Ignite Creation Date:
2024-05-06 @ 8:24 PM
Last Modification Date:
2024-10-26 @ 3:27 PM
Study NCT ID:
NCT06367569
Status:
COMPLETED
Last Update Posted:
2024-04-16
First Post:
2024-04-04
Brief Title:
Evaluation of MRI of the Pineal Gland in Retinoblastoma
Sponsor:
Amsterdam UMC location VUmc
Organization:
Amsterdam UMC location VUmc
Study Overview
Official Title:
Multicenter Evaluation of Baseline MRI Screening With Extended Follow-up of Pineal Cysts for Early Detection of Pineoblastoma in Children With Retinoblastoma
Status:
COMPLETED
Status Verified Date:
2024-04
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:
TRbFU
Brief Summary:
Rationale Currently baseline brain MRI magnetic resonance imaging with extended follow-up of pineal cysts is systematically performed in all new retinoblastoma Rb patients because children with hereditary retinoblastoma have an increased risk of primitive neuroectodermal tumors PNET that are histopathologically identical to the retinal tumors 1 The prevalence of developing a PNET in combination with unilateral or bilateral hereditary Rb is 5-15 2 Treatment is difficult and the prognosis is poor as only few survivors are reported Only patients with small asymptomatic PNETs 15 mm are potentially curable
Objective The main objective of this prospective multicenter study is to evaluate the current strategy of baseline MRI screening of the brain in newly diagnosed retinoblastoma patients with extended follow-up of selected patients with simple and complicated pineal cysts
Study design The investigators propose a prospective cohort study part of a larger multicenter study to investigate the diagnostic accuracy and survival of baseline MRI screening of the pineal gland in new patients with retinoblastoma with extended follow-up of selected patients with pineal cysts for early detection of pineoblastoma
Study population Within the European Retinoblastoma Imaging Collaboration ERIC about 150 new retinoblastoma patients are diagnosed every year About 10 percent of all new retinoblastoma patients will be diagnosed at the VUmc According to our sample size calculations the investigators will need 334 Rb patients
Main study parametersendpoints The primary endpoint of the study is pineoblastoma or supra- parasellar PNET on MRI index test Because a gold standard will not be available tumor cells in cerebrospinal fluid histopathological confirmation clinical disease progression during follow-up andor follow-up MRI diagnostics will be used as a composite reference standard in case of a positive index test and clinical diagnosis of pineoblastoma or supra- parasellar PNET within one year of the last MRI will be used as a composite reference standard in case of a negative index test
Objective The main objective of this prospective multicenter study is to evaluate the current strategy of baseline MRI screening of the brain in newly diagnosed retinoblastoma patients with extended follow-up of selected patients with simple and complicated pineal cysts
Study design The investigators propose a prospective cohort study part of a larger multicenter study to investigate the diagnostic accuracy and survival of baseline MRI screening of the pineal gland in new patients with retinoblastoma with extended follow-up of selected patients with pineal cysts for early detection of pineoblastoma
Study population Within the European Retinoblastoma Imaging Collaboration ERIC about 150 new retinoblastoma patients are diagnosed every year About 10 percent of all new retinoblastoma patients will be diagnosed at the VUmc According to our sample size calculations the investigators will need 334 Rb patients
Main study parametersendpoints The primary endpoint of the study is pineoblastoma or supra- parasellar PNET on MRI index test Because a gold standard will not be available tumor cells in cerebrospinal fluid histopathological confirmation clinical disease progression during follow-up andor follow-up MRI diagnostics will be used as a composite reference standard in case of a positive index test and clinical diagnosis of pineoblastoma or supra- parasellar PNET within one year of the last MRI will be used as a composite reference standard in case of a negative index test
Detailed Description:
1 INTRODUCTION AND RATIONALE Currently baseline brain MRI with extended follow-up of pineal cysts is systematically performed in all new retinoblastoma patients since children with hereditary retinoblastoma have an increased risk of primitive neuroectodermal tumors PNET that are histopathologically identical to the retinal tumors This combination is also known as trilateral retinoblastoma TRb The prevalence of developing a PNET in combination with unilateral or bilateral hereditary retinoblastoma is 5-15 The risk of developing TRb in Rb patients is less than 05 for sporadic unilateral disease The PNET usually arises in the pineal gland PG 77 but can also be a parasellar or suprasellar tumor A meta-analysis from 1999 including TRb patients from literature covering 1966 to 1998 they found that the interval between the ocular tumor and the intracranial tumor was 1 versus 22 months respectively in TRbs diagnosed in patients with screening versus patients who developed symptoms Of TRb cases found at screening half were present when Rb was diagnosed and that 75 might be detected within one year after Rb diagnosis Treatment is difficult and the prognosis is poor as only few survivors are reported In a previous retrospective multicenter study from the ERIC-group small asymptomatic PNETs 15 mm that were present synchronously with the eye cancer on baseline MRI showed to have a better prognosis Furthermore it was discovered that the majority of early stage pineoblastoma showed a cystic aspect sometimes hardly distinguishable from benign pineal cysts 91112 The prevalence of pineal cysts in hereditary Rb patients is 53 In the general population at an age of 1 to 5 years 16 11 in males and 22 in females of all patients have pineal cysts Current practice is based on evidence that early depiction of TRbs in retinoblastoma patients during baseline MRI and follow-up of selected patients with pineal cysts detects these aggressive tumors in a curable stage
2 OBJECTIVES The main objective of this prospective multicenter study is to evaluate the current clinical strategy of baseline MRI screening of the brain in newly diagnosed retinoblastoma patients with extended follow-up of selected patients with simple and complicated pineal cysts
To investigate this objective the investigators will try to answer the following question What is the diagnostic accuracy sensitivity and specificity of the baseline MRI screening and extended follow-up of patients with pineal cysts for the diagnosis of TRb and How can the investigators optimize this screening strategy in order to minimise patient burden by keeping number of MRIs to a minimum and to maximise diagnostic accuracy The investigators will evaluate the classification see section 37 of pineal cysts probably benign versus suspicious and pineoblastoma or supra- parasellar PNET
21 Secondary objectives
1 Evaluate epidemiological parameters
1 incidence of TRb patients at baseline MRI synchronous follow-up metachronous MRI and missed by MRI compared to historical data
2 survival of patients with positive TRb findings on MRI at baseline or follow-up compared to TRb patients missed by MRI and compared to historical data
2 Evaluate prognostic parameters age tumor size aspect time of diagnosis relative to Rb diagnosis etc
3 STUDY DESIGN The investigators propose a prospective multicenter cohort study to investigate the diagnostic accuracy of baseline MRI screening of the pineal gland in new patients with retinoblastoma with extended follow-up of selected patients with pineal cysts for early detection of pineoblastoma
31 Study population Within ERIC about 150 new retinoblastoma patients are diagnosed every year About 10 percent of all new retinoblastoma patients will be diagnosed at the VUmc
32 Inclusion criteria
All new hereditary and non-hereditary retinoblastoma patients undergoing a baseline MRI diagnosed at one of the ERIC centers
Availability of MR sequences see section 371 required by the study
33 Exclusion criteria
A patient will be excluded from the study if
baseline MRI has not been performed
MR protocol or quality not adjusted to the required protocol
Follow-up not possible or available
34 Study quality In 2003 The STARD standards for the reporting of diagnostic accuracy studies statement has been published by Bussuyt et al as a tool to help researchers to improve the accuracy and completeness of reporting of studies of diagnostic accuracy This should allow readers to assess internal validity potential bias and external validity generalisability of a study The investigators will use STARD to ensure that - where possible - the design of this study meets those standards and that the final publication is clear on possible risk of bias and generalisability
35 Sample size calculation In the VUmc and the other ERIC centers 150 new retinoblastoma patients are diagnosed each year All new Rb patients receive a baseline MRI for clinical diagnostic purposes When a pineal cyst is detected on baseline MRI a follow-up MRI will be done see section 37 for the follow-up protocol The investigators consider the baseline MRI and the follow-up MRI as one diagnostic test the index test and the investigators will calculate sample sizes based on that As mentioned in section 1 75 of TRb cases can be diagnosed during follow-up within one year of which 50 can be diagnosed synchronously with Rb The other 25 of cases develop at a later stage the investigators will not consider those as false negatives of our test There are no previous studies on diagnostic accuracy on comparable tests but on the basis of clinical experience the investigators estimate a sensitivity of at least 95 and a specificity of about 80 Prevalence in the hereditary Rb group 40 of patients is about 10 giving us a prevalence of four per cent
Sensitivity depends on the number of cases therefore the investigators calculate the needed number of cases according to the estimated sensitivity of 95 The sample size the investigators calculate has a probability of at least 85 1 - β that the 95 1 - α lower confidence limit is 60 These input variables result in a required number of cases of ten Entering the number of cases in the previously mentioned formula gives us 240 controls The investigators can then calculate the 95 lower confidence limit of the expected specificity of 80 With a probability of at least 85 this number of controls gives us a 95 lower confidence limit of 72
The number of required Rb patients is 240 controls 10 cases 250 and since 75 of TRb cases can be diagnosed in the first year the investigators need 334 Rb patients for this study About 10 of Rb patients included in this study will be from the VUmc The investigators expect almost all Rb patients to participate in the study With a study duration of about two to three years the investigators expect to be able to include the required number of Rb patients This sample size calculation is based on rough estimates and could therefore vary Because of the low number of cases it is especially important to obtain a sufficient number of TRb cases for this study and depending on the number of found cases the duration of this study may vary
The prevalence of pineal cysts in hereditary Rb patients is about 5 and the investigators estimate the prevalence of pineal cysts in the non-hereditary group is similar to the general population which is about 16 These numbers amount to 53 40 16 60 334 10 patients with a pineal cyst who will receive follow-up MRIs
36 Study procedures
The ERIC guideline for imaging retinoblastoma states that brain screening for pineoblastoma should be performed in every new patient with retinoblastoma uni- and bilateral Pineal lesions depicted on baseline MRI are classified as
1 normal pineal gland no further follow-up
2 probably benign pineal cyst this group contains patients with a cystic pineal gland with a discrete rim enhancement and a thin smooth wall Pineal glands with thin intracystic septa will also be classified as probably benign pineal cysts Follow-up MR imaging will be done once after 3 months and further follow-up is not necessary if the cysts remains stable
3 suspicious pineal cyst irregularly thickened 2 mm cyst wall or fine nodular aspect of the wall MRI follow-up also after 3 months If stable no further follow-up If any doubt persists another follow-up after 3 months
4 pineoblastoma or supra- parasellar PNET
In case a patient receives chemotherapy a scan 3 months after chemotherapy is done to exclude a possible chemotherapy effect on the PNET growth
361 MRI protocol This screening is primarily achieved by a post-contrast 3D T1-weighted sequence with 1 mm slice thickness or post Gadolinium thin slice 3mm T1-weighted The preferred sequence for initial evaluation and follow-up are thin slice 3mm T2-weighted T2-TSE or CISS-images Follow-up should be performed with the same T2-weighted and post-contrast 3D-T1 weighted sequence
37 Follow-up of subjects withdrawn from treatment Survival data and disease progression will be followed up in all included Rb patients
4 STATISTICAL ANALYSIS Sensitivity and specificity will be the main measures of outcome of this study The low number of expected TRb cases will probably not allow for subset analyses The diagnostic index test the investigators are evaluating the baseline MRI and the follow-up MRI lacks a uniform reference standard however it is possible to construct a composite reference standard For positive index test results it might be difficult to determine false positives in some cases because in case of a positive index test treatment will have been started which could make it hard to distinguish effect of treatment from a false positive index test result when a reference test is carried out at a later stage than the MRI A good reference standard is especially critical for patients where MRI results are not clear cut See table 1 for the expected test results based on the data the investigators used in our sample size calculation see section 35
Reference standard for patients with a positive index test any combination of
tumor cells in cerebrospinal fluid
histopathological confirmation gold standard
clinical disease progression during follow-up
follow-up MRI diagnostics
absence of alpha-fetoprotein AFP beta human chorionic gonadotropin β-hCG in cerebrospinal fluid or blood
Reference standard for patients with a negative index test
clinical diagnosis of TRb within one year of the last MRI
The investigators have set a limit of one year for the reference standard of a negative index test to try to avoid patients who develop TRb after the last MRI The investigators realize that this could falsely classify patients with fast growing tumors that develop after the last MRI who present with clinical symptoms within a year as true positives The investigators will evaluate the effect of this one year limit on sensitivity and specificity by varying this limit
41 Secondary objectives After a follow-up period of 5 years survival data will be analyzed Survival curves will be presented as Kaplan-Meier plots The log-rank test will be used to compare our date with data from historical patient series Results will be corrected for potential confounders like differences in treatment and lead time bias Stratifications will be made according to tumor size pineal TRb versus ectropic intracranial TRb and time between Rb diagnosis and TRb diagnosis
2 OBJECTIVES The main objective of this prospective multicenter study is to evaluate the current clinical strategy of baseline MRI screening of the brain in newly diagnosed retinoblastoma patients with extended follow-up of selected patients with simple and complicated pineal cysts
To investigate this objective the investigators will try to answer the following question What is the diagnostic accuracy sensitivity and specificity of the baseline MRI screening and extended follow-up of patients with pineal cysts for the diagnosis of TRb and How can the investigators optimize this screening strategy in order to minimise patient burden by keeping number of MRIs to a minimum and to maximise diagnostic accuracy The investigators will evaluate the classification see section 37 of pineal cysts probably benign versus suspicious and pineoblastoma or supra- parasellar PNET
21 Secondary objectives
1 Evaluate epidemiological parameters
1 incidence of TRb patients at baseline MRI synchronous follow-up metachronous MRI and missed by MRI compared to historical data
2 survival of patients with positive TRb findings on MRI at baseline or follow-up compared to TRb patients missed by MRI and compared to historical data
2 Evaluate prognostic parameters age tumor size aspect time of diagnosis relative to Rb diagnosis etc
3 STUDY DESIGN The investigators propose a prospective multicenter cohort study to investigate the diagnostic accuracy of baseline MRI screening of the pineal gland in new patients with retinoblastoma with extended follow-up of selected patients with pineal cysts for early detection of pineoblastoma
31 Study population Within ERIC about 150 new retinoblastoma patients are diagnosed every year About 10 percent of all new retinoblastoma patients will be diagnosed at the VUmc
32 Inclusion criteria
All new hereditary and non-hereditary retinoblastoma patients undergoing a baseline MRI diagnosed at one of the ERIC centers
Availability of MR sequences see section 371 required by the study
33 Exclusion criteria
A patient will be excluded from the study if
baseline MRI has not been performed
MR protocol or quality not adjusted to the required protocol
Follow-up not possible or available
34 Study quality In 2003 The STARD standards for the reporting of diagnostic accuracy studies statement has been published by Bussuyt et al as a tool to help researchers to improve the accuracy and completeness of reporting of studies of diagnostic accuracy This should allow readers to assess internal validity potential bias and external validity generalisability of a study The investigators will use STARD to ensure that - where possible - the design of this study meets those standards and that the final publication is clear on possible risk of bias and generalisability
35 Sample size calculation In the VUmc and the other ERIC centers 150 new retinoblastoma patients are diagnosed each year All new Rb patients receive a baseline MRI for clinical diagnostic purposes When a pineal cyst is detected on baseline MRI a follow-up MRI will be done see section 37 for the follow-up protocol The investigators consider the baseline MRI and the follow-up MRI as one diagnostic test the index test and the investigators will calculate sample sizes based on that As mentioned in section 1 75 of TRb cases can be diagnosed during follow-up within one year of which 50 can be diagnosed synchronously with Rb The other 25 of cases develop at a later stage the investigators will not consider those as false negatives of our test There are no previous studies on diagnostic accuracy on comparable tests but on the basis of clinical experience the investigators estimate a sensitivity of at least 95 and a specificity of about 80 Prevalence in the hereditary Rb group 40 of patients is about 10 giving us a prevalence of four per cent
Sensitivity depends on the number of cases therefore the investigators calculate the needed number of cases according to the estimated sensitivity of 95 The sample size the investigators calculate has a probability of at least 85 1 - β that the 95 1 - α lower confidence limit is 60 These input variables result in a required number of cases of ten Entering the number of cases in the previously mentioned formula gives us 240 controls The investigators can then calculate the 95 lower confidence limit of the expected specificity of 80 With a probability of at least 85 this number of controls gives us a 95 lower confidence limit of 72
The number of required Rb patients is 240 controls 10 cases 250 and since 75 of TRb cases can be diagnosed in the first year the investigators need 334 Rb patients for this study About 10 of Rb patients included in this study will be from the VUmc The investigators expect almost all Rb patients to participate in the study With a study duration of about two to three years the investigators expect to be able to include the required number of Rb patients This sample size calculation is based on rough estimates and could therefore vary Because of the low number of cases it is especially important to obtain a sufficient number of TRb cases for this study and depending on the number of found cases the duration of this study may vary
The prevalence of pineal cysts in hereditary Rb patients is about 5 and the investigators estimate the prevalence of pineal cysts in the non-hereditary group is similar to the general population which is about 16 These numbers amount to 53 40 16 60 334 10 patients with a pineal cyst who will receive follow-up MRIs
36 Study procedures
The ERIC guideline for imaging retinoblastoma states that brain screening for pineoblastoma should be performed in every new patient with retinoblastoma uni- and bilateral Pineal lesions depicted on baseline MRI are classified as
1 normal pineal gland no further follow-up
2 probably benign pineal cyst this group contains patients with a cystic pineal gland with a discrete rim enhancement and a thin smooth wall Pineal glands with thin intracystic septa will also be classified as probably benign pineal cysts Follow-up MR imaging will be done once after 3 months and further follow-up is not necessary if the cysts remains stable
3 suspicious pineal cyst irregularly thickened 2 mm cyst wall or fine nodular aspect of the wall MRI follow-up also after 3 months If stable no further follow-up If any doubt persists another follow-up after 3 months
4 pineoblastoma or supra- parasellar PNET
In case a patient receives chemotherapy a scan 3 months after chemotherapy is done to exclude a possible chemotherapy effect on the PNET growth
361 MRI protocol This screening is primarily achieved by a post-contrast 3D T1-weighted sequence with 1 mm slice thickness or post Gadolinium thin slice 3mm T1-weighted The preferred sequence for initial evaluation and follow-up are thin slice 3mm T2-weighted T2-TSE or CISS-images Follow-up should be performed with the same T2-weighted and post-contrast 3D-T1 weighted sequence
37 Follow-up of subjects withdrawn from treatment Survival data and disease progression will be followed up in all included Rb patients
4 STATISTICAL ANALYSIS Sensitivity and specificity will be the main measures of outcome of this study The low number of expected TRb cases will probably not allow for subset analyses The diagnostic index test the investigators are evaluating the baseline MRI and the follow-up MRI lacks a uniform reference standard however it is possible to construct a composite reference standard For positive index test results it might be difficult to determine false positives in some cases because in case of a positive index test treatment will have been started which could make it hard to distinguish effect of treatment from a false positive index test result when a reference test is carried out at a later stage than the MRI A good reference standard is especially critical for patients where MRI results are not clear cut See table 1 for the expected test results based on the data the investigators used in our sample size calculation see section 35
Reference standard for patients with a positive index test any combination of
tumor cells in cerebrospinal fluid
histopathological confirmation gold standard
clinical disease progression during follow-up
follow-up MRI diagnostics
absence of alpha-fetoprotein AFP beta human chorionic gonadotropin β-hCG in cerebrospinal fluid or blood
Reference standard for patients with a negative index test
clinical diagnosis of TRb within one year of the last MRI
The investigators have set a limit of one year for the reference standard of a negative index test to try to avoid patients who develop TRb after the last MRI The investigators realize that this could falsely classify patients with fast growing tumors that develop after the last MRI who present with clinical symptoms within a year as true positives The investigators will evaluate the effect of this one year limit on sensitivity and specificity by varying this limit
41 Secondary objectives After a follow-up period of 5 years survival data will be analyzed Survival curves will be presented as Kaplan-Meier plots The log-rank test will be used to compare our date with data from historical patient series Results will be corrected for potential confounders like differences in treatment and lead time bias Stratifications will be made according to tumor size pineal TRb versus ectropic intracranial TRb and time between Rb diagnosis and TRb diagnosis
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