Avoiding the Hippocampus During Whole-Brain Radiation Therapy in Treating Patients With Brain Metastases

Unspecified Adult Solid Tumor, Protocol Specific Clinical Trial

Official title:

A Phase II Trial of Hippocampal Avoidance During Whole Brain Radiotherapy for Brain Metastases

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01227954
• Other study ID #: RTOG-0933
• Secondary ID: CDR0000687490
• Status: Completed
• Phase: Phase 2
• First received: October 22, 2010
• Last updated: September 25, 2017
• Start date: March 2011
• Est. completion date: December 2016

Study information

• Verified date: September 2017
• Source: Radiation Therapy Oncology Group
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

RATIONALE: Radiation therapy uses high energy x-rays to kill tumor cells.

PURPOSE: This phase II trial is studying how well avoiding the hippocampus during whole-brain radiation therapy works in treating patients with brain metastases.

Description:

OBJECTIVES:

Primary

• Evaluate delayed recall as assessed by the Hopkins Verbal Learning Test-Revised (HVLT-R) at 4 months after hippocampal avoidance during whole-brain radiotherapy (HA-WBRT) in patients with brain metastasis.

Secondary

• Evaluate auditory and visual learning and memory, as assessed by two CogState tests (International Shopping List Test and One Card Learning Test), after HA-WBRT in these patients.

• Compare psychometric properties of the 2 CogState tests to the HVLT-R for the assessment of memory decline after HA-WBRT in these patients.

• Evaluate health-related quality of life [as assessed by the Functional Assessment of Cancer Therapy with Brain Subscale (FACT-BR) and the Barthel Index of Activities of Daily Living (ADLs)] after HA-WBRT in these patients.

• Evaluate time to radiographic progression after HA-WBRT in these patients.

• Evaluate overall survival of these patients after HA-WBR.

• Evaluate the adverse events of HA-WBR.

• Evaluate predictive biomarkers of cognitive function.

OUTLINE: This is a multicenter study.

Patients undergo 10 fractions of intensity-modulated whole-brain radiotherapy (WBRT), avoiding hippocampal (HA) regions, once daily, 5 days a week, for 2-2½ weeks.

Patients neurocognitive functions (delayed recall, auditory and visual learning, and memory) are evaluated by the Hopkins Verbal Learning Test-Revised (HVTL-R), The One Card Learning Test (OCLT), and the International Shopping List Test (ISLT) at baseline and periodically during study.

Patients may undergo serum, plasma, or whole blood collection at baseline and at 4 months after completion of HA-WBRT for correlative studies.

Patients may complete the Functional Assessment of Cancer Therapy with Brain Subscale (FACT-BR), and the Barthel Index of Activities of Daily Living (ADLs) quality-of-life questionnaires at baseline and periodically during study and follow up.

After completion of study therapy, patients are followed up periodically.

Other known NCT identifiers

• NCT01366755

Recruitment information / eligibility

• Status: Completed
• Enrollment: 113
• Est. completion date: December 2016
• Est. primary completion date: May 2013
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 120 Years

Eligibility

INCLUSION CRITERIA:

• Histologically or cytologically confirmed non-hematopoietic malignancy within the past 5 years

• If histologic proof of malignancy is from > 5 years ago, then a more recent pathological confirmation is required (e.g., from systemic metastatic or brain metastasis)

• Patients with metastasis of unknown primary tumor are permitted

• Measurable brain metastasis outside a 5-mm margin around either hippocampus on gadolinium contrast-enhanced MRI obtained within the past 30 days

• Have not been or will not be treated with stereotactic radiosurgery (SRS) or surgical resection

• These treatment options are allowed only at relapse

• Patients who have brain metastases at initial presentation allowed and do not need to demonstrate 3 months of stable scans

• At least 1 week since open biopsy

• Karnofsky performance status 70-100%

• Fertile patients must use effective contraception

• Negative pregnancy test 2 weeks or less prior to study entry

• Patients must be English proficient, with patients who speak English as a second language eligible

EXCLUSION CRITERIA:

• Small cell lung cancer or germ cell malignancy

• Leptomeningeal metastases

• Non-small cell lung cancer-associated brain metastases with = 2 organ sites of extracranial metastases

• Radiologic evidence of hydrocephalus

• Serum creatinine > 1.4 mg/dL within 30 days prior to study entry

• Pregnant or nursing

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

• Severe, active co-morbidity including any of the following:

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

• Transmural myocardial infarction within the past 6 months

• Acute bacterial or fungal infection requiring intravenous antibiotics

• 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

• Uncontrolled, clinically significant cardiac arrhythmias

• Prior radiotherapy to the brain

• Plan for chemotherapy or targeted therapies during WBRT or during the subsequent 7 days

Related Conditions & MeSH terms

• Cognitive/Functional Effects
• Metastatic Cancer
• Neoplasm Metastasis
• Unspecified Adult Solid Tumor, Protocol Specific

Intervention

Radiation:
• intensity-modulated radiation therapy
30 Gy in 10 fractions to the whole brain using intensity-modulated radiation therapy excluding the hippocampal avoidance area. Bilateral hippocampal contours manually generated on the fused planning MRI CT image set by the treating physician according to protocol-specified contouring instructions. Hippocampal avoidance regions generated by three-dimensionally expanding the hippocampal contours by 5 mm.

Locations

Country	Name	City	State
Canada	London Regional Cancer Program at London Health Sciences Centre	London	Ontario
Canada	Saskatoon Cancer Centre at the University of Saskatchewan	Saskatoon	Saskatchewan
Canada	Princess Margaret Hospital	Toronto	Ontario
United States	Rosenfeld Cancer Center at Abington Memorial Hospital	Abington	Pennsylvania
United States	Summa Center for Cancer Care at Akron City Hospital	Akron	Ohio
United States	New York Oncology Hematology, PC at Albany Regional Cancer Care	Albany	New York
United States	Piedmont Hospital	Atlanta	Georgia
United States	Greenebaum Cancer Center at University of Maryland Medical Center	Baltimore	Maryland
United States	Texas Oncology, PA at Harris Center HEB	Bedford	Texas
United States	Billings Clinic - Downtown	Billings	Montana
United States	UAB Comprehensive Cancer Center	Birmingham	Alabama
United States	Bryn Mawr Hospital	Bryn Mawr	Pennsylvania
United States	Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill	Chapel Hill	North Carolina
United States	University of Virginia Cancer Center	Charlottesville	Virginia
United States	Rush University Medical Center	Chicago	Illinois
United States	Adena Regional Medical Center	Chillicothe	Ohio
United States	Case Comprehensive Cancer Center	Cleveland	Ohio
United States	Cleveland Clinic Taussig Cancer Center	Cleveland	Ohio
United States	Arthur G. James Cancer Hospital and Richard J. Solove Research Institute at Ohio State University Comprehensive Cancer Center	Columbus	Ohio
United States	NSMC Cancer Center - Peabody	Danvers	Massachusetts
United States	Barbara Ann Karmanos Cancer Institute	Detroit	Michigan
United States	Regional Cancer Center - Erie	Erie	Pennsylvania
United States	Willamette Valley Cancer Center - Eugene	Eugene	Oregon
United States	Klabzuba Cancer Center at Harris Methodist Fort Worth Hospital	Fort Worth	Texas
United States	Adams Cancer Center	Gettysburg	Pennsylvania
United States	Center for Cancer Care at Goshen General Hospital	Goshen	Indiana
United States	Penn State Hershey Cancer Institute at Milton S. Hershey Medical Center	Hershey	Pennsylvania
United States	M. D. Anderson Cancer Center at University of Texas	Houston	Texas
United States	Memorial Hermann Hospital - Memorial City	Houston	Texas
United States	Indiana University Melvin and Bren Simon Cancer Center	Indianapolis	Indiana
United States	Methodist Cancer Center at Methodist Hospital	Indianapolis	Indiana
United States	Baptist Cancer Institute - Jacksonville	Jacksonville	Florida
United States	St. Barnabas Medical Center Cancer Center	Livingston	New Jersey
United States	Veterans Affairs Medical Center - Long Beach	Long Beach	California
United States	Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai Medical Center	Los Angeles	California
United States	Baptist-South Miami Regional Cancer Program	Miami	Florida
United States	University of Miami Sylvester Comprehensive Cancer Center - Miami	Miami	Florida
United States	Southwest General Health Center	Middleburg Heights	Ohio
United States	Jon and Karen Huntsman Cancer Center at Intermountain Medical Center	Murray	Utah
United States	CCOP - Christiana Care Health Services	Newark	Delaware
United States	Val and Ann Browning Cancer Center at McKay-Dee Hospital Center	Ogden	Utah
United States	Oklahoma University Cancer Institute	Oklahoma City	Oklahoma
United States	Nebraska Medical Center	Omaha	Nebraska
United States	Florida Cancer Center - Palatka	Palatka	Florida
United States	Arizona Center for Cancer Care - Peoria	Peoria	Arizona
United States	OSF St. Francis Medical Center	Peoria	Illinois
United States	Kimmel Cancer Center at Thomas Jefferson University - Philadelphia	Philadelphia	Pennsylvania
United States	Providence Cancer Center at Providence Portland Medical Center	Portland	Oregon
United States	Rapid City Regional Hospital	Rapid City	South Dakota
United States	Virginia Commonwealth University Massey Cancer Center	Richmond	Virginia
United States	Mayo Clinic Cancer Center	Rochester	Minnesota
United States	Radiological Associates of Sacramento Medical Group, Incorporated	Sacramento	California
United States	University of California Davis Cancer Center	Sacramento	California
United States	Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis	Saint Louis	Missouri
United States	Huntsman Cancer Institute at University of Utah	Salt Lake City	Utah
United States	Mayo Clinic Scottsdale	Scottsdale	Arizona
United States	CCOP - Virginia Mason Research Center	Seattle	Washington
United States	Cancer Care Northwest - Spokane South	Spokane	Washington
United States	Texas Oncology, PA at Texas Oncology Cancer Center Sugar Land	Sugar Land	Texas
United States	Arizona Cancer Center at University of Arizona Health Sciences Center	Tucson	Arizona
United States	Arizona Oncology - Tucson	Tucson	Arizona
United States	Lankenau Cancer Center at Lankenau Hospital	Wynnewood	Pennsylvania
United States	York Cancer Center at Apple Hill Medical Center	York	Pennsylvania

Sponsors (3)

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

Countries where clinical trial is conducted

United States,  Canada, 

References & Publications (1)

Gondi V, Pugh SL, Tome WA, Caine C, Corn B, Kanner A, Rowley H, Kundapur V, DeNittis A, Greenspoon JN, Konski AA, Bauman GS, Shah S, Shi W, Wendland M, Kachnic L, Mehta MP. Preservation of memory with conformal avoidance of the hippocampal neural stem-cel — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percent Change in Delayed Recall at 4 Months as Measured by the Hopkins Verbal Learning Test-Revised (HVLT-R)	Change in Hopkins Verbal Learning Test-Revised delayed recall (HVLT_R DR) score from baseline to 4 months after the start of treatment calculated as (baseline score - 4 month score)/ baseline score. A positive change indicates a decline in function. The HVLT-R assesses verbal learning and memory. It incorporates 6 different forms, helping to mitigate practice effects of repeated administrations. Each form includes 12 nouns (targets) with 4 words drawn from 3 semantic categories, which differ across the 6 forms. Delayed recall involves recalling a list of 12 targets after a 20-minute delay. The score is the sum of the number of targets correctly recalled. Percent change calculated as 100*[(baseline score - 4 month score)/ baseline score]	Baseline and 4 months from start of treatment
Secondary	Percent Change at 4 Months in Auditory Learning Measured by Cogstate's International Shopping List Test (ISLT)	The score is the total number of correct responses made in remembering the list on three consecutive trials in a single session. A higher score indicates a better performance. Each patient served as her or his own control, and the percent change in ISLT score from baseline to 4 months was calculated as 100*[(baseline score - 4 month score)/ baseline score].	Baseline and 4 months from start of treatment
Secondary	Percent Change at 4 Months in Visual Learning Measured by Cogstate's One Card Learning Test (OCLT)	The score is the arcsine of the square root of the proportion of correct responses. A higher score indicates a better performance. Each patient served as her or his own control, and the percent change in OCLT score from baseline to 4 months was calculated as 100*[(baseline score - 4 month score)/ baseline score].	Baseline and 4 months from start of treatment
Secondary	Quality of Life as Measured by the Functional Assessment of Cancer Therapy-Brain (FACT-Br)	The 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. The FACT-G is a validated, 27-item measure where a higher score represents higher QOL. In addition to a total QOL score, subscale scores for physical, functional, social and emotional well-being are produced. There are 5 responses options, 0=Not a lot to 4=Very much. All subscale items are added together, multiplied by the number of items in the subscale, then divided by the number of items answered to obtain subscale totals. Scores range 0-108 for FACT-G total, 0-28 for physical, social, functional subscales, 0-24 for emotional subscale, 0-76 for brain subscale. Certain items must be reversed before it is added by subtracting the response from 4. Subscale requires >= 50% of items to be completed while the overall response rate must be > 80%. If items are missing, the subscale scores can be prorated.	Baseline and 4 months from start of treatment
Secondary	Quality of Life as Measured by the Barthel Index of Activities of Daily Living (ADL)	The Barthel Index of Activities of Daily Living (ADL) is a 10-item assessment. Patient scores on the ADL range from 0 to 20 with lower scores indicating declining functional status.	Baseline and 4 months from start of treatment
Secondary	Overall Survival	Overall survival was measured from registration to the date of death or last known follow-up (censored). Kaplan-Meier estimator was used to median survival time and 95% confidence interval.	Analysis occurs after all patients have been on study for at least 4 months. (Patients are followed from registration to death or study termination whichever occurs first.)
Secondary	Progression-free Survival	Progression (radiographic) is defined as an increase in perpendicular bidimensional tumor area (at lease 50% for lesions < 1cm, at least 25% for lesions >=1cm) for any of the 1-3 tracked brain metastases, or the appearance of any new brain metastasis on a follow-up MRI. Progression-free survival was calculated instead of time to progression. Progression-free survival time was measured from registration to the date of progression, death, or last known follow-up (censored). The Kaplan-Meier method used to determine median time (along with 95% confidence intervals).	Analysis occurs after all patients have been on study for at least 4 months. (Patients are followed from registration to death or study termination whichever occurs first.)
Secondary	The Frequency of Patients With Grade 3 and Higher Adverse Events (AE) Related to Treatment	For each patient the highest grade adverse event related to treatment was calculated. Those with their highest grade of 3 or higher were counted. Adverse events are graded using CTCAE v4.0. Grade refers to the severity of the AE. The CTCAE v4.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE	From start of treatment to 12 months from start of treatment
Secondary	ApoE4 Genotype and Other Potentially Predictive Biomarkers of Cognitive Function	Per the protocol, the feasibility of the proposed translational studies were to be assessed following completion of accrual and sample collection. The decision was made not to pursue this outcome measure. No assays were performed and no data were collected for this Outcome Measure	Baseline and 4 months from start of treatment