RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. It is not yet known which combination chemotherapy regimen is more effective for metastatic cancer of an unknown site of origin. PURPOSE: Randomized phase III trial to compare the effectiveness of two combination chemotherapy regimens in treating patients who have metastatic cancer of an unknown site of origin.

OBJECTIVES: I. Compare the efficacy of the regimens, in terms of tumor response, progression-free survival, and overall survival of vincristine, doxorubicin, and cyclophosphamide vs epirubicin, cisplatin, and fluorouracil in patients with metastatic carcinoma of unknown primary. II. Compare the toxicity of these regimens in these patients. III. Compare quality of life and symptom control in patients treated with these regimens.

PROTOCOL OUTLINE: This is a randomized, open-label, multicenter study. Patients are stratified according to presence of liver metastases (yes vs no) and type of tumor (adenocarcinoma vs non-adenocarcinoma). Patients are randomized to one of two treatment arms. Arm I: Patients receive vincristine IV, doxorubicin IV, and cyclophosphamide IV on day 1. Arm II: Patients receive epirubicin IV and cisplatin IV over 4 hours on day 1 and fluorouracil IV continuously on days 1-21. Treatment in both arms repeats every 3 weeks for 3-6 courses in the absence of disease progression or unacceptable toxicity. Quality of life is assessed at baseline, at the end of courses 2, 4, and 6, and 1 month after completion of therapy. Patients are followed at 1 month and then until death.

PROJECTED ACCRUAL: A total of 398 patients (199 per treatment arm) will be accrued for this study.

Ages Eligible for Study:  18 Years and above

Criteria

PROTOCOL ENTRY CRITERIA:

--Disease Characteristics--

• Histologically confirmed metastatic carcinoma of unknown primary; Adenocarcinoma or non-adenocarcinoma
• No axillary lymph node metastases as sole site of disease in female patients
• No peritoneal carcinomatosis in female patients
• No squamous cell carcinoma in cervical lymph nodes
• No neuroendocrine tumors
• No elevated alpha-fetoprotein, beta-HCG, or PSA

--Prior/Concurrent Therapy--

• Biologic therapy: Not specified
• Chemotherapy: No prior chemotherapy for carcinoma of unknown primary
• Endocrine therapy: Not specified
• Radiotherapy: Prior radiotherapy allowed except to sole site of measurable or evaluable disease; Concurrent palliative radiotherapy allowed except to sole site of measurable or evaluable disease
• Surgery: Not specified
• Other: No other concurrent experimental drugs

--Patient Characteristics--

• Age: 18 and over
• Performance status: Karnofsky 60-100%
• Life expectancy: More than 3 months
• Hematopoietic: WBC at least 3,000/mm3; Absolute neutrophil count at least 1,500/mm3; Platelet count at least 100,000/mm3; Hemoglobin at least 10 g/dL
• Hepatic: Bilirubin less than 1.8 mg/dL
• Renal: Creatinine less than 1.5 times upper limit of normal (ULN); Urea less than 1.5 times ULN; Glomerular filtration rate at least 60 mL/min
• Cardiovascular: LVEF at least 50% by echocardiogram or MUGA scan; No uncontrolled angina pectoris; No heart failure; No clinically significant uncontrolled cardiac arrhythmias; No abnormal EKG
• Other: Not pregnant or nursing; Negative pregnancy test; Fertile patients must use effective contraception during and for 1 year after study; No other prior malignancy except adequately treated non-melanoma skin cancer or carcinoma in situ of the cervix; No medical or psychiatric condition that would preclude study; No other serious uncontrolled medical condition