ Cell Tumor, Childhood Malignant Testicular Germ Cell Tumor, Childhood Teratoma, Ovarian Embryonal Carcinoma, Ovarian Yolk Sac Tumor, Stage IIA Ovarian Germ Cell Tumor, Stage IIB Ovarian Germ Cell Tumor, Stage IIC Ovarian Germ Cell Tumor, Stage IIIA Ovarian Germ Cell Tumor, Stage IIIB Ovarian Germ Cell Tumor, Stage IIIC Ovarian Germ Cell Tumor, Stage III Malignant Testicular Germ Cell Tumor, Stage II Malignant Testicular Germ Cell Tumor, Testicular Choriocarcinoma and Yolk Sac Tumor, Testicular Embryonal Carcinoma
Conditions
Brief summary
This phase III trial is studying surgery followed by combination chemotherapy to see how well it works in treating children with germ cell tumors that are not located in the head. Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug, and giving them after surgery, may kill any remaining tumor cells following surgery. It is not yet known whether combination chemotherapy is effective in decreasing the recurrence of childhood germ cell tumors.
Detailed description
OBJECTIVES: I. Determine whether children with newly diagnosed low- or intermediate-risk extracranial germ cell tumors (GCTs) can maintain a 3-year event-free survival of at least 92% (for intermediate-risk tumors only) and overall survival of at least 95% (both low-risk and intermediate-risk tumors) after treatment with surgery followed by compressed cisplatin, etoposide, and bleomycin (low-risk disease closed to accrual as of 01/20/10). II. Determine the percentage of patients with stage I ovarian or stage I testicular GCTs for whom chemotherapy can be eliminated. III. Determine the percentage of intermediate-risk patients who require only 3 courses of therapy. IV. Determine the acute toxic effects of compressed therapy in these patients. V. Determine the long-term sequelae in patients treated with this regimen. VI. Determine the number of hospital days and total drug doses required for patients treated with compressed therapy. VII. Compare the number of protocol-directed treatment days used in CCG-8882 vs the number of treatment days used in this study. VIII. Determine the cytogenetic and molecular genetic features in patients treated with this regimen. OUTLINE: Patients are stratified according to disease risk (low vs intermediate). SURGERY: Patients undergo surgical resection. Low-risk disease: Patients with gonadal primaries and no evidence of disease after surgery undergo monitoring for disease progression. Patients who remain disease free receive no further treatment. Patients who have disease progression after surgery receive compressed induction chemotherapy. (closed to accrual as of 01/20/2010) Intermediate-risk disease: After surgery, patients proceed to compressed induction chemotherapy. COMPRESSED INDUCTION CHEMOTHERAPY: Patients receive cisplatin IV over 90 minutes and etoposide IV over 90 minutes on days 1-3 and bleomycin IV over ≥ 10 minutes on day 1. Treatment repeats every 3 weeks for 3 courses (weeks 0, 3, and 6). After completion of compressed induction chemotherapy, patients who have no change in disease status or disease progression are removed from study. Patients with no evidence of disease receive no further therapy. Patients with a partial response or who have abnormal tumor markers proceed to second-look surgery and/or 3 more courses of compressed consolidation chemotherapy. SECOND-LOOK SURGERY: Patients undergo surgical resection of residual tumor. After surgery, patients who are in pathologic complete response and have normal tumor markers receive no further therapy. Patients who remain with a partial response after surgery receive compressed consolidation chemotherapy. COMPRESSED CONSOLIDATION CHEMOTHERAPY: Patients receive cisplatin, etoposide, and bleomycin as in induction chemotherapy in weeks 10, 13, and 16. Patients are followed up monthly for 6 months, every 3 months for 18 months, and then annually for up to 10 years.
Interventions
PROCEDUREconventional surgery
DRUGcisplatin
Given IV
DRUGetoposide
Given IV
BIOLOGICALbleomycin sulfate
Given IV
OTHERlaboratory biomarker analysis
Correlative studies
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
No minimum to 21 Years
Healthy volunteers
No
Inclusion criteria
* Extracranial germ cell tumor that contains 1 of the following malignant histologies: NOTE: Mixed germ cell tumors that include mature/immature teratoma are eligible provided 1 of the 3 histologies listed above is also present in the tumor. * Yolk sac tumor * Embryonal carcinoma * Choriocarcinoma * Low-risk disease (closed to accrual as of 01/20/10) * Stage I gonadal tumors (ovarian and testicular) * Must have undergone complete surgical and radiologic staging to exclude the possibility of \> stage I disease * Intermediate-risk disease * Stage II, III, or IV malignant testicular GCT * Stage II or III malignant ovarian GCT * Stage I or II malignant extragonadal GCT * Previously stage I gonadal patients who have relapsed on the low-risk (observation) stratum of this study(closed to accrual as of 01/20/10) * Patients with immature teratoma or mature teratoma who relapse with a malignant component * No patients with any of the following diagnoses: * Stage IV ovarian and stage III-IV extragonadal GCT * Intracranial GCT * Pure mature or immature teratoma, pure dysgerminoma, or seminoma * Patients with a non-germ cell component in their GCT (e.g., primitive neuroectodermal tumors or rhabdomyosarcoma) * Alpha-fetoprotein and beta human chorionic gonadotropin tumor markers known * If \> 5 days have elapsed from the time of obtaining original markers, tumor markers must be repeated before enrollment of low-risk patients and before initiating therapy in intermediate-risk patients (the results of the repeated tumor markers do not have to be known at the time of study enrollment) * Must be enrolled within 6 weeks of original diagnostic surgery * Creatinine clearance or radioisotope GFR ≥ 70 mL/min OR a serum creatinine based on age/gender as follows: * ≤ 0.4 mg/dL (for patients 1 to 5 months of age) * ≤ 0.5 mg/dL (for patients 6 to 11 months of age) * ≤ 0.6 mg/dL (for patients 1 year of age) * ≤ 0.8 mg/dL (for patients 2 to 5 years of age) * ≤ 1.0 mg/dL (for patients 6 to 9 years of age) * ≤ 1.2 mg/dL (for patients 10 to 12 years of age) * ≤ 1.4 mg/dL (for female patients ≥ 13 years of age) * ≤ 1.5 mg/dL (for male patients 13 to 15 years of age) * ≤ 1.7 mg/dL (for male patients ≥ 16 years of age) * No prior chemotherapy * No prior radiotherapy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Event-Free Survival (EFS) | 3 Years after enrollment | Proportion of patients event free at 3 years following enrollment. Event-free survival is not a primary outcome measure for Arm 2 patients. |
| Overall Survival (OS) | 3 Years after enrollment | Percentage probability of being alive at 3 years following enrollment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Days Hospitalized for Patients Who Receive Chemotherapy | Up to 126 days after the start of chemotherapy | Calculated to quantify the treatment cost associated with this regimen. |
| Toxicity Associated With Chemotherapy: Grade 3 or Higher. Toxicity as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) v4.0 | Up to 126 days after the start of chemotherapy | The number of patients assigned to receive chemotherapy that experience CTC Version 4 grade 3 or higher at any time during protocol therapy |
Countries
Australia, Canada, New Zealand, Puerto Rico, Switzerland, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm I Experimental | 190 |
| Arm 2 No intervention | 112 |
| Total | 302 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Disease at new site | 1 | 0 |
| Overall Study | Ineligible | 8 | 8 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Physician Decision | 11 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Arm 2 | Total | Arm I |
|---|---|---|---|
| Age, Continuous | 5.41 years STANDARD_DEVIATION 5.93 | 8.02 years STANDARD_DEVIATION 6.09 | 9.57 years STANDARD_DEVIATION 5.65 |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 10 Participants | 24 Participants | 14 Participants |
| Race (NIH/OMB) Black or African American | 8 Participants | 30 Participants | 22 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 3 Participants | 4 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 18 Participants | 42 Participants | 24 Participants |
| Race (NIH/OMB) White | 72 Participants | 200 Participants | 128 Participants |
| Region of Enrollment Australia | 8 participants | 9 participants | 1 participants |
| Region of Enrollment Canada | 8 participants | 24 participants | 16 participants |
| Region of Enrollment Guam | 0 participants | 1 participants | 1 participants |
| Region of Enrollment New Zealand | 3 participants | 5 participants | 2 participants |
| Region of Enrollment Switzerland | 2 participants | 2 participants | 0 participants |
| Region of Enrollment United States | 91 participants | 261 participants | 170 participants |
| Sex: Female, Male Female | 29 Participants | 174 Participants | 145 Participants |
| Sex: Female, Male Male | 83 Participants | 128 Participants | 45 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 104 | 78 / 182 |
| serious Total, serious adverse events | 0 / 104 | 0 / 182 |
Outcome results
Primary
Event-Free Survival (EFS)
Proportion of patients event free at 3 years following enrollment. Event-free survival is not a primary outcome measure for Arm 2 patients.
Time frame: 3 Years after enrollment
Population: 181 patients were evaluated for event free survival through 3 years for patients enrolled on Arm 1. Event-free survival is not a primary outcome measure for Arm 2 patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1 | Event-Free Survival (EFS) | 87.0 Percent probability |
Primary
Overall Survival (OS)
Percentage probability of being alive at 3 years following enrollment.
Time frame: 3 Years after enrollment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm 1 | Overall Survival (OS) | 97.0 Percent Probability |
| Arm 2 | Overall Survival (OS) | 99.0 Percent Probability |
Secondary
Days Hospitalized for Patients Who Receive Chemotherapy
Calculated to quantify the treatment cost associated with this regimen.
Time frame: Up to 126 days after the start of chemotherapy
Population: 182 patients were enrolled on intermediate risk chemotherapy and were evaluable for this secondary endpoint
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 | Days Hospitalized for Patients Who Receive Chemotherapy | 14.08 Days in the hospital | Standard Deviation 10.27 |
Secondary
Toxicity Associated With Chemotherapy: Grade 3 or Higher. Toxicity as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) v4.0
The number of patients assigned to receive chemotherapy that experience CTC Version 4 grade 3 or higher at any time during protocol therapy
Time frame: Up to 126 days after the start of chemotherapy
Population: 182 patients were enrolled on intermediate risk chemotherapy and were evaluable for this secondary endpoint
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm 1 | Toxicity Associated With Chemotherapy: Grade 3 or Higher. Toxicity as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) v4.0 | Abdominal pain | 3 patients |
| Arm 1 | Toxicity Associated With Chemotherapy: Grade 3 or Higher. Toxicity as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) v4.0 | Acute kidney injury | 1 patients |
| Arm 1 | Toxicity Associated With Chemotherapy: Grade 3 or Higher. Toxicity as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) v4.0 | Lymphocyte count decrease | 2 patients |
| Arm 1 | Toxicity Associated With Chemotherapy: Grade 3 or Higher. Toxicity as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) v4.0 | Iincrease in alanine aminotransferase | 1 patients |
| Arm 1 | Toxicity Associated With Chemotherapy: Grade 3 or Higher. Toxicity as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) v4.0 | Neutrophil count decrease | 58 patients |
| Arm 1 | Toxicity Associated With Chemotherapy: Grade 3 or Higher. Toxicity as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) v4.0 | Anemia | 10 patients |
| Arm 1 | Toxicity Associated With Chemotherapy: Grade 3 or Higher. Toxicity as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) v4.0 | Increase in aspartate aminotransferase | 1 patients |
| Arm 1 | Toxicity Associated With Chemotherapy: Grade 3 or Higher. Toxicity as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) v4.0 | Catheter related infection | 1 patients |
| Arm 1 | Toxicity Associated With Chemotherapy: Grade 3 or Higher. Toxicity as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) v4.0 | Constipation | 1 patients |
| Arm 1 | Toxicity Associated With Chemotherapy: Grade 3 or Higher. Toxicity as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) v4.0 | Dehydration | 1 patients |
| Arm 1 | Toxicity Associated With Chemotherapy: Grade 3 or Higher. Toxicity as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) v4.0 | Encephalopathy | 1 patients |
| Arm 1 | Toxicity Associated With Chemotherapy: Grade 3 or Higher. Toxicity as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) v4.0 | Febrile neutropenia | 9 patients |
| Arm 1 | Toxicity Associated With Chemotherapy: Grade 3 or Higher. Toxicity as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) v4.0 | Fever | 3 patients |
| Arm 1 | Toxicity Associated With Chemotherapy: Grade 3 or Higher. Toxicity as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) v4.0 | Hyperglycemia | 1 patients |
| Arm 1 | Toxicity Associated With Chemotherapy: Grade 3 or Higher. Toxicity as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) v4.0 | Hyperkalemia | 1 patients |
| Arm 1 | Toxicity Associated With Chemotherapy: Grade 3 or Higher. Toxicity as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) v4.0 | Hypocalcemia | 2 patients |
| Arm 1 | Toxicity Associated With Chemotherapy: Grade 3 or Higher. Toxicity as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) v4.0 | Hypokalemia | 1 patients |
| Arm 1 | Toxicity Associated With Chemotherapy: Grade 3 or Higher. Toxicity as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) v4.0 | Hypomagnesemia | 1 patients |
| Arm 1 | Toxicity Associated With Chemotherapy: Grade 3 or Higher. Toxicity as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) v4.0 | Hyponatremia | 1 patients |
| Arm 1 | Toxicity Associated With Chemotherapy: Grade 3 or Higher. Toxicity as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) v4.0 | Hypophosphatemia | 6 patients |
| Arm 1 | Toxicity Associated With Chemotherapy: Grade 3 or Higher. Toxicity as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) v4.0 | Small intestine obstruction | 1 patients |
| Arm 1 | Toxicity Associated With Chemotherapy: Grade 3 or Higher. Toxicity as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) v4.0 | Nausea | 5 patients |
| Arm 1 | Toxicity Associated With Chemotherapy: Grade 3 or Higher. Toxicity as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) v4.0 | Non-cardiac chest pain | 1 patients |
| Arm 1 | Toxicity Associated With Chemotherapy: Grade 3 or Higher. Toxicity as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) v4.0 | Other gastrointestinal disorders | 1 patients |
| Arm 1 | Toxicity Associated With Chemotherapy: Grade 3 or Higher. Toxicity as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) v4.0 | Other infection | 10 patients |
| Arm 1 | Toxicity Associated With Chemotherapy: Grade 3 or Higher. Toxicity as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) v4.0 | Platelet count decrease | 7 patients |
| Arm 1 | Toxicity Associated With Chemotherapy: Grade 3 or Higher. Toxicity as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) v4.0 | Syncope | 1 patients |
| Arm 1 | Toxicity Associated With Chemotherapy: Grade 3 or Higher. Toxicity as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) v4.0 | Vomiting | 4 patients |
| Arm 1 | Toxicity Associated With Chemotherapy: Grade 3 or Higher. Toxicity as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) v4.0 | White blood cell decrease | 17 patients |
| Arm 1 | Toxicity Associated With Chemotherapy: Grade 3 or Higher. Toxicity as Assessed by the Common Terminology Criteria for Adverse Events (CTCAE) v4.0 | Wound infection | 1 patients |