Observation or Radiation Therapy in Treating Patients With Newly Diagnosed Grade II Meningioma That Has Been Completely Removed by Surgery

Intracranial Meningioma Clinical Trial

Official title:

Phase III Trial of Observation Versus Irradiation for a Gross Totally Resected Grade II Meningioma

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03180268
• Other study ID #: NRG-BN003
• Secondary ID: NCI-2016-01619NR
• Status: Recruiting
• Phase: Phase 3
• Start date: June 14, 2017
• Est. completion date: August 31, 2027

Study information

• Verified date: February 2024
• Source: NRG Oncology
• Contact: C. Leland Rogers, MD
• Phone: 602-406-6761
• Email: leland.rogers[@]dignityhealth.org
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This randomized phase III trial studies how well radiation therapy works compared with observation in treating patients with newly diagnosed grade II meningioma that has been completely removed by surgery. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors.

Description:

PRIMARY OBJECTIVES:

I. To determine, in terms of progression-free survival (PFS), the extent of clinical benefit of the addition of adjuvant radiotherapy (RT) to gross total resection (GTR) for patients with newly diagnosed World Health Organization (WHO) grade II meningioma.

SECONDARY OBJECTIVES:

I. Overall survival (OS). II. Disease-specific survival (DSS). III. Toxicity (grade 3+, exclusive of expected alopecia). IV. Neurocognitive function (NCF). V. Outcomes and patient reported outcomes (PRO) measurements. VI. Adherence to protocol-specific target and normal tissue parameters. VII. Concordance measurements of central versus parent-institution pathology. VIII. Tissue microarray construction, and assessment of pHH3 mitotic index and molecular correlates to OS.

OUTLINE: Patients are randomized to 1 of 2 arms after undergoing gross total resection.

ARM I: Patients undergo observation.

ARM II: Patients undergo radiation therapy 5 days a week over 6.5-7 weeks for a total of 33 fractions (59.4 Gy in 33 daily fractions of 1.8 Gy each).

After completion of study treatment, patients are followed up at 3, 6, and 12 months, every 6 months for year 2 and 3, then yearly for 10 years.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 148
• Est. completion date: August 31, 2027
• Est. primary completion date: June 15, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• PRIOR TO STEP 1 REGISTRATION:

• The patient must have a newly diagnosed unifocal intracranial meningioma, gross totally resected, and histologically confirmed as WHO grade II based upon pathology findings at the enrolling institution; WHO grade will be assigned according to WHO 2016 criteria

• Gross total resection (GTR) will be interpreted as modified Simpson grade 1-3 without gross residual dural-based or extradural tumor; GTR must be confirmed both by modified Simpson grade and by post-operative magnetic resonance imaging (MRI) findings

• Step 1 registration must occur within 180 days of the initial surgery; within this 180 day interval, a second surgery is permitted in order to achieve GTR, but even with a second surgery, step 1 registration must occur within 180 days of the initial resection

• For step 1 registration the operating neurosurgeon must provide the modified Simpson grade

• GTR must be confirmed on post-operative imaging following the most recent surgery; submission of both pre-operative and post-operative MRIs is required for patients; if a second surgery is performed, submission of post-operative MRI is required and pre-operative MRI is required only if obtained; all sequences obtained in the pre- and post-operative MR imaging are to be submitted to National Radiology Group (NRG) Oncology for study registration; imaging subsequent to enrollment must include pre and post gadolinium contrast-enhanced three-dimensional spoiled gradient (SPGR), magnetization-prepared rapid gradient echo (MP-RAGE), or turbo field echo (TFE) MRI scan and an axial T2 fluid attenuated inversion recovery (FLAIR) sequence; to yield acceptable image quality, the gadolinium contrast-enhanced three-dimensional SPGR, MP-RAGE, or TFE axial MRI scan should use the smallest possible axial slice thickness not exceeding 1.5 mm; the post-operative MRI must be completed within sufficient time to permit step 1 registration within 180 days of the initial resection; these same conditions apply in the setting of a second surgical procedure, although if a second surgery is completed, step 1 registration must still occur with 180 days of initial surgery; computed tomography (CT) imaging is not required, but may be obtained if desired clinically, for instance to assess calcifications or hyperostosis

• The patient or a legally authorized representative must provide study-specific informed consent prior to study entry

• If the patient is a primary English speaker, the patient must participate in the NCF and patient reported outcomes part of the study; if the patient is a primary French or Spanish speaker, the patient must participate in the patient reported outcomes part of the study

• NOTE: Central pathology review must occur between steps 1 and 2 of registration; once appropriate pathology specimens are received, central pathology review will occur within 15 days, and must confirm WHO grade II meningioma before the patient can proceed to step 2 registration and randomization

• PRIOR TO STEP 2 REGISTRATION:

• Histologically confirmed diagnosis of WHO grade II meningioma confirmed by central pathology review prior to step 2 registration

• History/physical examination, including neurologic examination within 60 days prior to step 2 registration

• Post-operative Zubrod performance status 0-1 within 60 days prior to step 2 registration

• If the patient is a woman is of childbearing potential, a serum pregnancy test, obtained within 14 days prior to step 2 registration, must be negative, and, if randomized to receive radiation therapy, the woman must agree to use contraception

Exclusion Criteria:

• Optic nerve sheath meningioma, spinal or other extracranial meningioma, multiple meningiomas, hemangiopericytoma

• Definitive evidence of metastatic meningioma

• Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 3 years (carcinoma in situ of the breast, oral cavity, cervix, melanoma in situ, or other non-invasive malignancies are permissible)

• Previous radiotherapy to the scalp, cranium, brain, or skull base and radiation-induced meningiomas

• Major medical illnesses or psychiatric impairments, which in the investigators opinion, will prevent administration or completion of the protocol therapy and/or preclude informed consent; these include, but are not restricted to:

• Unstable angina and/or congestive heart failure requiring hospitalization at the time of step 2 registration

• Transmural myocardial infarction within the last 6 months prior to step 2 registration

• Acute bacterial or fungal infection requiring intravenous antibiotics at the time of step 2 registration

• Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of step 2 registration

• Type II neurofibromatosis (NF2)

• Ailments entailing substantial increases in sensitivity and side effect risk from radiation therapy (ataxia telangiectasia, Nijmegen breakage syndrome, and human immunodeficiency virus (HIV) with CD4 count < 200 cells/microliter); HIV testing is not required for eligibility for this protocol, and known HIV positive patients 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 2 registration

• Inability to undergo MRI with and without contrast (e.g. claustrophobia, non-MRI compatible implant or foreign body, etc) or receive gadolinium; note that patients with severe claustrophobia are permitted on this study if they are willing and able to undergo MRI with adequate sedation or anesthesia

• Pregnancy and/or nursing females

Related Conditions & MeSH terms

• Grade II Meningioma
• Intracranial Meningioma
• Meningioma

Intervention

Other:
• Clinical Observation
Undergo observation

Radiation:
• Radiation Therapy
Undergo radiation therapy

Locations

Country	Name	City	State
Canada	Tom Baker Cancer Centre	Calgary	Alberta
Canada	Cross Cancer Institute	Edmonton	Alberta
Canada	Juravinski Cancer Centre at Hamilton Health Sciences	Hamilton	Ontario
Canada	London Regional Cancer Program	London	Ontario
Canada	CHUM - Centre Hospitalier de l'Universite de Montreal	Montreal	Quebec
Canada	The Research Institute of the McGill University Health Centre (MUHC)	Montreal	Quebec
Canada	Allan Blair Cancer Centre	Regina	Saskatchewan
Canada	University Health Network-Princess Margaret Hospital	Toronto	Ontario
India	Tata Memorial Hospital	Mumbai
Japan	Hiroshima University Hospital	Hiroshima City
Japan	Kyorin University Hospital	Mitaka-shi	Tokyo
Japan	Saitama Medical University International Medical Center	Saitama
Japan	Hokkaido University Hospital	Sapporo	Hokkaido
Japan	Keio University	Shinjuku-ku	Tokyo
Japan	Iwate Medical University Hospital	Shiwa-gun	Iwate
Japan	National Cancer Center Hospital	Tokyo
Saudi Arabia	King Faisal Specialist Hospital and Research Centre	Riyadh
United States	University of New Mexico Cancer Center	Albuquerque	New Mexico
United States	American Fork Hospital / Huntsman Intermountain Cancer Center	American Fork	Utah
United States	Kaiser Permanente-Anaheim	Anaheim	California
United States	Saint Joseph Mercy Hospital	Ann Arbor	Michigan
United States	University of Michigan Comprehensive Cancer Center	Ann Arbor	Michigan
United States	Langlade Hospital and Cancer Center	Antigo	Wisconsin
United States	Emory Proton Therapy Center	Atlanta	Georgia
United States	Emory Saint Joseph's Hospital	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	Sutter Cancer Centers Radiation Oncology Services-Auburn	Auburn	California
United States	Maryland Proton Treatment 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	MaineHealth Coastal Cancer Treatment Center	Bath	Maine
United States	Saint Luke's University Hospital-Bethlehem Campus	Bethlehem	Pennsylvania
United States	University of Alabama at Birmingham Cancer Center	Birmingham	Alabama
United States	Boca Raton Regional Hospital	Boca Raton	Florida
United States	Prisma Health Cancer Institute - Spartanburg	Boiling Springs	South Carolina
United States	Tufts Medical Center	Boston	Massachusetts
United States	New York-Presbyterian/Brooklyn Methodist Hospital	Brooklyn	New York
United States	Christiana Care Health System-Concord Health Center	Chadds Ford	Pennsylvania
United States	UNC Lineberger Comprehensive Cancer Center	Chapel Hill	North Carolina
United States	Medical University of South Carolina	Charleston	South Carolina
United States	Saint Joseph Mercy Chelsea	Chelsea	Michigan
United States	Northwestern University	Chicago	Illinois
United States	Rush University Medical Center	Chicago	Illinois
United States	University of Illinois	Chicago	Illinois
United States	Case Western Reserve University	Cleveland	Ohio
United States	Cleveland Clinic Foundation	Cleveland	Ohio
United States	Henry Ford Macomb Hospital-Clinton Township	Clinton Township	Michigan
United States	MU Health - University Hospital/Ellis Fischel Cancer Center	Columbia	Missouri
United States	Ohio State University Comprehensive Cancer Center	Columbus	Ohio
United States	Memorial Sloan Kettering Commack	Commack	New York
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	UT Southwestern/Simmons Cancer Center-Dallas	Dallas	Texas
United States	Geisinger Medical Center	Danville	Pennsylvania
United States	Decatur Memorial Hospital	Decatur	Illinois
United States	UM Sylvester Comprehensive Cancer Center at Deerfield Beach	Deerfield Beach	Florida
United States	Iowa Methodist Medical Center	Des Moines	Iowa
United States	Ascension Saint John Hospital	Detroit	Michigan
United States	Henry Ford Hospital	Detroit	Michigan
United States	Kaiser Permanente Dublin	Dublin	California
United States	Essentia Health Cancer Center	Duluth	Minnesota
United States	Miller-Dwan Hospital	Duluth	Minnesota
United States	Marshfield Medical Center-EC Cancer Center	Eau Claire	Wisconsin
United States	Mercy Cancer Center-Elyria	Elyria	Ohio
United States	NorthShore University HealthSystem-Evanston Hospital	Evanston	Illinois
United States	Piedmont Fayette Hospital	Fayetteville	Georgia
United States	The New York Hospital Medical Center of Queens	Flushing	New York
United States	Northwestern Medicine Cancer Center Delnor	Geneva	Illinois
United States	NorthShore University HealthSystem-Glenbrook Hospital	Glenview	Illinois
United States	Benefis Healthcare- Sletten Cancer Institute	Great Falls	Montana
United States	Prisma Health Cancer Institute - Eastside	Greenville	South Carolina
United States	Prisma Health Cancer Institute - Faris	Greenville	South Carolina
United States	Prisma Health Cancer Institute - Greer	Greer	South Carolina
United States	Legacy Mount Hood Medical Center	Gresham	Oregon
United States	Memorial Sloan Kettering Westchester	Harrison	New York
United States	Hartford Hospital	Hartford	Connecticut
United States	NorthShore University HealthSystem-Highland Park Hospital	Highland Park	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	Indiana University/Melvin and Bren Simon Cancer Center	Indianapolis	Indiana
United States	IU Health Methodist Hospital	Indianapolis	Indiana
United States	University of Iowa/Holden Comprehensive Cancer Center	Iowa City	Iowa
United States	University of Mississippi Medical Center	Jackson	Mississippi
United States	Baptist MD Anderson Cancer Center	Jacksonville	Florida
United States	Kalispell Regional Medical Center	Kalispell	Montana
United States	University of Kansas Cancer Center	Kansas City	Kansas
United States	Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center	Lebanon	New Hampshire
United States	Geisinger Medical Oncology-Lewisburg	Lewisburg	Pennsylvania
United States	Lewistown Hospital	Lewistown	Pennsylvania
United States	University of Kentucky/Markey Cancer Center	Lexington	Kentucky
United States	Trinity Health Saint Mary Mercy Livonia Hospital	Livonia	Michigan
United States	Logan Regional Hospital	Logan	Utah
United States	Kaiser Permanente Los Angeles Medical Center	Los Angeles	California
United States	Los Angeles General Medical Center	Los Angeles	California
United States	USC / Norris Comprehensive Cancer Center	Los Angeles	California
United States	University of Wisconsin Carbone Cancer Center	Madison	Wisconsin
United States	Marshfield Medical Center-Marshfield	Marshfield	Wisconsin
United States	Loyola University Medical Center	Maywood	Illinois
United States	Froedtert Menomonee Falls Hospital	Menomonee Falls	Wisconsin
United States	UH Seidman Cancer Center at Lake Health Mentor Campus	Mentor	Ohio
United States	Miami Cancer Institute	Miami	Florida
United States	University of Miami Miller School of Medicine-Sylvester Cancer Center	Miami	Florida
United States	Memorial Sloan Kettering Monmouth	Middletown	New Jersey
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Abbott-Northwestern Hospital	Minneapolis	Minnesota
United States	Marshfield Clinic-Minocqua Center	Minocqua	Wisconsin
United States	Memorial Medical Center	Modesto	California
United States	Memorial Sloan Kettering Bergen	Montvale	New Jersey
United States	Intermountain Medical Center	Murray	Utah
United States	Vanderbilt University/Ingram Cancer Center	Nashville	Tennessee
United States	Rutgers Cancer Institute of New Jersey	New Brunswick	New Jersey
United States	Yale University	New Haven	Connecticut
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	NYP/Weill Cornell Medical 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	Rutgers New Jersey Medical School	Newark	New Jersey
United States	Piedmont Newnan Hospital	Newnan	Georgia
United States	Drexel Town Square Health Center	Oak Creek	Wisconsin
United States	Kaiser Permanente Oakland-Broadway	Oakland	California
United States	McKay-Dee Hospital 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	Kaiser Permanente-Ontario	Ontario	California
United States	UC Irvine Health/Chao Family Comprehensive Cancer Center	Orange	California
United States	AdventHealth East Orlando	Orlando	Florida
United States	AdventHealth Orlando	Orlando	Florida
United States	University of Kansas Cancer Center-Overland Park	Overland Park	Kansas
United States	Stanford Cancer Institute Palo Alto	Palo Alto	California
United States	Capital Health Medical Center-Hopewell	Pennington	New Jersey
United States	Fox Chase Cancer Center	Philadelphia	Pennsylvania
United States	Temple University Hospital	Philadelphia	Pennsylvania
United States	Thomas Jefferson University Hospital	Philadelphia	Pennsylvania
United States	Mayo Clinic Hospital in Arizona	Phoenix	Arizona
United States	Saint Joseph's Hospital and Medical Center	Phoenix	Arizona
United States	Legacy Good Samaritan Hospital and Medical Center	Portland	Oregon
United States	Maine Medical Center-Bramhall Campus	Portland	Maine
United States	Geisinger Cancer Services-Pottsville	Pottsville	Pennsylvania
United States	Utah Valley Regional Medical Center	Provo	Utah
United States	Kaiser Permanente-Rancho Cordova Cancer Center	Rancho Cordova	California
United States	Beebe Health Campus	Rehoboth Beach	Delaware
United States	Marshfield Medical Center-Rice Lake	Rice Lake	Wisconsin
United States	Virginia Commonwealth University/Massey Cancer Center	Richmond	Virginia
United States	Riverton Hospital	Riverton	Utah
United States	Mayo Clinic in Rochester	Rochester	Minnesota
United States	University of Rochester	Rochester	New York
United States	Rohnert Park Cancer Center	Rohnert Park	California
United States	Sutter Cancer Centers Radiation Oncology Services-Roseville	Roseville	California
United States	The Permanente Medical Group-Roseville Radiation Oncology	Roseville	California
United States	South Sacramento Cancer Center	Sacramento	California
United States	Sutter Medical Center Sacramento	Sacramento	California
United States	Ascension Saint Mary's Hospital	Saginaw	Michigan
United States	Norris Cotton Cancer Center-North	Saint Johnsbury	Vermont
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	Regions Hospital	Saint Paul	Minnesota
United States	Siteman Cancer Center at Saint Peters Hospital	Saint Peters	Missouri
United States	LDS Hospital	Salt Lake City	Utah
United States	University of Texas Health Science Center at San Antonio	San Antonio	Texas
United States	MaineHealth Cancer Care Center of York County	Sanford	Maine
United States	Kaiser Permanente Medical Center - Santa Clara	Santa Clara	California
United States	Maine Medical Center- Scarborough Campus	Scarborough	Maine
United States	Mayo Clinic in Arizona	Scottsdale	Arizona
United States	TidalHealth Nanticoke / Allen Cancer Center	Seaford	Delaware
United States	University of Washington Medical Center - Montlake	Seattle	Washington
United States	Prisma Health Cancer Institute - Seneca	Seneca	South Carolina
United States	LSU Health Sciences Center at Shreveport	Shreveport	Louisiana
United States	ProCure Proton Therapy Center-Somerset	Somerset	New Jersey
United States	Robert Wood Johnson University Hospital Somerset	Somerville	New Jersey
United States	Kaiser Permanente Cancer Treatment Center	South San Francisco	California
United States	Ascension Saint Michael's Hospital	Stevens Point	Wisconsin
United States	Marshfield Medical Center-River Region at Stevens Point	Stevens Point	Wisconsin
United States	Piedmont Henry Hospital	Stockbridge	Georgia
United States	ProMedica Flower Hospital	Sylvania	Ohio
United States	Moffitt Cancer Center	Tampa	Florida
United States	Banner University Medical Center - Tucson	Tucson	Arizona
United States	University of Arizona Cancer Center-North Campus	Tucson	Arizona
United States	University of Arizona Cancer Center-Orange Grove Campus	Tucson	Arizona
United States	Memorial Sloan Kettering Nassau	Uniondale	New York
United States	Westchester Medical Center	Valhalla	New York
United States	Sutter Solano Medical Center/Cancer Center	Vallejo	California
United States	Legacy Salmon Creek Hospital	Vancouver	Washington
United States	Saint John Macomb-Oakland Hospital	Warren	Michigan
United States	Northwestern Medicine Cancer Center Warrenville	Warrenville	Illinois
United States	Aspirus Regional Cancer Center	Wausau	Wisconsin
United States	Henry Ford West Bloomfield Hospital	West Bloomfield	Michigan
United States	UHHS-Westlake Medical Center	Westlake	Ohio
United States	Diagnostic and Treatment Center	Weston	Wisconsin
United States	Geisinger Wyoming Valley/Henry Cancer Center	Wilkes-Barre	Pennsylvania
United States	Aspirus Cancer Care - Wisconsin Rapids	Wisconsin Rapids	Wisconsin
United States	Lankenau Medical Center	Wynnewood	Pennsylvania

Sponsors (2)

Lead Sponsor	Collaborator
NRG Oncology	National Cancer Institute (NCI)

Countries where clinical trial is conducted

United States,  Canada,  India,  Japan,  Saudi Arabia, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression-Free Survival (PFS)	Kaplan-Meier method will be used to calculate the PFS rates for each of the two arms (Kaplan 1958). Hazard ratio (HR) on the treatment effect will be calculated using the Cox proportional hazard model (Cox 1972). A one-sided log-rank test will be used to test the difference in PFS between the two arms (Peto 1972).	From randomization to the first documented disease progression, or death due to any cause, whichever comes first, assessed up to 10 years.
Secondary	Overall Survival (OS)	Kaplan-Meier method will be used to calculate the OS rates for each of the two arms (Kaplan 1958). Hazard ratio (HR) on the treatment effect will be calculated using the Cox proportional hazard model (Cox 1972). A one-sided log-rank test will be used to test the difference in OS between the two arms (Peto 1972). Cox proportional hazard model will be used to determine the adjusted treatment effect on OS, with patient pretreatment characteristics as covariates.	From randomization to death due to any cause, assessed up to 10 years
Secondary	5 Year Overall Survival (OS)	Will be calculated based on the Kaplan-Meier curve.	At 5 years after randomization
Secondary	Disease-Specific Survival (DSS)	Will be calculated using the cumulative incidence function for each arm. The HR for the treatment effect on DSS will be calculated using Gray's method under the competing risk approach, with death due to non-disease related cause treated as the competing risk (Gray 1988). Multivariate analysis on DSS will be performed using the Fine-Gray model, with patient pretreatment characteristics as covariates (Fine 1999).	From randomization to disease-related death, assessed up to 10 years
Secondary	3 Year Disease-Specific Survival (DSS)	Will be calculated using the cumulative incidence function for each arm.	At 3 years after randomization
Secondary	5 Year Disease-Specific Survival (DSS)	Will be calculated using the cumulative incidence function for each arm.	At 5 years after randomization
Secondary	3 Year Progression-Free Survival (PFS)	Will be calculated based on the Kaplan-Meier curve.	From randomization to the first documented disease progression, or death due to any cause, whichever comes first, assessed at 3 years after randomization.
Secondary	5 Year Progression-Free Survival (PFS)	Will be calculated based on the Kaplan-Meier curve.	From randomization to the first documented disease progression, or death due to any cause, whichever comes first, assessed up to 5 years after randomization.
Secondary	Neurocognitive Function (NCF)	Longitudinal analysis will be performed to compare NCF over time between the 2 arms, using the NCF Clinical Trial Battery (CTB) composite score. Early change from baseline in CTB composite score will be evaluated and compared between the 2 arms using 2-sample t tests.	Baseline up to 60 months after randomization
Secondary	Patient Reported Outcomes (PRO) as assessed by MDASI-BT	Longitudinal analysis will be performed to compare symptom burden over time between the 2 arms, using the MDASI-BT. Early change from baseline in symptom burden will be evaluated and compared between the 2 arms using 2-sample t tests.	Baseline up to 60 months after randomization
Secondary	Assessment of pHH3 mitotic index	The Kaplan-Meier method will be used to estimate the PFS and OS rates by pHH3 category. The HRs on the effect of pHH3 on PFS and OS, respectively will be calculated using the Cox proportional hazard model and will be tested using the log-rank test. Multivariate analyses will be conducted with patient pretreatment characteristics, such as age and Simpson resection grade, included as covariates.	Up to 10 years after randomization
Secondary	Incidence of adverse events as measured by the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4 (exclusive of alopecia)	The number of adverse events will be measured using the CTCAE, version 4	Up to 3 years after randomization