Comparing the Addition of Radiation Either Before or After Surgery for Patients With Brain Metastases

Metastatic Malignant Neoplasm in the Brain Clinical Trial

Official title:

A Randomized Phase III Trial of Pre-Operative Compared to Post-Operative Stereotactic Radiosurgery in Patients With Resectable Brain Metastases

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05438212
• Other study ID #: NRG-BN012
• Secondary ID: NCI-2022-04804NR
• Status: Recruiting
• Phase: Phase 3
• Start date: August 31, 2022
• Est. completion date: March 16, 2032

Study information

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

Clinical Trial Summary

This phase III trial compares the addition of stereotactic radiosurgery before or after surgery in treating patients with cancer that has spread to the brain (brain metastases). Stereotactic radiosurgery is a type of radiation therapy that delivers a high dose of radiation only to the small areas of cancer in the brain and avoids the surrounding normal brain tissue. Surgery and radiation may stop the tumor from growing for a few months or longer and may reduce symptoms of brain metastases.

Description:

PRIMARY OBJECTIVE:

I. To determine if the time to composite adverse endpoint (CAE) (defined as: 1) local tumor progression within the surgical bed; and/or 2) Adverse Radiation Effect (ARE), the imaging correlate of post-stereotactic radiosurgery (SRS) radiation necrosis; and/or 3) nodular meningeal disease (nMD) is improved in patients treated with pre-resection SRS to the intact lesion versus those treated with post-resection SRS.

SECONDARY OBJECTIVES:

I. To assess the trajectory of symptom burden in patients treated with pre-resection SRS to the intact lesion versus those treated to the post-resection surgical cavity as measured by MD Anderson Symptom Inventory for brain tumor (MDASI-BT) II. To determine whether there is improved overall survival (OS) in patients with resected brain metastases who undergo pre-resection SRS compared to patients who receive post-resection SRS.

III. To compare rates of ARE, the imaging correlate of radiation necrosis, in patients who receive pre-resection SRS to patients who receive post-resection SRS.

IV. To determine whether there is increased time to whole brain radiotherapy (WBRT) in patients who receive pre-resection SRS compared to patients who receive post-resection SRS.

V. To assess the trajectory of neuro-cognitive function in patients treated with pre-resection SRS to the intact lesion versus those treated to the post-resection surgical cavity as measured by the Montreal Cognitive Assessment (MoCA).

VI. To compare rates of nodular meningeal disease in patients who receive pre-resection SRS to patients who receive post-resection SRS.

VII. To compare rates of local recurrence in the resection cavity for patients who receive pre-resection SRS to patients who receive post-resection SRS.

VIII. To compare rates of local recurrence of intact, non-index metastases treated with SRS.

IX. To compare rates of distant brain failure in patients who receive pre-resection SRS to patients who receive post-resection SRS.

X. To assess toxicity in the two treatment arms.

EXPLORATORY OBJECTIVE:

I. To explore if the type of surgical resection (piece-meal versus [vs.] en-bloc) may be associated with the rate of nodular meningeal disease.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients undergo surgery per standard of care. Within 10-30 days after surgery, patients undergo stereotactic radiosurgery for 1 fraction.

ARM II: Within 7 days before surgery, patients undergo stereotactic radiosurgery for 1 fraction. Patients undergo surgery per standard of care.

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

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 236
• Est. completion date: March 16, 2032
• Est. primary completion date: March 16, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Radiographic confirmation of 1-4 brain metastases, one of which requires resection, as defined by magnetic resonance imaging (MRI) with contrast obtained within 14 days prior to registration

• The maximum diameter of the lesion to be resected on the post-contrast MRI, as measured on any orthogonal plane (axial, sagittal, coronal), must measure > 2.0 cm and < 5.0 cm.

• The maximum diameter of the lesions not to be resected must measure < 4.0 cm

• Known active or history of invasive non-central nervous system (CNS) primary cancer based on documented pathologic diagnosis within the past 3 years

• All brain metastases must be located > 5 mm from the optic chiasm and outside the brainstem

• Patient is able to medically tolerate surgery and SRS

• The lesion chosen for surgical therapy must be deemed an appropriate target for safe, gross total resection by the treating surgeon

• History/physical examination within 14 days prior to registration

• Age >= 18

• Karnofsky performance status (KPS) >= 60 within 14 days prior to registration

• A negative urine or serum pregnancy test (in persons of childbearing potential) within =< 14 days prior to registration. Childbearing potential is defined as any person who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal for at least 12 consecutive months

• Participants who are sexually active must agree to use medically acceptable forms of contraception during treatment on this study to prevent pregnancy

• The patient or a legally authorized representative must provide study-specific informed consent prior to study entry and, for patients treated in the United States (U.S.), authorization permitting release of personal health information

Exclusion Criteria:

• Prior cranial radiotherapy, including whole brain radiotherapy, or SRS to the resection site

• Note: The index lesion to be resected cannot have been previously treated with SRS (i.e. repeat radiosurgery to the same location/lesion is not allowed on this protocol). Previous SRS to other lesions is allowed

• Evidence of leptomeningeal disease (LMD)

• Note: For the purposes of exclusion, LMD is a clinical diagnosis, defined as positive cerebrospinal fluid (CSF) cytology and/or unequivocal radiologic or clinical evidence of leptomeningeal involvement. Patients with leptomeningeal symptoms in the setting of leptomeningeal enhancement by imaging (MRI) would be considered to have LMD even in the absence of positive CSF cytology. In contrast, an asymptomatic or minimally symptomatic patient with mild or nonspecific leptomeningeal enhancement (MRI) would not be considered to have LMD. In that patient, CSF sampling is not required to formally exclude LMD, but can be performed at the investigator's discretion based on level of clinical suspicion

• Any medical conditions which would make this protocol unreasonably hazardous, including, but not limited to: contraindications to general endotracheal anesthesia; intracranial surgery; and stereotactic radiosurgery

• Primary histology of germ cell tumor, small cell carcinoma or lymphoma

• More than one brain metastasis planned for resection

• Inability to undergo MRI with contrast

• Planned administration of cytotoxic chemotherapy or tyrosine/multi-kinase inhibitors within the 3 days prior to, the day of, or within 3 days after the completion of SRS

• Note: chemotherapy and immunotherapy outside of this window are allowed

Related Conditions & MeSH terms

• Brain Neoplasms
• Metastatic Malignant Neoplasm in the Brain
• Neoplasms

Intervention

Procedure:
• Brain Surgery
Undergo surgery per standard of care

Other:
• Quality-of-Life Assessment
Ancillary studies
• Questionnaire Administration
Ancillary studies

Radiation:
• Stereotactic Radiosurgery
Undergo stereotactic radiosurgery

Locations

Country	Name	City	State
United States	University of Michigan Comprehensive Cancer Center	Ann Arbor	Michigan
United States	Piedmont Hospital	Atlanta	Georgia
United States	University of Maryland/Greenebaum Cancer Center	Baltimore	Maryland
United States	Advocate Good Shepherd Hospital	Barrington	Illinois
United States	Indu and Raj Soin Medical Center	Beavercreek	Ohio
United States	Billings Clinic Cancer Center	Billings	Montana
United States	Montefiore Medical Center - Moses Campus	Bronx	New York
United States	Montefiore Medical Center-Einstein Campus	Bronx	New York
United States	Montefiore Medical Center-Weiler Hospital	Bronx	New York
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	Aurora Cancer Care-Southern Lakes VLCC	Burlington	Wisconsin
United States	Centralia Oncology Clinic	Centralia	Illinois
United States	Medical University of South Carolina	Charleston	South Carolina
United States	Carolinas Medical Center/Levine Cancer Institute	Charlotte	North Carolina
United States	Northwestern University	Chicago	Illinois
United States	University of Chicago Comprehensive Cancer Center	Chicago	Illinois
United States	Ohio State University Comprehensive Cancer Center	Columbus	Ohio
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	AMG Crystal Lake - Oncology	Crystal Lake	Illinois
United States	Carle at The Riverfront	Danville	Illinois
United States	Cancer Care Specialists of Illinois - Decatur	Decatur	Illinois
United States	Decatur Memorial Hospital	Decatur	Illinois
United States	UM Sylvester Comprehensive Cancer Center at Deerfield Beach	Deerfield Beach	Florida
United States	Wayne State University/Karmanos Cancer Institute	Detroit	Michigan
United States	Advocate Good Samaritan Hospital	Downers Grove	Illinois
United States	Northeast Radiation Oncology Center	Dunmore	Pennsylvania
United States	Carle Physician Group-Effingham	Effingham	Illinois
United States	Crossroads Cancer Center	Effingham	Illinois
United States	Inova Schar Cancer Institute	Fairfax	Virginia
United States	Weisberg Cancer Treatment Center	Farmington Hills	Michigan
United States	Gibbs Cancer Center-Gaffney	Gaffney	South Carolina
United States	CaroMont Regional Medical Center	Gastonia	North Carolina
United States	Aurora Health Care Germantown Health Center	Germantown	Wisconsin
United States	Aurora Cancer Care-Grafton	Grafton	Wisconsin
United States	Benefis Healthcare- Sletten Cancer Institute	Great Falls	Montana
United States	Aurora BayCare Medical Center	Green Bay	Wisconsin
United States	Gibbs Cancer Center-Pelham	Greer	South Carolina
United States	Advocate South Suburban Hospital	Hazel Crest	Illinois
United States	Penn State Milton S Hershey Medical Center	Hershey	Pennsylvania
United States	Mayo Clinic in Florida	Jacksonville	Florida
United States	Saint Luke's Hospital of Kansas City	Kansas City	Missouri
United States	Aurora Cancer Care-Kenosha South	Kenosha	Wisconsin
United States	Kettering Medical Center	Kettering	Ohio
United States	Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center	Lebanon	New Hampshire
United States	AMG Libertyville - Oncology	Libertyville	Illinois
United States	Covenant Medical Center-Lakeside	Lubbock	Texas
United States	University of Wisconsin Carbone Cancer Center	Madison	Wisconsin
United States	Carle Physician Group-Mattoon/Charleston	Mattoon	Illinois
United States	Miami Cancer Institute	Miami	Florida
United States	University of Miami Miller School of Medicine-Sylvester Cancer Center	Miami	Florida
United States	Aurora Cancer Care-Milwaukee	Milwaukee	Wisconsin
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	Mount Sinai Chelsea	New York	New York
United States	Mount Sinai Hospital	New York	New York
United States	Mount Sinai West	New York	New York
United States	Cancer Care Center of O'Fallon	O'Fallon	Illinois
United States	Advocate Christ Medical Center	Oak Lawn	Illinois
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	UC Irvine Health/Chao Family Comprehensive Cancer Center	Orange	California
United States	Vince Lombardi Cancer Clinic - Oshkosh	Oshkosh	Wisconsin
United States	Stanford Cancer Institute Palo Alto	Palo Alto	California
United States	The Valley Hospital-Luckow Pavilion	Paramus	New Jersey
United States	Advocate Lutheran General Hospital	Park Ridge	Illinois
United States	Capital Health Medical Center-Hopewell	Pennington	New Jersey
United States	Thomas Jefferson University Hospital	Philadelphia	Pennsylvania
United States	Saint Joseph's Hospital and Medical Center	Phoenix	Arizona
United States	UPMC-Presbyterian Hospital	Pittsburgh	Pennsylvania
United States	UPMC-Shadyside Hospital	Pittsburgh	Pennsylvania
United States	Aurora Cancer Care-Racine	Racine	Wisconsin
United States	Renown Regional Medical Center	Reno	Nevada
United States	Ascension Saint Mary's Hospital	Rhinelander	Wisconsin
United States	CJW Medical Center - Johnston-Willis Campus	Richmond	Virginia
United States	Henrico Doctor's Hospital	Richmond	Virginia
United States	Virginia Commonwealth University/Massey Cancer Center	Richmond	Virginia
United States	Valley Hospital	Ridgewood	New Jersey
United States	University of Rochester	Rochester	New York
United States	William Beaumont Hospital-Royal Oak	Royal Oak	Michigan
United States	University of California Davis Comprehensive Cancer Center	Sacramento	California
United States	Huntsman Cancer Institute/University of Utah	Salt Lake City	Utah
United States	University of Texas Health Science Center at San Antonio	San Antonio	Texas
United States	Vince Lombardi Cancer Clinic-Sheboygan	Sheboygan	Wisconsin
United States	Spartanburg Medical Center	Spartanburg	South Carolina
United States	Memorial Medical Center	Springfield	Illinois
United States	Southern Illinois University School of Medicine	Springfield	Illinois
United States	Springfield Clinic	Springfield	Illinois
United States	Ascension Saint Michael's Hospital	Stevens Point	Wisconsin
United States	Aurora Medical Center in Summit	Summit	Wisconsin
United States	William Beaumont Hospital - Troy	Troy	Michigan
United States	Banner University Medical Center - Tucson	Tucson	Arizona
United States	University of Arizona Cancer Center-North Campus	Tucson	Arizona
United States	MGC Hematology Oncology-Union	Union	South Carolina
United States	Carle Cancer Center	Urbana	Illinois
United States	Northwestern Medicine Cancer Center Warrenville	Warrenville	Illinois
United States	UW Cancer Center at ProHealth Care	Waukesha	Wisconsin
United States	Aspirus Regional Cancer Center	Wausau	Wisconsin
United States	Aurora Cancer Care-Milwaukee West	Wauwatosa	Wisconsin
United States	Aurora West Allis Medical Center	West Allis	Wisconsin
United States	Good Samaritan University Hospital	West Islip	New York
United States	Valley Health System-Hematology/Oncology	Westwood	New Jersey
United States	Novant Health Cancer Institute Radiation Oncology - Wilmington	Wilmington	North Carolina
United States	Wake Forest University Health Sciences	Winston-Salem	North Carolina
United States	Aspirus Cancer Care - Wisconsin Rapids	Wisconsin Rapids	Wisconsin

Sponsors (2)

Lead Sponsor	Collaborator
NRG Oncology	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Type of surgical resection	Will compare if the type of surgical resection (piece-meal vs. en-bloc) may be associated with the rate of nodular meningeal disease. The competing risk approach by Gray (Gray 1988) will be used to compare the cumulative incidences of nMD by surgical type, where death prior to nMD will be treated as a competing risk event.	Up to 4 years
Primary	Time to Composite Adverse Endpoint (CAE)	Analysis for this endpoint will consist of testing the cause-specific hazard ratio in a Cox proportional hazards model.	Time from surgery (with the post-operative MRI as the 'baseline' for purposes of disease assessment) to local tumor progression (within the surgical bed), nodular meningeal disease, or radiation necrosis, whichever occurs first, assessed up to 4 years
Secondary	Overall Survival (OS)	Analysis for this endpoint will consist of estimation of the OS distribution of each treatment arm via the Kaplan-Meier method and a stratified log-rank test.	Time from randomization to death due to any cause, assessed up to 4 years
Secondary	Rate of local tumor progression	The time origin for these imaging-based endpoints will be time of surgery (with the post-operative magnetic resonance imaging [MRI] as the 'baseline' for purposes of disease assessment). These analyses will involve estimating the cumulative incidence function of local progression, radiation necrosis, nodular meningeal disease, and distant brain failures in the presence of competing event of deaths. The Gray's test will be used to evaluate the difference in the distribution of local progression, radiation necrosis, nodular meningeal disease, and distant brain failures between treatment arms.	Up to 4 years
Secondary	Rate of radiation necrosis	The time origin for these imaging-based endpoints will be time of surgery (with the post-operative MRI as the 'baseline' for purposes of disease assessment). These analyses will involve estimating the cumulative incidence function of local progression, radiation necrosis, nodular meningeal disease, and distant brain failures in the presence of competing event of deaths. The Gray's test will be used to evaluate the difference in the distribution of local progression, radiation necrosis, nodular meningeal disease, and distant brain failures between treatment arms.	Up to 4 years
Secondary	Rate of nodular meningeal disease	The time origin for these imaging-based endpoints will be time of surgery (with the post-operative MRI as the 'baseline' for purposes of disease assessment). These analyses will involve estimating the cumulative incidence function of local progression, radiation necrosis, nodular meningeal disease, and distant brain failures in the presence of competing event of deaths. The Gray's test will be used to evaluate the difference in the distribution of local progression, radiation necrosis, nodular meningeal disease, and distant brain failures between treatment arms.	Up to 4 years
Secondary	Rate of distant brain failures	The time origin for these imaging-based endpoints will be time of surgery (with the post-operative MRI as the 'baseline' for purposes of disease assessment). These analyses will involve estimating the cumulative incidence function of local progression, radiation necrosis, nodular meningeal disease, and distant brain failures in the presence of competing event of deaths. The Gray's test will be used to evaluate the difference in the distribution of local progression, radiation necrosis, nodular meningeal disease, and distant brain failures between treatment arms.	Up to 4 years
Secondary	Frequency of adverse events (AEs)	AEs will be graded according to Common Terminology Criteria for Adverse Events version 5.0. Comprehensive summaries of all AEs by treatment arm will be generated and examined. Counts and frequencies of worst (highest score) AE per patient will be presented overall and by AE type category, separately by assigned treatment group. The proportion of patients with at least one grade 3 or higher AE will be compared between treatment arms. Any frequencies to be tested will be evaluated using the chi-square or exact test as appropriate, with two-sided significance level 0.05.	Up to 4 years
Secondary	Change in MD Anderson Symptom Inventory - Brain Tumor (MDASI-BT)	Will implement mixed effects models for repeated measures to evaluate the MDASI-BT scores longitudinally.	Baseline up to 2 years after surgery
Secondary	Change in cognitive function	Measured by Montreal Cognitive Assessment (MoCA). Will implement mixed effects models for repeated measures to evaluate the MoCA scores longitudinally.	Baseline up to 2 years after surgery