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Neurocognitive Outcome of Conformal WBRT w/wo Hippocampal Avoidance for Brain Metastases

Primary Purpose

Metastatic Malignant Neoplasm to Brain

Status

Unknown status

Phase

Not Applicable

Locations

Taiwan

Study Type

Interventional

Intervention

Hippocampal avoidance WBRT

Conformal WBRT

About this trial

This is an interventional treatment trial for Metastatic Malignant Neoplasm to Brain focused on measuring Brain Metastases, Whole Brain Radiotherapy, Neurocognitive function

Eligibility Criteria

20 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion criteria:

To be eligible for inclusion, patients must fulfill the following criteria:

Patients with a histologic diagnosis of non-hematopoietic malignancy and radiographic evidence of brain metastases
Patients with brain metastasis outside a 5-mm margin around either hippocampus on gadolinium contrast enhanced MRI obtained within 30 days prior to registration
Patients with brain metastasis who have not been or will not be treated with stereotactic radiosurgery (SRS) or have received SRS for≤ 5 intracranial metastatic lesions
No evidence of leptomeningeal metastasis on gadolinium-enhanced MRI within 30 days prior registration
Age ≥ 20 years
Karnofsky Performance Status ≥ 60%
Life expectancy of ≥ 4 months.
Women of childbearing potential and male participants must practice adequate contraception
Patients must be able to comply with the study protocol and follow-up schedules and provide study- specific informed consent

Exclusion criteria:

Patients fulfill any of the following criteria will be excluded from this trial

Prior radiotherapy to brain or SRS to > 5 intracranial metastatic lesion(s) or the biological equivalent dose in 2-Gy fractions was greater than 7.3 Gy to 40% of the volume of bilateral hippocampus from prior SRS
Serum creatinine > 2.0 mg/dL within 30 days prior registration
Contraindication to MRI such as implanted metal devices or foreign bodies, severe claustrophobia
Patients with leptomeningeal metastases
Severe, active comorbidities which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and adverse events of the protocol, or limit compliance with study requirements, defined as follows:
1. Uncontrolled active infection requiring intravenous antibiotics at the time of registration
2. Transmural myocardial infarction ≤ 6 months prior to registration
3. Unstable angina or congestive heart failure requiring hospitalization ≤ 6 months prior to registration
4. Life-threatening uncontrolled clinically significant cardiac arrhythmias
5. Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects
6. Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration
7. Uncontrolled psychiatric disorder
8. Uncontrolled, clinically significant cardiac arrhythmias
Will receive any other investigational agent or chemotherapy and/or target therapies during WBRT
Women of childbearing potential and male participants who are sexually active and not willing/able to use medically acceptable forms of contraception; this exclusion is necessary because the radiation treatment involved in this study may be significantly teratogenic

Sites / Locations

National Taiwan University Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Hippocampal avoidance WBRT

Conformal WBRT

Arm Description

Conformal whole brain radiotherapy with hippocampal avoidance

Conformal whole brain radiotherapy without hippocampal avoidance

Outcomes

Primary Outcome Measures

Hopkins Verbal Learning Test-Revised (HVTL-R) delayed recall score

Decline in Hopkins Verbal Learning Test-Revised (HVTL-R) delayed recall score from baseline to 4 months after the start of conformal whole brain radiotherapy with or without hippocampal avoidance for brain metastases

Secondary Outcome Measures

Neurocognitive function by a standardized neurocognitive battery

Evaluate neurocognitive function by a standardized neurocognitive battery (HVTL-R, Trail Making Test Part A & B, forward & backward Digit Span).

Patient reported outcome (Quality of Life questionnaire)

EORTC Quality of Life-Core 30 questionnaire module and Quality of Life questionnaire -brain

Acute toxicity (Common Toxicity Criteria for Adverse Events version 4)

Common Toxicity Criteria for Adverse Events version 4

Late toxicity (Common Toxicity Criteria for Adverse Events version 4)

Common Toxicity Criteria for Adverse Events version 4

Intracranial progression (Number of participant with intracranial progression on MRI of brain)

Number of participant with intracranial progression on MRI of brain

Overall survival

Number of patients died

Full Information

NCT ID

NCT02393131

First Posted

February 23, 2015

Last Updated

July 17, 2019

Sponsor

National Taiwan University Hospital

1. Study Identification

Unique Protocol Identification Number

NCT02393131

Brief Title

Neurocognitive Outcome of Conformal WBRT w/wo Hippocampal Avoidance for Brain Metastases

Official Title

Neurocognitive Outcome of Conformal Whole Brain Radiotherapy With or Without Hippocampal Avoidance for Brain Metastases: A Phase II Single Blind Randomized Trial

Study Type

Interventional

2. Study Status

Record Verification Date

March 2019

Overall Recruitment Status

Unknown status

Study Start Date

March 3, 2015 (Actual)

Primary Completion Date

June 2019 (Actual)

Study Completion Date

December 2020 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

National Taiwan University Hospital

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

Brain metastases are the most common brain tumors in adults. It is estimated that around 10-30% of cancer patients would develop brain metastases during the course of their illness. Whole brain radiotherapy (WBRT) is the treatment of choice for the majority of patients with brain metastases. WBRT yields high radiologic response rate (27~56%) and is effective in rapid palliation of neurologic symptoms as well as prolongs time to neurocognitive function decline caused by intracranial lesions. By using conventional fractionation, 33% of patients developed late neurocognitive toxicity while memory impairment was the most common symptom. The incidence is even higher when a formal and sensitive neurocognitive assessment was prospectively evaluated. With more long-term survivors nowadays, it has become increasingly important to minimize neurocognitive function decline and maintain quality of life in patients with brain metastasis. The function of hippocampus is cooperation in learning, consolidation and retrieval of information and essential for formation of new memories. Bilateral and unilateral radiation injury of the hippocampus is known to alter learning and memory formation. Several preclinical studies support the hypothesis of hippocampus-mediated cognitive dysfunction by ionizing radiation. Clinical studies show increase in radiation dose to hippocampus is associated with subsequent neurocognitive function impairment in adult and pediatric patients. Furthermore, the preliminary result of Radiation Therapy Oncology Group (RTOG) 0933 suggested hippocampal avoidance significant reduce the mean relative decline at 4 months from 30% in historical cohort with WBRT to 7% in experimental cohort. Previous studies showed brain structures other than hippocampus are also associated with radiation-induced decline in neurocognitive function. There is presence of placebo effect for interventions seeking improvement in neurocognitive function. In present study, a single blind randomized phase II trial is designed to investigate the effectiveness of neurocognitive function preservation using conformal WBRT with or without hippocampal avoidance.

Detailed Description

This is a single institutional, randomized phase II study to assess the neurocognitive outcome of conformal WBRT with or without hippocampal avoidance in patients with multiple brain metastases. Patients will be randomly assigned 1:1 to receive conformal WBRT with or without hippocampal avoidance using permuted blocks within strata that are defined by Graded Prognostic Assessment (GPA) score and baseline neurocognitive status. All patients and co-investigators except the principal investigator and attending radiation oncologists will be blinded for treatment groups. The whole brain planning target volume (PTV) will receive 30 Gy in 10 fractions. Treatment will be delivered once daily, 5 fractions per week, over 2 to 2.5 weeks. Breaks in treatment should be minimized. Hippocampal Avoidance WBRT: The dose is prescribed such as 90% of cranial content PTV is covered by the prescription dose. Maximum dose to 2% of the PTV (D2%) is 37.5 Gy, and minimum dose to 98% of the PTV (D98%) is 25 Gy. Minimum dose to 100% of the hippocampal avoidance regions is 10 Gy, and dose to any point within the hippocampal avoidance regions cannot exceed 17 Gy. Conformal WBRT: The dose is prescribed such as 95% of cranial content PTV is covered by the prescription dose. Maximum dose to 1% of the PTV (D1%) is 36 Gy, and minimum dose to 99% of the PTV (D99%) is 27 Gy. Follow-up & Assessment Side effect evaluation: Acute (≤ 90 days from WBRT start) toxicities (CTCAE ver.4) Late (> 90 days from WBRT start) toxicities (CTCAE ver.4) Functional evaluation: at baseline, 2-, 4- ,and 6-month, every 3 months for 12 months until intracranial disease progression or death after WBRT Neurocognitive function Self-reported cognitive functioning (two items from EORTC Quality of Life Questionnaire-C30 Taiwan) Health-related quality of life specific for brain neoplasms (EORTC Quality of Life Questionnaire-Brain Neoplasm Taiwan) Efficacy evaluation: Follow-up brain MRI at 4-, 9- ,and 12-month until intracranial disease progression, or death. Overall survival

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Metastatic Malignant Neoplasm to Brain

Keywords

Brain Metastases, Whole Brain Radiotherapy, Neurocognitive function

7. Study Design

Primary Purpose

Treatment

Study Phase

Not Applicable

Interventional Study Model

Parallel Assignment

Masking

Participant

Allocation

Randomized

Enrollment

70 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Hippocampal avoidance WBRT

Arm Type

Experimental

Arm Description

Conformal whole brain radiotherapy with hippocampal avoidance

Arm Title

Conformal WBRT

Arm Type

Active Comparator

Arm Description

Conformal whole brain radiotherapy without hippocampal avoidance

Intervention Type

Radiation

Intervention Name(s)

Hippocampal avoidance WBRT

Intervention Description

Conformal Whole Brain Radiotherapy 30 Gy in 10 fractions with Hippocampal Avoidance using Intensity modulated radiotherapy, Volumetric arc therapy, or Tomotherapy

Intervention Type

Radiation

Intervention Name(s)

Conformal WBRT

Intervention Description

Conformal Whole Brain Radiotherapy 30 Gy in 10 fractions with Hippocampal Avoidance using Intensity modulated radiotherapy, Volumetric arc therapy, or Tomotherapy

Primary Outcome Measure Information:

Title

Hopkins Verbal Learning Test-Revised (HVTL-R) delayed recall score

Description

Time Frame

At 4 months after radiotherapy

Secondary Outcome Measure Information:

Title

Neurocognitive function by a standardized neurocognitive battery

Description

Evaluate neurocognitive function by a standardized neurocognitive battery (HVTL-R, Trail Making Test Part A & B, forward & backward Digit Span).

Time Frame

at 1, 2, 4, 6, 9, 12 months after radiotherapy, and then every 3 months until date of death from any cause, assessed up to 24 months

Title

Patient reported outcome (Quality of Life questionnaire)

Description

EORTC Quality of Life-Core 30 questionnaire module and Quality of Life questionnaire -brain

Time Frame

at 1, 2, 4, 6, 9, 12 months after radiotherapy, and then every 3 months until date of death from any cause, assessed up to 24 months

Title

Acute toxicity (Common Toxicity Criteria for Adverse Events version 4)

Description

Common Toxicity Criteria for Adverse Events version 4

Time Frame

From date of radiotherapy until 90 days after radiotherapy starts

Title

Late toxicity (Common Toxicity Criteria for Adverse Events version 4)

Description

Common Toxicity Criteria for Adverse Events version 4

Time Frame

From 90 days after radiotherapy starts until the date of death from any cause, up to 60 months

Title

Intracranial progression (Number of participant with intracranial progression on MRI of brain)

Description

Number of participant with intracranial progression on MRI of brain

Time Frame

From date of enrolment until the date of first documented intracranial progression or date of death from any cause, whichever came first, assessed up to 60 months

Title

Overall survival

Description

Number of patients died

Time Frame

From date of enrollment until the date of death from any cause, assessed up to 60 months

Other Pre-specified Outcome Measures:

Title

Genomic risk of neurocognitive decline after WBRT

Description

Number of participants with Genomic risk of neurocognitive impairment after WBRT

Time Frame

At 4 months after radiotherapy

10. Eligibility

Sex

All

Minimum Age & Unit of Time

20 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion criteria: To be eligible for inclusion, patients must fulfill the following criteria: Patients with a histologic diagnosis of non-hematopoietic malignancy and radiographic evidence of brain metastases Patients with brain metastasis outside a 5-mm margin around either hippocampus on gadolinium contrast enhanced MRI obtained within 30 days prior to registration Patients with brain metastasis who have not been or will not be treated with stereotactic radiosurgery (SRS) or have received SRS for≤ 5 intracranial metastatic lesions No evidence of leptomeningeal metastasis on gadolinium-enhanced MRI within 30 days prior registration Age ≥ 20 years Karnofsky Performance Status ≥ 60% Life expectancy of ≥ 4 months. Women of childbearing potential and male participants must practice adequate contraception Patients must be able to comply with the study protocol and follow-up schedules and provide study- specific informed consent Exclusion criteria: Patients fulfill any of the following criteria will be excluded from this trial Prior radiotherapy to brain or SRS to > 5 intracranial metastatic lesion(s) or the biological equivalent dose in 2-Gy fractions was greater than 7.3 Gy to 40% of the volume of bilateral hippocampus from prior SRS Serum creatinine > 2.0 mg/dL within 30 days prior registration Contraindication to MRI such as implanted metal devices or foreign bodies, severe claustrophobia Patients with leptomeningeal metastases Severe, active comorbidities which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and adverse events of the protocol, or limit compliance with study requirements, defined as follows: Uncontrolled active infection requiring intravenous antibiotics at the time of registration Transmural myocardial infarction ≤ 6 months prior to registration Unstable angina or congestive heart failure requiring hospitalization ≤ 6 months prior to registration Life-threatening uncontrolled clinically significant cardiac arrhythmias 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 psychiatric disorder Uncontrolled, clinically significant cardiac arrhythmias Will receive any other investigational agent or chemotherapy and/or target therapies during WBRT Women of childbearing potential and male participants who are sexually active and not willing/able to use medically acceptable forms of contraception; this exclusion is necessary because the radiation treatment involved in this study may be significantly teratogenic

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Feng-Ming Hsu, MD

Organizational Affiliation

National Taiwan University Hospital

Official's Role

Principal Investigator

Facility Information:

Facility Name

National Taiwan University Hospital

City

Taipei

ZIP/Postal Code

100

Country

Taiwan

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

32789503

Citation

Yang WC, Chen YF, Yang CC, Wu PF, Chan HM, Chen JL, Chen GY, Cheng JC, Kuo SH, Hsu FM. Hippocampal avoidance whole-brain radiotherapy without memantine in preserving neurocognitive function for brain metastases: a phase II blinded randomized trial. Neuro Oncol. 2021 Mar 25;23(3):478-486. doi: 10.1093/neuonc/noaa193. Erratum In: Neuro Oncol. 2021 Dec 1;23(12):2125.

Results Reference

derived

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Neurocognitive Outcome of Conformal WBRT w/wo Hippocampal Avoidance for Brain Metastases

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