Neurocognitive Outcome of Bilateral or Unilateral Hippocampal Avoidance WBRT With Memantine for Brain Metastases

Metastatic Malignant Neoplasm to Brain Clinical Trial

Official title:

Neurocognitive Outcome of Conformal Whole Brain Radiotherapy With Bilateral or Unilateral Hippocampal Avoidance Plus Memantine for Brain Metastases: A Phase II Single Blind Randomized Trial

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04801342
• Other study ID #: 201901084MINA
• Status: Recruiting
• Phase: Phase 2
• Start date: April 1, 2021
• Est. completion date: February 28, 2025

Study information

• Verified date: January 2021
• Source: National Taiwan University Hospital
• Contact: Feng-Ming Hsu, MD, PhD
• Phone: +886-2-23123456
• Email: hsufengming[@]ntuh.gov.tw
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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, more than one- third 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 result of phase III randomized trials suggested hippocampal avoidance plus Memantine significantly reduce the risk of neurocognitive impairment at 6 months from 68.2% in control arm with standard WBRT to 59.5% in experimental arm. In the investigator's prior investigation, patients received conformal WBRT with bilateral hippocampal avoidance also had significant less declines in verbal memory at 6 months. Previous studies showed the right and left hippocampus exert different neurocognitive functions. Several retrospective studies also demonstrated that the radiation dose to the left hippocampus is more related to neurocognitive impairment. Planning study and investigation showed that by avoiding the left hippocampus alone, the radiation dose to the spared unilateral hippocampus is further decreased. In present study, a single blind randomized phase II trial is designed to investigate the effectiveness of neurocognitive function preservation using conformal WBRT with bilateral or unilateral hippocampal avoidance and memantine.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 72
• Est. completion date: February 28, 2025
• Est. primary completion date: January 1, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 20 Years and older

Eligibility

Inclusion 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 SRS, or have received SRS for = 5 intracranial metastatic lesion(s)
• No evidence of diffuse leptomeningeal metastasis on gadolinium- enhanced MRI within 30 days prior registration
• Age = 20 years
• Karnofsky Performance Status = 60%
• Life expectancy of = 6 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:

• Prior radiotherapy to brain or radiosurgery to > 5 intracranial metastatic lesion(s) or the biological equivalent dose in 2-Gy fractions was greater than 7.3Gy to 40% of the volume of bilateral hippocampus from prior radiosurgery
• Serum creatinine > 2.0 mg/dL within 30 days prior registration
• Serum urea nitrogen > 20 mg/dL within 30 days prior registration
• Contraindication to MR imaging such as implanted metal devices or foreign bodies, severe claustrophobia
• 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

• Will receive any other investigational agent or chemotherapy during WBRT
• Current use of Memantine HCL or Allergy to Memantine HCL
• 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
• Pregnant or breast-feeding women

Related Conditions & MeSH terms

• Metastatic Malignant Neoplasm to Brain
• Neoplasm Metastasis
• Neoplasms

Intervention

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

Drug:
• Memantine Hydrochloride
Start from day 1 of WBRT orally for 24 weeks and escalating doses over the first 4 weeks

Locations

Country	Name	City	State
Taiwan	National Taiwan University Hospital	Taipei

Sponsors (1)

Lead Sponsor	Collaborator
National Taiwan University Hospital

Country where clinical trial is conducted

Taiwan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Genomic risk of neurocognitive decline after WBRT	Number of participants with Genomic risk of neurocognitive impairment after WBRT	At 4 months after radiotherapy
Primary	Hopkins Verbal Learning Test-Revised (HVLT-R) memory score	Decline in Hopkins Verbal Learning Test-Revised (HVLT-R) memory score (sum of total recall and recognition index) from baseline to 6 months after the start of conformal whole brain radiotherapy (WBRT) with bilateral or unilateral hippocampal avoidance for multiple brain metastases. HVLT-R Total recall raw scores ranged from 0 to 36, recognition index ranged from 0 to 12. The higher the score indicated better short term memory preservation	At 6 months after WBRT
Secondary	Neurocognitive function by a standardized neurocognitive battery Hopkins Verbal Learning Test-Revised (HVLT-R)	Evaluate neurocognitive function by a standardized neurocognitive battery Hopkins Verbal Learning Test-Revised (HVLT-R) with Total recall score (range from 0 to 36), delayed recall score (range from 0 to 12) and recognition index (range from 0 to 12). The higher the score indicated better short term memory preservation.	at 1, 2, 4, 6, 9, 12 months after WBRT, and then every 3 months until date of death from any cause, assessed up to 24 months
Secondary	Neurocognitive function by a standardized neurocognitive battery Trail Making Test Part A & B	Evaluate neurocognitive function by a standardized neurocognitive battery Trail Making Test Part A & B. TMT-A and B tested the executive function documented with time needed for complete test with no upper limit of range. The longer the time needed, the worse executive function patients preserved.	at 1, 2, 4, 6, 9, 12 months after WBRT, and then every 3 months until date of death from any cause, assessed up to 24 months
Secondary	Neurocognitive function by a standardized neurocognitive battery Controlled Oral Word Association Test	Evaluate neurocognitive function by a standardized neurocognitive battery Controlled Oral Word Association Test. Patients are given one phoneme at a time and instructed to say aloud as many words beginning with that phoneme as they could within 1 minute, for a total of three phonemes in 3 minutes. The more the words patients able to say in limit time, the better outcome presented.	at 1, 2, 4, 6, 9, 12 months after WBRT, and then every 3 months until date of death from any cause, assessed up to 24 months
Secondary	Patient reported outcome (Quality of Life questionnaire)	EORTC Quality of Life-Core 30 questionnaire module (at question 1 to 27, range from 1 to 4; at question 29 and 30, range from 1 to 7) Quality of Life questionnaire-Brain.	at 1, 2, 4, 6, 9, 12 months after WBRT, and then every 3 months until date of death from any cause, assessed up to 24 months
Secondary	Patient reported outcome (Cognitive Functioning questionnaire)	Function Assessment Cancer Therapy for patients with Cognitive function issue	at 1, 2, 4, 6, 9, 12 months after WBRT, and then every 3 months until date of death from any cause, assessed up to 24 months
Secondary	Acute toxicity (Common Toxicity Criteria for Adverse Events version 4)	Common Toxicity Criteria for Adverse Events version 4	From date of WBRT until 90 days after radiotherapy starts
Secondary	Late toxicity (Common Toxicity Criteria for Adverse Events version 4)	Common Toxicity Criteria for Adverse Events version 4	From 90 days after WBRT starts until the date of death from any cause, up to 60 months
Secondary	Intracranial progression (Number of participant with intracranial progression on MRI of brain)	Number of participant with intracranial progression on MRI of brain	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
Secondary	Overall survival	Number of patients died	From date of enrollment until the date of death from any cause, assessed up to 60 months