Ignite Creation Date:
2024-05-06 @ 7:27 PM
Last Modification Date:
2024-10-26 @ 3:07 PM
Study NCT ID:
NCT06014398
Status:
NOT_YET_RECRUITING
Last Update Posted:
2023-08-28
First Post:
2023-07-24
Brief Title:
Improving Survivorship and Health-related Quality of Life in Patients With Primary Brain Tumours
Sponsor:
Royal College of Surgeons Ireland
Organization:
Royal College of Surgeons Ireland
Study Overview
Official Title:
Improving Survivorship and Health-related Quality of Life in Patients With Primary Brain Tumours
Status:
NOT_YET_RECRUITING
Status Verified Date:
2023-07
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Background
Approximately 480 primary non-pituitary brain tumours were diagnosed in Ireland each year between 1994 and 2013 Recent developments in treatment have greatly improved survival for younger patients in the 15-54 age range The Irish National Neurosurgical Centre and the St Lukes Radiation Oncology Centre at Beaumont Hospital and treat approximately 200 patients with brain tumours per year with a combination of surgery radiotherapy RT and chemotherapy with RT being the most commonly used treatment modality With improved survivorship the prospect of individuals living for several decades with co-morbidities induced by the tumour itself or surgical and RT treatments raises new and complex issues for patients and clinicians
The hypothalamus and pituitary gland in the brain are the key regulators of hormone action They control several hormone systems including reproductive function FSH LH growth growth hormone thyroid TSH and adrenal function ACTH as well as many other homeostatic mechanisms It has long been recognised that therapeutic cranial RT to the pituitary gland causes hypothalamic-pituitary dysfunction hypopituitarism Traditionally high-risk groups for post-irradiation hypopituitarism were considered to be patients with pituitary tumours survivors of childhood cancer and patients who received high-dose RT to treat nasopharyngeal cancers The potential for cranial radiotherapy to cause significant pituitary dysfunction in adult patients with brain tumours has received little attention The assumption has been that the hypothalamic-pituitary axis is more resistant in adults than in children to the effect of cranial RT However it is likely that the higher doses of RT used to treat primary brain tumours in adults causes significant hypothalamic-pituitary dysfunction resulting in hypopituitarism Preliminary data from the National Pituitary Centre in Beaumont Hospital has revealed that adult patients treated with cranial radiotherapy for primary non-pituitary brain tumours are at risk of hypopituitarism Approximately 40 of patients had pituitary deficiencies in at least one hormone axis while 25 of patients had deficiencies in multiple hormone axes Hypopituitarism confers significant morbidity and increased mortality to patients At present adult survivors of brain tumours are referred to the pituitary service for assessment on an ad-hoc basis meaning that many patients with hypopituitarism may go undiagnosed
In addition to the challenges caused by hypopituitarism long-term neuropsychological outcomes following a brain tumour cause significant functional impairments and reduced HR-QOL Patients can present with impairments in specific cognitive domains such as memory and executive functioning or more global systems such as attention as well as significant issues with fatigue In addition to these primary deficits patients can also present with significant distress fluctuant mood and anxiety Despite the impact of brain tumours can exert the National Cancer Control Programs National Survivorship Needs Assessment Review 2019 did not identify any studies reporting the needs of adult survivors of brain tumours in Ireland
There is an urgent need to understand the impact of hypopituitarism and its treatment on HR-QOL and neuropsychological functioning The proposed study will add to the limited existing literature on the prevalence of hypopituitarism in adult survivors of brain tumours treated with radiotherapy and generate detailed information on deficiency rates for individual pituitary hormones and how these deficiencies emerge over time This will also be the first study to examine if treatment of radiotherapy-induced hypopituitarism as part of routine clinical care is associated with improved HR-QOL and neuropsychological functioning
Approximately 480 primary non-pituitary brain tumours were diagnosed in Ireland each year between 1994 and 2013 Recent developments in treatment have greatly improved survival for younger patients in the 15-54 age range The Irish National Neurosurgical Centre and the St Lukes Radiation Oncology Centre at Beaumont Hospital and treat approximately 200 patients with brain tumours per year with a combination of surgery radiotherapy RT and chemotherapy with RT being the most commonly used treatment modality With improved survivorship the prospect of individuals living for several decades with co-morbidities induced by the tumour itself or surgical and RT treatments raises new and complex issues for patients and clinicians
The hypothalamus and pituitary gland in the brain are the key regulators of hormone action They control several hormone systems including reproductive function FSH LH growth growth hormone thyroid TSH and adrenal function ACTH as well as many other homeostatic mechanisms It has long been recognised that therapeutic cranial RT to the pituitary gland causes hypothalamic-pituitary dysfunction hypopituitarism Traditionally high-risk groups for post-irradiation hypopituitarism were considered to be patients with pituitary tumours survivors of childhood cancer and patients who received high-dose RT to treat nasopharyngeal cancers The potential for cranial radiotherapy to cause significant pituitary dysfunction in adult patients with brain tumours has received little attention The assumption has been that the hypothalamic-pituitary axis is more resistant in adults than in children to the effect of cranial RT However it is likely that the higher doses of RT used to treat primary brain tumours in adults causes significant hypothalamic-pituitary dysfunction resulting in hypopituitarism Preliminary data from the National Pituitary Centre in Beaumont Hospital has revealed that adult patients treated with cranial radiotherapy for primary non-pituitary brain tumours are at risk of hypopituitarism Approximately 40 of patients had pituitary deficiencies in at least one hormone axis while 25 of patients had deficiencies in multiple hormone axes Hypopituitarism confers significant morbidity and increased mortality to patients At present adult survivors of brain tumours are referred to the pituitary service for assessment on an ad-hoc basis meaning that many patients with hypopituitarism may go undiagnosed
In addition to the challenges caused by hypopituitarism long-term neuropsychological outcomes following a brain tumour cause significant functional impairments and reduced HR-QOL Patients can present with impairments in specific cognitive domains such as memory and executive functioning or more global systems such as attention as well as significant issues with fatigue In addition to these primary deficits patients can also present with significant distress fluctuant mood and anxiety Despite the impact of brain tumours can exert the National Cancer Control Programs National Survivorship Needs Assessment Review 2019 did not identify any studies reporting the needs of adult survivors of brain tumours in Ireland
There is an urgent need to understand the impact of hypopituitarism and its treatment on HR-QOL and neuropsychological functioning The proposed study will add to the limited existing literature on the prevalence of hypopituitarism in adult survivors of brain tumours treated with radiotherapy and generate detailed information on deficiency rates for individual pituitary hormones and how these deficiencies emerge over time This will also be the first study to examine if treatment of radiotherapy-induced hypopituitarism as part of routine clinical care is associated with improved HR-QOL and neuropsychological functioning
Detailed Description:
Hypothesis Adult survivors of primary non-pituitary brain tumours have an increased risk of hypopituitarism and experience impairments in HR-QOL and neuropsychological functioning We hypothesise that diagnosis of these deficiencies and the subsequent active replacement of pituitary hormone deficits as part of routine clinical care will lead to an improvement in neuropsychological functioning and HR-QOL in adult survivors of primary brain tumours
Objectives
1 To examine the impact of radiotherapy on pituitary hormone function in adult survivors of primary non-pituitary brain tumours
2 To assess HR-QOL and neuropsychological functioning in adult survivors of primary non-pituitary brain tumours
3 To examine the impact of pituitary hormone replacement and optimisation as part of routine clinical care on HR-QOL and neuropsychological functioning in adult survivors of primary non-pituitary brain tumours
Methods
Study Design Setting
A cross-sectional study will be conducted in the RCSI clinical research centre located on the Beaumont Hospital campus The study will be conducted over three years from September 2023 to September 2025
Participants
The study population will consist of adults who have previously received cranial radiotherapy for a primary non-pituitary brain tumour
Patient Recruitment
Participants will be identified in Professor Clare Fauls Dr David Fitzpatricks and Dr Nazmi ElBeltagis clinic in St Lukes Radiation Oncology Centre at Beaumont Hospital
Patients will be approached by the research fellow during routine clinical consultations
The nature purpose benefits and risks of the study will be discussed with potential participants They will be given the opportunity ask questions about the study The patients medical history will be reviewed to ensure they meet the study inclusion criteria
Patients will be given a patient information leaflet and asked to read this at home
The research fellow will follow up with a phone call within 72 hours and offer patients the opportunity to participate in the study A first research study visit will be arranged for those who agree to participate
Study Procedure
Study Visit One
Consent
Participants will be asked to attend study visit one in the RCSI Clinical Research Centre CRC
Participants will be given the opportunity to ask questions and to have any concerns addressed by the research team
They will then be asked by the research fellow to provide their informed consent to i participate in the study and ii allow their data to be processed by the research team
Assessments
Participants will be asked to fast from midnight the previous evening as per Beaumont Hospital protocol for dynamic testing of pituitary function
They will be advised to take their usual medications with a small sip of water on the morning of the test
The research fellow will assess the participants blood pressure height weight and body composition using the bioimpedance technique with the Tanita BC-418 segmental body composition analyser
Women of childbearing age will be questioned to ensure they are not pregnancy If there is any uncertainty they will be asked to take a pregnancy test
Baseline blood sampling
A fasting 9am blood sample will be taken to assess pituitary function ACTH cortisol FSH LH oestrogen in females testosterone in males sex hormone binding globulin thyroid function tests prolactin IGF-1 and metabolic phenotype full blood count renal liver profile cholesterol HbA1c homeostatic model assessment for insulin resistance HOMA-IR
Dynamic testing of pituitary function
Patients will undergo dynamic testing of the ACTH and growth hormone axes using a glucagon stimulation test GST
The Beaumont Hospital GST protocol will be followed throughout
A cannula will be inserted into the patients forearm Baseline serum samples for glucose cortisol and growth hormone will be drawn from the cannula
Glucagon will then be injected into the lateral aspect of the mid quadriceps vastus lateralis by the research nurse fellow A glucagon dose of 1mg will be used in adults less than 90kg and 15mg in adults greater than 90kg
Serum samples will be drawn from the cannula for glucose cortisol and GH at 90 120 150 and 180 minutes
Neuropsychological assessment
A battery of neuropsychological tests to assess for cognitive memory language and visuo-spatial dysfunction will be performed These tests are fully validated and have been widely used in the research setting
Cognitive dysfunction Stroop colour-word test phonemic verbal fluency backward digital span
Language dysfunction Boston naming test
Memory dysfunction Logical memory verbal paired associate and auditory delayed recognition task
Visuo-spatial dysfunction Rey-osterrieth complex figure test
HR-QOL assessment
Participants HR-QOL will be measured using extensively validated assessment tools including the Short Form-36 SF-36 Nottingham Health Profile and EQ-5D-5L
The SF-36 is a widely used HR-QOL assessment tool consisting of 4 physical and 4 mental domains which are combined to give physical and mental component summary scores The Nottingham Health Profile consists of two components a subjective assessment of their general health and the impact on their activities of daily living The EQ-5D-5L assesses level of difficulty with five aspects of daily living
The research fellow will ask participants the assessment questions document their responses and calculate the overall scores where necessary
Study visit one is then complete
Review of Pituitary Assessments
Baseline and dynamic test results will be reviewed after study visit one by the principal investigator and research fellow
Selected patients whose GST identifies cortisol deficiency will be asked to attend the RCSI-CRC for an additional study visit to undergo a short synacthen test SST This is to confirm adrenal insufficiency as the GST has a false positive rate of approximately 20 for ACTH deficiency
A SST involves a cannula being inserted into the forearm and baseline serum samples for ACTH and cortisol being taken Synacthen 250mcg will then be administered intravenously A second cortisol sample will be taken after 30 mins
Patients diagnosed with hypopituitarism will have their hormone deficits replaced as per best clinical practice by the endocrinology service In the event of a patient being diagnosed with growth hormone deficiency growth hormone replacement will be discussed with the radiation oncology team is not appropriate in all types of brain tumours
Patients will be counselled on the diagnosis of hypopituitarism and any questions or concerns addressed
Follow up blood tests may be required to assess the adequacy of pituitary hormone replacement as per routine clinical practice
Treatment History and Radiotherapy Dose Calculation
The patients tumour histology staging and neurosurgical treatment history will be obtained from their physical and electronic medical records in Beaumont Hospital and St Lukes Centre Radiation Oncology at Beaumont Hospital
The type dose dose per fraction of radiotherapy received by the hypothalamus pituitary which will be estimated from planning scans using the biological equivalent dose will be recorded in collaboration with Professor Clare Faul Dr David Fitzpatricks and Dr Nazmi ElBeltagis in St Lukes Radiation Oncology Centre at Beaumont Hospital
Study Visit Two All study participants will be asked to return for a second study visit four months after their first visit
Repeat measurements will be taken including
o Weight blood pressure and body composition
o Fasting 9am blood samples to assess baseline pituitary function and metabolic phenotype as previously outlined
All patients will have their HR-QOL and neuropsychological functioning reassessed to measure the change over the course of the study
End of study
Patients diagnosed with hypopituitarism during the study will be followed up in the endocrinology clinic in Beaumont Hospital as is the case for all patients with hypopituitarism
Objectives
1 To examine the impact of radiotherapy on pituitary hormone function in adult survivors of primary non-pituitary brain tumours
2 To assess HR-QOL and neuropsychological functioning in adult survivors of primary non-pituitary brain tumours
3 To examine the impact of pituitary hormone replacement and optimisation as part of routine clinical care on HR-QOL and neuropsychological functioning in adult survivors of primary non-pituitary brain tumours
Methods
Study Design Setting
A cross-sectional study will be conducted in the RCSI clinical research centre located on the Beaumont Hospital campus The study will be conducted over three years from September 2023 to September 2025
Participants
The study population will consist of adults who have previously received cranial radiotherapy for a primary non-pituitary brain tumour
Patient Recruitment
Participants will be identified in Professor Clare Fauls Dr David Fitzpatricks and Dr Nazmi ElBeltagis clinic in St Lukes Radiation Oncology Centre at Beaumont Hospital
Patients will be approached by the research fellow during routine clinical consultations
The nature purpose benefits and risks of the study will be discussed with potential participants They will be given the opportunity ask questions about the study The patients medical history will be reviewed to ensure they meet the study inclusion criteria
Patients will be given a patient information leaflet and asked to read this at home
The research fellow will follow up with a phone call within 72 hours and offer patients the opportunity to participate in the study A first research study visit will be arranged for those who agree to participate
Study Procedure
Study Visit One
Consent
Participants will be asked to attend study visit one in the RCSI Clinical Research Centre CRC
Participants will be given the opportunity to ask questions and to have any concerns addressed by the research team
They will then be asked by the research fellow to provide their informed consent to i participate in the study and ii allow their data to be processed by the research team
Assessments
Participants will be asked to fast from midnight the previous evening as per Beaumont Hospital protocol for dynamic testing of pituitary function
They will be advised to take their usual medications with a small sip of water on the morning of the test
The research fellow will assess the participants blood pressure height weight and body composition using the bioimpedance technique with the Tanita BC-418 segmental body composition analyser
Women of childbearing age will be questioned to ensure they are not pregnancy If there is any uncertainty they will be asked to take a pregnancy test
Baseline blood sampling
A fasting 9am blood sample will be taken to assess pituitary function ACTH cortisol FSH LH oestrogen in females testosterone in males sex hormone binding globulin thyroid function tests prolactin IGF-1 and metabolic phenotype full blood count renal liver profile cholesterol HbA1c homeostatic model assessment for insulin resistance HOMA-IR
Dynamic testing of pituitary function
Patients will undergo dynamic testing of the ACTH and growth hormone axes using a glucagon stimulation test GST
The Beaumont Hospital GST protocol will be followed throughout
A cannula will be inserted into the patients forearm Baseline serum samples for glucose cortisol and growth hormone will be drawn from the cannula
Glucagon will then be injected into the lateral aspect of the mid quadriceps vastus lateralis by the research nurse fellow A glucagon dose of 1mg will be used in adults less than 90kg and 15mg in adults greater than 90kg
Serum samples will be drawn from the cannula for glucose cortisol and GH at 90 120 150 and 180 minutes
Neuropsychological assessment
A battery of neuropsychological tests to assess for cognitive memory language and visuo-spatial dysfunction will be performed These tests are fully validated and have been widely used in the research setting
Cognitive dysfunction Stroop colour-word test phonemic verbal fluency backward digital span
Language dysfunction Boston naming test
Memory dysfunction Logical memory verbal paired associate and auditory delayed recognition task
Visuo-spatial dysfunction Rey-osterrieth complex figure test
HR-QOL assessment
Participants HR-QOL will be measured using extensively validated assessment tools including the Short Form-36 SF-36 Nottingham Health Profile and EQ-5D-5L
The SF-36 is a widely used HR-QOL assessment tool consisting of 4 physical and 4 mental domains which are combined to give physical and mental component summary scores The Nottingham Health Profile consists of two components a subjective assessment of their general health and the impact on their activities of daily living The EQ-5D-5L assesses level of difficulty with five aspects of daily living
The research fellow will ask participants the assessment questions document their responses and calculate the overall scores where necessary
Study visit one is then complete
Review of Pituitary Assessments
Baseline and dynamic test results will be reviewed after study visit one by the principal investigator and research fellow
Selected patients whose GST identifies cortisol deficiency will be asked to attend the RCSI-CRC for an additional study visit to undergo a short synacthen test SST This is to confirm adrenal insufficiency as the GST has a false positive rate of approximately 20 for ACTH deficiency
A SST involves a cannula being inserted into the forearm and baseline serum samples for ACTH and cortisol being taken Synacthen 250mcg will then be administered intravenously A second cortisol sample will be taken after 30 mins
Patients diagnosed with hypopituitarism will have their hormone deficits replaced as per best clinical practice by the endocrinology service In the event of a patient being diagnosed with growth hormone deficiency growth hormone replacement will be discussed with the radiation oncology team is not appropriate in all types of brain tumours
Patients will be counselled on the diagnosis of hypopituitarism and any questions or concerns addressed
Follow up blood tests may be required to assess the adequacy of pituitary hormone replacement as per routine clinical practice
Treatment History and Radiotherapy Dose Calculation
The patients tumour histology staging and neurosurgical treatment history will be obtained from their physical and electronic medical records in Beaumont Hospital and St Lukes Centre Radiation Oncology at Beaumont Hospital
The type dose dose per fraction of radiotherapy received by the hypothalamus pituitary which will be estimated from planning scans using the biological equivalent dose will be recorded in collaboration with Professor Clare Faul Dr David Fitzpatricks and Dr Nazmi ElBeltagis in St Lukes Radiation Oncology Centre at Beaumont Hospital
Study Visit Two All study participants will be asked to return for a second study visit four months after their first visit
Repeat measurements will be taken including
o Weight blood pressure and body composition
o Fasting 9am blood samples to assess baseline pituitary function and metabolic phenotype as previously outlined
All patients will have their HR-QOL and neuropsychological functioning reassessed to measure the change over the course of the study
End of study
Patients diagnosed with hypopituitarism during the study will be followed up in the endocrinology clinic in Beaumont Hospital as is the case for all patients with hypopituitarism
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None