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

Children's Oncology Group

Status and phase

Completed

Phase 2

Conditions

Central Nervous System Tumors

Brain Tumor

Childhood Germ Cell Tumor

Treatments

Drug: etoposide

Procedure: neoadjuvant therapy

Procedure: conventional surgery

Procedure: peripheral blood stem cell transplantation

Procedure: adjuvant therapy

Drug: ifosfamide

Drug: thiotepa

Radiation: radiation therapy

Drug: carboplatin

Study type

Interventional

Funder types

NETWORK

NIH

Identifiers

NCT00047320

COG-ACNS0122 (Other Identifier)

ACNS0122

CDR0000257664 (Other Identifier)

Details and patient eligibility

About

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.

Full 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.

Enrollment

104 patients

Sex

All

Ages

3 to 24 years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion 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

Trial design

Primary purpose

Treatment

Allocation

N/A

Interventional model

Single Group Assignment

Masking

None (Open label)

104 participants in 1 patient group

Radiation Therapy (CR from Induction)

Experimental group

Description:

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.

Treatment: