S0008: Chemotherapy Plus Biological Therapy in Treating Patients With Melanoma

OBJECTIVES:

• Compare the overall survival and disease-free survival of patients with high-risk melanoma treated with interferon alfa vs cisplatin, vinblastine, and dacarbazine plus interferon alfa and interleukin-2.
• Compare the toxic effects of these treatment regimens in these patients.
• Determine the relationship between minimal residual disease (MRD) status at 12 weeks and 52 weeks and overall survival of patients treated with these regimens.
• Compare the effects of these treatment regimens on the MRD status of these patients.
• Determine the relationship between clinical characteristics (number of involved lymph nodes, ulcerated primary, and extracapsular extension) and MRD in patients treated with these regimens.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to nodal status (N1 or N2 vs N3), degree of lymph node involvement (micrometastases only vs any macrometastases, including satellite/in-transit metastases), and ulceration of the primary tumor (yes vs no vs unknown primary). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive interferon alfa IV on days 1-5 of weeks 1-4 followed by interferon alfa subcutaneously (SC) on days 1, 3, and 5 of weeks 5-52 in the absence of disease progression or unacceptable toxicity.
• Arm II: Patients receive cisplatin IV over 30 minutes followed by vinblastine IV on days 1-4. Patients also receive dacarbazine IV over 1 hour on day 1, interleukin-2 IV over 96 hours on days 1-4, and interferon alfa SC on days 1-5, 8, 10, and 12. In addition, patients receive filgrastim (G-CSF) SC on days 6-15. Treatment repeats every 3 weeks for 3 courses in the absence of disease progression or unacceptable toxicity.

Patients are followed every 3 months for 2 years, every 6 months for 3 years, and then annually for 5 years.

PROJECTED ACCRUAL: A total of 410 patients (205 per treatment arm) will be accrued for this study within 3 years.

DISEASE CHARACTERISTICS:

• Histologically proven melanoma of cutaneous origin or from unknown primary at initial presentation of primary or first clinically detected nodal or satellite/in-transit recurrence

• No distant metastases
• No melanoma of ocular, mucosal, or other non-cutaneous origin
• One of the following criteria must apply for patients with newly diagnosed melanoma OR a previously diagnosed primary with current subsequent, clinical, regional nodal disease and/or satellite/in-transit disease:

• Ulcerated primary melanoma with 1 or more involved lymph nodes (micro/occult or macro/clinically overt)
• Non-ulcerated or unknown primary melanoma with one macro/clinically overt lymph node metastasis, including a single matted nodal mass

• No non-ulcerated or unknown primary tumor and a single micrometastatic lymph node
• Non-ulcerated melanoma with two or more lymph node metastases (micro/occult or macro/clinically overt) and/or matted nodes
• Any satellite/in transit metastasis with or without lymph node involvement
• Patients with recurrent disease must have recurrent disease in the regional nodal basin of a prior complete lymphadenectomy
• Multiple regional nodal basin involvement allowed if they are appropriate anatomic drainage basins for primary site
• Patients must be disease free at time of enrollment based on the following surgical criteria:

• Patients at initial presentation of melanoma must undergo adequate wide excision of primary lesion
• Patients with previously diagnosed melanoma must have all disease resected with pathologically negative margins and no disease at primary site or second resection of primary
• Full lymphadenectomy required of all patients including those with positive sentinel nodes or positive satellite/in-transit metastasis
• No more than 56 days since prior lymphadenectomy OR surgery to remove recurrent disease after prior complete lymphadenectomy
• Must be willing to participate in minimal residual disease studies if registered on the study on 3/1/2003 or later

PATIENT CHARACTERISTICS:

Age:

• 18 and over

Performance status:

• Zubrod 0-1

Life expectancy:

• Not specified

Hematopoietic:

• Absolute granulocyte count at least 1,500/mm^3
• Platelet count at least 100,000/mm^3

Hepatic:

• Bilirubin no greater than 1.5 times upper limit of normal (ULN)
• SGOT or SGPT no greater than 2 times ULN
• LDH and alkaline phosphatase no greater than 2 times ULN (above normal value requires a contrast-enhanced CT scan or MRI of liver)
• No known recent hepatitis positivity by PCR

Renal:

• Creatinine no greater than 1.5 mg/dL OR
• Creatinine clearance at least 75 mL/min

Cardiovascular:

• No congestive heart failure
• No coronary artery disease
• No serious cardiac arrhythmia
• No prior myocardial infarction
• Normal cardiac stress test required if any of the following are present:

• Over age 50
• Abnormal EKG
• History of cardiac disease

Pulmonary:

• No symptomatic pulmonary disease

Other:

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No autoimmune disorders or conditions of immunosuppression
• No other prior malignancy within the past 5 years except the following:

• Adequately treated basal cell or squamous cell skin cancer
• Carcinoma in situ of the cervix
• Adequately treated stage I or II cancer in remission
• HIV negative
• No known AIDS or HIV-1 associated complex

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• No prior immunotherapy, including interferon, interleukin, levamisole, or other biologic response modifiers
• No other concurrent biologic therapy

Chemotherapy:

• No prior chemotherapy (including infusion or perfusion therapy)
• No other concurrent chemotherapy

Endocrine therapy:

• No concurrent systemic corticosteroids or topical steroid creams
• Concurrent steroid antihistamines allowed if no alternative
• No concurrent hormonal therapy

Radiotherapy:

• No prior radiotherapy

• Prior postlumpectomy radiotherapy for breast cancer allowed
• No concurrent radiotherapy

Surgery:

• See Disease Characteristics
• No concurrent surgery

Other:

• No concurrent anti-hypertensive medications (arm II only)
• No concurrent immunosuppressive agents
• No other concurrent anticancer therapy
• Antihistamines allowed if no alternative medication suitable