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    Clinical Trial Results:
    Accuracy of lymph node imaging in prostate cancer: A prospective cohort study to determine the concordance between two imaging modalities, “Combidex” magnetic resonance imaging (Nano MRI) and 68Ga-PSMA positron emission tomography (PET).

    Summary
    EudraCT number
    		 2015-005016-15
    Trial protocol
    		 NL  
    Global end of trial date
    30 Oct 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 Oct 2024
    First version publication date
    30 Oct 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NL55589.091.16
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03223064
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Radboudumc
    Sponsor organisation address
    Geert Grooteplein Zuid 10,, Nijmegen, Netherlands,
    Public contact
    Radiology and Nuclear Medicine, Radboudumc, 0031 243615105, trialbureau.radng@radboudumc.nl
    Scientific contact
    Radiology and Nuclear Medicine, Radboudumc, 0031 243615105, trialbureau.radng@radboudumc.nl
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    01 Oct 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 Sep 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Oct 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This study aimed to evaluate the effectiveness of ePLND in removing metastatic LNs in men with primary intermediate and high-risk prostate cancer and assess the value of nMRI and PSMA-PET/CT in detecting small metastatic LNs.
    Protection of trial subjects
    Both 68 Ga-PSMA-PET/CT and Nano-MR Lymphography (Ferumoxtran-10) have been used for over 5 years for the detection of metastases in patients with prostate cancer at intermediate to high risk. Pelvic Lymph Node Dissection and image directed dissection can be considered as the gold standard for such patients. All patients received both imaging modalities by 2 experienced (> 5 years experience) radiologists (nMRI) and four experienced (> 5 years experience) nuclear medicine physicians (68 Ga-PSMA-PET/CT). The standard imaging protocol within the hospital was used including patient and physician safety measures. Similarly for Pelvic Lymphnode dissection (PLND), the standard surgical protocol was used within the hospital with its patient and physician safety measures. Pelvic Lymphnode dissection was performed by an experienced surgeon (> 20 years) with the outcome of the nMRI and 68 Ga-PSMA-PET/CT imaging procedures. If suspicious lymphnodes on pre-operative imaging were also visible on postoperative MRI (six weeks after PLND) these were considered as not removed by PNLD. Positive LNs on preoperative nMRI and/or 68 Ga-PSMA-PET/CT were re-identified on postoperative MRI based on location, size and shape. The protocol was approved by the local institution review boards (NL55589.091.16).
    Background therapy
    		 Extended lymph node dissection (ePLND) is the current reference-standard for nodal (N)-staging and should be performed in men with prostate cancer (PCa) and >5% risk of lymph node metastases (LNMs) according to the European Association of Urology (EAU) guidelines.
    Evidence for comparator
    		 Conventional imaging techniques such as CT and MRI rely on lymph node (LN) size and morphology and therefore are of limited value. Two new molecular imaging techniques have demonstrated their ability to detect small LNMetastases (LNMs), combined with high specificity. These are nano-(n)MRI, which uses ultra-small iron oxide particles as contrast agent (ferumoxtran-10, Ferrotran®, SPL-Medical, Nijmegen, The Netherlands) and 68Ga PSMA-HBED-CC PET/CT (PSMA-PET/CT). With nMRI, very small LNMs can be detected with high sensitivity (91%). PSMA-PET/CT uses radio-labelled tracers that target the PSMA receptors which are overexpressed in prostate cancer cells. This enables total-body body imaging of LNMs and other metastases. Both techniques have the potential to improve N-staging and could be valuable tools to complement PLND. However, validation studies using PLND as a reference-standard are scarce and show high differences in sensitivity and specificity. Most studies are limited by the abscence of postoperative imaging to verify whether LNMs are removed. They also lack detailed histological validation on a node-by-node or regional basis and follow-up. Nevertheless, initial retrospective comparison of PSMA-PET/CT and nMRI has shown that both are able to identify small suspicious LNs in all anatomical regions of the pelvis, with nMRI detecting more and smaller suspicious LNs. However, a prospective validation study is needed to compare the diagnostic performance of PSMA-PET/CT and nMRI.
    Actual start date of recruitment
    01 Apr 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 42
    Worldwide total number of subjects
    42
    EEA total number of subjects
    42
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    22
    From 65 to 84 years
    20
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Forty-two men with newly diagnosed PCa and an estimated risk of metastatic LNs exceeding 5%, based on the Memorial Sloan Kettering Cancer Center nomogram (https://www.mskcc.org/nomograms/prostate/pre_op), were included in the study. These men underwent a nMRI and a 68Ga PSMA-HBED-CC PET/CT (PSMA-PET/CT) scan.

    Pre-assignment
    Screening details
    		 42 Patients were included after giving verbal and written informed consent.

    Pre-assignment period milestones
    Number of subjects started
    		 42
    Number of subjects completed
    		 42

    Period 1
    Period 1 title
    nano-MRI and PLND and PSMA-PET-CT (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    No Blinding implementation details

    Arms
    Arm title
    		 Nano-MRI and PSMA-PET-CT and PLND
    Arm description
    		 Patients with nano-MRI, PSMA-PET/CT and PLND
    Arm type
    		 1-arm study

    Investigational medicinal product name
    ferumoxtran
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solvent for parenteral use
    Routes of administration
    Intravenous use
    Dosage and administration details
    (2.6 mg/kg body weight

    Investigational medicinal product name
    PSMA-PET-CT
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    2 MBq/kg body weight

    Number of subjects in period 1
    		Nano-MRI and PSMA-PET-CT and PLND
    Started
    42
    Completed
    42

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    nano-MRI and PLND and PSMA-PET-CT
    Reporting group description
    		 -

    Reporting group values
    		 nano-MRI and PLND and PSMA-PET-CT Total
    Number of subjects
    		 42 42
    Age categorical
    The median age of 38 patients was 67 years with a range of 63-71 years.
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 22 22
        From 65-84 years
    		 20 20
        85 years and over
    		 0 0
    Age continuous
    The median age in 38 patients was 67 with a range of 63-71 years.
    Units: years
        median (full range (min-max))
    		 67 (63 to 71) -
    Gender categorical
    males
    Units: Subjects
        Female
    		 0 0
        Male
    		 42 42
    Subject analysis sets

    Subject analysis set title
    Per Protocol Analysis
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    38 Patients received all study procedures and are included in the final analysis

    Subject analysis sets values
    		 Per Protocol Analysis
    Number of subjects
    38
    Age categorical
    The median age of 38 patients was 67 years with a range of 63-71 years.
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
        Newborns (0-27 days)
    0
        Infants and toddlers (28 days-23 months)
    0
        Children (2-11 years)
    0
        Adolescents (12-17 years)
    0
        Adults (18-64 years)
    20
        From 65-84 years
    18
        85 years and over
    0
    Age continuous
    The median age in 38 patients was 67 with a range of 63-71 years.
    Units: years
        median (full range (min-max))
    67 (63 to 71)
    Gender categorical
    males
    Units: Subjects
        Female
    0
        Male
    38

    End points

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    End points reporting groups
    Reporting group title
    Nano-MRI and PSMA-PET-CT and PLND
    Reporting group description
    		 Patients with nano-MRI, PSMA-PET/CT and PLND

    Subject analysis set title
    Per Protocol Analysis
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    38 Patients received all study procedures and are included in the final analysis

    Primary: Correlation ePLND with postoperative MRI

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    End point title
    		 Correlation ePLND with postoperative MRI [1]
    End point description
    On the postoperative MRI 60 of the 74 (81%) nMRI-positive LNs and 23 of the 29 (79%) PSMA-PET/CT-positive LNs were still present. On a per-patient level, this was 17 of the 29 (59%) men for nMRI and 13 of the 19 (68%) for PSMA-PET/CT. No LNs with positive findings on imaging were extracted from the para-aortic, common iliac, presacral, and para-rectal regions. The largest number of LNs with suspected positive findings on imaging were removed from the external iliac region (48%).
    End point type
    Primary
    End point timeframe
    6 weeks
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Simple comparative statistics was used.
    End point values
    		 Per Protocol Analysis
    Number of subjects analysed
    Units: 38
    38
    No statistical analyses for this end point

    Primary: Histopathologic results

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    End point title
    		 Histopathologic results [2]
    End point description
    Among the 38 men analyzed, 13 (34%) had histopathological confirmed metastatic LN. Of the 915 resected LNs, 22 (2.4%) contained metastasis with a median size of 3 mm (range 2-18 mm). Fifteen (68%) of these metastatic LNs were smaller than 4 mm. Nano-MRI identified 13 out of 22 lymph nodes as true positives (TP), 1 as false positive (FP), and missed 9 as false negatives (FN; Table 2). Among the 13 correctly identified LNs, 5 were larger than 5mm, 6 ranged from 2-5mm, and 2 were smaller than 2mm. The PSMA-PET/CT examination revealed 6 out of 22 (27%) true positive LNs, 1 out of 22 (4.5%) false positive LN, and 16 out of 22 (73%) false negative LNs. Among these, 6 out of 22 LNs were metastatic, with 4 being larger than 5 mm, 1 between 2 to 5 mm, and 1 smaller than 2 mm. At the patient level, nMRI identified 1 out of 13 (8%) false negative patients, while PSMA-PET/CT identified 7 out of 13 (54%) false negative patients.
    End point type
    Primary
    End point timeframe
    4 weeks
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Simple comparative statistics was used.
    End point values
    		 Per Protocol Analysis
    Number of subjects analysed
    Units: 38
    38
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    from 2016-2017
    Adverse event reporting additional description
    No adverse events
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 LAREB
    Dictionary version
    1
    Frequency threshold for reporting non-serious adverse events: 0.1%
    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: To our knowledge there were no adverse events reported

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    A major limitation of the study is the presence of a high number of non-removed, preoperatively suspected LNs on imaging, which hinders the validation of the diagnostic accuracy of both imaging methods using histopathology as the reference standard.
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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