High Risk Prostate CancerPROSTAGENCT03537391
Novel Imaging in Staging of Primary Prostate Cancer
A study testing Whole body contrast enhanced computer tomography, 99mTC-HMDP planar bone scintigraphy (BS) and 99mTc-HMDP single photon emission computer tomography/computer tomography in people with High Risk Prostate Cancer, run by Turku University Hospital at 1 site in Finland.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 years and older, men only
- Conditions the study is for
- High Risk Prostate Cancer
- What is being tested?
- Whole body contrast enhanced computer tomography, 99mTC-HMDP planar bone scintigraphy (BS) and 99mTc-HMDP single photon emission computer tomography/computer tomography
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 80 participants
- Where
- 1 siteFinland
- Study dates
- 1 Mar 2018to 2 May 2022
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- Men only
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Imaging for Prostate Cancer Metastasis Detection - Traditional Imaging (Bone Scan and CT) Versus PSMA-PET-CT, SPECT-CT and Whole-Body MRI
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.
Read the detailed description
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.
- Conditions
- High Risk Prostate Cancer
- Being tested
- Whole body contrast enhanced computer tomography, 99mTC-HMDP planar bone scintigraphy (BS), 99mTc-HMDP single photon emission computer tomography/computer tomography, Whole-body magnetic resonance imaging, Fluorine-18-prostate specific membrane antigen-1007- positron emission tomography/computer tomography
- Keywords
- 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)
- Medical subject headings
- Prostatic Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Whole body contrast enhanced computer tomographyDiagnostic test
Also called wbCE-CT
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.
99mTC-HMDP planar bone scintigraphy (BS)Diagnostic test
Also called Planar BS
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.
99mTc-HMDP single photon emission computer tomography/computer tomographyDiagnostic test
Also called SPECT/CT
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.
Whole-body magnetic resonance imagingDiagnostic test
Also called wbMRI
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.
Fluorine-18-prostate specific membrane antigen-1007- positron emission tomography/computer tomographyDiagnostic test
Also called 18F-PSMA-1007-PET/CT
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.
| Study group | Role | What they receive |
|---|---|---|
| Imaging based staging of high risk PC | Experimental | Each individual study patient will be imaged for PC metastasis detection with each different imaging modalities as follows:
Traditional imaging (clinical standard imaging);
1. Whole-body contrast enhanced computer tomography
2. Planar bone scintigraphy
Novel imaging (investigational imaging);
3. SPECT/CT (investigational imaging)
4. 18F-PSMA-PET/CT (investigational imaging)
5. 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. Receives: 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 |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 1 year
Secondary outcomes (5)
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 1 year
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted25 May 2018
- Study start1 Mar 2018
- Primary completion22 Sep 2019
- Study completion2 May 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (34)Papers the sponsor has linked to this study.
- Other trials for High Risk Prostate CancerStudies of the same condition, open and under way.
- More trials run by Turku University HospitalThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Diagnosis
- Allocation
- Not applicable
- Intervention model
- Single group
- 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)
- Enrolment
- 80 participants (actual)
Sponsor and investigators
- Lead sponsor
- Turku University Hospital
- Sponsor type
- Other government
- Collaborators
- University of Turku
- Responsible party
- Sponsor
- Investigators
- Peter Boström, M.D.Ph.D, Principal investigator, Department of urology, Turku University Hospital, VSSHP
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03537391
- Sponsor's protocol ID
- T95/2018
- Acronym
- PROSTAGE
- Status last verified
- May 2022
- First submitted
- 26 Apr 2018
- Last updated
- 4 May 2022
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Publications
Seikkula HA, Kaipia AJ, Rantanen ME, Pitkaniemi JM, Malila NK, Bostrom PJ. Stage-specific mortality and survival trends of prostate cancer patients in Finland before and after introduction of PSA. Acta Oncol. 2017 Jul;56(7):971-977. doi: 10.1080/0284186X.2017.1288298. Epub 2017 Feb 13.
PubMed 28406044Heidenreich A, Bastian PJ, Bellmunt J, Bolla M, Joniau S, van der Kwast T, Mason M, Matveev V, Wiegel T, Zattoni F, Mottet N; European Association of Urology. EAU guidelines on prostate cancer. part 1: screening, diagnosis, and local treatment with curative intent-update 2013. Eur Urol. 2014 Jan;65(1):124-37. doi: 10.1016/j.eururo.2013.09.046. Epub 2013 Oct 6.
PubMed 24207135Suh CH, Shinagare AB, Westenfield AM, Ramaiya NH, Van den Abbeele AD, Kim KW. Yield of bone scintigraphy for the detection of metastatic disease in treatment-naive prostate cancer: a systematic review and meta-analysis. Clin Radiol. 2018 Feb;73(2):158-167. doi: 10.1016/j.crad.2017.08.004. Epub 2017 Sep 25.
PubMed 28958581Even-Sapir E. Imaging of malignant bone involvement by morphologic, scintigraphic, and hybrid modalities. J Nucl Med. 2005 Aug;46(8):1356-67.
PubMed 16085595Van den Wyngaert T, Strobel K, Kampen WU, Kuwert T, van der Bruggen W, Mohan HK, Gnanasegaran G, Delgado-Bolton R, Weber WA, Beheshti M, Langsteger W, Giammarile F, Mottaghy FM, Paycha F; EANM Bone & Joint Committee and the Oncology Committee. The EANM practice guidelines for bone scintigraphy. Eur J Nucl Med Mol Imaging. 2016 Aug;43(9):1723-38. doi: 10.1007/s00259-016-3415-4. Epub 2016 Jun 4.
PubMed 27262701Even-Sapir E, Metser U, Mishani E, Lievshitz G, Lerman H, Leibovitch I. The detection of bone metastases in patients with high-risk prostate cancer: 99mTc-MDP Planar bone scintigraphy, single- and multi-field-of-view SPECT, 18F-fluoride PET, and 18F-fluoride PET/CT. J Nucl Med. 2006 Feb;47(2):287-97.
PubMed 16455635Helyar V, Mohan HK, Barwick T, Livieratos L, Gnanasegaran G, Clarke SE, Fogelman I. The added value of multislice SPECT/CT in patients with equivocal bony metastasis from carcinoma of the prostate. Eur J Nucl Med Mol Imaging. 2010 Apr;37(4):706-13. doi: 10.1007/s00259-009-1334-3. Epub 2009 Dec 17.
PubMed 20016889Silver DA, Pellicer I, Fair WR, Heston WD, Cordon-Cardo C. Prostate-specific membrane antigen expression in normal and malignant human tissues. Clin Cancer Res. 1997 Jan;3(1):81-5.
PubMed 9815541Eder M, Schafer M, Bauder-Wust U, Hull WE, Wangler C, Mier W, Haberkorn U, Eisenhut M. 68Ga-complex lipophilicity and the targeting property of a urea-based PSMA inhibitor for PET imaging. Bioconjug Chem. 2012 Apr 18;23(4):688-97. doi: 10.1021/bc200279b. Epub 2012 Mar 13.
PubMed 22369515Perera M, Papa N, Christidis D, Wetherell D, Hofman MS, Murphy DG, Bolton D, Lawrentschuk N. Sensitivity, Specificity, and Predictors of Positive 68Ga-Prostate-specific Membrane Antigen Positron Emission Tomography in Advanced Prostate Cancer: A Systematic Review and Meta-analysis. Eur Urol. 2016 Dec;70(6):926-937. doi: 10.1016/j.eururo.2016.06.021. Epub 2016 Jun 28.
PubMed 27363387Fendler WP, Schmidt DF, Wenter V, Thierfelder KM, Zach C, Stief C, Bartenstein P, Kirchner T, Gildehaus FJ, Gratzke C, Faber C. 68Ga-PSMA PET/CT Detects the Location and Extent of Primary Prostate Cancer. J Nucl Med. 2016 Nov;57(11):1720-1725. doi: 10.2967/jnumed.116.172627. Epub 2016 Jun 3.
PubMed 27261520Rhee H, Thomas P, Shepherd B, Gustafson S, Vela I, Russell PJ, Nelson C, Chung E, Wood G, Malone G, Wood S, Heathcote P. Prostate Specific Membrane Antigen Positron Emission Tomography May Improve the Diagnostic Accuracy of Multiparametric Magnetic Resonance Imaging in Localized Prostate Cancer. J Urol. 2016 Oct;196(4):1261-7. doi: 10.1016/j.juro.2016.02.3000. Epub 2016 May 21.
PubMed 27220897van Leeuwen PJ, Emmett L, Ho B, Delprado W, Ting F, Nguyen Q, Stricker PD. Prospective evaluation of 68Gallium-prostate-specific membrane antigen positron emission tomography/computed tomography for preoperative lymph node staging in prostate cancer. BJU Int. 2017 Feb;119(2):209-215. doi: 10.1111/bju.13540. Epub 2016 Jun 18.
PubMed 27207581Janssen JC, Meissner S, Woythal N, Prasad V, Brenner W, Diederichs G, Hamm B, Makowski MR. Comparison of hybrid 68Ga-PSMA-PET/CT and 99mTc-DPD-SPECT/CT for the detection of bone metastases in prostate cancer patients: Additional value of morphologic information from low dose CT. Eur Radiol. 2018 Feb;28(2):610-619. doi: 10.1007/s00330-017-4994-6. Epub 2017 Aug 4.
PubMed 28779400Cardinale J, Schafer M, Benesova M, Bauder-Wust U, Leotta K, Eder M, Neels OC, Haberkorn U, Giesel FL, Kopka K. Preclinical Evaluation of 18F-PSMA-1007, a New Prostate-Specific Membrane Antigen Ligand for Prostate Cancer Imaging. J Nucl Med. 2017 Mar;58(3):425-431. doi: 10.2967/jnumed.116.181768. Epub 2016 Oct 27.
PubMed 27789722
Study at a glance
From the registry record, last updated by the sponsor on 4 May 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Imaging for Prostate Cancer Metastasis Detection - Traditional Imaging (Bone Scan and CT) Versus PSMA-PET-CT, SPECT-CT and Whole-Body MRI
- ClinicalTrials.gov ID
- NCT03537391
- Acronym / sponsor ID
- PROSTAGE / T95/2018
- Conditions
- High Risk Prostate Cancer
- Keywords
- 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
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 80 participants (actual)
- Lead sponsor
- Turku University HospitalOther government
- Collaborators
- University of Turku
- Study start
- 1 Mar 2018 (actual)
- Primary completion
- 22 Sep 2019 (actual)
- Study completion
- 2 May 2022 (actual)
- First posted
- 25 May 2018 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
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.
Study design
- Primary purpose
- Diagnosis
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
- 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
| Arm | Type | Receives |
|---|---|---|
| Imaging based staging of high risk PC | Experimental | 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 tomographyEach individual study patient will be imaged for PC metastasis detection with each different imaging modalities as follows: Traditional imaging (clinical standard imaging); 1. Whole-body contrast enhanced computer tomography 2. Planar bone scintigraphy Novel imaging (investigational imaging); 3. SPECT/CT (investigational imaging) 4. 18F-PSMA-PET/CT (investigational imaging) 5. 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- Male only
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- 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
Key exclusion criteria (3 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Whole body contrast enhanced computer tomographyAlso: wbCE-CTComputed 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. | Diagnostic test | Imaging based staging of high risk PC |
| 99mTC-HMDP planar bone scintigraphy (BS)Also: Planar BSPlanar 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. | Diagnostic test | Imaging based staging of high risk PC |
| 99mTc-HMDP single photon emission computer tomography/computer tomographyAlso: SPECT/CTSPECT/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. | Diagnostic test | Imaging based staging of high risk PC |
| Whole-body magnetic resonance imagingAlso: wbMRIMagnetic 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. | Diagnostic test | Imaging based staging of high risk PC |
| Fluorine-18-prostate specific membrane antigen-1007- positron emission tomography/computer tomographyAlso: 18F-PSMA-1007-PET/CT18F-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. | Diagnostic test | Imaging based staging of high risk PC |
Primary outcome
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.
Time frame: 1 year
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.
5 secondary outcomes
Sensitivity of each imaging modality will be measured in initial staging of nodal, soft tissue and bone metastasis
Time frame: 1 year
Specificity of each imaging modality will be measured in initial staging of nodal, soft tissue and bone metastasis
Time frame: 1 year
Diagnostic accuracy each imaging modality will be measured in initial staging of nodal, soft tissue and bone metastasis
Time frame: 1 year
The effect of staging on clinical treatment-decisions
Time frame: 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
Time frame: 1 year
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 4 May 2022.
- Background: PubMed 28406044Seikkula HA, Kaipia AJ, Rantanen ME, Pitkaniemi JM, Malila NK, Bostrom PJ. Stage-specific mortality and survival trends of prostate cancer patients in Finland before and after introduction of PSA. Acta Oncol. 2017 Jul;56(7):971-977. doi: 10.1080/0284186X.2017.1288298. Epub 2017 Feb 13.
- Background: PubMed 24207135Heidenreich A, Bastian PJ, Bellmunt J, Bolla M, Joniau S, van der Kwast T, Mason M, Matveev V, Wiegel T, Zattoni F, Mottet N; European Association of Urology. EAU guidelines on prostate cancer. part 1: screening, diagnosis, and local treatment with curative intent-update 2013. Eur Urol. 2014 Jan;65(1):124-37. doi: 10.1016/j.eururo.2013.09.046. Epub 2013 Oct 6.
- Background: PubMed 28958581Suh CH, Shinagare AB, Westenfield AM, Ramaiya NH, Van den Abbeele AD, Kim KW. Yield of bone scintigraphy for the detection of metastatic disease in treatment-naive prostate cancer: a systematic review and meta-analysis. Clin Radiol. 2018 Feb;73(2):158-167. doi: 10.1016/j.crad.2017.08.004. Epub 2017 Sep 25.
- Background: PubMed 16085595Even-Sapir E. Imaging of malignant bone involvement by morphologic, scintigraphic, and hybrid modalities. J Nucl Med. 2005 Aug;46(8):1356-67.
- Background: PubMed 27262701Van den Wyngaert T, Strobel K, Kampen WU, Kuwert T, van der Bruggen W, Mohan HK, Gnanasegaran G, Delgado-Bolton R, Weber WA, Beheshti M, Langsteger W, Giammarile F, Mottaghy FM, Paycha F; EANM Bone & Joint Committee and the Oncology Committee. The EANM practice guidelines for bone scintigraphy. Eur J Nucl Med Mol Imaging. 2016 Aug;43(9):1723-38. doi: 10.1007/s00259-016-3415-4. Epub 2016 Jun 4.
- Background: PubMed 16455635Even-Sapir E, Metser U, Mishani E, Lievshitz G, Lerman H, Leibovitch I. The detection of bone metastases in patients with high-risk prostate cancer: 99mTc-MDP Planar bone scintigraphy, single- and multi-field-of-view SPECT, 18F-fluoride PET, and 18F-fluoride PET/CT. J Nucl Med. 2006 Feb;47(2):287-97.
- Background: PubMed 20016889Helyar V, Mohan HK, Barwick T, Livieratos L, Gnanasegaran G, Clarke SE, Fogelman I. The added value of multislice SPECT/CT in patients with equivocal bony metastasis from carcinoma of the prostate. Eur J Nucl Med Mol Imaging. 2010 Apr;37(4):706-13. doi: 10.1007/s00259-009-1334-3. Epub 2009 Dec 17.
- Background: PubMed 9815541Silver DA, Pellicer I, Fair WR, Heston WD, Cordon-Cardo C. Prostate-specific membrane antigen expression in normal and malignant human tissues. Clin Cancer Res. 1997 Jan;3(1):81-5.
- Background: PubMed 22369515Eder M, Schafer M, Bauder-Wust U, Hull WE, Wangler C, Mier W, Haberkorn U, Eisenhut M. 68Ga-complex lipophilicity and the targeting property of a urea-based PSMA inhibitor for PET imaging. Bioconjug Chem. 2012 Apr 18;23(4):688-97. doi: 10.1021/bc200279b. Epub 2012 Mar 13.
- Background: PubMed 27363387Perera M, Papa N, Christidis D, Wetherell D, Hofman MS, Murphy DG, Bolton D, Lawrentschuk N. Sensitivity, Specificity, and Predictors of Positive 68Ga-Prostate-specific Membrane Antigen Positron Emission Tomography in Advanced Prostate Cancer: A Systematic Review and Meta-analysis. Eur Urol. 2016 Dec;70(6):926-937. doi: 10.1016/j.eururo.2016.06.021. Epub 2016 Jun 28.
- Background: PubMed 27261520Fendler WP, Schmidt DF, Wenter V, Thierfelder KM, Zach C, Stief C, Bartenstein P, Kirchner T, Gildehaus FJ, Gratzke C, Faber C. 68Ga-PSMA PET/CT Detects the Location and Extent of Primary Prostate Cancer. J Nucl Med. 2016 Nov;57(11):1720-1725. doi: 10.2967/jnumed.116.172627. Epub 2016 Jun 3.
- Background: PubMed 27220897Rhee H, Thomas P, Shepherd B, Gustafson S, Vela I, Russell PJ, Nelson C, Chung E, Wood G, Malone G, Wood S, Heathcote P. Prostate Specific Membrane Antigen Positron Emission Tomography May Improve the Diagnostic Accuracy of Multiparametric Magnetic Resonance Imaging in Localized Prostate Cancer. J Urol. 2016 Oct;196(4):1261-7. doi: 10.1016/j.juro.2016.02.3000. Epub 2016 May 21.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Peter Boström, M.D.Ph.D principal investigator
Department of urology, Turku University Hospital, VSSHP
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Whole body contrast enhanced computer tomography, 99mTC-HMDP planar bone scintigraphy (BS) and 99mTc-HMDP single photon emission computer tomography/computer tomography in people with High Risk Prostate Cancer, run by Turku University Hospital at 1 site in Finland.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 3 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 4 May 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Finland. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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. (time frame: 1 year). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03537391, which also lists 34 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 4 May 2022.