Combination Chemotherapy in Treating Children With Newly Diagnosed Malignant Germ Cell Tumors

OBJECTIVES:

• Determine the maximum tolerated dose and toxicity profile of cyclophosphamide in combination with bleomycin, etoposide, and cisplatin in pediatric patients with newly diagnosed high-risk extracranial, extragonadal malignant germ cell tumors.
• Determine the response rate in patients treated with this regimen.

OUTLINE: This is a pilot, multicenter, dose-escalation study of cyclophosphamide.

• Induction therapy: Patients receive bleomycin IV over 10-20 minutes on day 1, etoposide IV over 1 hour and cisplatin IV over 4 hours on days 1-5, and cyclophosphamide IV over 1 hour on day 1. Patients also receive filgrastim (G-CSF) subcutaneously once daily beginning on day 6 and continuing until blood counts recover. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.

Cohorts of 6 patients receive escalating doses of cyclophosphamide until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity.

Patients are evaluated after 4 courses of therapy. Patients with partial response or stable disease undergo second-look surgery, receive 2 more courses of induction therapy, and are then re-evaluated. Patients who do not achieve complete response (CR) after a total of 6 courses may undergo a third surgery. Patients who still have tumor that cannot be removed are removed from study therapy. Patients who achieve a CR at anytime are followed.

Patients are followed monthly for 1 year, every 6 months for 1 year, and then annually for 3 years.

PROJECTED ACCRUAL: A total of 6-18 patients will be accrued for this study within 1.3 years.

DISEASE CHARACTERISTICS:

• Histologically confirmed newly diagnosed extracranial germ cell tumors, including 1 of the following types:

• Yolk sac carcinoma (endodermal sinus tumor)
• Embryonal carcinoma
• Choriocarcinoma
• Teratoma with mixed malignant elements (malignant teratoma)
• High-risk disease, defined as stage III or IV extragonadal germ cell tumors
• Must be enrolled on study within 21 days of diagnostic surgical procedure

PATIENT CHARACTERISTICS:

Age

• 21 and under (at original diagnosis)

Performance status

• ECOG 0-2

• Karnofsky 50-100% (in patients over 16 years of age)
• Lansky 50-100% (in patients 16 years of age and under)

Life expectancy

• At least 2 months

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

• Not specified

Renal

• Creatinine clearance or radioisotope glomerular filtration rate at least 70 mL/min OR
• Creatinine based on age as follows:

• No greater than 0.8 mg/dL (5 years and under)
• No greater than 1.0 mg/dL (6-10 years)
• No greater than 1.2 mg/dL (11-15 years)
• No greater than 1.5 mg/dL (over 15 years)

Pulmonary

• FEV_1/FVC greater than 60% OR
• Children who are uncooperative must meet all of the following criteria:

• No dyspnea at rest
• No exercise intolerance
• Pulse oximetry greater than 94%

Other

• Not pregnant or nursing
• Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Not specified

Chemotherapy

• No prior chemotherapy

Endocrine therapy

• Not specified

Radiotherapy

• No prior radiotherapy

Surgery

• See Disease Characteristics