Radiation Therapy and Stereotactic Radiosurgery With or Without Temozolomide or Erlotinib in Treating Patients With Brain Metastases Secondary to Non-Small Cell Lung Cancer
- Conditions
- Recurrent Non-Small Cell Lung CarcinomaStage IV Non-Small Cell Lung Cancer AJCC v7Metastatic Malignant Neoplasm in the Brain
- Interventions
- Radiation: 3-Dimensional Conformal Radiation TherapyRadiation: Stereotactic Radiosurgery
- Registration Number
- NCT00096265
- Lead Sponsor
- National Cancer Institute (NCI)
- 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.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 126
-
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
- 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)
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Arm III Erlotinib Hydrochloride 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. Arm III Stereotactic Radiosurgery 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. Arm I 3-Dimensional Conformal Radiation Therapy 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 I Stereotactic Radiosurgery 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 3-Dimensional Conformal Radiation Therapy 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 II Stereotactic Radiosurgery 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 3-Dimensional Conformal Radiation Therapy 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. Arm II 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.
- Primary Outcome Measures
Name Time Method Overall Survival 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 Outcome Measures
Name Time Method Change in Functional Assessment of Cancer Therapy-Brain (FACT-Br) Score at 3 Months From randomization to three months. The Functional Assessment of Cancer Therapy-Brain (FACT-Br) is a 19-item self-report instrument designed to measure multidimensional quality of life in patients with brain cancer. It is to be administered with the FACT-General. There are 5 responses options, with 0=Not a lot and 4=Very much. All items are added together to obtain a total score, which ranges from 0 to 76. Certain items must be reversed before it is added by subtracting the response from 4. It requires at least 50% of the items to be completed while the overall response rate of the FACT-Br including the FACT-G must be greater than 80%. If items are missing, the subscale scores can be prorated. A higher score indicates better QOL. A change of 5 points will be considered a minimal clinically meaningful change. Change from baseline at three months (3 month score - baseline score) will be categorized as improvement if increased, stable if no change, or deterioration if decreased.
Change in Steroid Dependence at Six Months From randomization to six months. Daily steroid dose will be collected at baseline and follow-up, as one of the following: 0-4 mg, \>4 to ≤ 8 mg, \>8 to ≤12 mg, and \>12 mg. Change from baseline at six months will be evaluated to have decreased, remained stable, or increased, based on these categories.
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. Patients were considered to have died neurologic deaths (coded as "Brain Metastases") if they had stable systemic disease and progressive neurologic disease consisting of expanding intracranial masses, CNS hemorrhages, hydrocephalus resulting in herniation or fulminant meningeal carcinomatosis.
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. CNS progression is 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). For lesions smaller than 1 cm in maximum diameter, a maximum increase of 50% in perpendicular bi-dimensional treatment area is necessary to score as progression. This caveat is included to account for potential variability in measurement, which is most susceptible to proportionate errors at smaller sizes. For greater than 1 cm lesions, the definition uses a 25% rule for change. Rates of CNS progression estimated by the cumulative incidence method, with death treated as a competing risk.
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. Quality-adjusted life years (QALY) incorporate the societal-based utilities of health states into expected life years for a health condition. The QALY model is QALY(h,y) where h is a health state and y is the years of life. Higher quality-adjusted life year values represent a better outcome. A patient's health state will be determined from the index score of the EQ-5D-5L patient questionnaire.The EQ-5D-5L is a 2-part self-assessment questionnaire, a 5-item index score and a visual analogue scale, but only the index score is used for quality-adjusted survival. The index score has 5 items (mobility, self care, usual activities, pain/discomfort, anxiety/depression) each with 5 problem levels (1-none to 5-extreme). The 5-item index score is transformed into a utility score between 0 (worst health state) and 1 (best health state).
Change in Performance Status at Six Months From randomization to six months. Compared between two treatment arms using a two-group chi-squared test. Zubrod score will be collected at baseline and follow-up. The Zubrod performance score runs from 0 to 5, with 0 denoting perfect health and 5 death. Change from baseline is calculated as 6-month value - baseline value. Patients with a baseline score who have died by six months will be included in the analysis with a score of 5 at six months.
Trial Locations
- Locations (83)
McGill University Department of Oncology
🇨🇦Montreal, Quebec, Canada
Parkview Hospital Randallia
🇺🇸Fort Wayne, Indiana, United States
Integrated Community Oncology Network-Flager Cancer Center
🇺🇸Saint Augustine, Florida, United States
John B Amos Cancer Center
🇺🇸Columbus, Georgia, United States
Northwest Community Hospital
🇺🇸Arlington Heights, Illinois, United States
Tallahassee Memorial HealthCare
🇺🇸Tallahassee, Florida, United States
Saint John's Hospital
🇺🇸Springfield, Illinois, United States
Christiana Care Health System-Christiana Hospital
🇺🇸Newark, Delaware, United States
Finley Hospital
🇺🇸Dubuque, Iowa, United States
University of Maryland/Greenebaum Cancer Center
🇺🇸Baltimore, Maryland, United States
Coborn Cancer Center at Saint Cloud Hospital
🇺🇸Saint Cloud, Minnesota, United States
Saint Agnes Hospital
🇺🇸Baltimore, Maryland, United States
Reading Hospital
🇺🇸West Reading, Pennsylvania, United States
Natalie Warren Bryant Cancer Center at Saint Francis
🇺🇸Tulsa, Oklahoma, United States
Thomas Jefferson University Hospital
🇺🇸Philadelphia, Pennsylvania, United States
McKay-Dee Hospital Center
🇺🇸Ogden, Utah, United States
Fairview Ridges Hospital
🇺🇸Burnsville, Minnesota, United States
Unity Hospital
🇺🇸Fridley, Minnesota, United States
Saint Cloud Hospital
🇺🇸Saint Cloud, Minnesota, United States
Radiation Therapy Oncology Group
🇺🇸Philadelphia, Pennsylvania, United States
UT Southwestern/Simmons Cancer Center-Dallas
🇺🇸Dallas, Texas, United States
Fairview-Southdale Hospital
🇺🇸Edina, Minnesota, United States
Saint Louis University Hospital
🇺🇸Saint Louis, Missouri, United States
Metro Minnesota Community Oncology Research Consortium
🇺🇸Saint Louis Park, Minnesota, United States
Summa Akron City Hospital/Cooper Cancer Center
🇺🇸Akron, Ohio, United States
Arlington Cancer Center
🇺🇸Arlington, Texas, United States
Ridgeview Medical Center
🇺🇸Waconia, Minnesota, United States
Intermountain Medical Center
🇺🇸Murray, Utah, United States
Sentara Norfolk General Hospital
🇺🇸Norfolk, Virginia, United States
Mission Hospital-Memorial Campus
🇺🇸Asheville, North Carolina, United States
Ottawa Hospital-Civic Campus
🇨🇦Ottawa, Ontario, Canada
Massachusetts General Hospital Cancer Center
🇺🇸Boston, Massachusetts, United States
Cleveland Clinic Foundation
🇺🇸Cleveland, Ohio, United States
Arizona Oncology Services Foundation
🇺🇸Scottsdale, Arizona, United States
Providence Saint Joseph Medical Center/Disney Family Cancer Center
🇺🇸Burbank, California, United States
Kaiser Permanente Los Angeles Medical Center
🇺🇸Los Angeles, California, United States
M D Anderson Cancer Center
🇺🇸Houston, Texas, United States
Virginia Mason Medical Center
🇺🇸Seattle, Washington, United States
Pomona Valley Hospital Medical Center
🇺🇸Pomona, California, United States
Scottsdale Health Care-Osborn
🇺🇸Scottsdale, Arizona, United States
Integrated Community Oncology Network-Florida Cancer Center Beaches
🇺🇸Jacksonville Beach, Florida, United States
Baptist MD Anderson Cancer Center
🇺🇸Jacksonville, Florida, United States
Integrated Community Oncology Network-Southside Cancer Center
🇺🇸Jacksonville, Florida, United States
Baptist Medical Center South
🇺🇸Jacksonville, Florida, United States
21st Century Oncology-Orange Park
🇺🇸Orange Park, Florida, United States
21st Century Oncology-Palatka
🇺🇸Palatka, Florida, United States
Bay Medical Center
🇺🇸Panama City, Florida, United States
Northwestern University
🇺🇸Chicago, Illinois, United States
Mercy Hospital
🇺🇸Coon Rapids, Minnesota, United States
United Hospital
🇺🇸Saint Paul, Minnesota, United States
University of Rochester
🇺🇸Rochester, New York, United States
Delaware County Memorial Hospital
🇺🇸Drexel Hill, Pennsylvania, United States
University of Miami Miller School of Medicine-Sylvester Cancer Center
🇺🇸Miami, Florida, United States
IU Health Methodist Hospital
🇺🇸Indianapolis, Indiana, United States
Abbott-Northwestern Hospital
🇺🇸Minneapolis, Minnesota, United States
University of Minnesota/Masonic Cancer Center
🇺🇸Minneapolis, Minnesota, United States
CancerCare Manitoba
🇨🇦Winnipeg, Manitoba, Canada
Saint Mary's Hospital and Regional Medical Center
🇺🇸Grand Junction, Colorado, United States
Huntsman Cancer Institute/University of Utah
🇺🇸Salt Lake City, Utah, United States
LDS Hospital
🇺🇸Salt Lake City, Utah, United States
Thompson Cancer Survival Center
🇺🇸Knoxville, Tennessee, United States
Renown Regional Medical Center
🇺🇸Reno, Nevada, United States
Fox Chase Cancer Center
🇺🇸Philadelphia, Pennsylvania, United States
Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital
🇺🇸New Brunswick, New Jersey, United States
Nevada Cancer Research Foundation CCOP
🇺🇸Las Vegas, Nevada, United States
Saint Alphonsus Cancer Care Center-Boise
🇺🇸Boise, Idaho, United States
University of Wisconsin Hospital and Clinics
🇺🇸Madison, Wisconsin, United States
Wheaton Franciscan Cancer Care - All Saints
🇺🇸Racine, Wisconsin, United States
Riverview Medical Center/Booker Cancer Center
🇺🇸Red Bank, New Jersey, United States
Sparta Cancer Treatment Center
🇺🇸Sparta, New Jersey, United States
Wayne State University/Karmanos Cancer Institute
🇺🇸Detroit, Michigan, United States
Park Nicollet Clinic - Saint Louis Park
🇺🇸Saint Louis Park, Minnesota, United States
North Memorial Medical Health Center
🇺🇸Robbinsdale, Minnesota, United States
Virginia Commonwealth University/Massey Cancer Center
🇺🇸Richmond, Virginia, United States
University of Michigan Comprehensive Cancer Center
🇺🇸Ann Arbor, Michigan, United States
Froedtert and the Medical College of Wisconsin
🇺🇸Milwaukee, Wisconsin, United States
West Michigan Cancer Center
🇺🇸Kalamazoo, Michigan, United States
University of Texas Medical Branch
🇺🇸Galveston, Texas, United States
UF Cancer Center at Orlando Health
🇺🇸Orlando, Florida, United States
Norton Suburban Hospital and Medical Campus
🇺🇸Louisville, Kentucky, United States
Medical University of South Carolina
🇺🇸Charleston, South Carolina, United States
Ingalls Memorial Hospital
🇺🇸Harvey, Illinois, United States
Franciscan Saint Margaret Health-Hammond Campus
🇺🇸Hammond, Indiana, United States