Temozolomide and Radiation Therapy in Treating Patients With Brain Metastasis Secondary to Non-Small Cell Lung Cancer

• Time to CNS progression
• Time to systemic (non-CNS) progression
• Survival

• 1-year Neurologic (Central Nervous System, CNS) Progression Free Rate [ Time Frame: assessed every 3 months for 2 years ] [ Designated as safety issue: No ]
  1-year CNS progression free rate is the percentage of patients who had no CNS progression after being followed for 1 year . Progressive disease (CNS) was defined as a 25% or greater increase in the sum of the product(s) of the maximal cross-sections on MRI scan, reappearance of any lesion that has disappeared, development of any new lesion(s), stable disease with a deterioration of neurologic exam, or clear worsening of any evaluable disease.
• Time to Non-CNS (Systemic) Progression [ Time Frame: assessed every 3 months for 2 years ] [ Designated as safety issue: No ]
  Time to non-CNS progression was calculated from time of protocol entry to time of first systemic progressive disease or death. Patients alive and non-CNS progression-free at last follow-up were censored. Disease progression was defined as at least a 20% increase in the sum of the longest diameters of target lesions, taking as reference the baseline sum longest diameter (per RECIST criteria). Development of new lesions in non-CNS sites also constituted non-CNS progression. The 21 eligible and treated patients were included in the analysis.
• Overall Survival Time [ Time Frame: assessed every 3 months for 2 years ] [ Designated as safety issue: No ]
  Overall survival (months) was calculated from time of protocol entry to time of death from any cause. Patients alive at last follow-up were censored. The 21 eligible and treated patients were included in the analysis.

RATIONALE: Radiation therapy uses high-energy x-rays to damage tumor cells. Drugs such as temozolomide may make the tumor cells more sensitive to radiation therapy. Combining temozolomide with radiation therapy may kill more tumor cells.

PURPOSE: This phase II trial is studying how well giving temozolomide together with whole-brain radiation therapy works in treating patients with brain metastasis secondary to non-small cell lung cancer.

OBJECTIVES:

Primary

• Determine the intracranial response rate in patients with brain metastasis secondary to non-small cell lung cancer treated with whole brain radiotherapy and temozolomide.

Secondary

• Determine the time to radiological progression in patients treated with this regimen.
• Determine the time to neurological progression (confirmed by magnetic resonance imaging (MRI)) in patients treated with this regimen.
• Determine the overall survival of patients treated with this regimen.
• Determine the toxicity of this regimen in these patients.

OUTLINE: This is a multicenter study.

Patients undergo whole brain radiotherapy once daily, 5 days a week, for 2 weeks (10 fractions). Patients also receive concurrent oral temozolomide once daily on days 1-14.

Beginning 3 weeks after the completion of chemoradiotherapy, patients receive oral temozolomide once daily on days 1-5. Treatment repeats every 28 days for up to 6 courses in the absence of neurologic (Central Nervous System, CNS) progression or unacceptable toxicity.

Patients were followed every 3 months for 2 years.

ACCRUAL: A total of 26 patients were accrued for this study.

• Lung Cancer
• Metastatic Cancer

• Drug: Temozolomide
  Temozolomide (TMZ) to be given at a dose of 75 mg/m2/day for 14 days, starting on D1 of whole brain radiotherapy (WBRT). Three weeks after completion of WBRT, TMZ will be given at a dose of 200 mg/m2/day x 5 days (or 150 mg/m2/day if prior chemotherapy) every 28-days,for an additional two cycles.
  Other Name: Temodar
• Radiation: Radiation therapy
  Standard whole brain radiation therapy 30 Gy in ten fractions.
  Other Name: Whole brain radiation therapy

Inclusion Criteria:

• Histologically confirmed non-small cell lung cancer (NSCLC), including the following histologies:

  • Squamous cell carcinoma
  • Adenocarcinoma
  • Large cell carcinoma
  • Bronchoalveolar carcinoma
  • All variants of NSCLC

• At least 1 bidimensionally measurable brain metastasis

  • Confirmed by MRI within the past two weeks, and computed tomography (CT) scan is not acceptable
  • Biopsy is not required
  • Not eligible for surgical resection or radiosurgery of brain metastasis
• Systemic disease not in immediate need of chemotherapy
• Age>=18 years
• ECOG Performance status of 0-1
• More than 12 weeks of life expectancy

• Adequate hematologic, renal, and liver function as demonstrated by laboratory values performed within two weeks, inclusive, prior to administration of study drug or registration

  • Absolute neutrophil count ≥ 1,500/mm^3
  • Platelet count ≥ 100,000/mm^3
  • Hemoglobin ≥ 10 g/dL
  • Bilirubin ≤ 2 times upper limit of normal (ULN)
  • Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) ≤ 2 times upper limit of normal (5 times ULN if liver metastases are present)
  • Alkaline phosphatase ≤ 2 times ULN (5 times ULN if liver metastases are present)
  • Creatinine ≤ 1.6 mg/dL
• Fertile patients must use effective contraception
• Prior biologic therapy allowed
• More than 4 weeks since prior chemotherapy
• Prior radiotherapy for local control or palliative therapy for painful bony lesions allowed
• Prior surgery for brain metastasis allowed

• At least 4 weeks since prior radiotherapy to ≥ 15% of bone marrow (2 weeks for < 15% of bone marrow) and recovered

  • No prior radiotherapy to ≥ 50% of bone marrow
• Concurrent radiotherapy to painful bony lesions allowed provided no more than 15% of bone marrow is irradiated

Exclusion Criteria:

• HIV positive
• AIDS-related illness
• Poor medical risks due to active nonmalignant systemic disease
• Frequent vomiting
• There is medical condition that would interfere with oral medication intake (e.g., partial bowel obstruction)
• Pregnant or nursing
• Prior temozolomide
• Prior radiotherapy to the brain, including stereotactic radiosurgery to a different lesion
• Concurrent intensity modulated radiotherapy or 3-D cranial radiotherapy
• Other concurrent investigational agents
• Other concurrent treatment for brain metastasis
• Other concurrent chemotherapy during study radiotherapy
• Concurrent growth factors to induce elevations in blood counts for the purposes of administration of study drug at scheduled dosing interval or to allow treatment with study drug at a higher dose