A Phase III Trial Comparing Whole Brain Radiation and Stereotactic Radiosurgery Alone Versus With Temozolomide or Erlotinib in Patients With Non-Small Cell Lung Cancer and 1-3 Brain Metastases
Overview
- Phase
- Phase 3
- Intervention
- 3-Dimensional Conformal Radiation Therapy
- Conditions
- Metastatic Malignant Neoplasm in the Brain
- Sponsor
- National Cancer Institute (NCI)
- Enrollment
- 126
- Locations
- 83
- Primary Endpoint
- Overall Survival
- Status
- Terminated
- Last Updated
- 8 years ago
Overview
Brief Summary
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.
Detailed Description
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.
Investigators
Eligibility Criteria
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 not exceed 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
Exclusion Criteria
- Not provided
Arms & Interventions
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.
Intervention: 3-Dimensional Conformal Radiation Therapy
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.
Intervention: 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.
Intervention: 3-Dimensional Conformal Radiation Therapy
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.
Intervention: 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.
Intervention: Temozolomide
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.
Intervention: 3-Dimensional Conformal Radiation Therapy
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.
Intervention: Erlotinib Hydrochloride
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.
Intervention: Stereotactic Radiosurgery
Outcomes
Primary Outcomes
Overall Survival
Time Frame: From randomization to date of death or last follow-up, up to 48.1 months. Analysis occurs after all patients have been potentially followed for 9 months.
Survival time is defined as time from randomization to date of death from any cause and estimated by the Kaplan-Meier method. Patients last known to be alive are censored at date of last contact.
Secondary Outcomes
- Change in Functional Assessment of Cancer Therapy-Brain (FACT-Br) Score at 3 Months(From randomization to three months.)
- Change in Steroid Dependence at Six Months(From randomization to six months.)
- Cause of Death (Neurologic vs Other)(From randomization to last follow-up, up to 48.1 months. Analysis occurs after all patients have been potentially followed for 9 months.)
- Rate of CNS Progression (One Year)(From randomization to last follow-up, up to 48.1 months. Analysis occurs after all patients have been potentially followed for 9 months.)
- Quality-adjusted Survival as Measured by EuroQol 5-dimension Instrument(From randomization to last follow-up, up to 48.1 months. Analysis occurs after all patients have been potentially followed for 9 months.)
- Change in Performance Status at Six Months(From randomization to six months.)