Whole-Brain Radiation Therapy With or Without Hippocampal Avoidance in Treating Patients With Limited Stage or Extensive Stage Small Cell Lung Cancer

Extensive Stage Small Cell Lung Carcinoma Clinical Trial

Official title:

Randomized Phase II/III Trial of Prophylactic Cranial Irradiation With or Without Hippocampal Avoidance for Small Cell Lung Cancer

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02635009
• Other study ID #: NRG-CC003
• Secondary ID: NCI-2015-01548NR
• Status: Active, not recruiting
• Phase: Phase 2/Phase 3
• Start date: December 7, 2015
• Est. completion date: April 2027

Study information

• Verified date: January 2024
• Source: NRG Oncology
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This randomized phase II/III trial studies how well whole-brain radiation therapy works and compares it with or without hippocampal avoidance in treating patients with small cell lung cancer that is found in one lung, the tissues between the lungs, and nearby lymph nodes only (limited stage) or has spread outside of the lung in which it began or to other parts of the body (extensive stage). Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. The hippocampus is part of the brain that is important for memory. Avoiding the hippocampus during whole-brain radiation could decrease the chance of side effects on memory and thinking. It is not yet known whether giving whole-brain radiation therapy is more effective with or without hippocampal avoidance in treating patients with small cell lung cancer.

Description:

PRIMARY OBJECTIVES:

I. Determine whether the 12-month intracranial relapse rate following hippocampal avoidance (HA)-prophylactic cranial irradiation (PCI) is non-inferior compared to the rate following PCI for patients with small cell lung cancer (SCLC). (Randomized Phase II Component [Non-Inferiority]) II. Determine whether HA-PCI reduces the likelihood of 6-month deterioration from baseline in Hopkins Verbal Learning Test (HVLT)-Revised (R) delayed recall compared to PCI for patients with SCLC. (Phase III Component [Efficacy])

SECONDARY OBJECTIVES:

I. Compare time to cognitive failure, as measured by a battery of tests (HVLT-R, Controlled Oral Word Association [COWA] test, and Trail Making Test [TMT] parts A and B), after PCI versus HA-PCI in SCLC.

II. Compare time to cognitive failure as separately measured by each test (HVLT-R for Total Recall and Delayed Recognition, COWA test, and TMT parts A and B), after PCI versus HA-PCI for SCLC.

III. Compare patient-reported cognitive functioning and other quality of life domains (assessed by the European Organization for Research and Treatment of Cancer [EORTC] Quality of Life Questionnaire [QLQ]-Core [C]30 and BN20) between PCI versus HA-PCI for patients with SCLC.

IV. Compare overall survival after PCI versus HA-PCI for patients with SCLC. V. Compare 12-month intracranial relapse rate (at completion of phase III) and time to intracranial relapse after PCI versus HA-PCI for patients with SCLC.

VI. Evaluate adverse events according to Common Terminology Criteria for Adverse Events (CTCAE) criteria.

VII. Correlate changes in health-related quality of life (HRQOL) domains with changes in cognitive testing outcomes following PCI versus HA-PCI for patients with SCLC.

VIII. Assess cost-effectiveness of HA-PCI (intensity modulated radiation therapy [IMRT]) and PCI (3-dimensional conformal radiation therapy [3DCRT]) using the EuroQual (EQ)-5-Dimensions (5D)-5L.

IX. Correlate miRNA signatures with cognitive failure in SCLC patients who received PCI and HA-PCI.

X. Evaluate APOE genotyping as potential predictor of neurocognitive decline, hippocampal atrophy after brain irradiation and/or differential benefit from hippocampal avoidance.

XI. Evaluate baseline MR imaging biomarkers of white matter injury and hippocampal volumetry as potential predictors of cognitive decline and differential benefit from HA-PCI as compared to PCI.

TERTIARY OBJECTIVES:

I. Collect serum, whole blood, and urine for future translational research analyses.

II. Evaluate baseline magnetic resonance (MR) imaging biomarkers of white matter injury and hippocampal volumetry as potential predictors of cognitive decline and differential benefit from HAPCI as compared to PCI.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients undergo PCI using 3DCRT daily for 2 weeks.

ARM II: Patients undergo PCI with HA using IMRT daily for 2 weeks.

After completion of study treatment, patients are followed every 3 months for 1 year, then every 6 months until 3 years and then annually until death.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 418
• Est. completion date: April 2027
• Est. primary completion date: May 18, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• PRIOR TO STEP 1 REGISTRATION

• Histologic proof or unequivocal cytologic proof (fine needle aspiration, biopsy or two positive sputa) of SCLC within 250 days prior to Step 1 registration

• High-grade neuroendocrine carcinoma or combined SCLC and NSCLC is permitted.

• Patients must have received chemotherapy and be registered to Step 1 registration no earlier than 7 days and no later than 56 days after completing chemotherapy. Note:

• Post-chemotherapy restaging imaging must be completed no more than 56 days prior to Step 1 registration.

• For patients with extensive-stage small cell lung cancer who are being considered for consolidative thoracic radiotherapy after chemotherapy, concomitant administration of consolidative thoracic radiotherapy and protocol-specified prophylactic cranial irradiation with or without hippocampal avoidance is permitted.

• Patients must have a gadolinium contrast-enhanced three-dimensional (3D), spoiled gradient (SPGR), magnetization-prepared rapid gradient echo (MP-RAGE), or turbo field echo (TFE) MRI scan (see section 11.3 regarding axial T2/FLAIR sequence). To yield acceptable image quality, the gadolinium contrast-enhanced three-dimensional SPGR, MP-RAGE or TFE axial MRI scan must use the smallest possible axial slice thickness not exceeding 1.5 mm. Sites may contact the Imaging Co-Chairs for further information or assistance if needed.

• This MRI must be obtained within 56 days prior to Step 1 registration. Note: The MRI study is mandatory irrespective of randomization to the experimental or control arm of this study.

• Prior to chemotherapy +/- thoracic radiotherapy, patients must be defined as limited-stage or extensive-stage SCLC after clinical staging evaluation involving the following:

1. History/physical examination;

2. CT of the chest and abdomen with contrast (does not have to be done if the patient has had a PET/CT scan prior to initiating chemotherapy or thoracic radiotherapy);

3. MRI of the brain with contrast or diagnostic head CT with contrast;

4. For patients without evidence of extensive-stage SCLC on chest and abdomen CT and brain MRI or head CT, a PET/CT or bone scan is required to confirm limited-stage SCLC.

• After chemotherapy, patients must be restaged prior to Step 1 registration using the same diagnostic work-up as required pre-chemotherapy. Repeat PET/CT or bone scan is not required. Patients must have:

• History/physical examination within 30 days of Step 1 registration;

• No CNS metastases (Repeat MRI required; see Section 3.2.3 for details) within 56 days prior to Step 1 registration;

• No progression in any site;

• Radiographic partial or complete response to chemotherapy in at least one disease site within 56 days prior to Step 1 registration.

1. If PET/CT was obtained prior to chemotherapy, either a repeat PET/CT or CT of the chest and abdomen with contrast can be obtained for response assessment.

2. Patients who underwent resection for limited-stage SCLC prior to chemotherapy and have no radiographically evident disease for response assessment remain eligible if post-chemotherapy imaging demonstrates no progression.

• Zubrod performance status 0-2

• Women of childbearing potential and male participants must practice adequate contraception

• Women of childbearing potential must have a negative qualitative serum pregnancy test =< 2 weeks prior to study entry

• Patients who are primary English or French speakers are eligible

• Patients must sign a study-specific informed consent prior to study entry

• PRIOR TO STEP 2 REGISTRATION

• The following baseline neurocognitive assessments must be completed and uploaded within 10 calendar days after or at the time of Step 1 registration: HVLT-R (recall, delayed recall, and recognition), TMT (Parts A and B), and COWA. The neurocognitive assessments will be uploaded into the NRG Oncology RAVE System for evaluation by Dr. Wefel. Once the upload is complete, within 3 business days, a notification email will be sent to the site to proceed to Step 2 registration. At minimum, the HVLT-R delayed recall must be able to be scored (i.e. completed without error) in order to be eligible.

• Patients must have a baseline raw score greater than 2 on the HVLT-R delayed recall

Exclusion Criteria:

• Prior radiotherapy to the head or neck (except for T1 glottic cancer), resulting in overlap of radiation fields

• Radiographic evidence of CNS metastases

• Radiographic evidence of hydrocephalus or other architectural distortion of the ventricular system, including placement of external ventricular drain or ventriculoperitoneal shunt

• Planned concurrent chemotherapy or anti-tumor agent during PCI

• Concurrent atezolizumab permitted

• Concomitant invasive malignancy or invasive malignancy within the past five years other than non-melanomatous skin cancer; history of in situ carcinoma (e.g. ductal carcinoma in situ of breast, in situ carcinoma of the cervix, vulva or larynx) is permitted

• Contraindication to MR imaging, such as implanted metal devices or foreign bodies or severe claustrophobia

• Severe, active comorbidity, defined as follows:

• Unstable angina and/or congestive heart failure requiring hospitalization within the last 6 months

• Transmural myocardial infarction within the last 6 months

• Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration

• Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects

• Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration

• Uncontrolled, clinically significant cardiac arrhythmias

• HIV positive with CD4 count < 200 cells/microliter;

1. Note: Patients who are HIV positive are eligible, provided they are under treatment with highly active antiretroviral therapy (HAART) and have a CD4 count = 200 cells/microliter within 30 days prior to Step 1 registration.

2. Note: HIV testing is not required for eligibility for this protocol.

• Pregnant or lactating women or women of childbearing potential and male participants who are sexually active and not willing/able to use medically acceptable forms of contraception

Related Conditions & MeSH terms

• Carcinoma
• Extensive Stage Small Cell Lung Carcinoma
• Limited Stage Small Cell Lung Carcinoma
• Lung Neoplasms
• Small Cell Lung Carcinoma

Intervention

Radiation:
• 3-Dimensional Conformal Radiation Therapy
Undergo PCI using 3DCRT

Other:
• Cognitive Assessment
Ancillary studies

Radiation:
• Intensity-Modulated Radiation Therapy
Undergo PCI with HA using IMRT

Other:
• Laboratory Biomarker Analysis
Correlative studies
• Quality-of-Life Assessment
Ancillary studies

Locations

Country	Name	City	State
Canada	Kingston Health Sciences Centre	Kingston	Ontario
Canada	London Regional Cancer Program	London	Ontario
Canada	CHUM - Centre Hospitalier de l'Universite de Montreal	Montreal	Quebec
Canada	CHUM - Hopital Notre-Dame	Montreal	Quebec
Canada	McGill University Department of Oncology	Montreal	Quebec
Canada	The Research Institute of the McGill University Health Centre (MUHC)	Montreal	Quebec
Canada	Stronach Regional Health Centre at Southlake	Newmarket	Ontario
Canada	Ottawa Hospital and Cancer Center-General Campus	Ottawa	Ontario
Canada	CHU de Quebec-L'Hotel-Dieu de Quebec (HDQ)	Quebec City	Quebec
Canada	Allan Blair Cancer Centre	Regina	Saskatchewan
Canada	Saskatoon Cancer Centre	Saskatoon	Saskatchewan
Canada	Centre Hospitalier Universitaire de Sherbrooke-Fleurimont	Sherbrooke	Quebec
Canada	University Health Network-Princess Margaret Hospital	Toronto	Ontario
United States	The Cancer Center of Hawaii-Pali Momi	'Aiea	Hawaii
United States	Jefferson Abington Hospital	Abington	Pennsylvania
United States	Cleveland Clinic Akron General	Akron	Ohio
United States	Summa Health System - Akron Campus	Akron	Ohio
United States	Mayo Clinic Health System in Albert Lea	Albert Lea	Minnesota
United States	University of New Mexico Cancer Center	Albuquerque	New Mexico
United States	AnMed Health Cancer Center	Anderson	South Carolina
United States	Ascension Saint Vincent Anderson	Anderson	Indiana
United States	Saint Joseph Mercy Hospital	Ann Arbor	Michigan
United States	Anne Arundel Medical Center	Annapolis	Maryland
United States	Langlade Hospital and Cancer Center	Antigo	Wisconsin
United States	Emory University Hospital Midtown	Atlanta	Georgia
United States	Emory University Hospital/Winship Cancer Institute	Atlanta	Georgia
United States	Grady Health System	Atlanta	Georgia
United States	Northside Hospital	Atlanta	Georgia
United States	Piedmont Hospital	Atlanta	Georgia
United States	Johns Hopkins University/Sidney Kimmel Cancer Center	Baltimore	Maryland
United States	MedStar Franklin Square Medical Center/Weinberg Cancer Institute	Baltimore	Maryland
United States	MedStar Good Samaritan Hospital	Baltimore	Maryland
United States	University of Maryland Medical Center	Baltimore	Maryland
United States	University of Maryland/Greenebaum Cancer Center	Baltimore	Maryland
United States	Memorial Sloan Kettering Basking Ridge	Basking Ridge	New Jersey
United States	McLaren Cancer Institute-Bay City	Bay City	Michigan
United States	Northwell Health Imbert Cancer Center	Bay Shore	New York
United States	UM Upper Chesapeake Medical Center	Bel Air	Maryland
United States	Central Vermont Medical Center/National Life Cancer Treatment	Berlin	Vermont
United States	Billings Clinic Cancer Center	Billings	Montana
United States	University of Alabama at Birmingham Cancer Center	Birmingham	Alabama
United States	Sanford Bismarck Medical Center	Bismarck	North Dakota
United States	Boca Raton Regional Hospital	Boca Raton	Florida
United States	Prisma Health Cancer Institute - Spartanburg	Boiling Springs	South Carolina
United States	Saint Alphonsus Cancer Care Center-Boise	Boise	Idaho
United States	Saint Luke's Cancer Institute - Boise	Boise	Idaho
United States	Hartford HealthCare - Saint Vincent's Medical Center	Bridgeport	Connecticut
United States	Saint Joseph Mercy Brighton	Brighton	Michigan
United States	Montefiore Medical Center - Moses Campus	Bronx	New York
United States	Montefiore Medical Center-Einstein Campus	Bronx	New York
United States	Ascension Southeast Wisconsin Hospital - Elmbrook Campus	Brookfield	Wisconsin
United States	New York-Presbyterian/Brooklyn Methodist Hospital	Brooklyn	New York
United States	Crozer-Keystone Regional Cancer Center at Broomall	Broomall	Pennsylvania
United States	Henry Ford Cancer Institute-Downriver	Brownstown	Michigan
United States	Bryn Mawr Hospital	Bryn Mawr	Pennsylvania
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	Lahey Hospital and Medical Center	Burlington	Massachusetts
United States	University of Vermont Medical Center	Burlington	Vermont
United States	Saint Alphonsus Cancer Care Center-Caldwell	Caldwell	Idaho
United States	Saint Francis Medical Center	Cape Girardeau	Missouri
United States	Mercy Hospital	Cedar Rapids	Iowa
United States	Saint Luke's Hospital	Cedar Rapids	Iowa
United States	Christiana Care Health System-Concord Health Center	Chadds Ford	Pennsylvania
United States	Geauga Hospital	Chardon	Ohio
United States	Atrium Health Pineville/LCI-Pineville	Charlotte	North Carolina
United States	Atrium Health University City/LCI-University	Charlotte	North Carolina
United States	Carolinas Medical Center/Levine Cancer Institute	Charlotte	North Carolina
United States	Saint Joseph Mercy Chelsea	Chelsea	Michigan
United States	John H Stroger Jr Hospital of Cook County	Chicago	Illinois
United States	Northwestern University	Chicago	Illinois
United States	Rush University Medical Center	Chicago	Illinois
United States	Adena Regional Medical Center	Chillicothe	Ohio
United States	McLaren Cancer Institute-Clarkston	Clarkston	Michigan
United States	Michigan Healthcare Professionals Clarkston	Clarkston	Michigan
United States	Case Western Reserve University	Cleveland	Ohio
United States	Cleveland Clinic Cancer Center/Fairview Hospital	Cleveland	Ohio
United States	Cleveland Clinic Foundation	Cleveland	Ohio
United States	Henry Ford Macomb Hospital-Clinton Township	Clinton Township	Michigan
United States	Central Maryland Radiation Oncology in Howard County	Columbia	Maryland
United States	Mount Carmel Health Center West	Columbus	Ohio
United States	Ohio State University Comprehensive Cancer Center	Columbus	Ohio
United States	Memorial Sloan Kettering Commack	Commack	New York
United States	Atrium Health Cabarrus/LCI-Concord	Concord	North Carolina
United States	UM Sylvester Comprehensive Cancer Center at Coral Gables	Coral Gables	Florida
United States	Siteman Cancer Center at West County Hospital	Creve Coeur	Missouri
United States	Northside Hospital-Forsyth	Cumming	Georgia
United States	Geisinger Medical Center	Danville	Pennsylvania
United States	Dayton Physician LLC-Miami Valley Hospital North	Dayton	Ohio
United States	Beaumont Hospital - Dearborn	Dearborn	Michigan
United States	Decatur Memorial Hospital	Decatur	Illinois
United States	Iowa Methodist Medical Center	Des Moines	Iowa
United States	Henry Ford Hospital	Detroit	Michigan
United States	Wayne State University/Karmanos Cancer Institute	Detroit	Michigan
United States	Wentworth-Douglass Hospital	Dover	New Hampshire
United States	Saint Luke's Hospital of Duluth	Duluth	Minnesota
United States	Northeast Radiation Oncology Center	Dunmore	Pennsylvania
United States	Mayo Clinic Health System Eau Claire Hospital-Luther Campus	Eau Claire	Wisconsin
United States	Mayo Clinic Health System-Eau Claire Clinic	Eau Claire	Wisconsin
United States	Crossroads Cancer Center	Effingham	Illinois
United States	Arnot Ogden Medical Center/Falck Cancer Center	Elmira	New York
United States	Mercy Cancer Center-Elyria	Elyria	Ohio
United States	Englewood Hospital and Medical Center	Englewood	New Jersey
United States	Swedish Medical Center	Englewood	Colorado
United States	Sanford Roger Maris Cancer Center	Fargo	North Dakota
United States	Michigan Healthcare Professionals Farmington	Farmington Hills	Michigan
United States	Genesys Hurley Cancer Institute	Flint	Michigan
United States	McLaren Cancer Institute-Flint	Flint	Michigan
United States	Poudre Valley Hospital	Fort Collins	Colorado
United States	Broward Health Medical Center	Fort Lauderdale	Florida
United States	Parkview Hospital Randallia	Fort Wayne	Indiana
United States	Parkview Regional Medical Center	Fort Wayne	Indiana
United States	Ascension Saint Francis - Reiman Cancer Center	Franklin	Wisconsin
United States	University of Texas Medical Branch	Galveston	Texas
United States	Northwestern Medicine Cancer Center Delnor	Geneva	Illinois
United States	Adams Cancer Center	Gettysburg	Pennsylvania
United States	UM Baltimore Washington Medical Center/Tate Cancer Center	Glen Burnie	Maryland
United States	Crozer Regional Cancer Center at Brinton Lake	Glen Mills	Pennsylvania
United States	Goshen Center for Cancer Care	Goshen	Indiana
United States	Aurora Cancer Care-Grafton	Grafton	Wisconsin
United States	Spectrum Health at Butterworth Campus	Grand Rapids	Michigan
United States	Trinity Health Grand Rapids Hospital	Grand Rapids	Michigan
United States	Benefis Healthcare- Sletten Cancer Institute	Great Falls	Montana
United States	Aurora BayCare Medical Center	Green Bay	Wisconsin
United States	Marin General Hospital	Greenbrae	California
United States	Prisma Health Cancer Institute - Eastside	Greenville	South Carolina
United States	Prisma Health Cancer Institute - Faris	Greenville	South Carolina
United States	Self Regional Healthcare	Greenwood	South Carolina
United States	Legacy Mount Hood Medical Center	Gresham	Oregon
United States	Memorial Sloan Kettering Westchester	Harrison	New York
United States	The Radiation Oncology Center-Hilton Head/Bluffton	Hilton Head Island	South Carolina
United States	Edward Hines Jr VA Hospital	Hines	Illinois
United States	Queen's Medical Center	Honolulu	Hawaii
United States	The Cancer Center of Hawaii-Liliha	Honolulu	Hawaii
United States	M D Anderson Cancer Center	Houston	Texas
United States	Cleveland Clinic Cancer Center Independence	Independence	Ohio
United States	UW Cancer Center Johnson Creek	Johnson Creek	Wisconsin
United States	Freeman Health System	Joplin	Missouri
United States	West Michigan Cancer Center	Kalamazoo	Michigan
United States	North Kansas City Hospital	Kansas City	Missouri
United States	Saint Luke's Hospital of Kansas City	Kansas City	Missouri
United States	University of Kansas Cancer Center	Kansas City	Kansas
United States	University of Kansas Cancer Center - North	Kansas City	Missouri
United States	Aurora Cancer Care-Kenosha South	Kenosha	Wisconsin
United States	Thompson Cancer Survival Center	Knoxville	Tennessee
United States	Gundersen Lutheran Medical Center	La Crosse	Wisconsin
United States	Mayo Clinic Health System-Franciscan Healthcare	La Crosse	Wisconsin
United States	Northwell Health/Center for Advanced Medicine	Lake Success	New York
United States	Lancaster Radiation Therapy Center	Lancaster	South Carolina
United States	McLaren Cancer Institute-Lapeer Region	Lapeer	Michigan
United States	Lawrence Memorial Hospital	Lawrence	Kansas
United States	UTMB Cancer Center at Victory Lakes	League City	Texas
United States	Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center	Lebanon	New Hampshire
United States	Geisinger Medical Oncology-Lewisburg	Lewisburg	Pennsylvania
United States	University of Kentucky/Markey Cancer Center	Lexington	Kentucky
United States	Condell Memorial Hospital	Libertyville	Illinois
United States	Trinity Health Saint Mary Mercy Livonia Hospital	Livonia	Michigan
United States	Los Angeles General Medical Center	Los Angeles	California
United States	USC / Norris Comprehensive Cancer Center	Los Angeles	California
United States	Lowell General Hospital	Lowell	Massachusetts
United States	Michigan Healthcare Professionals Macomb	Macomb	Michigan
United States	University of Wisconsin Carbone Cancer Center	Madison	Wisconsin
United States	Mayo Clinic Health Systems-Mankato	Mankato	Minnesota
United States	Blount Memorial Hospital	Maryville	Tennessee
United States	Loyola University Medical Center	Maywood	Illinois
United States	Riddle Memorial Hospital	Media	Pennsylvania
United States	Froedtert Menomonee Falls Hospital	Menomonee Falls	Wisconsin
United States	UH Seidman Cancer Center at Lake Health Mentor Campus	Mentor	Ohio
United States	Mercy UC Davis Cancer Center	Merced	California
United States	Saint Luke's Cancer Institute - Meridian	Meridian	Idaho
United States	Miami Cancer Institute	Miami	Florida
United States	University of Miami Miller School of Medicine-Sylvester Cancer Center	Miami	Florida
United States	UH Seidman Cancer Center at Southwest General Hospital	Middleburg Heights	Ohio
United States	Memorial Sloan Kettering Monmouth	Middletown	New Jersey
United States	Aurora Saint Luke's Medical Center	Milwaukee	Wisconsin
United States	Aurora Sinai Medical Center	Milwaukee	Wisconsin
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Abbott-Northwestern Hospital	Minneapolis	Minnesota
United States	Community Medical Hospital	Missoula	Montana
United States	Atrium Health Union/LCI-Union	Monroe	North Carolina
United States	Memorial Sloan Kettering Bergen	Montvale	New Jersey
United States	West Virginia University Healthcare	Morgantown	West Virginia
United States	McLaren Cancer Institute-Macomb	Mount Clemens	Michigan
United States	Virtua Memorial	Mount Holly	New Jersey
United States	McLaren Cancer Institute-Central Michigan	Mount Pleasant	Michigan
United States	IU Health Ball Memorial Hospital	Muncie	Indiana
United States	Trinity Health Muskegon Hospital	Muskegon	Michigan
United States	Saint Alphonsus Cancer Care Center-Nampa	Nampa	Idaho
United States	Saint Luke's Cancer Institute - Nampa	Nampa	Idaho
United States	Vanderbilt University/Ingram Cancer Center	Nashville	Tennessee
United States	Yale University	New Haven	Connecticut
United States	Tulane University School of Medicine	New Orleans	Louisiana
United States	Lenox Hill Hospital	New York	New York
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center	New York	New York
United States	Christiana Care Health System-Christiana Hospital	Newark	Delaware
United States	Helen F Graham Cancer Center	Newark	Delaware
United States	University of Kansas Cancer Center at North Kansas City Hospital	North Kansas City	Missouri
United States	Mayo Clinic Radiation Therapy-Northfield	Northfield	Minnesota
United States	Kaiser Permanente Oakland-Broadway	Oakland	California
United States	TidalHealth Richard A Henson Cancer Institute	Ocean Pines	Maryland
United States	Ogden Regional Medical Center	Ogden	Utah
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	Saint Joseph Hospital - Orange	Orange	California
United States	Orlando Health Cancer Institute	Orlando	Florida
United States	Vince Lombardi Cancer Clinic - Oshkosh	Oshkosh	Wisconsin
United States	University of Kansas Cancer Center-Overland Park	Overland Park	Kansas
United States	McLaren Cancer Institute-Owosso	Owosso	Michigan
United States	University Hospitals Parma Medical Center	Parma	Ohio
United States	Illinois CancerCare-Peoria	Peoria	Illinois
United States	Methodist Medical Center of Illinois	Peoria	Illinois
United States	OSF Saint Francis Medical Center	Peoria	Illinois
United States	McLaren Cancer Institute-Northern Michigan	Petoskey	Michigan
United States	Fox Chase Cancer Center	Philadelphia	Pennsylvania
United States	Jefferson Torresdale Hospital	Philadelphia	Pennsylvania
United States	Temple University Hospital	Philadelphia	Pennsylvania
United States	Thomas Jefferson University Hospital	Philadelphia	Pennsylvania
United States	Saint Joseph Mercy Oakland	Pontiac	Michigan
United States	McLaren-Port Huron	Port Huron	Michigan
United States	Legacy Good Samaritan Hospital and Medical Center	Portland	Oregon
United States	Ascension All Saints Hospital	Racine	Wisconsin
United States	Kaiser Permanente-Rancho Cordova Cancer Center	Rancho Cordova	California
United States	Rapid City Regional Hospital	Rapid City	South Dakota
United States	Penn State Health Saint Joseph Medical Center	Reading	Pennsylvania
United States	Renown Regional Medical Center	Reno	Nevada
United States	Virginia Commonwealth University/Massey Cancer Center	Richmond	Virginia
United States	Mayo Clinic in Rochester	Rochester	Minnesota
United States	University of Rochester	Rochester	New York
United States	Rock Hill Radiation Therapy Center	Rock Hill	South Carolina
United States	Sutter Cancer Centers Radiation Oncology Services-Roseville	Roseville	California
United States	The Permanente Medical Group-Roseville Radiation Oncology	Roseville	California
United States	William Beaumont Hospital-Royal Oak	Royal Oak	Michigan
United States	Sutter Medical Center Sacramento	Sacramento	California
United States	University of California Davis Comprehensive Cancer Center	Sacramento	California
United States	Norris Cotton Cancer Center-North	Saint Johnsbury	Vermont
United States	Lakeland Medical Center Saint Joseph	Saint Joseph	Michigan
United States	Mercy Hospital Saint Louis	Saint Louis	Missouri
United States	Missouri Baptist Medical Center	Saint Louis	Missouri
United States	Siteman Cancer Center-South County	Saint Louis	Missouri
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Park Nicollet Clinic - Saint Louis Park	Saint Louis Park	Minnesota
United States	TidalHealth Peninsula Regional	Salisbury	Maryland
United States	Huntsman Cancer Institute/University of Utah	Salt Lake City	Utah
United States	California Pacific Medical Center-Pacific Campus	San Francisco	California
United States	Kaiser Permanente Medical Center - Santa Clara	Santa Clara	California
United States	Lewis Cancer and Research Pavilion at Saint Joseph's/Candler	Savannah	Georgia
United States	Memorial Health University Medical Center	Savannah	Georgia
United States	Atrium Health Cleveland/LCI-Cleveland	Shelby	North Carolina
United States	Sanford USD Medical Center - Sioux Falls	Sioux Falls	South Dakota
United States	Memorial Medical Center	Springfield	Illinois
United States	Staten Island University Hospital	Staten Island	New York
United States	Marshfield Medical Center-River Region at Stevens Point	Stevens Point	Wisconsin
United States	Cleveland Clinic Cancer Center Strongsville	Strongsville	Ohio
United States	Aurora Medical Center in Summit	Summit	Wisconsin
United States	State University of New York Upstate Medical University	Syracuse	New York
United States	Moffitt Cancer Center	Tampa	Florida
United States	UM Saint Joseph Medical Center	Towson	Maryland
United States	GenesisCare USA - Troy	Troy	Michigan
United States	William Beaumont Hospital - Troy	Troy	Michigan
United States	Gene Upshaw Memorial Tahoe Forest Cancer Center	Truckee	California
United States	Banner University Medical Center - Tucson	Tucson	Arizona
United States	Lewis and Faye Manderson Cancer Center	Tuscaloosa	Alabama
United States	Saint Luke's Cancer Institute - Twin Falls	Twin Falls	Idaho
United States	Vince Lombardi Cancer Clinic-Two Rivers	Two Rivers	Wisconsin
United States	Memorial Sloan Kettering Nassau	Uniondale	New York
United States	Carle Cancer Center	Urbana	Illinois
United States	Sutter Solano Medical Center/Cancer Center	Vallejo	California
United States	Virtua Voorhees	Voorhees	New Jersey
United States	Northwestern Medicine Cancer Center Warrenville	Warrenville	Illinois
United States	Aspirus Regional Cancer Center	Wausau	Wisconsin
United States	Aurora West Allis Medical Center	West Allis	Wisconsin
United States	Henry Ford West Bloomfield Hospital	West Bloomfield	Michigan
United States	Reading Hospital	West Reading	Pennsylvania
United States	UHHS-Westlake Medical Center	Westlake	Ohio
United States	Diagnostic and Treatment Center	Weston	Wisconsin
United States	Marshfield Medical Center - Weston	Weston	Wisconsin
United States	Wheeling Hospital/Schiffler Cancer Center	Wheeling	West Virginia
United States	Ascension Via Christi Hospitals Wichita	Wichita	Kansas
United States	Wesley Medical Center	Wichita	Kansas
United States	Geisinger Wyoming Valley/Henry Cancer Center	Wilkes-Barre	Pennsylvania
United States	Aspirus Cancer Care - Wisconsin Rapids	Wisconsin Rapids	Wisconsin
United States	Cleveland Clinic Wooster Family Health and Surgery Center	Wooster	Ohio
United States	UMass Memorial Medical Center - University Campus	Worcester	Massachusetts
United States	Lankenau Medical Center	Wynnewood	Pennsylvania
United States	WellSpan Health-York Cancer Center	York	Pennsylvania

Sponsors (3)

Lead Sponsor	Collaborator
NRG Oncology	National Cancer Institute (NCI), Radiation Therapy Oncology Group

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	White matter injury and hippocampal volume on neurocognitive function	The change from baseline to 6 months will be compared between arms using the t-test (or Wilcoxon test if not normally distributed) in the total score and the two subscale scores (agency and pathway). These scores will be correlated with the EORTC- QLQ-C30 total score using a Pearson correlation coefficient. A general linear model will be used to assess hopefulness, performed separately for the AHS total score and subscale scores, between treatment arms while adjusting for depression.	Baseline to 6 months
Primary	HVLT-R delayed recall deterioration status, defined using the Reliable Change Index (RCI) (Phase III)	Compared using Fisher's exact test at a significance level of 0.05.	6 months from start of treatment
Primary	Intracranial relapse rate (Phase II)	It will be compared between arms using a binomial test of difference in proportions at a significance level of 0.1. If the rate of relapse in the HA-PCI arm is significantly greater than that of the PCI only arm, this study will not continue to the phase III portion.	12 months
Secondary	Cost-effectiveness as measured by the EQ-5D (Phase III)	Quality-adjusted life years (QALY's) will be assessed as the area under the preference-weighted survival curve. Cost will be assessed using a societal perspective. The primary cost-effectiveness outcome will be the pooled incremental cost-per QALY ratio for HA-PCI versus standard PCI. The incremental cost per QALY ratio will be calculated as the total cost of the HA-PCI minus total cost of standard PCI which will be divided by the quality adjusted survival of the patients treated with HA-PCI minus the quality adjusted survival of patients receiving standard PCI.	Up to 3 years
Secondary	Incidence of adverse events (AEs), as measured by the CTCAE v.4 (Phase III)	Counts of all AEs by grade will be provided by treatment arm. Counts and frequencies will be provided for the worst grade AE experienced by the patient by treatment arm.	Up to 3 years
Secondary	Intracranial relapse rate (Phase III)	The occurrence of intracranial relapse will be defined as appearance of brain metastasis in brain. Cumulative incidence approach will be used to estimate the median time to intracranial relapse to account for the competing risk of death. Gray's test will be used to test for statistically significant difference in the distribution of intracranial relapse times. Cause-specific Cox proportional hazards regression model will be used to evaluate effect of stratification variables (age, stage, and planned concurrent memantine use) and other baseline characteristics, on time to intracranial relapse.	Up to 12 months
Secondary	Overall survival (Phase III)	Estimated using the Kaplan-Meier method and differences between treatment arms will be tested using the log rank test. The Cox proportional hazard model will be performed with the stratification variables and other baseline characteristics as fixed variables to assess the treatment effect while adjusting for patient-specific risk factors.	From the date of randomization to the date of death, or, otherwise, the last follow-up date on which the patient was reported alive, assessed up to 3 years
Secondary	Patient-reported HRQOL, as measured by the EORTC QLQ-C30 and BN20 (Phase III)	Correlation of changes in HRQOL domains measured by the EORTC QLQ-C30 and BN20 with changes in cognitive function will be assessed. Additionally cognitive function decline at 3, 6, 12, 18 and 24 months will also be assessed and compared using Fisher's exact test. Decline from baseline to each time point (3, 6, 12, 18, and 24 months from the start of treatment) in the following subscales will also be assessed and compared using Fisher's exact test: global QOL, physical functioning, role functioning, emotional functioning, and social functioning domains along with fatigue and pain items.	Up to 24 months
Secondary	Preservation of neurocognitive function, as measured by neurocognitive decline for HVLT-R, COWA test, TMT Parts A and B, and Clinical Trial Battery Composite (CTB COMP) score (Phase III)	Standardized scores that adjust for age, education, and gender when necessary will be analyzed. For discrete time point analyses, the change from baseline to each follow-up time point (3, 6, 12, 18, and 24 months from the start of treatment) will be calculated and compared between treatment arms using a t-test or Wilcoxon-Mann- Whitney test, depending on the normality of the data. Neurocognitive decline using the RCI for the HVLT-R, COWA, and TMT also will be compared between treatment arms at each follow-up time point using Fisher's exact test.	Up to 24 months
Secondary	Time to neurocognitive failure, where a failure is defined using the RCI criteria, as measured by HVLT-R, COWA test, and TMT Parts A and B (Phase III)	The cumulative incidence approach will be used to estimate the median time to neurocognitive failure to account for the competing risk of death. Gray's test will be used to test for statistically significant difference in the distribution of neurocognitive failure times. The cause-specific Cox proportional hazards regression model will be used to evaluate the effect of stratification variables (age, stage, and planned concurrent memantine use) and other baseline characteristics, on time to neurocognitive decline.	Up to 3 years