Radiation Therapy Combined With Either Gefitinib or Temozolomide in Pats With NSCLC and Brain Metastases

OBJECTIVES:

Primary

• Compare the efficacy of whole-brain radiotherapy combined with either gefitinib or temozolomide, in terms of overall survival, in patients with non-small cell lung cancer and brain metastases.

Secondary

• Compare the tolerability and toxicity of these regimens in these patients.
• Compare the time to neurological disease progression, time to extracranial disease progression, and time to overall disease progression, in patients treated with these regimens.
• Compare adverse events in patients treated with these regimens.
• Compare cognitive function and quality of life of patients treated with these regimens.

OUTLINE: This is a randomized, open-label, parallel-group, multicenter study. Patients are stratified according to extracranial disease (yes vs no), number of brain metastases (1-3 vs ≥ 4), prior chemotherapy (yes vs no), WHO performance status (0-1 vs 2), and participating center. Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients undergo whole-brain radiotherapy (WBRT) once daily on days 1-5 and 8-12 and receive oral gefitinib once daily on days 1-28. Gefitinib treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.
• Arm II: Patients undergo WBRT as in arm I and receive oral temozolomide once daily on days 1-21. Temozolomide treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

Quality of life is assessed at baseline and on day 1 of courses 2, 3, and 5.

After completion of study therapy, patients are followed every 3 months.

PROJECTED ACCRUAL: A total of 30-86 patients (15-43 per treatment arm) will be accrued for this study within 3 years.

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed non-small cell lung cancer AND newly diagnosed brain metastases meeting 1 of the following criteria:

• Multiple brain metastases
• Single brain metastasis not amenable to potentially curative treatment
• No advanced extracranial disease severely compromising vital functions and performance

PATIENT CHARACTERISTICS:

Age

• 18 and over

Performance status

• WHO 0-2

Life expectancy

• Not specified

Hematopoietic

• Hemoglobin > 10 g/dL
• Absolute neutrophil count > 1,500/mm^3
• Platelet count > 100,000/mm^3

Hepatic

• Bilirubin ≤ 1.5 times upper limit of normal (ULN)
• AST and ALT ≤ 2.5 times ULN
• Alkaline phosphatase ≤ 2.5 times ULN (5 times ULN in the presence of documented bone metastases)
• No unstable or uncompensated hepatic disease that would preclude study participation

Renal

• Creatinine clearance ≥ 40 mL/min
• No unstable or uncompensated renal disease that would preclude study participation

Cardiovascular

• No myocardial infarction within the past 3 months
• No unstable or uncompensated cardiac disease that would preclude study participation

Pulmonary

• No clinically active interstitial lung disease

• Patients with chronic stable radiographic changes who are asymptomatic eligible
• No other unstable or uncompensated respiratory disease that would preclude study participation

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 12 months after completion of study treatment
• No nausea, vomiting, inability to swallow whole tablets/capsules, or malabsorption syndrome that would preclude oral medication ingestion or absorption
• No psychiatric disorder that would preclude giving informed consent or study compliance
• No active infection
• No uncontrolled diabetes mellitus
• No other medical condition that would preclude study participation

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Not specified

Chemotherapy

• No prior temozolomide

Endocrine therapy

• Concurrent corticosteroids allowed provided dose has been stable or decreasing for ≥ 4 days before study entry

Radiotherapy

• No prior brain irradiation

Surgery

• Not specified

Other

• No prior gefitinib or erlotinib
• More than 30 days since prior investigational clinical trial participation
• No other concurrent experimental drugs
• No other concurrent anticancer therapy
• No concurrent treatment with any of the following:

• Phenytoin
• Carbamazepine
• Rifampin
• Barbiturates
• Hypericum perforatum (St. John's wort)
• Other enzyme-inducing anti-epileptic drugs or tuberculostatic treatments
• Any drug that contraindicates administration with study drugs