Novel Imaging in Staging of Primary Prostate Cancer

Study Overview
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Brief Summary
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Prostate cancer (PC) is the most common cancer among men and one quarter of diagnosed PC are metastatic at the time of diagnosis. Accurate staging is paramount as the stage is the most important factor when treatment decisions are made. The stage is also the single most important prognostic factor. Currently, traditional imaging methods for detection of PC metastasis, including bone scan (BS) and contrast enhanced whole-body computer tomography (CT), are rather inaccurate. Respectively, novel imaging techniques are evolving and novel imaging modalities are emerging in PC diagnostics and staging, but their clinical relevance is unclear and lacking prospective studies comparing traditional imaging with novel imaging. This prospective single-institutional study compares the diagnostic accuracy of novel imaging modalities to traditional imaging modalities aiming to find the most appropriate staging modality in high-risk PC at the time of initial staging.

Detailed Description
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Prostate cancer (PC) is the most common cancer among men. The incidence of PC has increased dramatically in Finland since 1980´s and lately approximately 4.500 new PC cases have been diagnosed annually in Finland. About one quarter of diagnosed PC are metastatic at the time of diagnosis. Accurate staging is extremely important, as the stage is single most important factor when treatment decisions are made and stage is the single most important prognostic factor. Localized PC is treated with active surveillance (low risk cases), or with treatment modalities with curative intent (radical prostatectomy or radiotherapy).Although recently radical treatments have been suggested to play a role in low volume metastatic disease, the standard treatment of metastatic disease is castration therapy. In PC staging the most important anatomic locations to be imaged are i) bone, ii) lymph nodes (especially pelvic lymph nodes), and iii) extranodal soft tissues. Detection of tumor bone metastases is commonly performed by BS. However, the results of recent studies have raised many doubts whether BS is as effective for confirming or excluding metastatic bone disease. Moreover, the sensitivity for 99mTc-methylene diphosphonate bone scintigraphy (99mTc-MDP BS) is only 50-70%. The detection of bone metastases in patients with high-risk PC is significantly improved by SPECT compared to planar BS. Other imaging modalities with potentially improved accuracy to detect bone metastases in PC include PET-scan and whole body MRI. The value of positron emission tomography (PET) imaging depends on the suitability of used isotope tracer to identify lesions of the imaged tumor type. When bone is imaged with PET, 18F-fluoride has been the most commonly used tracer. Other commonly used PET tracers in PC include 18F-FDG, and 18F/11C-choline, but both have been late more or less replaced by PSMA-PET. Prostate-specific membrane antigen (PSMA) is a trans-membrane protein with an increased expression on cell membranes of PC cells. 68Ga-PSMA HBED-CC (Glu-NH-CO-NH-Lys- (Ahx)-[68Ga(HBED-CC)]) was designed as an extracellular PSMA inhibitor for PET imaging and has been shown to demonstrate high specificity for PSMA-expressing tumor cell. PSMA-PET results have been reported in several studies, but only in three prospective, one including 20-30 patients. Of those studies only study by Fendler and coworkers investigated overall staging, the other two studies by van Leeuwen focused on intraprostatic tumor detection or nodal metastases. Nevertheless, PSMA-PET/CT is a promising imaging modality both for soft tissues and bone. Recently 68Ga-PSMA was reported to outperform 99mTc-DPD-SPECT in detection of bone metastases in PC. Recently, the novel PET tracer 18F-PSMA-1007 has been developed as a promising PSMA ligand to even outperform 68Ga-PSMA-PET in overall staging. 18F-PSMA-1007 have advantages in comparison to 68Ga-PSMA-PET including primary elimination of 18F-PSMA-1007 via the hepatobiliary excretion route leading to less isotope activity in urinary tract. Consequently, 18F-PSMA-1007 might lead to better local staging because of its favorable pharmacokinetics and tumor-specific uptake. 18F-PSMA-1007-PET combined with CT or even MRI could truly offer a 1-stop solution for both metastatic screening and local staging, but more prospective studies are needed to confirm this hypothesis. Whole-body T1-weighted MRI is an effective method for bone imaging and is superior when compared to 99mTc-MDP BS. If combined with soft tissue imaging, bone and nodal imaging may be performed in single imaging session. Diffusion-weighted imaging (DWI) as a part of routine MRI examination is a promising tool for detection of an early intramedullary malignant lesion before cortical destruction or reactive processes due to bone marrow metastasis. DWI performs high contrast resolution between tumor and normal tissue. Individual variability of the mean apparent diffusion coefficient (ADC) values, as the result of DWI, may decrease the diagnostic accuracy of DWI. Diagnostic accuracy of DWI for detection of malignant lesion is better than 18-fluoro-deoxy-glucose (FDG) and for detection of bone metastasis is comparable to 11C-choline. However, it is unclear if it is superior compared to the standard T1-weighted imaging or STIR fat suppression technique. Currently there is not sufficient data comparing MRI and PSMA-PET/CT accuracy on bone imaging in PC. In addition to bone, the possible tumor spread to soft tissues, especially pelvic lymph node is common in PC staging. Traditionally contrast enhanced abdomen and pelvic CT or MRI are used but the sensitivity of these imaging modalities is very limited. Diffusion-weighted MRI may improve the diagnostic accuracy when normal sized lymph nodes are evaluated. Still, different PET-tracers and recently especially 68Ga-PSMA and novel 18F-PSMA have both been considered as the most promising modalities for pelvic lymph node metastasis detection in PC and preliminary results suggest superior diagnostic accuracy of PSMA-PET compared to other modalities. The investigators have previously investigated different imaging modalities for detection of bone metastases in prospective setting (Skeleta-trial). According to that study, 18F-NaF PET-CT and whole-body MRI are superior when compared to 99mTc-MDP SPECT-CT or 99mTc-MDP planar bone scan. Nevertheless, that study needs validation and further investigations as it was limited by low number (n=27) of PC patients, and PSMA-PET was not included in the study. Clinicians face challenges when choosing optimal imaging modality/modalities for individual patient. Guidelines do not support any imaging in low risk cases. For some intermediate risk cases, and also for high-risk cases, if local treatment is planned, accurate staging of pelvic lymph node is important. In contrary, in very high-risk cases the knowledge of distant metastases is the single most important staging data. Optimally for clinicians most appropriate imaging technique would be chosen based on patient related risk factors or a single imaging modality would offer all aspects of needed staging information. The rationale for the present study is to find the most appropriate staging modality in high-risk PC at the time of initial staging.

Official Title
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Imaging for Prostate Cancer Metastasis Detection - Traditional Imaging (Bone Scan and CT) Versus PSMA-PET-CT, SPECT-CT and Whole-Body MRI

Conditions
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High Risk Prostate Cancer

Intervention / Treatment
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* Diagnostic Test: Whole body contrast enhanced computer tomography
* Diagnostic Test: 99mTC-HMDP planar bone scintigraphy (BS)
* Diagnostic Test: 99mTc-HMDP single photon emission computer tomography/computer tomography
* Diagnostic Test: Whole-body magnetic resonance imaging
* Diagnostic Test: Fluorine-18-prostate specific membrane antigen-1007- positron emission tomography/computer tomography


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed PC without previous PC treatment High-risk PC defined with one or more of the following criteria: Gleason ≥4+3, PSA ≥20, cT≥3a Adequate physical status defined (by treating clinician) as capability to undergo some form of active treatment for the PC and the physical status allowing the patient to undergo all study imaging modalities Signed informed consent Exclusion Criteria: Previous PC treatment. Short-term androgen deprivation therapy is permitted if necessary for symptomatic and/or very high-risk PC patients Contraindications for MRI (cardiac pacemaker, intracranial clips etc.) Claustrophobia

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Intervention Model: Single Group Assignment
Interventional Model Description: This is a prospective single-institutional study comparing the diagnostic accuracy of novel imaging modalities to traditional imaging modalities among high risk prostate cancer patients at initial diagnosis
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Imaging based staging of high risk PC<br>Each individual study patient will be imaged for PC metastasis detection with each different imaging modalities as follows: Traditional imaging (clinical standard imaging); Whole-body contrast enhanced computer tomography Planar bone scintigraphy Novel imaging (investigational imaging); SPECT/CT (investigational imaging) 18F-PSMA-PET/CT (investigational imaging) Whole-body MRI (investigational imaging) In order to define the true nature of the findings from each different imaging modality, comparison with best valuable comparator (BvC) is made. Consensus reading of all imaging modalities and follow-up data of clinical, imaging, histopathological and laboratory results are used to define BvC. | Diagnostic Test: Whole body contrast enhanced computer tomography<br>* Computed tomography of the thorax, abdomen and pelvis will be performed as a part of routine clinical evaluation protocol. The imaging will be done with contrast agent if there are no clinical contraindications for the use of contrast agent.<br>* Other names: wbCE-CT;Diagnostic Test: 99mTC-HMDP planar bone scintigraphy (BS)<br>* Planar bone scintigraphy will be performed as a part of routine clinical evaluation protocol. The subjects will be positioned supine on a Discovery NM/CT 670 CZT, a digital SPECT/CT scanner (General Electric Healthcare). The scanner includes a dual-detector, free-geometry integrated nuclear imaging camera with the advanced digital CZT detector technology combined with the high-performance Optima CT540 subsystem. Whole-body planar images will be scanned from the anterior and posterior views three hours after the intravenous injection of 670 MBq of 99mTc-HMDP. A wide-energy high-resolution (WEHR) collimator, a scan speed of 13 cm/min, a zoom of 1.0 and a matrix size of 256 x 1024 are used in the scintigraphy.<br>* Other names: Planar BS;Diagnostic Test: 99mTc-HMDP single photon emission computer tomography/computer tomography<br>* SPECT/CT imaging will be carried out after acquisition of the planar images with the same scanner. Three bed positions of SPECT data will be acquired from the top of the head to mid femoral level using WEHR collimators. A non-circular orbit, 60 views with 15-s scanning time per view will be acquired during 180 degrees of rotation. A 128 x 128 matrix size, a zoom of 1.0 and 15% photopeak and lower scatter energy windows are used. After SPECT a CT topogram and a low-dose tomogram with a modulated mAs (noise index   70), 120 kVp, a pitch of 1.35 and a 2.5-mm slice thickness are scanned. The co-registration of SPECT and CT data is verified after which the SPECT images are reconstructed using modern iterative ordered subsets expectation (OSEM) reconstruction algorithm from General Electric or Hermes Medical Solutions, which includes, e.g., 10 iterations and 5 subsets and attenuation, collimator and scatter corrections.<br>* Other names: SPECT/CT;Diagnostic Test: Whole-body magnetic resonance imaging<br>* Magnetic resonance imaging examination will be performed using a 1.5T (Philips 1.5T Ingenia, Best, Netherlands and/or Siemens 1.5T Aera/Avant, Erlangen, Germany) or 3T (Philips 3T Ingenia, Best, Netherlands and/or Siemens 3T Skyra fit, Erlangen, German) MR system. The body matrix coil in combination with a spinal coil will be used for image acquisition. T1-weighted anatomic imaging, STIR fat suppressed images and DWI will be performed in axial and coronal directions. DWI will be obtained with single-shot 2D spin-echo echo-planar imaging. The total scan time will be approximately 50 minutes.<br>* Other names: wbMRI;Diagnostic Test: Fluorine-18-prostate specific membrane antigen-1007- positron emission tomography/computer tomography<br>* 18F-PSMA-1007 is produced by radiolabelling with fluorine-18 produced by irradiating oxygen-18. Administration of the formulated solution is done shortly (<10h) after production. Imaging is carried out with digital PET/CT scanner (Discovery MI;General Electric Medical Systems, Milwaukee, WI, USA). The patients receive intravenous injection of 200-300 MBq (3 MB/kg) of 18F-PSMA-1007 diluted in 3-5 ml of saline as a 60-sec bolus which will be promptly flushed with saline. Before data acquisition patients will be asked to void. A static emission scan will be acquired 60-min from tracer injection over whole body. The sinogram data will be corrected for deadtime, decay and photon attenuation and reconstructed in a 256x256 matrix. Image reconstruction follows a fully 3D maximum likelihood ordered subsets expectation maximization algorithm incorporating random and scatter correction with two iterations and 28 subsets.The final in-plane full-width half-maximum of the systems is < 6 mm.<br>* Other names: 18F-PSMA-1007-PET/CT;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To compare the diagnostic accuracy of 18F-PSMA-1007-PET/CT (PSMA-PET/CT) to 99mTc-HMDP planar bone scintigraphy (planar BS) in pessimistic, patient-based analysis detecting of bone metastases in the initial staging of high-risk PC patients. | Comparison of area under curve (AUC) values in receiver operating characteristic (ROC) curve of PSMA-PET/CT to planar BS in pessimistic, patient-based analysis detecting of bone metastases. The power calculations are made on the basis of previously published work, the SKELETA trial. To be able to detect the 0,19 difference (in AUC values) using a two-tailed test with a power of 80% at a significance level of 0.05 in a 2:1 ratio of sample sizes in negative/positive groups, 48 negative cases and 24 positive cases are required. Equivocal findings of the imaging modalities will be classified either as suggestive for metastases (pessimistic analysis) or suggestive for non-metastatic origin (optimistic analysis). AUC values will be calculated using the trapezoid rule and compared using a method described by Hanley and McNeil, two-sided p-values will be calculated. | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sensitivity of each imaging modality will be measured in initial staging of nodal, soft tissue and bone metastasis | Sensitivity of PSMA-PET/CT, wbMRI, SPECT/CT, planar BS and wbCE-CT will be determined on patient-, regional- and lesion-level separately in detecting of nodal (regional lymph node/s), soft tissue (excluding regional nodal metastasis) and bone metastasis. The outcome measure unit is a percentage. | 1 year | 
| Specificity of each imaging modality will be measured in initial staging of nodal, soft tissue and bone metastasis | Specificity of PSMA-PET/CT, wbMRI, SPECT/CT, planar BS and wbCE-CT will be determined on patient-, regional- and lesion-level separately in detecting of nodal (regional lymph node/s), soft tissue (excluding regional nodal metastasis) and bone metastasis. The outcome measure unit is a percentage. | 1 year | 
| Diagnostic accuracy each imaging modality will be measured in initial staging of nodal, soft tissue and bone metastasis | Diagnostic accuracy of PSMA-PET/CT, wbMRI, SPECT/CT, planar BS and wbCE-CT will be determined on patient-, regional- and lesion-level separately in detecting of nodal (regional lymph node/s), soft tissue (excluding regional nodal metastasis) and bone metastasis. The outcome measure unit is a percentage. | 1 year | 
| The effect of staging on clinical treatment-decisions | The effect of staging on clinical treatment-decisions is based on clinical judgement done retrospectively by multi-disciplinary team consensus. | 1 year | 
| AUC values from receiver operating characteristic curve of each imaging modality will be measured in initial staging of nodal, soft tissue and bone metastasis | AUC values of PSMA-PET/CT, wbMRI, SPECT/CT, planar BS and wbCE-CT will be determined on patient-, regional- and lesion-level separately in detecting of nodal (regional lymph node/s), soft tissue (excluding regional nodal metastasis) and bone metastasis. The outcome measure is numeric unit 0-1. | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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prostate cancer, imaging of prostate cancer, staging of prostate cancer, prostate specific membrane antigen (PSMA), positron emission tomography, bone scintigraphy, whole body magnetic resonance imaging, whole body computer tomography, single photon emission tomography (SPECT)