Combination Chemotherapy in Treating Patients With Extensive-Stage Small Cell Lung Cancer

OBJECTIVES:

• Compare the overall survival of patients with chemotherapy-naive extensive stage small cell lung cancer treated with cisplatin and oral topotecan vs cisplatin and etoposide.
• Compare the response rates, response duration, and time to progression in patients treated with these regimens.
• Compare the tolerability of these regimens in these patients.
• Compare the patient-perceived disease status and well being in patients treated with these regimens.

OUTLINE: This is a randomized, open-label, multicenter study. Patients are stratified according to gender, ECOG performance status (0 vs 1 vs 2), lactate dehydrogenase (less than 1.5 times upper limit of normal (ULN) vs 1.5 times ULN or greater), and country. Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive oral topotecan once daily on days 1-5 and cisplatin IV on day 5.
• Arm II: Patients receive cisplatin IV on day 1 and etoposide IV over at least 30 minutes on days 1-3.

Treatment in both arms repeats every 21 days for at least 4 courses in the absence of disease progression or unacceptable toxicity.

Quality of life is assessed at baseline, prior to each course, at 4 weeks after study, and then every 4 weeks for 16 weeks.

Patients are followed at 4 weeks, every 4 weeks for 16 weeks, and then every 3 months thereafter.

PROJECTED ACCRUAL: Approximately 760 patients (380 per treatment arm) will be accrued for this study within 18 months.

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed extensive stage small cell lung carcinoma (SCLC)
• No prior chemotherapy for SCLC OR
• No chemotherapy within 5 years of diagnosis of SCLC
• Prior radiotherapy to measurable or nonmeasurable disease field allowed provided radiotherapy was completed at least 6 weeks ago and the disease is demonstrated to be progressing
• No clinical signs or symptoms of brain and/or leptomeningeal metastases by CT scan or MRI

• Brain and/or leptomeningeal metastases that are asymptomatic on neurologic exam are allowed provided metastases do not require corticosteroid therapy to control symptoms

PATIENT CHARACTERISTICS:

Age:

• 18 and over

Performance status:

• ECOG 0-2

Life expectancy:

• At least 3 months

Hematopoietic:

• Hemoglobin at least 9.0 g/dL
• WBC at least 3,500/mm3
• Platelet count at least 100,000/mm3
• Neutrophil count at least 1,500/mm3

Hepatic:

• Bilirubin no greater than 2.0 mg/dL
• SGOT and SGPT no greater than 2 times the upper limit of normal (ULN) (5 times ULN if liver metastases present)
• Alkaline phosphatase no greater than 2 times ULN (5 times ULN if liver metastases present)

Renal:

• Creatinine no greater than 1.5 mg/dL
• Creatinine clearance at least 60 mL/min
• No pre-existing renal impairment that would preclude cisplatin use

Gastrointestinal:

• No clinical evidence of any gastrointestinal (GI) conditions including:

• Removal of a portion of the stomach
• History of recent obstruction of the GI tract
• GI autonomic neuropathy
• Ulcerative colitis
• Crohn's disease
• Malabsorption syndrome
• Treatment with cyclosporine that would alter absorption or GI motility
• No other conditions that would preclude absorption of oral topotecan

Other:

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception for 3 months prior to study, during, and for at least 1 month after study
• No active infection
• No other prior or concurrent malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, or localized low-grade prostate cancer
• No other concurrent severe medical problems that would expose the patient to extreme risk or preclude study compliance
• No prior allergic reactions to compounds chemically related to study drugs
• No pre-existing hearing impairment that would preclude cisplatin use
• No overall medical condition for which study drugs would be inappropriate

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• No concurrent immunotherapy for SCLC

Chemotherapy:

• See Disease Characteristics
• No other concurrent chemotherapy for SCLC

Endocrine therapy:

• See Disease Characteristics
• No concurrent hormonal therapy for SCLC

Radiotherapy:

• See Disease Characteristics
• At least 24 hours since prior radiotherapy with no expected bone marrow suppression
• Recovered from prior palliative radiotherapy (e.g, nausea and vomiting from radiation of the epigastrium)
• No concurrent radiotherapy for SCLC
• No concurrent radiotherapy for palliation of bone metastases or CNS lesions unless approved by the investigator

Surgery:

• At least 3 weeks since prior major surgery (a shorter period is allowed if deemed in the best interest of the patient)

Other:

• More than 30 days or 5 half-lives (whichever is longer) since prior investigational drugs
• No other concurrent investigational therapy for SCLC
• No concurrent cyclosporine
• No concurrent drugs that would preclude absorption of oral topotecan