Radiation Therapy and Stereotactic Radiosurgery With or Without Temozolomide or Erlotinib in Treating Patients With Brain Metastases Secondary to Non-Small Cell Lung Cancer

• Time to CNS Progression [ Time Frame: From the date of randomization to date of progression, death, or last follow-up. Analysis occurs at the same time as the primary outcome analysis. ] [ Designated as safety issue: No ]
  CNS progression will be defined as any increase in perpendicular bi-dimensional tumor area for any of the 1-3 tracked brain metastases, by any amount, or the appearance of any new brain metastasis on a follow-up MRI (SRS planning scan will not be used to evaluate CNS progression).
• Quality-adjusted Survival as Measured by EuroQol 5-dimension Instrument [ Time Frame: From randomization to date of death or last follow-up. Analysis occurs after the primary outcome analysis. ] [ Designated as safety issue: No ]
  Compared between two treatment arms using a two-group t-test.
• Change in Functional Assessment of Cancer Therapy-Brain Subscale Questionnaire [ Time Frame: From randomization to three months. ] [ Designated as safety issue: No ]
  Compared between two treatment arms using a two-group chi-squared test.
• Change in Performance Status [ Time Frame: From randomization to six months. ] [ Designated as safety issue: No ]
  Compared between two treatment arms using a two-group chi-squared test.
• Change in Steroid Dependence [ Time Frame: From randomization to six months. ] [ Designated as safety issue: No ]
  Compared between two treatment arms using a two-group chi-squared test.
• Cause of Death (Neurologic vs Other) [ Time Frame: From randomization to date of death. ] [ Designated as safety issue: No ]
  Compared between two arms using a two-group chi-squared test. Summarized in a 2x2 frequency table.

This randomized phase III trial is studying whole-brain radiation therapy and stereotactic radiosurgery with or without temozolomide or erlotinib to see how well they work compared to whole-brain radiation therapy and stereotactic radiosurgery in treating patients with brain metastases secondary to non-small cell lung cancer. Radiation therapy uses high-energy x-rays to kill tumor cells. Stereotactic radiosurgery may be able to deliver x-rays directly to the tumor and cause less damage to normal tissue. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop tumor cells from dividing so they stop growing or die. Erlotinib may stop the growth of tumor cells by blocking the enzymes necessary for their growth and by blocking blood flow to the tumor. It is not yet known whether radiation therapy and stereotactic radiosurgery are more effective with or without temozolomide or erlotinib in treating brain metastases

PRIMARY OBJECTIVES:

I. Compare survival in patients with non-small cell lung cancer and brain metastases treated with whole brain radiotherapy and stereotactic radiosurgery with vs without temozolomide or erlotinib.

SECONDARY OBJECTIVES:

I. Compare time to CNS progression in patients treated with these regimens. II. Compare quality-adjusted survival in patients treated with these regimens. III. Compare 3-month quality of life in patients treated with these regimens. IV. Compare the 6-month performance status of patients treated with these regimens.

V. Compare 6-month steroid dependence in patients treated with these regimens. VI. Compare cause of death (neurologic vs other) in patients treated with these regimens.

VII. Determine the effects of non-protocol chemotherapy in these patients.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to age and the presence of extracranial metastases (< 65 years old AND no extracranial metastases vs ≥ 65 years old OR extracranial metastases), number of metastases (1 vs 2 or 3), and extent of extracranial disease (none vs present). Patients are randomized to 1 of 3 treatment arms.

ARM I: Patients undergo whole brain radiotherapy (WBRT) once daily on days 1-5, 8-12, and 15-19. Within 14 days after completion of WBRT, patients undergo stereotactic radiosurgery.

ARM II: Patients undergo WBRT and stereotactic radiosurgery as in arm I. Beginning on the first day of WBRT, patients receive oral temozolomide once daily on days 1-21. Beginning 4 weeks after completion of WBRT, patients may receive oral temozolomide alone once daily on days 1-5. Treatment with temozolomide repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

ARM III: Patients undergo WBRT and stereotactic radiosurgery as in arm I. Beginning on the first day of WBRT, patients receive oral erlotinib once daily for up to 6 months.

In all arms, patients with recurrent brain metastases may undergo additional stereotactic radiosurgery.

Quality of life is assessed at baseline and at 3, 6, 9, 12, 18, and 24 months.

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

• Recurrent Non-small Cell Lung Cancer
• Stage IV Non-small Cell Lung Cancer
• Tumors Metastatic to Brain

• Drug: erlotinib hydrochloride
  Given orally
  Other Names:

  • CP-358,774
  • erlotinib
  • OSI-774
• Radiation: 3-dimensional conformal radiation therapy
  Patients undergo radiation therapy once daily for approximately 3 weeks
  Other Names:

  • 3D conformal radiation therapy
  • 3D-CRT
• Radiation: stereotactic radiosurgery
  Patients undergo surgery after radiation therapy
• Drug: temozolomide
  Given orally
  Other Names:

  • SCH 52365
  • Temodal
  • Temodar
  • TMZ

• Active Comparator: WBRT + SRS
  Patients undergo whole brain radiotherapy (WBRT) once daily on days 1-5, 8-12, and 15-19. Within 14 days after completion of WBRT, patients undergo stereotactic radiosurgery (SRS).
  Interventions:

  • Radiation: 3-dimensional conformal radiation therapy
  • Radiation: stereotactic radiosurgery
• Experimental: WBRT + SRS + Temozolomide
  Patients undergo WBRT and stereotactic radiosurgery as in arm I. Beginning on the first day of WBRT, patients receive oral temozolomide once daily on days 1-21. Beginning 4 weeks after completion of WBRT, patients may receive oral temozolomide alone once daily on days 1-5. Treatment with temozolomide repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
  Interventions:

  • Radiation: 3-dimensional conformal radiation therapy
  • Radiation: stereotactic radiosurgery
  • Drug: temozolomide
• Experimental: WBRT + SRS + Erlotinib
  Patients undergo WBRT and stereotactic radiosurgery as in arm I. Beginning on the first day of WBRT, patients receive oral erlotinib once daily for up to 6 months.
  Interventions:

  • Drug: erlotinib hydrochloride
  • Radiation: 3-dimensional conformal radiation therapy
  • Radiation: stereotactic radiosurgery

Inclusion Criteria:

• Histologically confirmed non-small cell lung cancer

• One to 3 intraparenchymal brain metastases by contrast-enhanced MRI, meeting the following criteria:

  • Well circumscribed tumor(s)

  • Maximum diameter ≤ 4.0 cm

    • If multiple lesions are present and one lesion is at the maximum diameter, the other lesions must be ≤ 3.0 cm in maximum diameter
  • No metastases within 10 mm of the optic apparatus such that a portion of the optic nerve or chiasm would be included in the high-dose stereotactic radiosurgery boost field
  • No metastases in the brainstem, midbrain, pons, or medulla

• No prior complete resection of all known brain metastases

  • Subtotal resection allowed provided residual disease is ≤ 4.0 cm in maximum diameter

• No clinical or radiographic evidence of progression (other than study lesion[s]) within the past month

  • Patients with brain metastases at initial presentation do not require 1 month of scans documenting stable disease

• Stable extracranial metastases allowed

  • No known or pre-existing liver metastases
• No leptomeningeal metastases by MRI or cerebrospinal fluid evaluation
• Synchronous brain metastases at initial diagnosis allowed
• Performance status - Zubrod 0-1
• Hemoglobin ≥ 8 g/dL
• Absolute neutrophil count ≥ 1,000/mm^3
• Platelet count ≥ 100,000/mm^3
• AST < 2 times upper limit of normal (ULN)
• Alkaline phosphatase < 2 times ULN unless due to elevated bone metastases
• Total bilirubin normal
• Lactic dehydrogenase < 2 times ULN
• Creatinine < 1.5 times ULN

• No clinically active interstitial lung disease

  • Chronic stable asymptomatic radiographic changes allowed
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• HIV negative
• Neurologic function status 0-2
• No other major medical illness or psychiatric impairment that would preclude study participation
• No history of allergic reaction attributed to compounds of similar chemical or biologic composition to erlotinib or temozolomide
• No concurrent immunotherapy
• No concurrent biologic therapy, excluding growth factors and epoetin alfa
• No prior temozolomide or erlotinib

• No other concurrent chemotherapy during study radiotherapy

  • Other concurrent chemotherapy allowed after study radiotherapy, except for the following:

    • Temozolomide or erlotinib (arm I only)
    • Erlotinib (arm II only)
    • Temozolomide (arm III only)
• No prior cranial radiotherapy
• No concurrent intensity-modulated radiotherapy

• Concurrent radiotherapy to painful bone lesions allowed

  • No concurrent radiotherapy to more than 15% of bone marrow
• No other concurrent therapy for brain metastases unless a recurrence is detected
• More than 30 days since prior investigational drugs

• No concurrent enzyme-inducing antiepileptic drugs including, but not limited to, any of the following (for patients randomized to receive erlotinib):

  • Phenytoin
  • Carbamazepine
  • Rifampin
  • Phenobarbital
  • Primidone
  • Oxcarbazepine
• No other concurrent investigational drugs
• No concurrent Hypericum perforatum (St. John's wort)
• No drugs that alter gastric pH (e.g., proton pump inhibitors or H2 antagonists) within 4 hours after erlotinib administration (arm III patients only)