Comparison of Diagnostic Accuracy of Luminal Index and MP MRI for Accelerated deTEction of Significant Prostate Cancer

Study Overview
=================
Brief Summary
-----------------
Multi-parametric (mp) MRI has now internationally been incorporated as standard of care in the work-up of participants with suspected prostate cancer. The standard mpMRI protocol requires 30-45 minutes to be performed and has a sensitivity and specificity of approximately 90% and 50% for the detection of clinically significant prostate cancer. Compared to the non-targeted systematic transrectal ultrasound (TRUS) biopsy approach in men with clinically suspected prostate cancer (e.g.: elevated PSA), performing mpMRI as a triage test allows to detect clinically significant cancer in more men (38% vs 26%) and clinically insignificant cancer in less men (9% vs 22%), while avoiding biopsy in roughly one third of men. However, there is need for improvement in the prostate diagnostic pathway even after incorporation of mp-MRI, specifically mpMRI can miss significant cancer in around 10% of cases and only 50% of positive scans turn out to harbor significant cancer at biopsy. Moreover, the key functional imaging sequence of mp-MRI (i.e.: DWI) often suffers from image artifacts causing difficulty in scan interpretation. To address these issues the investigators aim to investigate Luminal Index MRI (LI-MRI), a novel method of MR imaging that requires only up to 10 minutes to be performed and doesn't require the use of contrast media. LI-MRI has shown promising results for the characterization of prostate cancer. In this study the diagnostic performance of LI-MRI and mpMRI for the detection of prostate cancer will be directly compared.

Detailed Description
-----------------
Luminal Index MRI (LI-MRI). LI-MRI is a novel technique that allows the assessment of luminal water fraction (LWF). The normal prostate consists of a glandular lumen and cellular areas; cancer alters the balance of glandular to cellular spaces, reducing the fraction of glandular lumen. This fraction decreases further as the grade of tumor increases. Using a multiecho T2-weighted sequence, investigators can differentiate between long T2 values of the luminal space and the short T2 values of the stromal/epithelial space. The luminal index of an image pixel can be calculated as a fraction of the area of the luminal space to the sum of cellular-stromal and luminal space. Studies have shown a good correlation between LWF and its histological measurement, with potential to detect prostate cancer and predict tumor grade. From the results of preliminary studies, the optimized LI-MRI sequence has been very good at differentiating clinically significant and non-significant tumors. PURPOSE. The purpose of the study is to compare the diagnostic performance of LI-MRI (up to 10 minutes scan, no contrast required) and mp-MRI (35-40 min scan, intravenous contrast injection required) for the detection of clinically significant prostate cancer. DESIGN. This is a prospective, multi-centre, paired, non-randomised, comparative study. Patients with clinically suspected prostate cancer that are scheduled for mpMRI as part of their routine diagnostic workup will be asked to participate to the study. All participants will undergo an additional LI-MRI sequence during the clinical scan session. Mp-MRI and LI-MRI images will be interpreted independently by different radiologists, blinded to the results of the other test. Targeted biopsies will be performed for any suspicious lesion (i.e. MRI score 3-4-5) detected with mpMRI and/or LI-MRI, blinded to the source of the lesion. The diagnostic performance of the two techniques will then be assessed using the results of the targeted biopsy. An optional translational study will also be performed to investigate the ability of DNA methylation signatures in the plasma to identify men at high risk of metastases from high risk prostate cancer.

Official Title
-----------------
A Comparison of the Diagnostic Accuracy of Luminal Index Magnetic Resonance Imaging and Multi-parametric Magnetic Resonance Imaging for the Accelerated Detection of Significant Prostate Cancer

Conditions
-----------------
Prostate Cancer

Intervention / Treatment
-----------------
* Diagnostic Test: Luminal Index MRI (LI-MRI)
* Diagnostic Test: LI-MRI targeted prostate biopsy
* Diagnostic Test: Plasma methylation signature (ctMethSig)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Men with clinically suspected prostate cancer and referred for prostate MRI Willing and able to provide a written informed consent Exclusion Criteria: Prostate specific antigen (PSA) level > 20ng/ml within 6 months Previous diagnosis of prostate cancer Ongoing hormone treatment within 3 months prior to MRI, excluding antiandrogens or 5-alpha reductase inhibitors Contraindication to MRI scan Contraindication to administration of gadolinium-based contrast agents

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Diagnostic
Intervention Model: Single Group Assignment
Interventional Model Description: Paired, non-randomised, comparative study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: MRI scan<br>Mp-MRI, LI-MRI, plasma DNA methylation signature (optional) | Diagnostic Test: Luminal Index MRI (LI-MRI)<br>* Multiecho T2 sequence; eventual biopsy of lesion(s) detected with LI-MRI only.<br>Diagnostic Test: LI-MRI targeted prostate biopsy<br>* Biopsy targeted to suspicious lesions detected with LI-MRI only<br>Diagnostic Test: Plasma methylation signature (ctMethSig)<br>* Blood sample.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Diagnostic accuracy of mp-MRI and LI-MRI | Comparison of per-participant diagnostic accuracy of mp-MRI and LI-MRI for the detection of clinically significant prostate cancer (i.e. Gleason 3+4 or higher). Two endpoints are included in the primary outcome: difference in sensitivity and difference in specificity. | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Diagnostic accuracy of LI-MRI as an add-on test | Per-participant diagnostic accuracy of LI-MRI as an add-on test in combination with mp-MRI for the detection of clinically significant cancer. | 3 years | 
| Proportion of correct clinical recommendation | Comparison of the proportion of men who would receive a correct clinical recommendation that biopsy could be avoided using mp-MRI and LI-MRI by retrospective analysis. | 3 years | 
| Per-lesion diagnostic accuracy of mp-MRI and LI-MRI | Comparison of per-lesion diagnostic accuracy of LI-MRI and mp-MRI for clinically significant cancer (difference in sensitivity and specificity). | 3 years | 
| Proportion of non-significant cancer detection | Comparison of the proportion of men diagnosed with non-significant cancer (Gleason 3+3) based on LI-MRI and mp-MRI targeted biopsies. | 3 years | 
| Value of MRI in diagnostic models | Evaluation of the added value of MRI when included in a diagnostic model of clinically significant cancer based on the clinical features of age and PSA density. | 3 years | 
| Luminal Index quantitative analysis | Correlation between Luminal Index quantitative metric and tumor Gleason grade | 3 years | 
| Interobserver agreement on LI-MRI scores | Interobserver agreement among radiologists on LI-MRI scores. | 3 years | 
| Interobserver agreement on Gleason scores | Interobserver agreement among histopathologists on Gleason scores at biopsy. | 3 years | 
| ctMethSig true positive rate | Proportion of men with clinically significant cancer who are positive with ctMethSig. | 3 years | 
| ctMethSig false positive rate | Proportion of men without clinically significant cancer who are positive with ctMethSig. | 3 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Magnetic Resonance Imaging, Luminal Index MRI, Methylation Signature, Prostate Cancer