Imaging Center COE Articles

Articles

  • (44)Sc-PSMA-617 for radiotheragnostics in tandem with (177)Lu-PSMA-617-preclinical investigations in comparison with (68)Ga-PSMA-11 and (68)Ga-PSMA-617.

    The targeting of the prostate-specific membrane antigen (PSMA) is of particular interest for radiotheragnostic purposes of prostate cancer. Radiolabeled PSMA-617, a 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA)-functionalized PSMA ligand, revealed favorable kinetics with high tumor uptake, enabling its successful application for PET imaging ((68)Ga) and radionuclide therapy ((177)Lu) in the clinics.

    Published January 26, 2017
  • (68)Ga-PSMA PET/CT: Joint EANM and SNMMI procedure guideline for prostate cancer imaging: version 1.0.

    The aim of this guideline is to provide standards for the recommendation, performance, interpretation and reporting of (68)Ga-PSMA PET/CT for prostate cancer imaging. These recommendations will help to improve accuracy, precision, and repeatability of (68)Ga-PSMA PET/CT for prostate cancer essentially needed for implementation of this modality in science and routine clinical practice.

    Published March 13, 2017
  • 68 Ga-PSMA Uptake by Dermatofibroma in a Patient With Prostate Cancer.

    Prostate-specific membrane antigen (PSMA) is a typ. 2 transmembrane protein that is highly expressed in prostate cancer cells. Ga-PSMA PET/CT imaging is a modality used to determine the extent of prostate cancer.

    Published March 8, 2017
  • A Clinician’s Guide to Next Generation Imaging in Patients with Advanced Prostate Cancer (Prostate Cancer Radiographic Assessments for Detection of Advanced Recurrence [RADAR] III)

    The advanced prostate cancer therapeutic landscape has changed dramatically over the last several years, resulting in improved overall survival for patients with both castration-naive and castration-resistant disease. The evolution and development of novel next-generation imaging (NGI) techniques will affect diagnostic and therapeutic decision-making. Clinicians must navigate when and which NGI techniques to use and how to adjust treatment strategies based upon their results, oftentimes in the absence of correlative therapeutic data. Therefore, guidance is needed based on the best available information and current clinical experience.
    Published August 7, 2018
  • A Prospective Trial of Intensity Modulated Radiation Therapy (IMRT) Incorporating a Simultaneous Integrated Boost for Prostate Cancer: Long-term Outcomes Compared With Standard Image Guided IMRT: Beyond the Abstract

    Nearly 20 years ago, a new radiation therapy planning system was approved for clinical use ushering in the era of intensity modulated radiotherapy (IMRT). IMRT divides a large uniform field of radiation into many tiny beamlets, each of varying intensity or strength. This breakthrough allowed one to better conform the dose of radiotherapy to an irregular target and spare the adjacent normal tissues. Its use in prostate radiotherapy spread rapidly and today, IMRT is the most frequently used radiation modality for prostate cancer. In Arizona, at Mayo Clinic, we see a large number of men with prostate cancer.
    Published April 5, 2017
  • Appropriate Use Criteria for Imaging Evaluation of Biochemical Recurrence of Prostate Cancer After Definitive Primary Treatment

    Executive Summary

    Imaging is often used to evaluate men with biochemical recurrence (BCR) of prostate cancer after definitive primary treatment (radical prostatectomy [RP] or radiotherapy [RT]). The goal of imaging is to identify the source of elevated or rising serum prostate-specific antigen (PSA) levels because subsequent management depends on disease location and extent. Salvage therapy (with surgery or radiation) may be considered for select cases with BCR to provide additional potential opportunity for cure. The salvage treatment strategy may be extended to regional adenopathy. Patients with limited distant metastases on imaging, referred to as oligometastatic disease (#5 demonstrable lesions), may be candidates for close observation, systemic hormonal therapy, or metastases-directed therapies with or without local therapy, depending on sites of recurrence. Patients with metastatic disease are typically treated with systemic therapy.

    The purpose of this document is to describe the appropriate use of imaging in the diagnostic evaluation of patients with BCR after definitive primary treatment. The imaging modalities that were considered included CT, bone scan, and the U.S. Food and Drug Administration (FDA)–approved PET radiotracers that track malignancy-induced lipogenesis (11C-choline) and amino acid metabolism (18F-fluciclovine). The prostate-specific membrane antigen (PSMA)–targeted monoclonal antibody, 111In-capromab pendetide, is also included for historical perspective because it is neither available nor used clinically. The new class of PSMA-targeted PET radiotracers have generated considerable interest and are discussed briefly, although these agents are currently not approved for routine clinical use in the United States. Moreover, whole-body MRI (WB-MRI), with or without diffusion-weighted imaging, is excluded. Although WB-MRI may have utility in this clinical setting, particularly for the detection of bone metastases, the variability in availability, accessibility, quality, and standardization, as well as the fact that there are no currently established procedural terminology codes for reimbursement, has hindered its clinical adoption.1,2

    Representatives from the Society of Nuclear Medicine and Molecular Imaging (SNMMI), the European Association of Nuclear Medicine (EANM), the American Society of Clinical Oncology (ASCO), the American College of Nuclear Medicine (ACNM), the American Society for Radiation Oncology (ASTRO), the American Urological Association (AUA), the American College of Physicians (ACP), the American College of Radiology (ACR), and the World Molecular Imaging Society (WMIS) assembled under the auspices of an autonomous workgroup to develop the following appropriate use criteria (AUC). This process was performed in accordance with the Protecting Access to Medicare Act of 2014.3 This legislation requires that all referring physicians consult AUC by using a clinical decision support mechanism before ordering advanced diagnostic imaging services. These services include diagnostic MRI, CT, and nuclear medicine procedures such as PET, among other services specified by the Secretary of Health and Human Services in consultation with physician specialty organizations and other stakeholders. The AUC herein are intended to aid referring medical practitioners in the appropriate use of imaging for the diagnostic evaluation of patients with BCR of prostate cancer after definitive primary treatment.

    Prostate cancer is the second most commonly diagnosed cancer worldwide (13.5% of cancer diagnoses in men; 1,276,106 cases in 2018) and the fifth most common cause of cancer-related mortality among males (6.7%; 358,989 deaths in 2018).4 In the United States, prostate cancer is the most commonly diagnosed nonskin cancer in men (a projected 19% of all new cases of cancer; 164,690 cases in 2018) and the second most common cause of cancer-related mortality (a projected 29,430 deaths in 2018).5 Despite local definitive therapy, up to 40% of patients will develop recurrent disease.6 Most of these patients will have BCR with no evidence of metastasis on the basis of widely used standard imaging techniques (contrast-enhanced abdomen and pelvis CT, WB 99mTc-based bone scan, or pelvis multiparametric MRI), and the disease will manifest only with elevated serum PSA levels.

    The definition of BCR (also referred to as PSA relapse) depends on the type of prior definitive therapy. In patients who have undergone RP, the AUA defines BCR when the serum PSA level is ≥ 0.2 ng/mL, measured 6–13 wk after surgery, and confirmed by a second determination of a PSA level of > 0.2 ng/mL.7 In patients treated with RT, the ASTRO Phoenix Criteria defines BCR as a rise in PSA level of 2 ng/mL or more above the nadir regardless of androgen deprivation therapy (ADT).8

    The significance of biochemically recurrent disease varies considerably according to individual risk factors. One clinically important prognostic variable is PSA doubling time. For instance, prostate cancer–specific survival is approximately 90% in patients with a PSA doubling time of ≥ 15 mo (highest quartile), whereas it is about 20% for patients with a PSA doubling time of < 3 mo (lowest quartile).9 In part because of this wide variability in disease aggressiveness, coupled with competing causes of mortality and the typically long time to documented metastatic disease by standard imaging (median metastasis-free survival is 10 y in patients with BCR and no treatment), there is no defined standard management for this patient population.10 The development of metastasis in a patient signals that a change in treatment approach is warranted. Since the 1940s, the foundation of treatment for metastatic prostate cancer has been testosterone-lowering therapy. It is likely that the use of more sensitive imaging techniques will identify patients earlier who are at higher risk of developing overt metastases identified by more commonly used techniques. In some scenarios, earlier intervention in the disease process may result in improved outcomes for patients, as has been seen with postoperative RT.11

    RT after a prostatectomy is commonly used to eradicate microscopic residual disease in the prostate bed, thereby reducing the risk of recurrence. Defining who needs postoperative RT is most often based on surgical pathology and postoperative PSA because standard imaging does not have sufficient sensitivity to identify early recurrences in the PSA range where salvage treatment is more likely to be curative. There is growing evidence that genomic biomarkers (e.g., Decipher, GenomeDx Biosciences, San Diego, CA) can have utility in this clinical setting, although it remains unclear as to how this information affects imaging choice.12,13 In the adjuvant setting, pathology (pT3a/b or surgical margins positive for disease) currently drives the addition of RT. In the salvage setting, when men have persistently detectable PSA (PSA persistence) or a delayed rise in PSA level (≥ 0.2 ng/mL), conventional imaging does not have sufficient sensitivity to identify early recurrences. The ability to detect residual or recurrent disease within the pelvis can affect RT dose and target. In the absence of molecular imaging, the question of whether to include pelvic lymph nodes in the RT field in patients with pathologic node-negative disease is a question that has been studied by the Radiation Therapy Oncology Group (RTOG) 0534 trial and is awaiting final results. The first report from RTOG 0534 (3-arm randomized trial) shows gains in freedom from progression with the addition of short-term (4–6 mo) ADT to prostate bed radiation and further gains with the inclusion of pelvic lymph node RT and short-term ADT over a PSA level of 0.34 ng/mL.14 With the ability to visualize prostate cancer cells, molecular imaging can help define RT treatment fields. Similarly, molecular imaging can identify patients who have early metastatic disease and could avoid RT to the prostate fossa. The use of molecular imaging to identify oligometastatic prostate cancer has allowed for additional treatment strategies in patient care.15 Studies show a benefit (e.g., biochemical progression-free survival, distant progression free survival) to metastasis-directed stereotactic body RT in the setting of oligometastatic prostate cancer.16-18 Molecular imaging can enhance the postoperative treatment algorithm for prostate cancer patients by identifying targets for RT.

    This document is the product of an extensive literature search in combination with expert opinion. Its intent is to provide up-to-date information and recommendations for AUC for approved (in the United States) imaging technologies in the setting of BCR of prostate cancer after definitive treatment. We also discuss the outlook for upcoming imaging technologies that are anticipated to be approved in the United States relatively soon. 

    Methodology

    Expert Workgroup Selection

    The experts of this AUC workgroup were convened by the SNMMI to represent a multidisciplinary panel of health-care providers with substantive knowledge in the use of imaging evaluation of BCR of prostate cancer after definitive primary treatment. In addition to SNMMI members, representatives from ASCO, ASTRO, EANM, ACP, ACNM, AUA, ENETS, WMIS, and ACR were included in the workgroup. Fourteen physician members were ultimately selected to participate and contribute to the AUC. A complete list of workgroup participants and external reviewers can be found in Appendix A. Appendix B provides the disclosures and conflict of interest (COI) statements, and Appendix C describes the solicitation of public commentary.

    AUC Development

    The process for AUC development was modeled after the RAND/UCLA Appropriateness Method for AUC development.19 The process included the identification of a list of relevant clinical scenarios in which nuclear medicine can be used for imaging evaluation of BCR of prostate cancer after definitive primary treatment; a systematic review of evidence related to these clinical scenarios; and a systematic synthesis of available evidence, followed by the development of AUC for each of the various clinical scenarios by using a modified Delphi process. In addition, in this process we strove to adhere to the Institute of Medicine’s standards for developing trustworthy clinical guidance.20,21 The final document was drafted on the basis of group ratings and discussions.

    Scope and Development of Clinical Scenarios

    To begin this process, the workgroup discussed various potential clinical indications and applicable scenarios for the evaluation of BCR of prostate cancer after definitive primary therapy. For all indications, the relevant populations were patients with prostate cancer. The workgroup identified 2 clinical categories with 12 scenarios for this document. The categories are intended to be as representative of the relevant patient population as possible for the development of AUC. The resulting AUC are based on evidence and expert opinion regarding diagnostic accuracy and effects on clinical outcomes and clinical decision making as applied to each indication. Other factors affecting the AUC recommendations were potential harm—including long-term harm that may be difficult to capture—costs, availability, and patient preferences.

    Systematic Review

    ASCO conducted a systematic review to develop a comprehensive clinical practice guideline for optimum imaging strategies for advanced prostate cancer, and the same systematic review was used by the AUC workgroup. The workgroup selected the following key questions to guide the review:

    1. What is the goal of imaging in advanced prostate cancer?

    2. What imaging techniques are available for imaging advanced prostate cancer?

    3. What are the unmet needs and potential impact of imaging according to different advanced prostate cancer disease states?

    4. When and what type of imaging is appropriate in each scenario?

    The inclusion and exclusion criteria for papers for this review were based on the study parameters established by the workgroup, using the PICOTS (population, intervention, comparisons, outcomes, timing, and setting) approach. A protocol for each systematic review defined parameters for a targeted literature search. Additional parameters included relevant study designs, literature sources, types of reports, and prespecified inclusion and exclusion criteria for the literature identified. The protocol for this guideline was reviewed and approved by the ASCO Clinical Practice Guidelines Committee’s Genitourinary Cancer Guideline Advisory Group.

    PubMed and the Cochrane Collaboration Library electronic databases (with or without meeting abstracts) were searched for evidence that reported on outcomes of interest.

    Data Extraction

    Literature search results were reviewed and deemed appropriate for full text review by one ASCO staff reviewer in consultation with the expert panel cochairs (Edouard J Trabulsi, MD, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA, and Alberto Vargas, MD, Memorial Sloan Kettering Cancer Center, New York, NY). Data were extracted by 1 staff reviewer and subsequently checked for accuracy through an audit of the data by another ASCO staff member. Disagreements were resolved through discussion and consultation with the cochairs if necessary. Discrepancies were resolved through a consensus process.

    Study Quality Assessment

    Study quality was formally assessed for the studies identified. Design aspects related to the individual study quality were assessed by 1 reviewer and included factors such as blinding, allocation concealment, placebo control, intention to treat, funding sources, etc. The risk of bias was assessed as ‘‘low,’’ ‘‘intermediate,’’ or ‘‘high’’ for most of the identified evidence.

    Database searches resulted in 6,378 potentially relevant abstracts. After dual review of abstracts and titles, 66 articles were selected for full-text dual review. Of these, 35 studies were determined to meet inclusion criteria and were included in this review, including 17 systematic reviews and 18 primary research papers.

    Rating and Scoring

    In developing these criteria, the workgroup members used the following definition of appropriateness to guide their considerations and group discussions: ‘‘The concept of appropriateness, as applied to health care, balances risk and benefit of a treatment, test, or procedure in the context of available resources for an individual patient with specific characteristics.’’ At the beginning of the process, workgroup members convened via webinars to develop the initial clinical indications. On evaluating the evidence summary of the systematic literature review, the workgroup further refined its draft clinical indications to ensure their accuracy and to facilitate consistent interpretation when scoring each indication for appropriateness. Using the evidence summary, workgroup members were first asked individually to assess the appropriateness and to provide a score for each of the identified indications. Workgroup members then convened in a group setting for several successive webinars to discuss each indication and associated scores from the first round of individual scoring. After deliberate discussion, a consensus score was determined and then assigned to the associated appropriate use indication. For this scoring round, the expert panel was encouraged to include their clinical expertise in addition to the available evidence in determining the final scores. All members contributed to the final discussion, and no one was forced into consensus. After the rating process was completed, the final appropriate use ratings were summarized in a format similar to that outlined by the RAND/UCLA Appropriateness Method.

    The workgroup scored each indication as ‘‘appropriate,’’ ‘‘may be appropriate,’’ or ‘‘rarely appropriate’’ on a scale from 1 to 9. Scores 7–9 indicate that the use of the procedure is appropriate for the specific clinical indication and is generally considered acceptable. Scores 4–6 indicate that the use of the procedure may be appropriate for the specific indication. This implies that more research is needed to classify the indication definitively. Scores 1–3 indicate that the use of the procedure is rarely appropriate for the specific indication and is generally not considered acceptable.

    As stated by other societies that develop AUC, the division of these scores into 3 general levels of appropriateness is partially arbitrary, and the numeric designations should be viewed as a continuum. In addition, if there was a difference in clinical opinion for an indication such that workgroup members could not agree on a common score, that indication was given a ‘‘may be appropriate’’ rating to indicate a lack of agreement on appropriateness on the basis of available literature and the members’ collective clinical opinion, indicating the need for additional research.

    Clinical Categories and AUC Scores

    Category 1. BCR after prior definitive treatment with RP or RT—initial imaging investigation

    Category 2. BCR after prior definitive treatment with RP or RT—negative or equivocal results on initial standard imaging

    Clinical Categories and AUC Scores

    Table 1 presents the clinical category and final AUC scores for the use of imaging in the evaluation of BCR of prostate cancer after definitive primary treatment with RP or RT.

    Table 1. Category 1: Clinical Scenarios for BCR After Prior Definitive Treatment with RP or RT—Initial Imaging Investigation

    Clinical Scenarios for BCR After Prior Definitive Treatment with RP or RT

    Table 2 presents the clinical category and final AUC scores for the use of imaging in the evaluation of BCR of prostate cancer after definitive primary treatment with RP or RT, with negative or equivocal results on standard imaging.

    Table 2. Category 2: Clinical Scenarios for BCR After Prior Definitive Treatment with RP or RT—Negative Or Equivocal Results on Initial Standard Imaging

    Clinical Scenarios for BCR After Prior Definitive Treatment

    Category 1, Scenario 1: CT of the Abdomen and Pelvis with Intravenous Contrast (Score 8 – Appropriate). An abdominal and pelvis CT in prostate cancer treatment follow-up is used to focus on the assessment of metastatic disease in the lymph nodes, bone, and visceral organs. In the evaluation of nodal disease, CT relies on nodal size to detect tumors. Using a short-axis diameter of 1.0 cm as a cut point, studies have reported sensitivities of between 27% and 75% with specificities of between 66% and 100%.22 However, the sensitivity of abdominopelvic CT for the detection of low-volume recurrent disease is limited, particularly when PSA levels are low. Studies have shown CT results to be positive in only 11%–14% of men with biochemical relapse after RP.23 The mean PSA value associated with positive results for disease in a CT examination was 12.4 ng/mL, and the mean PSA velocity was 30.6 ng/mL/y.24 The usual pattern of vertical nodal spread beginning in the pelvis can be absent in nearly 75% of patients with disease recurrence after treatment.25 In these patients, most of whom have undergone previous pelvic lymph node dissection at the time of RP, only retroperitoneal adenopathy is commonly detected by CT. In addition, CT is useful to detect advanced disease in bone and visceral metastases and in RT treatment planning to define the prostate bed and locoregional and distant metastatic target volumes. Bone lesions from prostate cancer are often seen as sclerotic lesions, although there are numerous other benign causes for dense bone lesions. A bone scan is superior to CT in the diagnosis and follow-up of bone metastases, as it provides functional information about a bone lesion. In summary, despite the recognized limitations of an abdominopelvic CT, it is readily available at relatively low cost and has traditionally been considered as standard imaging in this clinical setting, which prompted the panel to recommend an appropriateness score of 8 (appropriate).

    Category 1, Scenario 2: CT of the Chest With Intravenous Contrast (Score 2 – Rarely Appropriate). Lung metastasis from prostate cancer is relatively uncommon. In an autopsy series, the relative ratio frequency of lung involvement was 14.2%–19.8%.26 Moreover, most lung metastases appear later in the disease and not early in the recurrence setting. Therefore, the panel recommended that CT of the chest receive an appropriateness score of 2 (rarely appropriate).

    Category 1, Scenario 3: Bone scan (99mTc-Methylene Diphosphonate [MDP] WB Scan, 18F-Sodium Fluoride [NaF] PET/CT) (Score 8 – Appropriate). In the clinical setting of primary staging, current National Comprehensive Cancer Network (NCCN) guidelines recommend an imaging evaluation with a bone scan in any patient with a PSA level of > 20 ng/mL, a Gleason score of 8 or greater, or a clinical stage of T3 or greater (high-risk and very highrisk groups) and in patients with any of 2 of the following: a PSA level of > 10 ng/mL, a Gleason score of 7 or over, and a clinical stage of T2b/T2c or greater (intermediate-unfavorable group). A recent systematic review of 54 studies encompassing a total sample size of 20,421 patients with treatment-na¨ıve cancer found yield rates of 4% with a PSA level of ≤ 10 ng/mL, 7% with a PSA level of 10 to ≤ 20 ng/mL, 42% with a PSA level of > 20 ng/mL, 4.1% with a Gleason score of 6 or less, 10% with a Gleason score of 7, and 28.79% with a Gleason score of 8 or greater.27 In subgroup analyses, a Gleason score of 7 with a PSA level of < 20 ng/mL had a 3% yield, whereas a Gleason score of 8 with a PSA level of ≤ 10 ng/mL had a yield of 20%, suggesting that a bone scan would be useful with a PSA level of > 20 ng/mL or a Gleason score of 8 or over.

    However, it is probable that the case for patients with BCR of prostate cancer is different. One study of 1,197 patients who had undergone RP found that those with a positive bone scan result always had a PSA level of at least 7 ng/mL,28 and another study of 100 patients after RP suggested an optimal trigger PSA level cutoff of 30–40 ng/mL.29 One study of 142 patients with PSA levels of up to 1 ng/mL after RP reported only a 2% bone scan yield.30 Therefore, these investigations suggest that the PSA trigger cutoff for a positive bone scan result in patients who have undergone RP may be in the range of 7–30 ng/mL and not lower.

    The PSA velocity (i.e., the rate of change of serum PSA levels over time) may also be relevant. A study of 132 patients after RP suggested that the PSA velocity was more important, with 0.5 ng/ mL/mo serving as an optimal cutoff.23 A study of 292 patients, most of whom had undergone RP, suggested a trigger PSA value of 5 ng/mL and a PSA doubling time of 10 mo,31 whereas another study of 128 patients after RP suggested cutoffs of 10 ng/mL for the PSA value and 6 mo for the PSA doubling time.32 Another investigation of 438 patients after RP also incorporated the presence or absence of ADT. Whereas with patients before being treated with ADT, a threshold PSA doubling time of 9 mo was a fairly effective cutoff (yield of 1%–5% for > 9 mo vs. 11%–44% for < 9 mo), for patients after ADT treatment, there was a yield of at least 10%, even with long PSA doubling times and low PSA levels (below 10 ng/mL).33 A study of 239 patients used trigger PSA values and PSA slope and velocity to create a monogram.34 The results concurred with the NCCN guidelines in recommending a bone scan with a PSA level of 20 ng/mL, or with a PSA level of 10 ng/mL with a Gleason score of 7 or greater or stage T2 or greater; a PSA doubling time of 9 mo or less was added as another indication.

    For 18F-NaF PET, dedicated studies that focus specifically on recurrence are few, and these studies do not separate patients who have undergone RP from those who have undergone RT. Theoretically, the higher photon flux and coincidence detection with PET and concurrent CT should increase sensitivity and specificity, respectively, over a planar WB scan, and multiple studies, albeit mostly for initial staging35 or mixed indications of initial staging and BCR.36-38 Interestingly, 1 study showed a decline in specificity from 82% to 54%,39 whereas another showed a small decrease from 88% to 82% vis-à-vis SPECT, but with an overall improvement in both sensitivity and specificity over a planar bone scan.40 Moreover, a large retrospective study of the National Oncologic PET Registry found a change in management over a bone scan in 12%–16% of cases.41 A recent study of 62 patients with mixed indications suggests a PSA cutoff of 6 ng/mL for previously treated patients, lower than that previously suggested for a bone scan.42

    A few studies have compared 18F-NaF to other PET tracers. These generally do not separate RP from RT.43 Results of studies that compared 18F-NaF to 18F-fluorocholine are mixed. Some show increased sensitivity (for bone lesions) at the expense of specificity.39,43 One study that focused on initial staging found a similar performance for bone lesions,44 whereas another, with a mix of initial and recurrent indications, showed some loss in specificity with 18F-NaF.45 When 18F-FDG and 18F-NaF are compared, the latter is more sensitive for detecting bone metastases at BCR even at PSA levels as low as 2–4 ng/mL, albeit at the expense of specificity.46-48 For PSMA tracers, mostly in a mixed primary and recurrent population, studies show a similar pattern, with 18F-NaF detecting more bone lesions at the expense of decreased specificity;49-51 1 study showed no significant difference.52 A consistent result is that, compared with other PET tracers, 18F-NaF is more sensitive for bone lesions at the expense of specificity. It outperforms conventional 99mTc-based bone scans, which may be relevant in clinical management decisions.53 In summary, a bone scan is considered standard imaging and received an appropriateness score of 8 (appropriate).

    Category 1, Scenario 4: MRI of the Pelvis With And Without Intravenous Contrast (Score 8 – Appropriate). An MRI of the pelvis can be effective in identifying sites of recurrent prostate cancer and its use is rapidly increasing (54). Most studies demonstrate that an MRI of the pelvis is reliable for the detection of local recurrence either at the site of the prostate bed in patients who have undergone RP or within the prostate in patients after RT treatment.55-59 The combination of diffusion-weighted, T2- weighted, and dynamic contrast enhancement MRI is particularly effective for detecting local recurrence.58,60 For pelvic nodal metastatic detection, a pelvic MRI has similar limitations to that of CT, namely, low sensitivity due to the dependence on size criteria. Many lymph nodes that test positive are too small to meet the 0.8- to 1-cm size threshold for positivity on MRI. Although there was initial enthusiasm for diffusion-weighted imaging for detecting normal-sized lymph nodes at initial staging, there is no evidence in the literature that this method is valid in patients with BCR,61 and the method has proven difficult outside of research settings. When lesions are present in the pelvic bones, MRI is highly sensitive, equaling PET scans in this regard, with the caveat that findings may not be specific for bone metastases.58 MRI can be predictive of response to salvage RT from the extent of the recurrent disease.62 Thus, a pelvic MRI provides useful information, in particular for local recurrence and bone metastases in the setting of BCR, which led to an appropriateness score of 8 (appropriate).

    Category 1, Scenario 5: 18F-FDG PET/CT (Skull Base to Midthigh) (Score 2 – Rarely Appropriate). Category 2, Scenario 1: 18F-FDG PET/CT (Skull Base to Midthigh) (Score 2 – Rarely Appropriate). 18F-FDG PET/CT has revolutionized the field of cancer imaging and has become one of the pillars of management of many cancers. This huge success is not reflected in prostate cancer, where many studies have documented disappointing detection capabilities or better alternative imaging tests. This is despite some results in the literature suggesting the potential utility of 18F-FDG PET/CT in prostate cancer; this discrepancy is likely because of variability in the standards of reference used or changing paradigms in the management of BCR. For example, using standard definitions, Öztürk and Karapolat63 evaluated 18FFDG PET/CT in 28 patients with BCR after RP or RT and found that imaging results were negative in 16 (57.1%) patients and positive in 12 (42.9%). However, no summary PSA statistics for the study group were included, and no mention of biopsy confirmation was made or other measures provided to assess the true positivity of the PET findings. Schöder et al.64 reported sensitivities of 71%–80% and specificities of 73%–77% for 18F-FDG PET in the recurrence setting, where the median PSA level was 2.4 ng/mL. These results probably overestimate the clinical utility of 18F-FDG PET/CT, given that many of the patients had positive findings on other standard imaging and the PSA thresholds are considerably above those that would trigger salvage RT in the contemporary setting (typically around 0.5 ng/mL). In a subset of patients with early BCR after RP (PSA level < 1 ng/mL), a more recent study reported 18F-FDG PET positivity in only 1 of 5 patients; on directed biopsy, only inflammatory tissue was identified at the site of 18F-FDG uptake in the thoracic spine (i.e., false positive).30 Jadvar et al.46 found 18F-FDG PET/CT detection rates of only 8.1% in a prospective study of 37 patients with BCR and negative results of standard imaging. The same group published a comparative performance study of PET tracers in prostate cancer BCR and found that 18F-FDG PET/CT exhibited the lowest detection rates compared with those of 11C-acetate, 11C- or 18Fcholine, anti-1-amino-3-18F-fluorocyclobutane-1-carboxylic acid (FACBC or 18F-fluciclovine), and radiolabeled ligand targeted to PSMA.65 However, 18F-FDG PET/CT may play a role later in the course of prostate cancer, particularly in the context of metastatic disease.66-69 In summary, 18F-FDG PET/CT is rarely appropriate for the evaluation of BCR of prostate cancer after RP or RT, even in the context of negative or equivocal standard imaging results, leading to an appropriateness score of 2 (rarely appropriate).

    Category 1, Scenario 6: 11C-Choline PET/CT (Skull Base to Midthigh) (Score 6 – May be Appropriate). Category 2, Scenario 2: 11C-Choline PET/CT (Skull Base to Midthigh) (Score 9 – Appropriate). 11C-choline PET/CT has long been used in BCR and is currently incorporated into NCCN and European Association of Urology guidelines. 11C-choline was approved in the United States on September 12, 2012, for PET imaging in recurrent prostate cancer.70 The fluorinated choline radiotracer (18F-fluorocholine) has also been investigated relatively extensively and is used clinically in many countries; however, the radiotracer is not FDA approved. Although the literature on 11C-choline PET/CT is relatively robust, most reports are retrospective and rarely compare 11C-choline PET/CT to standard imaging (abdominopelvic CT, bone scan, and pelvis MRI). This is particularly true for patients with prior definitive treatment with RT, for which only 2 retrospective studies have been reported.71,72 A first meta analysis provided a pooled sensitivity of 85.6% (95% confidence interval [CI]: 82.9%–88.1%) and a pooled specificity of 92.6% (95% CI: 90.1%–94.6%) for all sites of disease.73 A more recent meta analysis,74 which considered only 11C-choline, reported a pooled sensitivity of 89% (95% CI: 83%–93%) and a pooled specificity of 89% (95% CI: 73%–96%). For local relapse, the pooled sensitivity was 61% (95% CI: 40%–80%) and the pooled specificity 97% (95% CI: 87%–99%); for nodal disease, the pooled detection rate was 36% (95% CI: 22%–50%), whereas for bone metastases, the pooled detection rate was 25% (95% CI: 16%–34%). As with all PET imaging methods, choline PET/CT sensitivity is strongly dependent on the PSA level and kinetics (velocity, doubling time, acceleration).75 In patients with BCR after RP, choline PET/CT detection rates are only 5%– 24% when the PSA level is < 1 ng/mL, but rises to 67%–100% when the PSA level is > 5 ng/mL. Therefore, a PSA cutoff level of between 1 and 2 ng/mL has been suggested for choline PET/CT imaging. It may also be advantageous to consider PSA kinetics rather than PSA levels.76 In balancing its strengths (relatively abundant literature despite its stated limitations, FDA approval, incorporation into patient management guidelines) and weaknesses (need for on-site cyclotron and hence less accessibility, relatively high cost), the panel assessed that 11C-choline PET/CT may be appropriate (appropriateness score of 6) for the first imaging approach in patients with BCR in comparison to the widely available and less costly standard imaging. However, in patients with negative or equivocal conventional imaging results, the appropriateness score was raised to 9 (appropriate).

    Category 1, Scenario 7: 18F-Fluciclovine PET/CT (Skull Base to Midthigh) (Score 6 – May be Appropriate). Category 2, Scenario 3: 18F-Fluciclovine PET/CT (Skull Base to Midthigh) (Score 9 – Appropriate). 18F-fluciclovine (Axumin) was FDA approved on May 26, 2016, for PET imaging in men with suspected prostate cancer recurrence based on elevated PSA levels after prior treatment.77 It was prospectively shown in 89 patients that 18Ffluciclovine, in comparison to 11C-choline, is generally superior for detection of recurrence, especially for PSA values of , 2 ng/mL (18F-fluciclovine vs. 11C-choline: 21% vs. 14% for PSA level of , 1 ng/mL, 29% vs. 29% for PSA level of 1 to , 2 ng/mL, 45% vs. 36% for PSA level of 2 to , 3 ng/mL, and 59% vs. 50% for PSA level of $ 3 ng/mL).78 The overall sensitivity, specificity, and positive predictive values were 37%, 67%, and 97%, respectively, for 18F-fluciclovine and 32%, 40%, and 90%, respectively, for 11C-choline. In a large multisite study with 596 patients, an overall detection rate of 68% was reported. 18F-fluciclovine uptake suspicious for disease recurrence was found in the prostate bed and pelvic lymph node regions in 39% and 33% of scans, respectively. Metastatic involvement outside the pelvis was detected in 27% of scans. The corresponding positive predictive value was 62% for all detected lesions, with 92% for extraprostatic involvement and 72% for prostate/bed involvement.79 Another recent study that focused on patients with a PSA level of # 1 ng/mL reported an overall positive lesion detection rate of 46.4%, with local and nodal recurrences detected more often than distant metastases, and with a Gleason score of greater than 7 associated with positive scan results.80 The use of 18F-fluciclovine PET/ CT has an impact on the clinical management of patients with BCR of prostate cancer. The prospective multicenter LOCATE trial reported a change in management in 59% of patients. Within this cohort, there were changes from salvage or noncurative systematic therapy to watchful waiting in 25% of patients, from noncurative systematic therapy to salvage therapy in 24%, and from salvage therapy to noncurative systemic therapy in 9%.81 Another investigation reported change in salvage RT management of 41% of patients who had undergone a prostatectomy.82 Although not as sensitive as PSMA-targeted PET agents, 18F-fluciclovine is nevertheless approved in the United States in the setting of recurrent disease. Similar to its consideration of 11C-choline, the panel assessed that 18F-fluciclovine PET/CT may be appropriate (appropriateness score of 6) as the first imaging approach in patients with BCR in comparison to the widely available and lower cost standard imaging. However, in the setting of negative or equivocal conventional imaging results, the panel recommended a score of 9 (appropriate) for 18F-fluciclovine.

    Category 1, Scenario 8: 111In-Capromab Pendetide (Score 1 – Rarely Appropriate). Category 2, Scenario 4: 111In-Capromab Pendetide (Score 1 – Rarely Appropriate). 111In-capromab pendetide is a radioimmunoconjugate consisting of the murine IgG1 k-monoclonal antibody capromab (7E11-C5.3) conjugated to the linker-chelator glycyl-tyrosyl-(N,-diethylenetriaminepentaacetic acid)- lysine hydrochloride (GYK-DTPA-HCl) and labeled with radioisotope 111In, with ligand-binding and g-emitting activities. It binds to a cytoplasmic epitope of human PSMA, a cell transmembrane glycoprotein abundantly expressed by prostate epithelium, and is typically overexpressed by prostate cancer cells.83 Radioimmunoscintigraphy imaging with 111In-capromab pendetide was approved by the FDA on October 28, 1996, as a diagnostic imaging agent in newly diagnosed patients with biopsy-proven prostate cancer.84

    The utility of imaging with 111In-capromab pendetide for prostate cancer has been the subject of continual debate since its approval. Its disappointing low levels of both sensitivity and specificity significantly limited its use and acceptance. This seems to be an inherent property of the labeled antibody, which has not been shown to yield progressively better accuracy with the experience of the image interpreter, likely because of the agent’s dependence on cytoplasmic binding, which achieves better results with nonviable than with viable tumor tissue. Another major limitation of this agent is that the antibody remains in the blood, leading to high background signals and consequently reduced target-to-background ratios and detection rates.

    In a study of 30 men with biochemical relapse after prostatectomy who received salvage RT, 111In-capromab pendetide scan results were compared with postsalvage RT PSA response.85 In these patients, presalvage RT 111In-capromab pendetide scan findings outside the prostate fossa were not predictive of biochemical control after RT. Pucar et al.86 concluded that 111In-capromab pendetide had ‘‘no added benefit over other imaging modalities [available at that time] in evaluating postradical prostatectomy recurrence, due to its low sensitivity for detecting local recurrences and bone metastases.’’ Another study evaluated 111In-capromab pendetide against 18F-fluciclovine.87,88 It found that PET/CT with 18F-fluciclovine demonstrated superior sensitivity, specificity, and accuracy to that of 111In-capromab for the detection of disease, both in the prostatic bed and in extraprostatic sites.

    Notably, despite FDA approval and widespread use of 111Incapromab pendetide in the United States for more than 22 y, many health insurance providers will still not provide standard insurance coverage for imaging with 111In-capromab pendetide for prostate cancer, which continues to be categorized as ‘‘investigational,’’ with the notation that the current medical literature ‘‘is insufficient to support conclusions concerning efficacy, optimal use and impact on the diagnosis, treatment or clinical management of prostate cancer using radioimmunoscintigraphy imaging with 111In capromab pendetide’’.89,90 Thus, 111In-capromab pendetide (marketed exclusively as) is no longer recommended in the setting of BCR. As of July 9, 2018, the FDA also reports on their website that Aytu BioScience, the manufacturer of ProstaScint, reported voluntary discontinuation of the product.91 As a result, the panel assigned an appropriateness score of 1 (rarely appropriate) to 111In-capromab pendetide.

    Qualifying Statements

    Special Commentary

    In addition to the currently approved radiotracers for imaging of prostate cancer (18F-fluciclovine and 11C-choline), a new class of radiotracers has been developed that targets the PSMA.92,93 The most commonly used compound is 68Ga-PSMA-11, which is limited in production and distribution, as it is labeled with 68Ga (half-life 5 68 min) and is not yet approved in the United States.94,95 68Ga-PSMA-11 has been shown to have a higher detection sensitivity compared with that of 18F-fluorocholine96,97 and has also recently been compared with 18F-fluciclovine and shown to be superior in lesion detection.98,99 Recently, a 635-patient single-arm clinical trial of 68Ga-PSMA-11 demonstrated substantial interreader reproducibility and high detection sensitivity and accuracy compared with a composite endpoint in patients with BCR.100 68Ga-PSMA-11 PET localized recurrent prostate cancer in 75% of patients; detection rates significantly increased with PSA level: 38% for < 0.5 ng/mL, 57% for 0.5 to < 1.0 ng/mL, 84% for 1.0 to < 2.0 ng/mL, 86% for 2.0 to < 5.0 ng/mL, and 97% for ≥ 5.0 ng/mL. PSMA PET resulted in changes in RT plans in 53% of patients undergoing definitive RT.101,102 In the salvage setting, Calais et al.103,104 showed that of 270 patients with a PSA level of < 1 ng/mL, use of 68Ga-PSMA11 PET/CT had a major impact on RT planning in 19%, justifying a randomized imaging trial of salvage RT.

    Although much of the data with PSMA-targeted PET radiotracers have focused on 68Ga-labeled agents, the use of 18F as a radionuclide has several advantages, including nearly unlimited cyclotron-based production, feasible central distribution due to a 110-min physical half-life (vs. 68 min for 68Ga), higher positron yield, and lower positron energy (leading to shorter positron annihilation distances and higher spatial resolution).105,106 These intrinsic advantages may lead to the widespread adoption of 18F-labeled ligands as the worldwide demand for PSMA-targeted radiotracers continues to increase. 18F-labeled PSMA-targeted radiotracers have shown high sensitivity for the detection of putative sites of prostate cancer in men with BCR after attempted curative therapy. More recently, Giesel et al.107 used a different 18F-labeled radiotracer known as 18F-PSMA-1007 in a retrospective analysis of 251 patients with BCR of prostate cancer. This tracer exhibits more hepatic and less renal excretion, potentially simplifying evaluation of the pelvis. In total, 204 of 251 (81.3%) patients had findings on 18F-PSMA-1007 PET deemed to be evidence of a site or sites of recurrent disease. The patient detection efficiency at the PSA range of 0.2–0.5 ng/mL was 40 of 65 (61.5%). In another prospective investigation with 18F-DCPyL PET/CT in 31 patients with BCR after RP, the positive detection rate was 59.1% in patients with a PSA level of < 1.0 ng/mL and 88.9% in patients with a PSA level of > 1.0 ng/mL.108 Rousseau et al.109 reported a similar high detection efficacy with 18F-DCFPyL in 130 patients with BCR after curative intent primary therapy, with positive findings in 60% (PSA level ≥ 0.4 to < 0.5 ng/mL), 78% (≥ 0.5 to < 1.0 ng/mL), 72% (≥ 1.0 to < 2.0 ng/mL), and 92% (≥ 2.0 ng/mL) of cases. Currently, it is unclear whether there is a benefit of one PSMA targeted agent over another, but because of the physical advantages of 18F-labeled compounds, they will likely play a dominant role after they have been approved and become available.

    In summary, PSMA PET is anticipated to have a significant role in the imaging evaluation of patients with BCR given its higher sensitivity and accuracy, although currently we are awaiting approval of these agents in the United States. Aside from regulatory approval, ongoing and future prospective investigations will be needed to examine how PSMA-based theranostics provide added clinical value and have an impact on treatment strategy, patient outcome, and relative economic outlay.110

    Implementation of the AUC Guidance

    SNMMI has been developing the AUC for high-value nuclear medicine procedures since early 2015. This initiative was primarily undertaken to assist referring physicians and ordering professionals fulfill the requirements of the 2014 Protecting Access to Medicare Act (PAMA). Section 218(b) of PAMA established a new program under the statute for fee-for-service Medicare to promote the use of AUC for Advanced Diagnostic Imaging Services (ADIS), including CT, MRI, and all nuclear medicine procedures such as PET. PAMA requires referring physicians to consult AUC developed by a Centers for Medicare and Medicaid Services (CMS)–approved qualified provider-led entity, or Q-PLE, to ensure cost-effective and appropriate use of ADIS. After going through a rigorous and extensive application that required SNMMI to document their guideline development process, including COI adjudication and composition of expert panels, the society was approved as a Q-PLE in June 2016.

    The PAMA legislation requiring the development of AUC also stipulated the mechanism of their delivery through a ‘‘qualified clinical decision support mechanism’’ (Q-CDSM) before ordering any advanced imaging. Therefore, successful implementation and complete adoption of this program relies on integration of AUC developed by PLEs into these Q-CDSMs. The society has partnered with leading CDSM providers to facilitate the adoption and use of SNMMI AUC.

    Final implementation of the AUC program has been delayed until January 2020, in part so that the CMS can issue more substantive guidance for the priority clinical areas and exceptions for the ordering professionals for whom consultation with AUC would pose significant hardship. Delaying implementation also provides more preparation time for the referring physicians and health-care institutions to comply with the legislative requirements. 

    Acknowledgments

    The workgroup acknowledges staff support from the Pacific Northwest Evidence-Based Practice Center of Oregon Health and Science University (Roger Chou, MD, FACP, Director, and Miranda Pappas, MA, Project Manager, Research Associate).

    Appendix A: Workgroup Members and External Reviewers

    Workgroup

    The members of the workgroup are Hossein Jadvar, MD, PhD, MPH, MBA (Chair), University of Southern California Keck School of Medicine, Los Angeles, CA (SNMMI); Leslie K. Ballas, MD, University of Southern California Keck School of Medicine, Los Angeles, CA (ASTRO); Peter L. Choyke, MD, National Institutes of Health, Bethesda, MD (ASCO); Stefano Fanti, MD, University of Bologna, Bologna, Italy (EANM); James L. Gulley, MD, PhD, National Institutes of Health, Bethesda, MD (ACP); Ken Herrmann, MD, Department of Nuclear Medicine, Universit¨atsklinikum Essen, Essen, Germany, and Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA (EANM); Thomas A. Hope, MD, University of California San Francisco, San Francisco, CA (SNMMI); Alan K. Klitzke, MD, Roswell Comprehensive Cancer Center, Buffalo, NY (ACNM); Jorge Oldan, MD, University of North Carolina, Chapel Hill Hospitals, Chapel Hill, NC (ASCO, SNMMI); Martin G. Pomper, MD, PhD, Johns Hopkins University Medical School, Baltimore, MD (WMIS); Steven P. Rowe, MD, PhD, Johns Hopkins University Medical School, Baltimore, MD (SNMMI); Rathan M. Subramaniam, MD, PhD, MPH, University of Texas Southwestern Medical Center, Dallas, TX (ACNM, ACR); Samir S. Taneja, MD, NYU Langone Medical Center, New York, NY (AUA); Herbert Alberto Vargas, MD, Memorial Sloan Kettering Cancer Center, New York, NY (ASCO).

    External Reviewers

    The external (peer) reviewers were Soroush Rais-Bahrami, MD, University of Alabama, Birmingham, AL; Andrei Purysko, MD, Cleveland Clinic, Cleveland, OH; Jefferey Weinreb, MD, Yale New Haven Hospital, New Haven, CT; Laura Evangelista, MD, PhD, Istituto Oncologico Veneto IOV – IRCCS Padova, Italy; Bridget F. Koontz, MD, Duke University, Durham, NC; Mack Roach III, MD, University of California, San Francisco, CA.

    SNMMI

    The supporting staff from SNMMI are Sukhjeet Ahuja, MD, MPH, Sr. Director, Health Policy & Quality Department; Teresa Ellmer, MIS, CNMT, Senior Program Manager, Health Policy & Quality Department; Julie Kauffman, Program Manager, Health Policy & Quality Department.

    Appendix B: Disclosures and Conflicts of Interest (COIs)

    SNMMI rigorously attempted to avoid any actual, perceived, or potential COIs that might have arisen as a result of an outside relationship or personal interest on the part of the workgroup members or external reviewers. Workgroup members were required to provide disclosure statements of all relationships that might be perceived as real or potential COIs. These statements were reviewed and discussed by the workgroup chair and SNMMI staff and were updated and reviewed by an objective third party at the beginning of every workgroup meeting or teleconference. The disclosures of the workgroup members can be found in Table 3. A COI was defined as a relationship with industry—including consulting, speaking, research, and nonresearch activities—that exceeds $5,000 in funding over the previous or upcoming 12- month period. In addition, if an external reviewer was either the principal investigator of a study or another key member of the study personnel, that person’s participation in the review was considered likely to present a COI. All reviewers were asked about any potential COI. A COI was also considered likely if an external reviewer or workgroup member was either the principal investigator or a key member of a study directly related to the content of this AUC. All external reviewers were asked about any potential COI.

    Table 3. Relationships with Industry and Other Entities

    Relationships with Industry and Other Entities

    Appendix C: Public Commentary

    The workgroup solicited information from all communities through the SNMMI website and through direct solicitation of SNMMI members. The comments and input helped to shape the development of these AUC on imaging evaluation of BCR of prostate cancer after definitive primary treatment.

    Authors: Hossein Jadvar1, Leslie K. Ballas2, Peter L. Choyke3, Stefano Fanti4, James L. Gulley5, Ken Herrmann4, Thomas A. Hope1, Alan K. Klitzke6, Jorge D. Oldan1,3, Martin G. Pomper7, Steven P. Rowe1, Rathan M. Subramaniam6,8, Samir S. Taneja9, Herbert Alberto Vargas3, and Sukhjeet Ahuja1
    1. Society of Nuclear Medicine and Molecular Imaging, Reston, Virginia
    2. American Society for Radiation Oncology, Arlington, Virginia
    3. American Society of Clinical Oncology, Alexandria, Virginia
    4. European Association of Nuclear Medicine, Vienna, Austria
    5. American College of Physicians, Philadelphia, Pennsylvania
    6. American College of Nuclear Medicine, Reston, Virginia
    7. World Molecular Imaging Society, Culver City, California
    8. American College of Radiology, Reston, Virginia
    9. American Urological Association, Linthicum Heights, Maryland

    Related Content:
    View or Download: Appropriate Use Criteria for Imaging Evaluation of Biochemical Recurrence of Prostate Cancer After Definitive Primary Treatment
    View or Download: Condensed Fact sheet: Explanation of Appropriate Use Criteria (AUC) for Diagnostic Procedures 

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    51. Harmon SA, Bergvall E, Mena E, et al. A prospective comparison of 18Fsodium fluoride PET/CT and PSMA-targeted 18F-DCFBC PET/CT in metastatic prostate cancer. J Nucl Med. 2018;59:1665–1671.
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    57. Hayman J, Hole KH, Seierstad T, et al. Local failure is a dominant mode of recurrence in locally advanced and clinical node positive prostate cancer patients treated with combined pelvic IMRT and androgen deprivation therapy. Urol Oncol. 2019;37:289.e19–289.e26.
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    59. Sobol I, Zaid HB, Haloi R, et al. Contemporary mapping of post-prostatectomy prostate cancer relapse with 11C-choline positron emission tomography and multiparametric magnetic resonance imaging. J Urol. 2017;197:129–134.
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    62. Sharma V, Nehra A, Colicchia M, et al. Multiparametric magnetic resonance imaging is an independent predictor of salvage radiotherapy outcomes after radical prostatectomy. Eur Urol. 2018;73:879–887.
    63. Öztürk H, Karapolat I. 18F-fluorodeoxyglucose PET/CT for detection of disease in patients with prostate-specific antigen relapse following radical treatment of a local-stage prostate cancer. Oncol Lett. 2016;11:316–322.
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    65. Yu CY, Desai B, Ji L, Groshen SG, Jadvar H. Comparative performance of PET tracers in biochemical recurrence of prostate cancer: a critical analysis of literature. Am J Nucl Med Mol Imaging. 2014;4:580–601.
    66. Fox JJ, Gavane SC, Blanc-Autran E, et al. Positron emission tomography/computed tomography-based assessments of androgen receptor expression and glycolytic activity as a prognostic biomarker for metastatic castration-resistant prostate cancer. JAMA Oncol. 2018;4:217–224.
    67. Jadvar H, Desai B, Ji L, et al. Baseline 18F-FDG PET/CT parameters as imaging biomarkers of overall survival in castrate-resistant metastatic prostate cancer. J Nucl Med. 2013;54:1195–1201.
    68. Vargas HA, Wassberg C, Fox JJ, et al. Bone metastases in castration-resistant prostate cancer: associations between morphologic CT patterns, glycolytic activity, and androgen receptor expression on PET and overall survival. Radiology. 2014;271:220–229.
    69. Jadvar H, Velez EM, Desai B, Ji L, Colletti PM, Quinn DI. Prediction of time to hormonal treatment failure in metastatic castrate sensitive prostate cancer. J Nucl Med. 2019;60:1524–1530.
    70. FDA approves 11C-choline for PET in prostate cancer. J Nucl Med. 2012;53:11N.
    71. Rybalov M, Breeuwsma AJ, Leliveld AM, Pruim J, Dierckx RA, de Jong IJ. Impact of total PSA, PSA doubling time and PSA velocity on detection rates of 11C-Choline positron emission tomography in recurrent prostate cancer. World J Urol. 2013;31:319–323.
    72. Ceci F, Herrmann K, Castellucci P, et al. Impact of 11C-choline PET/CT on clinical decision making in recurrent prostate cancer: results from a retrospective two-center trial. Eur J Nucl Med Mol Imaging. 2014;41:2222–2231.
    73. Evangelista L, Zattoni F, Guttilla A, et al. Choline PET or PET/CT and biochemical relapse of prostate cancer: a systematic review and meta-analysis. Clin Nucl Med. 2013;38:305–314.
    74. Fanti S, Minozzi S, Castellucci P, et al. PET/CT with 11C-choline for evaluation of prostate cancer patients with biochemical recurrence: meta-analysis and critical review of available data. Eur J Nucl Med Mol Imaging. 2016;43:55–69.
    75. Treglia G, Ceriani L, Sadeghi R, Giovacchini G, Giovanella L. Relationship between prostate-specific antigen kinetics and detection rate of radiolabelled choline PET/CT in restaging prostate cancer patients: a meta-analysis. Clin Chem Lab Med. 2014;52:725–733.
    76. Castellucci P, Ceci F, Graziani T, et al. Early biochemical relapse after radical prostatectomy: which prostate cancer patients may benefit from a restaging 11C-choline PET/CT scan before salvage radiation therapy? J Nucl Med. 2014;55:1424–1429.
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    78. Nanni C, Zanoni L, Pultrone C, et al. 18F-FACBC (anti1-amino-3-18F-fluorocyclobutane1-carboxylic acid) versus 11C-choline PET/CT in prostate cancer relapse: results of a prospective trial. Eur J Nucl Med Mol Imaging. 2016;43:1601–1610.
    79. Bach-Gansmo T, Nanni C, Nieh PT, et al. Multisite experience of the safety, detection rate and diagnostic performance of fluciclovine (18F) positron emission tomography/computerized tomography imaging in the staging of biochemically recurrent prostate cancer. J Urol. 2017;197:676–683.
    80. England JR, Paluch J, Ballas LK, Jadvar H. 18F-fluciclovine PET/CT detection of recurrent prostate carcinoma in patients with serum PSA # 1 ng/mL after definitive primary treatment. Clin Nucl Med. 2019;44:e128–e132.
    81. Andriole GL, Kostakoglu L, Chau A, et al. The impact of positron emission tomography with 18F-fluciclovine on the treatment of biochemical recurrence of prostate cancer: results from the LOCATE trial. J Urol. 2019;201:322–331.
    82. Akin-Akintayo OO, Jani AB, Odewole O, et al. Change in salvage radiotherapy management based on guidance with FACBC (fluciclovine) PET/CT in postprostatectomy recurrent prostate cancer. Clin Nucl Med. 2017;42:e22–e28.
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    85. Thomas CT, Bradshaw PT, Pollock BH, et al. Indium-111-capromab pendetide radioimmunoscintigraphy and prognosis for durable biochemical response to salvage radiation therapy in men after failed prostatectomy. J Clin Oncol. 2003;21:1715–1721.
    86. Pucar D, Sella T, Schöder H. The role of imaging in the detection of prostate cancer local recurrence after radiation therapy and surgery. Curr Opin Urol. 2008;18:87–97.
    87. Schuster DM, Nieh PT, Jani AB, et al. Anti-3-[18F]FACBC positron emission tomography-computerized tomography and 111In-capromab pendetide single photon emission computerized tomography-computerized tomography for recurrent prostate carcinoma: results of a prospective clinical trial. J Urol. 2014;191:1446–1453.
    88. Schuster DM, Savir-Baruch B, Nieh PT, et al. Detection of recurrent prostate carcinoma with anti-1-amino-3-18F-fluorocyclobutane-1-carboxylic acid PETCT and 111In-capromab pendetide SPECT/CT. Radiology. 2011;259:852–861.
    89. BlueCross BlueShield of Tennessee Medical Policy Manual. Radioimmunoscintigraphy imaging (monoclonal antibody imaging) with Indium-111 capromab pendetide for prostate cancer. https://www.bcbst.com/mpmanual/Radioimmunoscintigraphy_ Imaging_Monoclonal_Antibody_Imaging_with_Indium-111_Capromab_Pendetide_for_Prostate_Cancer_.htm. Published November 10, 2007. Reviewed October 11, 2018. Accessed September 11, 2019.
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    91. Aytu BioScience discounting PROSTASCINT (Cpromab Pendetide) Kit [letter]. April 2018. http://www.radiopharmaceuticals.info/uploads/7/6/8/7/76874929/ prostascint_discontinue_letter_april_2018_final.pdf. Accessed September 11, 2019.
    92. Afshar-Oromieh A, Babich JW, Kratochwil C, et al. The rise of PSMA ligands for diagnosis and therapy of prostate cancer. J Nucl Med. 2016;57:79S–89S.
    93. Eiber M, Maurer T, Souvatzoglou M, et al. Evaluation of hybrid 68Ga-PSMA ligand PET/CT in 248 patients with biochemical recurrence after radical prostatectomy. J Nucl Med. 2015;56:668–674.
    94. Hope TA, Goodman JZ, Allen IE, Calais J, Fendler WP, Carroll PR. Metaanalysis of 68Ga-PSMA-11 PET accuracy for the detection of prostate cancer validated by histopathology. J Nucl Med. 2019;60:786–793.
    95. Perera M, Papa N, Christidis D, et al. 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;70:926–937.
    96. Morigi JJ, Stricker PD, van Leeuwen PJ, et al. Prospective comparison of 18Ffluoromethylcholine versus 68Ga-PSMA PET/CT in prostate cancer patients who have rising PSA after curative treatment and are being considered for targeted therapy. J Nucl Med. 2015;56:1185–1190.
    97. Afshar-Oromieh A, Zechmann CM, Malcher A, et al. Comparison of PET imaging with a 68Ga-labelled PSMA ligand and 18F-choline-based PET/CT for the diagnosis of recurrent prostate cancer. Eur J Nucl Med Mol Imaging. 2014;41:11–20.
    98. Calais J, Ceci F, Eiber M, et al. 18F-fluciclovine PET-CT and 68Ga-PSMA-11 PET/CT in patients with early biochemical recurrence after prostatectomy: a prospective, single-centre, single-arm, comparative imaging trial. Lancet Oncol. 2019;9:1286–1294.
    99. Lawhn-Heath C, Flavell RR, Behr SC, et al. Single-center prospective evaluation of 68Ga-PSMA-11 PET in biochemical recurrence of prostate cancer. AJR. 2019;213:266–274.
    100. Fendler WP, Calais J, Eiber M, et al. Assessment of 68Ga-PSMA-11 PET accuracy in localizing recurrent prostate cancer: a prospective single-arm clinical trial. JAMA Oncol. 2019;5:856–863.
    101. Wu SY, Boreta L, Shinohara K, et al. Impact of staging 68Ga-PSMA-11 PET scans on radiation treatment plans in patients with prostate cancer. Urology. 2019;125:154–162.
    102. Calais J, Fendler WP, Eiber M, et al. Impact of 68Ga-PSMA-11 PET/CT on the management of prostate cancer patients with biochemical recurrence. J Nucl Med. 2018;59:434–441.
    103. Calais J, Czernin J, Cao M, et al. 68Ga-PSMA-11 PET/CT mapping of prostate cancer biochemical recurrence after radical prostatectomy in 270 patients with a PSA level of less than 1.0 ng/mL: impact on salvage radiotherapy planning. J Nucl Med. 2018;59:230–237.
    104. Calais J, Czernin J, Fendler WP, Elashoff D, Nickols NG. Randomized prospective phase III trial of 68Ga-PSMA-11 PET/CT molecular imaging for prostate cancer salvage radiotherapy planning. BMC Cancer [PSMA-SRT]. 2019;19:18.
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    108. Rowe SP, Campbell SP, Mana-Ay M, et al. Prospective evaluation of PSMAtargeted 18F-DCFPyL PET/CT in men with biochemical failure after radical prostatectomy for prostate cancer. J Nucl Med. 2020;61:58–61.
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    Published May 20, 2020
  • ASCO 2020: CONDOR The Impact of PSMA-targeted Imaging with 18F-DCFPyL-PET/CT on Clinical Management of Patients with Biochemically Recurrent Prostate Cancer

    (UroToday.com) Men with biochemically recurrent prostate cancer after definitive local therapy currently have limited imaging modalities in the United States which are sensitive or specific enough to detect tumor recurrence. PSMA PET scans can improve on this detection by detecting cells expressing PSMA protein on their cell surface. Several PSMA tracers are under development, including 18F-DCFPyL, a fluorinated PSMA-targeted agent which has shown has shown reliable diagnostic performance in detecting metastatic or recurrent prostate cancer1. This study evaluates how PyL PET/CT may change clinical management for these men with biochemical recurrence.
    Published May 29, 2020
  • ASCO 2020: Is PSMA Right on Target?

    (UroToday.com) There are currently significant imaging deficiencies for men with prostate cancer (Figure 1), with the hope that PSMA imaging-based modalities will address a significant gap in this field. Prostate-specific membrane antigen PSMA is a transmembrane glycoprotein with folate hydrolase activity. It is very specific in differentiating benign and malignant prostate cells. It has been shown to be overexpressed in prostate cancer cells, and especially in metastatic and castrate-resistant disease.

    Published May 29, 2020
  • ASCO GU 2019: Randomized Phase III Trial of 68Ga-PSMA-11 PET/CT Molecular Imaging for Prostate Cancer Salvage Radiotherapy Planning

    San Francisco, CA (UroToday.com)  Salvage radiotherapy (SRT) for prostate cancer biochemical recurrence after radical prostatectomy (RP) is commonly administered to patients with PSA < 1 ng/mL, a threshold at which standard-of-care imaging is not sensitive enough to detect disease recurrence.  68Ga-PSMA-11 PET/CT (PSMA) PET/CT molecular imaging is highly sensitive for detecting regional and distant metastatic recurrent prostate cancer at low PSA levels. This lead to the assumption that PSMA can help guide and improve SRT.  
    Published February 15, 2019
  • ASCO GU 2019: Results of a 50 Patient Single-Centre Phase II Prospective Trial of Lutetium-177 PSMA-617 Theranostics in mCRPC

    San Francisco, CA (UroToday.com) PSMA is over-expressed in all prostate tissue, including prostatic carcinoma. Lutetium-177 (177Lu)-PSMA617 (LuPSMA) is a small radiolabeled molecule which binds to PSMA and delivers a dose of β radiation. Lutetium-177 is a good partner to help deliver the radiation because of the short range β radiation (maximal tissue penetration of <2mm), thereby decreasing the potential collateral damage to nearby organs. 

    Published February 16, 2019
  • ASCO GU 2020: Challenging Cases in Prostate Cancer – Case 1: PSMA PET/CT Imaging

    San Francisco, California (UroToday.com)  The first case presented was that of a 54-year-old otherwise healthy man who underwent radical prostatectomy after biopsy-confirmed prostate cancer. Pathology revealed a pT3b tumor, Gleason 4+3 = 7 with tertiary Gleason 5, pNx, negative surgical margins. The patient was lost to follow-up but then eventually returned and was found to have a PSA of 1.6 ng/mL, confirmed two weeks later at 1.8 ng/mL.

    Published February 14, 2020
  • ASCO GU 2020: PSMA PET Who Should Undergo Advanced Imaging in the Current Era

    San Francisco, California (UroToday.com) Advanced imaging is increasingly being used across all stages of prostate cancer. Dr. Jeremie Calais from UCLA Medical Center discussed who should undergo prostate specific membrane antigen (PSMA) PET imaging in the current era.

    Published February 13, 2020
  • Assessment of Simplified Methods for Quantification of 18F FDHT Uptake Scans in Patients with Metastasized Castrate-Resistant Prostate Cancer - Gem Kramer

    (Length of Presentation: 8 min)

    This presentation represents a study performed to assess if [18F]FDHT PET/CT could be a valuable imaging biomarker in patients with prostate cancer.

    Biographies:

    Gem Kramer, Radiology and Nuclear Medicine VU University Medical Center Amsterdam the Netherlands


    Read the Full Video Transcript

    Gem Kramer: Thank you very much for the introduction. First, this study was financially supported by the Movember Foundation. 

    So as we all know, the androgen receptor is critical for the development of prostate cancer and is one of the motors in early stage prostate cancer. However, even if the prostate cancer had progressed into castration-resistant prostate cancer, it remains to play a role in either through ligand-dependent activation, like overexpression or de novo androgenesis the tumor itself or through ligand-independent activation.

    So, recently, in recent years, all kinds of new therapies have been developed like enzalutamide or abiraterone targeting these androgen receptors, however, 50% of the patients receiving these treatments remain non-responders. And to avoid unnecessary treatment and costs it will be very nice to have a prognostic imaging biomarker, in this case, imaging, to evaluate response and to indicate which patients are going to respond to therapy and which not. 

    This is where the FDHT comes in. The F18 fluorodihydrotestosterone, so actually it's fluorine labeled to dihydrotestosterone, as we see on the picture to the right and this enables you to noninvasively image androgen receptors. So if you want to use this tracer as a biomarker you can do it using visualization, but if you want to adequately assess response one would need quantification as well.

    The golden standard, of course, is a non-linear regression. Only this is not generally applicable in clinical practice, so, therefore, we need more simplified methods.  The aim of this study was, therefore, to assess whether the simplified methods for quantification of FDHT uptake in patients with mCRPC are adequate. 

    So, what did we do in this study? First, we tried to determine which was the optimal non-linear model describing the pharmacokinetics of FDHT. Second, we looked at continuous arterial sampling versus image-derived input function, and calibrate for arterial and venous samples and see where it was possible to leave the continuous arterial sampling out. Second, we looked at linearization models like Patlak and Logan plots and compared them to non-linear regression. And last, but not least, we looked also at different static methods of simplification. So, the most simple of body weight but also tissue to blood ratio and sort of corrected for the parent plasma. As you see here, this line is the FDHT so the parent plasma of FDHT. And you see it rapidly metabolizes, so after 30 minutes there's almost nothing left. So we also correct for this rapid metabolization and through correcting for parent plasma and also for the area on the curve plasma. 

    We included eight patients for this study, both test and retest data. Four scans were available with continuous arterial sampling, arterial samples, and venous sampling. And 12 were available using only venous samples. And only patients with mCRPC were included, so they do have testosterone levels lower than 1.7 nanomoles per liter. And they had to have progressive disease according to PSA rise or new lesions according to imaging through RECIST or two new lesions on a bone scan. And they were excluded if they were already treated with anti-androgens, like enzalutamide, or at a low HB so you couldn't do the arterial sampling.

    So the scan protocol was as follows. First, there was a dynamic FDHT-PET scan for 30 minutes using continuous arterial sampling. And also we did five arterial manual samples to correct for metabolites later on, and three venous to compare those. After this first dynamic scan, we took a short break of 15 minutes, where the patient had to go to the toilet and when he came back we put him on the table again and we did a whole body FDHT-PET scan at 45 minutes post-injection. 

    Using the scans, we obtained than an image-derived input function by placing a writ of interest in the ascending aorta and calibrating those with the venous and arterial samples. And we did the same, we also obtained a writ of interest for the tumor TAC by using a 50 percent --. 

    Using this data, we performed a nonlinear aggression to obtain the optimal model like I already explained and we found that the two tissue 3K model with bloodborne infection was a model ultimately describing the pharmacokinetics. This is an irreversible model, we are going to be looking at Ki for now.

    We compared the Ki of the continuous sampling with the Kiof the image derived input function with corrected for venous sampling and we saw a near perfect correlation of 0.89 of 98th. So wherefore assumed that we can replace the arterial sampling by need of at least corrected for three venous samples. 

    We looked further. We went to the Patlak and Logan analysis and compared those and what we found was that the Patlak always gave normal varies where Logan had a lot of misfits, which we suspected cause Logan actually is more likely to, irreversible traces where this was more irreversible. And here if you compare the Ki on nonlinear aggression with the Patlak Ki, also see a good correlation. 

    The only thing of this method, the nonlinear regression is you need the extra scan, for cleaning would be nice to use the extra scan so we looked at SUV body weight and what we saw here was that the correlation went down to the S squared was only 0.77 but there seems to be kind of split in the data so we were looking further into this. And this data is actually of one patient while the other 12 patients are on the other line shown a really good correlation of still above 0.90. So looked into this individual patient previous, really early in the disease and also fast progressive so this might be a different kind of metabolism is not, faster metabolizer compared to the patient who is already further in their disease. This was one with no treatment, no dose, no nothing before this.

    So we tried to correct for this and actually was using the tissue to blood ratio and we found that actually here the surf corrected for the area of the curve of current plasma completely reversed the effect, no outline anymore. Suggesting also this is the metabolism of the tracer is different in this one patient and if you look for the other ways to simplify it you see that it doesn't really change. So if you correct serve only for the parent plasma or blood concentration the R squared stays more or less the same.

    In conclusion, quantification of FDHG update performed using the simplified method, it's possible. We can replace the continuous arterial sampling by -- if you use the surf correctly the area of the curve of parent plasma or the Patlak you get a near perfect correlation. However, you need an extra scan also to obtain the area on the curve of parent plasma and when you further simple case the methods this results in a decreased accuracy of the scans and the quantification. These are the acknowledgments, I would like to thank you for your attention.
    Published October 17, 2017
  • Axumin™ [Fluciclovine F18]: An Accurate Imaging Approach for Patients with Biochemically Recurrent Prostate Cancer

    Published in Everyday Urology - Oncology Insights: Volume 1, Issue 2
    Published Date: June 2016

    Prostate cancer [PCa] affects 1 man in 7 in the United States, making this the most commonly diagnosed non-cutaneous cancer in males.  Although an ever-increasing number of treatment options exist, an estimated 26,100 men will still die of the disease in the US in 2016, generally after primary local and systemic treatments for prostate cancer have failed.
    Published November 17, 2016
  • Clinical translation of a PSMA inhibitor for (99m)Tc-based SPECT.

    Prostate-specific membrane antigen (PSMA) is highly over-expressed in advanced prostate cancers. (68)Ga-labeled PSMA inhibitors (iPSMA) are currently used for prostate cancer detection by PET imaging.

    Published February 24, 2017
  • Co-Delivery of Docetaxel and p44/42 MAPK siRNA Using PSMA Antibody-Conjugated BSA-PEI Layer-by-Layer Nanoparticles for Prostate Cancer Target Therapy.

    How to overcome the low accumulation of chemotherapeutic agent in tumor tissue and exhibit multitherapeutics remains an ongoing challenge for cancer treatment. Here, a simple method is demonstrated that used to prepare prostate-specific membrane antigen antibody (PSMAab )-conjugated fluorescent bovine serum albumin (BSA)-branched polyethylenimine layer-by-layer nanoparticles (BSA-PEILBL NPs) for co-delivery of docetaxel (DTX) and p44/42 mitogen-activated protein kinase (MAPK) small interfering RNA (p44/42 MAPK siRNA) as synergistic and selective inhibition of cancer cell proliferation platform.

    Published February 3, 2017
  • Comparison of standard and delayed imaging to improve the detection rate of [(68)Ga]PSMA I&T PET/CT in patients with biochemical recurrence or prostate-specific antigen persistence after primary therapy for prostate cancer.

    The aim of this study was to assess the value of dual-time point imaging in PET/CT for detection of biochemically recurrent or persistent prostate cancer, using the prostate-specific membrane antigen (PSMA) ligand [(68)Ga]PSMA I&T.

    Published March 15, 2017
  • Controversies with PSMA-Based Imaging and Targeted Therapy

    Published in Everyday Urology - Oncology Insights: Volume 4, Issue 4

    Published Date: December 2019

    Prostate-specific membrane antigen (PSMA) is expressed 100 to 1,000 times more highly in prostatic adenocarcinoma than in benign prostate tissue, particularly in the setting of androgen deprivation.1 Around the world, we are seeing the rapid adoption of PSMA PET-CT/MRI, which is able to detect metastatic disease that is inapparent on conventional imaging (CT and bone scintigraphy). It remains unclear, however, if the earlier detection of asymptomatic metastatic disease improves clinical outcomes for patients. Various questions and controversies also surround the emerging field of PSMA-based targeted therapies.

    Published January 20, 2020
  • EAU 2019: The Imaging Specialist’s Perspective on MRI for Prostate Cancer

    Barcelona, Spain (UroToday.com) Dr. Rouviere presented the imaging specialist’s perspective on MRI use in prostate cancer. According to the European Association of Urology (EAU) guidelines prostate multiparametric MRI (mpMRI) was originally recommended after a negative prostate biopsy before a repeat biopsy (2015). Later, mpMRI was recommended before a confirmatory biopsy in candidates for active surveillance (2016), and recently it has been recommended before a first set of biopsy, in biopsy naïve men (2019).
    Published March 15, 2019
  • EAU 2019: Theranostics: The Future of Functional Imaging

    Barcelona, Spain (UroToday.com) Theranostics is an emerging field of medicine which utilizes targeted cancer therapy based on specific molecular-targeted diagnostic tests. As part of the Imaging in Prostate Cancer plenary session at the 2019 European Association of Urology (EAU) annual meeting in Barcelona, Spain, Dr. Stefano Fanti, Director of Nuclear Medicine and Professor of diagnostic imaging at the the University of Bologna, discussed the potential uses of theranostics as it relates to the future of prostate cancer treatment.
    Published March 19, 2019
  • EAU 2020: ProPSMA Study: A Prospective Randomised Multi-Centre Study of PSMA-PET/CT Imaging for Staging High Risk Prostate Cancer Prior to Curative-Intent Surgery or Radiotherapy

    (UroToday.com) As part of the “Game-Changing Session 1” plenary presentation at the 2020 European Association of Urology (EAU) Virtual Annual Meeting, Michael S. Hofman, MBBS (Hons), FRACP, FAANMS, presented results of the proPSMA study which was recently published in the Lancet.1
    Published July 18, 2020
  • ESMO 2019: Invited Discussant (LBA51, LBA52, 848PD, 849PD and 855PD) – Immunotherapy in mCRPC, PSMA Radionuclide Therapy and an Update M0 STAMPEDE Data

    Barcelona, Spain (UroToday.com)  Dr. Cora Sternberg summarized the findings from several posters, including three immunotherapy phase 1 or 2 trials, a phase 2 trial of 177Lu-PSMA-617, and updated longer term data from the M0 standard of care + docetaxel STAMPEDE arm.
    Published September 30, 2019
  • ESMO 2019: Preliminary Results of a Phase I/II Dose-escalation Study of Fractionated Dose 177Lu-PSMA-617 for Progressive mCRPC

    Barcelona, Spain (UroToday.com) PSMA is overexpressed in prostate cancer with limited expression in other organs. Furthermore, prostate cancer is radiosensitive with dose-response (PSA declines and OS); dose-fractionation allows delivery of higher total dose per cycle, which may result in less radio-resistance due to repopulation compared with doses 6-12 weeks apart. The initial phase I safety results of the dose-escalation portion of this study treating mCRPC with fractionated dose 177Lu-PSMA-617 were presented at ESMO 2018 and were without dose limiting toxicity at all dose levels. At the ESMO 2019 prostate cancer session Dr. Scott Tagawa and colleagues presented preliminary results of the phase I/II dose escalation study.

    Published September 29, 2019
  • ESOU 2019: Radiotherapy: High Quality Local Treatment in High Risk Localized Prostate Cancer

    Prague, Czech Republic (UroToday.com) Dr. Paul Nguyen took the stance for radiation therapy in this much-anticipated debate regarding appropriate local treatment in men with high risk localized prostate cancer.
    Published January 21, 2019
  • First Human Application of Novel PET Tracer for Prostate Cancer

    New tracer holds promise of monitoring targeted treatment of various cancers

    In the featured translational article in the August issue of The Journal of Nuclear Medicine, researchers at the University of Michigan demonstrate the potential of a new PET tracer, Carbon-11 labeled sarcosine (11C-sarcosine), for imaging prostate cancer, and set the stage for its possible use in monitoring other cancers.
    Published August 10, 2017
  • From the Desk of the Associate Editor: The Diverse Use of PET/CT Diagnostic Imaging for Prostate Cancer

    This comprehensive review summarizes important clinical concepts in the rapidly advancing field of positron emission tomography/computed tomography (PET/CT) for prostate cancer. The authors reviewed 18F-NaF-, choline-, fluciclovine- and prostate-specific membrane antigen (PSMA)-based modalities in primary disease staging and assessment of biochemical recurrence. The most thoroughly studied modality to date is choline PET/CT.
    Published October 18, 2018
  • Imaging of Prostate-Specific Membrane Antigen Expression in Metastatic Differentiated Thyroid Cancer Using 68Ga-HBED-CC-PSMA PET/CT.

    The prostate-specific membrane antigen (PSMA) was shown to be overexpressed on the neovasculature of several malignancies. Here, the role of Ga-HBED-CC-PSMA PET/CT for the detection of PSMA expression in patients with metastasized differentiated thyroid cancer (DTC) was evaluated.

    Published November 24, 2016
  • Imaging Response During Therapy with Radium-223 For Castration-Resistant Prostate Cancer With Bone Metastases—Analysis Of An International Multicenter Database

    BACKGROUND: The imaging response to radium-223 therapy is at present poorly described. We aimed to describe the imaging response to radium-223 treatment.

    METHODS: We retrospectively evaluated the computed tomography (CT) and bone scintigraphy response of metastatic castration-resistant prostate cancer (CRPC) patients treated with radium-223, in eight centers in three countries.
    Published June 1, 2017
  • MRI-Targeted or Standard Biopsy for Prostate-Cancer Diagnosis

    Background: Multiparametric magnetic resonance imaging (MRI), with or without targeted biopsy, is an alternative to standard transrectal ultrasonography–guided biopsy for prostate-cancer detection in men with a raised prostate-specific antigen level who have not undergone biopsy. However, comparative evidence is limited.
    Published March 19, 2018
  • Novel Nuclear Medicine Test Can Identify Kidney Transplant Infection

    Truckee, CA (UroToday.com)  German scientists have developed a novel nuclear medicine test that can determine whether a kidney transplant patient has developed infection in the transplanted tissue. The study, which utilizes positron emission tomography/magnetic resonance imaging (PET/MRI), is presented in the November issue of The Journal of Nuclear Medicine.  
    Published November 10, 2017
  • Novel PET Imaging Agent Targets Copper in Tumors to Detect Prostate Cancer Recurrence Early

    Truckee, CA (UroToday.com) An Italian study featured in the March issue of The Journal of Nuclear Medicine demonstrates that a novel nuclear medicine imaging agent targeting copper accumulation in tumors can detect prostate cancer recurrence early in patients with biochemical relapse (rising prostate-specific antigen [PSA] level). 
    Published March 7, 2018
  • Optimization of labeling PSMAHBED with 68Ga and its quality control systems.

    Radiolabeling of the prostate-specific membrane antigen (PSMA) inhibitor, Glu-NH-CO-NH-Lys (Ahx), using the (68)Ga chelator HBED-CC (PSMAHBED) allows imaging of lesions of prostate cancer due to the high expression of PSMA in prostate carcinoma cells as well as bone metastases and lymph nodes related to the disease.

    Published January 18, 2017
  • Patterns of failure after radical prostatectomy in prostate cancer – implications for radiation therapy planning after 68Ga-PSMA-PET imaging: Beyond the Abstract

    68Ga-PSMA-PET imaging seems to be becoming the new state of the art imaging modality in prostate cancer. Especially in a salvage setting it is often doubtful where sites of recurrence may be. Now this research intends to somewhat clear that question by uncovering typical sites of recurrence after prostatectomy. 
    Published July 13, 2017
  • PET imaging of (64)Cu-DOTA-scFv-anti-PSMA lipid nanoparticles (LNPs): Enhanced tumor targeting over anti-PSMA scFv or untargeted LNPs.

    Single chain (scFv) antibodies are ideal targeting ligands due to their modular structure, high antigen specificity and affinity. These monovalent ligands display rapid tumor targeting but have limitations due to their fast urinary clearance.

    Published February 2, 2017
  • PET Scan Identifies Which Prostate Cancer Patients Can Benefit from Salvage Radiation Treatment

    TRUCKEE, CA (UroToday.com) For prostate cancer patients who have rising levels of PSA (a cancer indicator) even after radical prostatectomy, early treatment makes a difference. In a study featured in the December issue of The Journal of Nuclear Medicine, Australian researchers demonstrate that PET scans can identify which of these prostate cancer patients would benefit from salvage radiation treatment (SRT).
    Published December 5, 2017
  • Practice-Changing Applications of Radiology and Nuclear Medicine in Genitourinary Malignancies

    Published in Everyday Urology - Oncology Insights: Volume 3, Issue 4
    Published Date: December 2018

    Experts at Harvard Business School first coined the term disruptive innovation to describe how small, poorly resourced companies could successfully challenge larger ones.1 More than two decades later, this concept is central in medicine, where innovations in everything from proteomics and wearables to electronic health records and health economics are upending our status quo.2,41
    Published February 27, 2019
  • Preclinical Evaluation of 11C-Sarcosine as a Substrate of Proton-Coupled Amino Acid Transporters and First Human Application in Prostate Cancer.

    Sarcosine is a known substrate of proton-coupled amino acid transporters (PATs), which are overexpressed in selected tissues and solid tumors. Sarcosine, an N-methyl derivative of the amino acid glycine and a metabolic product of choline, plays an important role for prostate cancer aggressiveness and progression. 
    Published August 10, 2017
  • Preparing Your Practice for the New Era of Theranostics

    Published in Everyday Urology - Oncology Insights: Volume 4, Issue 3

    Published Date: September 2019

    Patients whose metastatic castration-resistant prostate cancer (mCRPC) has progressed on taxane chemotherapy and second-generation anti-androgen agents have few alternatives to palliative care. However, radiolabeled prostate-specific membrane antigen (PSMA) conjugates are now in latephase studies. In this article, I discuss theranostics, the phase 3 VISION trial, and the questions we will need to consider when PSMA-targeted radioligand therapies become available for use in our advanced prostate cancer clinics.

    Published November 5, 2019
  • PSMA PET/CT Clearly Differentiates Prostate Cancer from Benign Tissue

    Truckee, CA (UroToday.com) Using nuclear medicine, German researchers have found a way to accurately differentiate cancerous tissue from healthy tissue in prostate cancer patients. The research is highlighted in the February issue of The Journal of Nuclear Medicine.
    Published February 6, 2018
  • Radium-223-Dichloride in Castration Resistant Metastatic Prostate Cancer-Preliminary Results of the Response Evaluation Using F-18-Fluoride PET/CT

    The purpose of this study was to evaluate the outcome after Radium-223-dichloride ((223)RaCl₂) treatment of patients with skeletal metastases of castration resistant prostate cancer using whole-body (18)F-Fluoride PET/CT.  
    Published April 7, 2017
  • Radium-223-Dichloride in Castration Resistant Metastatic Prostate Cancer-Preliminary Results of the Response Evaluation Using F-18-Fluoride PET/CT: Beyond the Abstract

    This article [1] is a comprehensive analysis of 10 prostate cancer patients who received Ra-223-treatments. These patients were imaged with multiple quantitative PET methods according to our own algorithm [2], including fluoro-18-choline-PET and sodium fluoride-18 PET. These patients were additionally treated with multidisciplinary methods, including other radiation therapies. We recently reported an overall survival of 8.4 years in 46 patients of high-risk T3-4NXM1 primarily metastatic prostate cancer [2].
    Published April 7, 2017
  • Randomized Prospective Phase III Trial of 68Ga-PSMA-11 PET/CT Molecular Imaging for Prostate Cancer Salvage Radiotherapy Planning [PSMA-SRT] - Beyond the Abstract

    Curative treatments for localized PCa include radical prostatectomy or radiotherapy2. After the failure of local therapy, recurrence is detected by rising serum PSA levels. Biochemical recurrence (BCR) occurs in 20 to 80% of patients within 10 years after radical prostatectomy. Locally recurrent disease after radical prostatectomy may be cured by salvage radiation therapy (SRT).
    Published January 31, 2019
  • Rare Sites of Metastases in Prostate Cancer Detected on Ga-68 PSMA PET/CT Scan-A Case Series.

    Ga-68 labeled prostate-specific membrane antigen (PSMA) whole body PET/CT scan is a novel upcoming modality for the evaluation of prostate cancer. We present three cases of prostate cancer showing rare sites of metastases like brain, penis, and liver detected on Ga-68 PSMA PET/CT scan thus emphasizing its role in lesion detection and staging.

    Published March 10, 2017
  • SIU 2019: An Epidemiologist’s View of Prostate Cancer Screening

    Athens, Greece (UroToday.com) Dr. Carlsson gave an encompassing presentation on prostate cancer screening from the perspective of an epidemiologist.

    She began discussing the factors that affect prostate cancer mortality. Three distinct factors can reduce the mortality of prostate cancer. These include:

    1. Removal of carcinogens
    2. Better treatments
    3. Screening

    The World Health Organization (WHO) defines screening as the presumptive identification of unrecognized disease in an apparently healthy, asymptomatic population by means of tests, examinations or other procedures that can be applied rapidly and easily to the target population. For prostate cancer, there are two main screening tests – digital rectal examination (DRE) and prostate-specific antigen (PSA) test.

    The use of PSA as a disease marker was initialized in 1987-1991 in the USA and Europe. The level of PSA in early midlife was found to identify men at an increased risk for prostate cancer metastases. It was shown that if PSA was at the top 10% (>=2.4 ng/ml) in young men (40-55 years) there was a 5% risk of metastases after 20 years.1 This risk dropped to 0.3% if PSA was below the median (<0.9 ng/ml.)1

    There have been three large randomized trials assessing prostate cancer PSA screening:

    1. 18 years ago - the Goteborg randomized trial2
    2. 17 years ago – the PLCO trial3
    3. 16 years ago – the ERSPC trial4

    The ERSPC trial, assessing men aged 50-70 years, showed that standard PSA screening every 2-4 years reduces prostate cancer mortality by 20% after 16 years with a relative risk of (RR 0.8 [95% CI 0.72-0.89, P<0.001]).4 The PLCO trial provided similar evidence.

    PSA screening has some benefits including a reduction in metastases rate and prostate cancer-specific death. On the other hand, the harms of PSA screening include false-positive results, overdiagnosis, and overtreatment. However, Dr. Carlsson notes that is important to remember that potential benefits and harms of screening ultimately depend on the geographic location of the patient. A good example is that in Northern Europe the incidence and mortality are higher compared to that of Mediterranean countries.

    Prostate cancer is the second most frequent cancer and the fifth leading cause of cancer death in men (Figure 1), with lung cancer remaining the leading cause of cancer incidence and mortality worldwide.

     Figure 1 – Ten most common cancers in males in 2018:

    SIU Epidemiologists View 1

    Importantly, prostate cancer is the most frequently diagnosed male cancer in more than half of the countries of the world (105 out of 185) (Figure 2). In Sweden and Greece for example, the yearly incidence rate is 95.5 and 16.2, respectively, per 100,000 men, showing the significantly higher rate of Northern European countries. 

     Figure 2 – Highest incidence of cancers in the world in 2018

    SIU Epidemiologists View 2

     Prostate cancer has also been shown to be the leading cause of cancer death among men in 46 countries, with 359,000 deaths reported in 2018 (Figure 3). 

     Figure 3 - Cancers with the highest mortality rates worldwide in 2018:

     SIU Epidemiologists View 3

    The mortality rate of prostate cancer has been increasing in some countries (Central and South America, Central and Eastern Europe, Asia) while decreasing in other countries (Northern America, Northern, and Western Europe, developed countries of Asia, and Oceania). The highest prostate cancer incidence and mortality rates have been reported in Guadeloupe and Barbados (Figure 4).

     Figure 4 – Worldwide incidence and mortality rates reported in 2018:

     SIU Epidemiologists View 4

    Dr. Carlsson moved on and summarized several of her reflections on the epidemiology of prostate cancer screening. First, prostate cancer screening can reduce prostate cancer mortality – this has been proven many times. However, screening can also cause harm (overdiagnosis, overtreatment). Importantly, we have the knowledge to screen in a “smarter” manner, which keeps the benefits and reduces the harm. Screening could be regarded as a public health need, but it depends on the setting/country of the patient, burden of prostate cancer, life expectancy in the specific country and available resources.

    Dr. Carlsson continued and described the 5 golden rules that she recommends regarding prostate cancer screening:

    1. Always get consent from the patient whether to perform screening (using shared decision making and discussing benefits and harms)
    2. Do not screen men who will not benefit from screening such as those with multiple comorbidities and short life expectancy 
    3. Do not perform a prostate biopsy without a compelling reason – as biopsies can lead to significant infectious complications
    4. Do not treat low-risk prostate cancer disease – make sure you utilize the strategy of active surveillance if appropriate
    5. If you have to treat, refer men to a high-volume provider, as data show that radical prostatectomy performed by experienced surgeons can have a significant impact on oncological and functional outcomes5

    Dr. Carlsson concluded her talk mentioning the addition of the multiparametric MRI (mpMRI) into the diagnosis of prostate cancer. mpMRI improves the detection of significant prostate cancer, decreases the number of unnecessary biopsies, and reduces overdiagnosis.6 However, a negative mpMRI does not obviate the need for systematic biopsy, as a negative mpMRI can miss 9-20% of clinically significant prostate tumors.7 Importantly, the negative predictive value of mpMRI depends on the disease prevalence. Moreover, all published studies on mpMRI performed in biopsy-naive patients have been conducted in specialized centers only, not necessarily manifesting the results of most centers, that consist of lower volumes. In order to be successful, the concept of mpMRI in biopsy-naïve patients requires access to high- quality mpMRI studies, optimal reading of scans, a robust training program for radiologists, and access to high-quality mpMRI- targeted biopsy. 

    Dr. Carlsson ended her talk mentioning the highlight points of her talk:

    1. Prostate cancer incidence and mortality vary greatly across the globe
    2. Male life expectancy and health care resource vary globally as well
    3. Prostate cancer is a heterogeneous disease
    4. Screening may or may not do more good than harm
    5. “One size” screening does not fit all

    Presented by: Sigrid Carlsson, MD, Ph.D., MPH, Assistant attending Epidemiologist at the Memorial Sloan Kettering Cancer Center,  New York, NY

    Written by: Hanan Goldberg, MD, Urology Department, SUNY Upstate Medical University, Syracuse, NY, USA, Twitter: @GoldbergHanan at the 39th Congress of the Société Internationale d'Urologie, SIU 2019, #SIUWorld #SIU2019, October 17-20, 2019, Athens, Greece

    References: 

    1. Vickers AJ, Ulmert D, Sjoberg DD, et al. Strategy for detection of prostate cancer based on relation between prostate specific antigen at age 40-55 and long term risk of metastasis: case-control study. BMJ : British Medical Journal 2013; 346: f2023.

    2. Hugosson J, Godtman RA, Carlsson SV, et al. Eighteen-year follow-up of the Goteborg Randomized Population-based Prostate Cancer Screening Trial: effect of sociodemographic variables on participation, prostate cancer incidence and mortality. 2018; 52(1): 27-37.

    3. Pinsky PF, Prorok PC, Yu K, et al. Extended mortality results for prostate cancer screening in the PLCO trial with median follow-up of 15 years. Cancer 2017; 123(4): 592-9.

    4. Hugosson J, Roobol MJ, Månsson M, et al. A 16-yr Follow-up of the European Randomized study of Screening for Prostate Cancer. European Urology 2019; 76(1): 43-51.

    5. Eastham JA. Do high-volume hospitals and surgeons provide better care in urologic oncology? Urologic oncology 2009; 27(4): 417-21.

    6. Kasivisvanathan V, Rannikko AS, Borghi M, et al. MRI-Targeted or Standard Biopsy for Prostate-Cancer Diagnosis. New England Journal of Medicine 2018; 378(19): 1767-77.

    7. Mottet N, Bellmunt J, Bolla M, et al. EAU-ESTRO-SIOG Guidelines on Prostate Cancer. Part 1: Screening, Diagnosis, and Local Treatment with Curative Intent. Eur Urol 2017; 71(4): 618-29.

     

    Published October 17, 2019
  • SIU 2019: PSMA in Prostate Cancer – Diagnostic to Theranostics

    Athens, Greece (UroToday.com) Dr. Renu Eapen gave an overview of the role of PET- prostate-specific membrane antigen (PSMA) in prostate cancer and gave a preview of what is to come in the near future of PET diagnostics, and the evolving field of theranostics.

    Published October 21, 2019
  • SNMMI 2016: 11C-acetate PET/CT accurately predicts prostate-cancer specific survival in patients with biochemical relapse after prostatectomy

    San Diego, CA. USA (UroToday.com) – 11Choline-acetate (11C-acetate) has been used as an investigational PET radiopharmaceutical to image patients with prostate cancer based on elevated transports in prostate cancers after prostatectomy to detect recurrence and metastasis upon biochemical relapse.  Its utility for predicting outcomes in this group of patients has not been reported.  Naresh Kumar Regula, from the Uppsala University, Sweden presented new data at the 2016 Society of Nuclear Medicine and Molecular Imaging annual meeting.  The question of whether parameters measured by 11C-acetate PET correlate with clinical outcomes including survival.
    Published July 11, 2016
  • SNMMI 2016: Application of 18F-labeled PSMA-imaging using [18F]DCFPyL at very low PSA-values may allow curative treatment in recurrent prostate cancer.

     

    San Diego, CA. USA (UroToday.com) – Newer and more sensitive radioligands are available for imaging PSMA to detect prostate cancer recurrence and metastasis upon biochemical relapse.  Ga-68 labeled PSMA-HBED-CC (or Ga-PMSA-11) is a Ga-68 labeled monoclonal antibody against PMSA while F-18 DCFPyL is a small molecule with high affinity to PSMA at nanomolar range. Both are investigational radiopharmaceuticals with high PSMA-affinity that hold great potential for clinical use.  They may be able to provide early diagnostic information for possible curative treatment of recurrent prostate cancers that are limited to the prostate fossa and regional lymph nodes.

    Published July 11, 2016
  • SNMMI 2016: Fluciclovine F18 (FACBC): An Amino Acid Tracer for the Staging of Recurrence Prostate Cancer

    San Diego, CA. USA (UroToday.com) – Coming off the recent FDA approval of Flucicovine F18 (FACBC), trade name Axumin®, it was with obvious excitement the CEO of Blue Earth Diagnostics discussed the research which lead to the recent news. Flucicovine is a synthetic amino acid based PET agent, which has been approved in men with suspected prostate cancer recurrence based on elevated PSA. 
    Published July 11, 2016
  • SNMMI 2016: Fluciclovine F18 PET-CT scanning in patients with high-risk primary prostate carcinoma

    San Diego, CA. USA (UroToday.com) – F-18 fluciclovine (FACBC) has been used as an investigational PET radiopharmaceutical to image patients with prostate cancer based on elevated amino acid transports in prostate cancers.  Its utility for disease staging has not been established for patients with high-risk primary prostate cancer. 
    Published July 11, 2016
  • SNMMI 2016: PET/CT Imaging of Prostate Cancer Proves Accurate Biopsy Guide



    Study shows imaging of prostate-specific membrane antigen leads to highly accurate tumor detection and delineation


    San Diego, Calif. (June 15, 2016) – Prostate cancer is the leading cancer among men, second only to skin cancer. With surgical removal at the frontline of defense, oncologists are considering prostate-specific molecular imaging at the point of initial biopsy and pre-operative planning to root out the full extent of disease, researchers revealed at the 2016 Annual Meeting of the Society of Nuclear Medicine and Molecular Imaging (SNMMI).

    Published July 11, 2016

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