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

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

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.

Study Overview

• Status: Terminated
• Conditions: Recurrent Non-Small Cell Lung Carcinoma; Metastatic Malignant Neoplasm in the Brain; Stage IV Non-Small Cell Lung Cancer AJCC v7
• Intervention / Treatment: Drug: Temozolomide; Drug: Erlotinib Hydrochloride; Radiation: 3-Dimensional Conformal Radiation Therapy; Radiation: Stereotactic Radiosurgery

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.

• Study Type: Interventional
• Enrollment (Actual): 126
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3E 0V9
      • CancerCare Manitoba
  • Ontario
    • Ottawa, Ontario, Canada, K1Y 4E9
      • Ottawa Hospital-Civic Campus
  • Quebec
    • Montreal, Quebec, Canada, H2W 1S6
      • McGill University Department of Oncology
• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85260
      • Arizona Oncology Services Foundation
    • Scottsdale, Arizona, United States, 85260
      • Scottsdale Health Care-Osborn
  • California
    • Burbank, California, United States, 91505
      • Providence Saint Joseph Medical Center/Disney Family Cancer Center
    • Los Angeles, California, United States, 90027
      • Kaiser Permanente Los Angeles Medical Center
    • Pomona, California, United States, 91767
      • Pomona Valley Hospital Medical Center
  • Colorado
    • Grand Junction, Colorado, United States, 81501
      • Saint Mary's Hospital and Regional Medical Center
  • Delaware
    • Newark, Delaware, United States, 19718
      • Christiana Care Health System-Christiana Hospital
  • Florida
    • Jacksonville, Florida, United States, 32207
      • Baptist MD Anderson Cancer Center
    • Jacksonville, Florida, United States, 32258
      • Baptist Medical Center South
    • Jacksonville, Florida, United States, 32207
      • Integrated Community Oncology Network-Southside Cancer Center
    • Jacksonville Beach, Florida, United States, 32250
      • Integrated Community Oncology Network-Florida Cancer Center Beaches
    • Miami, Florida, United States, 33136
      • University of Miami Miller School of Medicine-Sylvester Cancer Center
    • Orange Park, Florida, United States, 32073
      • 21st Century Oncology-Orange Park
    • Orlando, Florida, United States, 32806
      • UF Cancer Center at Orlando Health
    • Palatka, Florida, United States, 32177
      • 21st Century Oncology-Palatka
    • Panama City, Florida, United States, 32401
      • Bay Medical Center
    • Saint Augustine, Florida, United States, 32086
      • Integrated Community Oncology Network-Flager Cancer Center
    • Tallahassee, Florida, United States, 32308
      • Tallahassee Memorial HealthCare
  • Georgia
    • Columbus, Georgia, United States, 31904
      • John B Amos Cancer Center
  • Idaho
    • Boise, Idaho, United States, 83706
      • Saint Alphonsus Cancer Care Center-Boise
  • Illinois
    • Arlington Heights, Illinois, United States, 60005
      • Northwest Community Hospital
    • Chicago, Illinois, United States, 60611
      • Northwestern University
    • Harvey, Illinois, United States, 60426
      • Ingalls Memorial Hospital
    • Springfield, Illinois, United States, 62702
      • Saint John's Hospital
  • Indiana
    • Fort Wayne, Indiana, United States, 46805
      • Parkview Hospital Randallia
    • Hammond, Indiana, United States, 46320
      • Franciscan Saint Margaret Health-Hammond Campus
    • Indianapolis, Indiana, United States, 46202
      • IU Health Methodist Hospital
  • Iowa
    • Dubuque, Iowa, United States, 52001
      • Finley Hospital
  • Kentucky
    • Louisville, Kentucky, United States, 40207
      • Norton Suburban Hospital and Medical Campus
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland/Greenebaum Cancer Center
    • Baltimore, Maryland, United States, 21229
      • Saint Agnes Hospital
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital Cancer Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Comprehensive Cancer Center
    • Detroit, Michigan, United States, 48201
      • Wayne State University/Karmanos Cancer Institute
    • Kalamazoo, Michigan, United States, 49007
      • West Michigan Cancer Center
  • Minnesota
    • Burnsville, Minnesota, United States, 55337
      • Fairview Ridges Hospital
    • Coon Rapids, Minnesota, United States, 55433
      • Mercy Hospital
    • Edina, Minnesota, United States, 55435
      • Fairview-Southdale Hospital
    • Fridley, Minnesota, United States, 55432
      • Unity Hospital
    • Minneapolis, Minnesota, United States, 55407
      • Abbott-Northwestern Hospital
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota/Masonic Cancer Center
    • Robbinsdale, Minnesota, United States, 55422
      • North Memorial Medical Health Center
    • Saint Cloud, Minnesota, United States, 56303
      • Coborn Cancer Center at Saint Cloud Hospital
    • Saint Cloud, Minnesota, United States, 56303
      • Saint Cloud Hospital
    • Saint Louis Park, Minnesota, United States, 55416
      • Park Nicollet Clinic - Saint Louis Park
    • Saint Louis Park, Minnesota, United States, 55416
      • Metro Minnesota Community Oncology Research Consortium
    • Saint Paul, Minnesota, United States, 55102
      • United Hospital
    • Waconia, Minnesota, United States, 55387
      • Ridgeview Medical Center
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Saint Louis University Hospital
  • Nevada
    • Las Vegas, Nevada, United States, 89106
      • Nevada Cancer Research Foundation CCOP
    • Reno, Nevada, United States, 89502
      • Renown Regional Medical Center
  • New Jersey
    • New Brunswick, New Jersey, United States, 08903
      • Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital
    • Red Bank, New Jersey, United States, 07701
      • Riverview Medical Center/Booker Cancer Center
    • Sparta, New Jersey, United States, 07871
      • Sparta Cancer Treatment Center
  • New York
    • Rochester, New York, United States, 14642
      • University of Rochester
  • North Carolina
    • Asheville, North Carolina, United States, 28801
      • Mission Hospital-Memorial Campus
  • Ohio
    • Akron, Ohio, United States, 44304
      • Summa Akron City Hospital/Cooper Cancer Center
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Foundation
  • Oklahoma
    • Tulsa, Oklahoma, United States, 74136
      • Natalie Warren Bryant Cancer Center at Saint Francis
  • Pennsylvania
    • Drexel Hill, Pennsylvania, United States, 19026
      • Delaware County Memorial Hospital
    • Philadelphia, Pennsylvania, United States, 19111
      • Fox Chase Cancer Center
    • Philadelphia, Pennsylvania, United States, 19107
      • Thomas Jefferson University Hospital
    • Philadelphia, Pennsylvania, United States, 19103
      • Radiation Therapy Oncology Group
    • West Reading, Pennsylvania, United States, 19611
      • Reading Hospital
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
  • Tennessee
    • Knoxville, Tennessee, United States, 37916
      • Thompson Cancer Survival Center
  • Texas
    • Arlington, Texas, United States, 76012
      • Arlington Cancer Center
    • Dallas, Texas, United States, 75390
      • UT Southwestern/Simmons Cancer Center-Dallas
    • Galveston, Texas, United States, 77555-0565
      • University of Texas Medical Branch
    • Houston, Texas, United States, 77030
      • M D Anderson Cancer Center
  • Utah
    • Murray, Utah, United States, 84107
      • Intermountain Medical Center
    • Ogden, Utah, United States, 84403
      • McKay-Dee Hospital Center
    • Salt Lake City, Utah, United States, 84112
      • Huntsman Cancer Institute/University of Utah
    • Salt Lake City, Utah, United States, 84143
      • LDS Hospital
  • Virginia
    • Norfolk, Virginia, United States, 23507
      • Sentara Norfolk General Hospital
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University/Massey Cancer Center
  • Washington
    • Seattle, Washington, United States, 98101
      • Virginia Mason Medical Center
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin Hospital and Clinics
    • Milwaukee, Wisconsin, United States, 53226
      • Froedtert and the Medical College of Wisconsin
    • Racine, Wisconsin, United States, 53405
      • Wheaton Franciscan Cancer Care - All Saints

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

  • 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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 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.	Radiation: 3-Dimensional Conformal Radiation Therapy; Patients undergo radiation therapy once daily for approximately 3 weeks; Other Names: 3-dimensional radiation therapy; 3D CONFORMAL RADIATION THERAPY; 3D CRT; 3D-CRT; Conformal Therapy; Radiation Conformal Therapy; Radiation: Stereotactic Radiosurgery; Patients undergo surgery after radiation therapy; Other Names: Stereotactic External Beam Irradiation; stereotactic external-beam radiation therapy; stereotactic radiation therapy; Stereotactic Radiotherapy; stereotaxic radiation therapy; stereotaxic radiosurgery
Experimental: 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.	Drug: Temozolomide; Given orally; Other Names: Temodar; SCH 52365; Temodal; Temcad; Methazolastone; RP-46161; Temomedac; CCRG-81045; Imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, 3, 4-dihydro-3-methyl-4-oxo-; M & B 39831; M and B 39831; Radiation: 3-Dimensional Conformal Radiation Therapy; Patients undergo radiation therapy once daily for approximately 3 weeks; Other Names: 3-dimensional radiation therapy; 3D CONFORMAL RADIATION THERAPY; 3D CRT; 3D-CRT; Conformal Therapy; Radiation Conformal Therapy; Radiation: Stereotactic Radiosurgery; Patients undergo surgery after radiation therapy; Other Names: Stereotactic External Beam Irradiation; stereotactic external-beam radiation therapy; stereotactic radiation therapy; Stereotactic Radiotherapy; stereotaxic radiation therapy; stereotaxic radiosurgery
Experimental: 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.	Drug: Erlotinib Hydrochloride; Given orally; Other Names: Cp-358,774; Tarceva; OSI-774; Radiation: 3-Dimensional Conformal Radiation Therapy; Patients undergo radiation therapy once daily for approximately 3 weeks; Other Names: 3-dimensional radiation therapy; 3D CONFORMAL RADIATION THERAPY; 3D CRT; 3D-CRT; Conformal Therapy; Radiation Conformal Therapy; Radiation: Stereotactic Radiosurgery; Patients undergo surgery after radiation therapy; Other Names: Stereotactic External Beam Irradiation; stereotactic external-beam radiation therapy; stereotactic radiation therapy; Stereotactic Radiotherapy; stereotaxic radiation therapy; stereotaxic radiosurgery

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival	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.	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.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of CNS Progression (One Year)	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.	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	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).	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 Functional Assessment of Cancer Therapy-Brain (FACT-Br) Score at 3 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.	From randomization to three months.
Change in Performance Status at 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.	From randomization to six months.
Change in Steroid Dependence at 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.	From randomization to six months.
Cause of Death (Neurologic vs Other)	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.	From randomization to last follow-up, up to 48.1 months. Analysis occurs after all patients have been potentially followed for 9 months.

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Collaborators: Radiation Therapy Oncology Group
• Investigators: Principal Investigator: Paul Sperduto, Radiation Therapy Oncology Group

Study record dates

Study Major Dates

• Study Start (Actual): October 6, 2004
• Primary Completion (Actual): June 14, 2011
• Study Completion (Actual): April 1, 2012

Study Registration Dates

• First Submitted: November 9, 2004
• First Submitted That Met QC Criteria: November 8, 2004
• First Posted (Estimate): November 9, 2004

Study Record Updates

• Last Update Posted (Actual): March 9, 2018
• Last Update Submitted That Met QC Criteria: February 9, 2018
• Last Verified: February 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Respiratory Tract Diseases; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Brain Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Protein Kinase Inhibitors; Erlotinib Hydrochloride; Temozolomide
• Other Study ID Numbers: NCI-2009-00720 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); U10CA021661 (U.S. NIH Grant/Contract); CDR0000389490; RTOG 0320 (Other Identifier: Radiation Therapy Oncology Group); RTOG-0320 (Other Identifier: CTEP)