• Bronchial dysplasia number and grade at 6 months [ Designated as safety issue: No ]
  

• Biomarkers (Ki-67, Cyclin D1, bcl-2, bax, caspase-3) by immunohistochemistry at 6 and 12 months [ Designated as safety issue: No ]
  
• Biomarkers (5-HETE, LTB-4) by blood and BAL levels at 6 and 12 months [ Designated as safety issue: No ]
  
• Adverse events as measured by number and severity monthly [ Designated as safety issue: Yes ]
  

OBJECTIVES:

• Determine the efficacy of zileuton, in terms of number of sites and grade of dysplastic lesions in the bronchial epithelium, in patients with documented bronchial dysplasia.
• Correlate the regression of bronchial dysplasia (number and grade) and improvement in sputum cytology with the modulation of molecular biomarkers in patients treated with this drug.
• Determine the overall toxicity of this drug in these patients.
• Determine the 6-month natural history of bronchial dysplasia in patients who are randomized to receive treatment with a placebo.

OUTLINE: This is a randomized, double-blind, placebo-controlled study. Patients are stratified according to smoking status (current vs recently quit smoker), and prior cancer (none vs lung or head and neck). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive oral zileuton 4 times daily for 6 months in the absence of disease progression or unacceptable toxicity.
• Arm II: Patients receive oral placebo 4 times daily for 6 months in the absence of disease progression or unacceptable toxicity.

Patients are followed at 4 weeks.

PROJECTED ACCRUAL: Approximately 134 patients will be accrued for this study.

DISEASE CHARACTERISTICS:

• At high risk for dysplasia, defined by 1 of the following criteria:

  • Current or former smokers who have smoked at least 30 pack-years

    • Former smokers must be enrolled within 20 years of complete smoking cessation
  • Patients with curatively treated stage I non-small cell lung cancer*
  • Patients with curatively treated stage I or II squamous cell carcinoma of the head and neck (limited to oral cavity, pharynx, or larynx)* NOTE: *At least 12 months post-curative therapy

• Histologic confirmation of mild to severe bronchial dysplasia on bronchoscopic biopsy required

  • Moderate or severe atypia on sputum cytology required before bronchoscopy (not required for patients with prior lung or head and neck cancer)
• No evidence of malignancy by chest x-ray

PATIENT CHARACTERISTICS:

Age

• 18 and over (for patients with prior lung or head and neck malignancy)
• 35 and over (for all other patients)

Performance status

• SWOG 0-1

Life expectancy

• Not specified

Hematopoietic

• WBC at least 3,000/mm^3
• Platelet count at least 100,000/mm^3
• Hemoglobin at least 10.0 g/dL
• No bleeding disorder

Hepatic

• Bilirubin no greater than upper limit of normal (ULN)
• Liver enzymes no greater than ULN
• PT/PTT no greater than ULN
• No active or chronic liver disease (even if transaminases have normalized)

Renal

• Creatinine no greater than ULN

Cardiovascular

• No unstable angina
• No uncontrolled heart failure

Pulmonary

• No significant asthma or chronic obstructive pulmonary disease requiring chronic or periodic (at least once per year) steroids for flares
• No acute or chronic respiratory failure

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• Willing and able to undergo serial bronchoscopic examinations
• No ongoing alcohol use (i.e., at least 1 glass of wine, beer, or a mixed drink per day on a regular basis)
• No other medical condition that would preclude safety during study participation
• No other active or invasive malignancy within the past 5 years except basal cell skin cancer or carcinoma in situ of the cervix
• No hypersensitivity to study drug or any of its inactive ingredients

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Not specified

Chemotherapy

• Not specified

Endocrine therapy

• More than 3 months since prior corticosteroids*
• No concurrent corticosteroids*
• No concurrent anticancer hormonal agents NOTE: *Systemic or inhaled, including chronic administration

Radiotherapy

• No concurrent radiotherapy

Surgery

• Not specified

Other

• More than 3 months since prior lipoxygenase inhibitors*
• More than 3 months since prior investigational agents
• More than 3 months since prior nutritional supplements (except 1 daily multivitamin)
• No concurrent nutritional supplements (except 1 daily multivitamin)
• No other concurrent lipoxygenase inhibitors*
• No other concurrent investigational agents
• No concurrent warfarin, beta-blockers, or theophylline
• No other concurrent antineoplastic agents

• No concurrent or chronic daily use of non-steroidal anti-inflammatory agents (NSAIDS) (except cardioprotective doses of aspirin less than 100 mg/day)

  • Periodic use of NSAIDS allowed
• Concurrent participation in a smoking cessation program (including use of bupropion or nicotine gum or patch) allowed NOTE: *Systemic or inhaled, including chronic administration