Dutch National Randomized Study: PSMA-PET/CT as a Triage Tool for Pelvic Lymph Node Dissection in Prostatectomy Patients

Study Overview
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Brief Summary
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To determine if the use of Prostate-Specific Membrane Antigen Positron Emission Computer Tomography (PSMA PET/CT) as a selection tool for performing extended lymph node dissection (ePLND) for prostate cancer (PCa) in the primary staging setting results in fewer ePLND procedures and therefore lower overall healthcare costs, lower patient burden in terms of intervention-related complications and morbidity, with comparable disease prognosis, compared to the current European Guideline-recommended standard practice which includes performing ePLND in PCa patients who are candidates for active treatment with a nomogram-calculated lymph node involvement (LNI) risk >5%.

Detailed Description
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Background: Use of prostate-specific membrane antigen (PSMA) positron emission tomography (PET) - computer tomography (CT) has drastically improved the ability to detect and exclude presence of pelvic lymph node invasion (LNI) compared to conventional imaging. However, current standard of care still includes performing extended pelvic lymph node dissection (ePLND) in all patients with primary prostate cancer and a nomogram-based risk of LNI >5%. It is unclear if use of PSMA PET/CT as a triage test can safely reduce the number of ePLND and hence reduce the associated morbidity and costs, without negatively influencing disease prognosis. Objective: To assess whether PSMA PET/CT can be safely used as a triage test for selecting primary prostate cancer patients for ePLND. We will additionally assess cost-effectiveness of the PSMA PET/ CT triage strategy. Design, setting and Participants: THE PSMA-SELECT trial includes patients with biopsy-confirmed prostate cancer, without evidence of distant metastasis (M0) on PSMA PET/CT, opting for treatment with radical prostatectomy (RP), with a nomogram-calculated risk of LNI >5%. Patients will be randomized 1:1. In the intervention arm patients will only undergo ePLND in addition to robot-assisted radical prostatectomy (RARP) in case of suspected LNI on PSMA PET/CT (miN1), whereas ePLND will be omitted in those without PSMA positive lymph nodes (miN0). In the control arm, all patients will undergo ePLND in addition to RARP. Outcome measurements and statistical analysis: The primary endpoint of this study is biochemical recurrence rate at two years post-surgery. Secondary outcome measures are number of ePLNDs indicated and performed, treatment-related adverse events, initiation of salvage treatment, metastasis-free survival, patient-reported outcome measures and individual and cumulative healthcare costs.

Official Title
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Multi-institutional Evaluation of the Cost-effectiveness of PSMA-PET/CT for the Detection of Pelvic Lymph Node Invasion in Newly Diagnosed Prostate Cancer Patients

Conditions
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Prostate Cancer Metastatic, Prostate Cancer, Lymph Node Metastases

Intervention / Treatment
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* Device: PSMA-PET/CT
* Other: Nomogram


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Biopsy proven adenocarcinoma of the prostate Indication for ePLND combined with robot assisted radical prostatectomy (RARP) (MSKCC nomogram >5%, if not applicable when only MRI targeted biopsies are positive, the Briganti nomogram will be used) Suitable for robot-assisted ePLND and RARP Mentally competent and understanding of benefits and potential burden of the study Written informed consent No known allergies for PSMA tracer. Exclusion Criteria: History of prior diagnosed or treated PCa Known concomitant malignancies (except Basal Cell Carcinoma of the skin) Unwillingness or inability to undergo PSMA PET/CT and/or ePLND and RARP PSMA non-avid PCa (local tumor activity) Presence of distant metastasis (M1)

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Intervention PSMA PET/CT based indication for ePLND: Node-negative PSMA PET/CT [N0] and M0: do not perform ePLND Node-positive PSMA PET/CT [N1] and M0: perform ePLND Comparator Nomogram-based indication for ePLND (conform current EAU guidelines)
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PSMA PET/CT based indication for ePLND:<br>Node-negative PSMA PET/CT [N0] and M0: do not perform ePLND Node-positive PSMA PET/CT [N1] and M0: perform ePLND | Device: PSMA-PET/CT<br>* In the intervention arm patients will only undergo ePLND in addition to robot-assisted radical prostatectomy (RARP) in case of suspected LNI on PSMA PET/CT (miN1), whereas ePLND will be omitted in those without PSMA positive lymph nodes (miN0).<br>|
| Active Comparator: Nomogram-based indication for ePLND (standard of care)<br>Nomogram-based indication for ePLND (conform current EAU guidelines) | Other: Nomogram<br>* Current standard of care includes performing extended pelvic lymph node dissection (ePLND) in all patients with primary prostate cancer and a nomogram-based risk of LNI >5%<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in biochemical recurrence rate between groups. | Biochemical recurrence (BCR) is defined as the occurrence of measurable (>0.2 ng/ml) prostate specific antigen (PSA), during routinely follow-up up to five years after surgery, determined at two different occasions with at least one week between them.The BCR-rate between the control group and intervention groups will be compared. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total number of ePLNDs and PSMA PET/CTs performed and their intervention-related healthcare costs | Total number of ePLNDs and PSMA PET/CTs performed and their intervention-related healthcare costs such as consumption of operation room (OR) time, costs of complication-related interventions and associated (prolonged) hospital stay. | up to 5 years post-surgery | 
| Incidence and types of surgical complications after RARP and ePLND | Surgical complications are graded according to the Clavien-Dindo Classification, defined as: Grade 1 = Any deviation from the normal postoperative course. Grade 2 = Requiring pharmacological treatment with drugs other than such allowed for grade I complications. Grade 3 = Requiring surgical, endoscopic or radiological intervention, not under (Grade 3a) or under general anesthesia (Grade 3b). Grade 4 = Life-threatening complication with single organ (Grade 4a) or Multiorgan dysfunction (Grade 4b). Grade 5 = Death of a patient. | up to 1 year post-surgery | 
| Total nodes resected on ePLND and number of positive and negative nodes within and outside of the standard ePLND template | Total nodes resected on ePLND and number of positive and negative nodes within and outside of the standard ePLND template as described by the EAU guidelines. | up to 5 years post-surgery | 
| Occurrence of pelvic lymph node metastasis and distant metastasis (visceral, bone, distant lymph nodes, pelvic lymph nodes) on PSMA-PET/CT during follow-up | Time to appearance of pelvic lymph node metastasis (N1) and distant metastasis (M1) using PSMA PET/CT | up to 5 years post-surgery | 
| Initiation of salvage therapy | The time from surgery to the start of salvage therapy (salvage ePLND, salvage radiation treatment, systemic treatment [androgen deprivation therapy (ADT) and eventual additional chemotherapy]). | up to 5 years post-surgery | 
| Metastasis-free survival | The time from surgery to the time of the scan that showed first evidence of radiographically detected bone or soft tissue distant metastasis. | up to 5 years post-surgery | 
| Hormone-therapy free survival | The time from surgery to the start of hormone therapy (ADT) | up to 5 years post-surgery | 
| Diagnostic accuracy measures of PSMA PET/CT | Diagnostic accuracy measures including per-patient and per-template sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of PSMA PET/CT for the detection of lymph node metastasis at baseline and, 3, 6, 12, 18, 24, 30, 36, 42, 48, 54 and 60 months post-surgery. | up to 5 years post-surgery | 
| (Changes) in the EPIC-26 sexual functioning domain score between groups | Expanded Prostate Cancer Index Composite (EPIC)-26 will be used to measure sexual functioning. EPIC-26 contains five symptom domains (urinary incontinence, urinary irritative/obstructive, sexual, bowel, hormonal), scored from 0 (worst) to 100 (best). Questionnaires will be send out at baseline (diagnosis) and 12, 24, 36, 48 and 60 months following surgery. | up to 5 years post-surgery | 
| (Changes in) quality-adjusted life-years (EQ-5D-5L) in patients in the control group vs. intervention group | The EuroQol (EQ)-5 Dimension (D)-5 Level (L) is a health-related quality of life questionnaire which can be used to derive utilities from patients. The EQ-5D-5L descriptive system comprises five dimensions (mobility, self-care, usual activities, pain/discomfort and anxiety. Each domain has 5 response levels: (1) no problems, (2) slight problems (3) moderate problems (4) severe problems and (5) unable to/extreme problems. Questionnaires will be administered at baseline, 12, 24, 36, 48 and 60 months following diagnosis. | up to 5 years post-surgery | 
| Total health care related costs (iMTA MCQ) in patients in the control group vs. intervention group | The institute for Medical Technology Assessment (iMTA) Medical Consumption Questionnaire (MCQ) measures all relevant health care related costs. The iMCQ includes questions related to frequently occurring contacts with health care providers. Questionnaires will be send out at baseline and 3, 6, 12, 18, 24, 30, 36, 42, 48, 54 and 60 months post-surgery. | up to 5 years post-surgery | 
| Total loss of productivity and presenteeism (iMTA PCQ) in patients in the control group vs. intervention group | The institute for Medical Technology Assessment (iMTA) Productivity Cost Questionnaire (PCQ) measures loss of productivity due to illness or recovery in patients below the age of 65 years based on patient reported absences from paid (or unpaid) labor. Questionnaires will be send out to each individual patient at baseline and, 3, 6, 12, 18, 24, 30, 36, 42, 48, 54 and 60 months post-surgery. | up to 5 years post-surgery |