Localized Prostate Cancer COE Articles

Articles

  • ASCO GU 2020: Multiparametric MRI in the Management of Localized Prostate Cancer

    San Francisco, CA  (UroToday.com)  Dr. Ivo Schoots from the Netherlands discussed the optimal use of multiparametric MRI in the management of localized prostate cancer. On the prostate cancer disease spectrum, Dr. Schoots feels that prostate imaging, whether multiparametric MRI or next-generation imaging, will alter the proportion of patients in every disease state and will influence oncological outcomes. Multiparametric MRI is important for patients with (i) suspected prostate cancer, (ii) detected prostate cancer, and (iii) those with biochemical recurrence. 
    Published February 13, 2020
  • AUA 2019: 17-gene Genomic Prostate Score as a Predictor of Adverse Pathology for Men on Active Surveillance

    Chicago, IL (UroToday.com) Dr. Kornberg presented his talk on- A 17-gene Genomic Prostate Score as a Predictor of Adverse Pathology for Men on Active Surveillance. The Oncotype DX® Genomic Prostate Score (GPS) test is an RNA expression assay that can be performed on needle-core biopsies from men with prostate cancer (PCa). GPS has previously been validated as a predictor of adverse pathology in men with low-risk prostate cancer who undergo primary radical prostatectomy (RP). Dr. Kornberg and colleagues aimed to determine whether GPS was associated with increased risk of adverse pathology for men enrolled on active surveillance (AS) who later underwent RP. 
    Published May 8, 2019
  • Biomarker Strategies for Prostate Cancer Care During COVID-19

    Despite the recent disruptions in health care delivery due to the COVID-19 pandemic, patients at risk for developing prostate cancer as well as those diagnosed with prostate cancer still deserve timely and optimal decision making. Unfortunately, the uncertainty of the pandemic requires urologists to adopt innovative strategies in order to prioritize patient care while being mindful to mitigate the potential infectious risks of COVID-19 to their patients as well as to their healthcare team.
    Written by: Neal D. Shore, MD, FACS, and Michael S. Cookson, MD, MMHC
    References: 1. Hayes, Julia H., Daniel A. Ollendorf, Steven D. Pearson, Michael J. Barry, Philip W. Kantoff, Susan T. Stewart, Vibha Bhatnagar, Christopher J. Sweeney, James E. Stahl, and Pamela M. McMahon. "Active surveillance compared with initial treatment for men with low-risk prostate cancer: a decision analysis." Jama 304, no. 21 (2010): 2373-2380.
    Published June 24, 2020
  • Biomarker Strategies for Prostate Cancer Care During COVID-19

    Despite the recent disruptions in health care delivery due to the COVID-19 pandemic, patients at risk for developing prostate cancer as well as those diagnosed with prostate cancer still deserve timely and optimal decision making. Unfortunately, the uncertainty of the pandemic requires urologists to adopt innovative strategies in order to prioritize patient care while being mindful to mitigate the potential infectious risks of COVID-19 to their patients as well as to their healthcare team.
    Published June 24, 2020
  • CUOS 2019: Active Surveillance: Long-Term Data - We Continue to Learn

    Toronto, Ontario (UroToday.com) Dr. Laurence Klotz presented on the current status of active surveillance for prostate cancer. Through the years there has been greater recognition of the overtreatment problem of prostate cancer patients, and the concept of active surveillance has been more accepted. We have also learned more about the nature of high-grade occult disease and the predictive value of baseline parameters. The flaws of PSA kinetics as a trigger have been recognized, and the incorporation of mpMRI has become very common. Currently, new modeling studies are being developed, with longer follow-up, and there are approximately 3000 publications on active surveillance.
    Published January 10, 2019
  • EAU 2019: A Novel Predictor of Clinical Progression in Patients on Active Surveillance for Prostate Cancer

    Barcelona, Spain (UroToday.com) Active Surveillance (AS) for prostate cancer (PCa) is the standard of care of men with low-risk PCa. However, approximately 30-40% of men on AS will eventually progress to treatment – either due to choice or due to progression. Progression can either be due to grade or volume progression, on individual biopsies. Identifying predictors of progression at the outset of AS initiation may help select men who should perhaps get treatment up front. While numerous markers exist, ultimately, a combination of these features (clinical, histologic and other biomarkers) will likely be needed to best select these patients.
    Published March 15, 2019
  • EAU 2019: Natural History of Prostate Cancer on Active Surveillance: Stratification by MRI Using the PRECISE Recommendations

    Barcelona, Spain (UroToday.com) At the Active Surveillance vs Focal Therapy in Prostate Cancer session at EAU 2019, Dr. Francesco Giganti and colleagues from the United Kingdom presented results of their use of the PRECISE recommendations and outcome of men on active surveillance for prostate cancer.  The PRECISE recommendations for MRI in men on active surveillance include repeated measurement of each lesion and attribution of a PRECISE radiological progression score for the likelihood of clinically significant change over time 1. The assessment of the likelihood of radiographic progression on MRI in men on active surveillance (PRECISE score) is as follows:
    Published March 18, 2019
  • EAU 2019: The Urologist’s Perspective on Active Surveillance

    Barcelona, Spain (UroToday.com) Dr. van den Bergh presented on the current and future role of active surveillance in prostate cancer. Approximately 350 studies on active surveillance have been published per year in the last 5 years. This therapeutic strategy has been incorporated into all major urological guidelines and is increasingly being used for low-risk prostate cancer around the world (Figure 1). The usage of this modality varies by country, hospital and even physician, but in general the trend demonstrates a rise in its use. The eligibility for active surveillance should be a fixed part of screening policies.
    Published March 17, 2019
  • Epidemiologic Outcomes of Prostate Cancer Patients Undergoing Active Surveillance - Sigrid Carlsson

    Sigrid Carlsson joins Charles Ryan discussing the epidemiologic outcomes of men in the current era who are facing active surveillance. She reviews the long term data learned from the Memorial Sloan Kettering Cancer Center Experience which mirrors prior reports with low rates of metastasis or cancer-related deaths for patients on active surveillance. They also discuss the migration of pushing the envelope for active surveillance, how MRI is fitting into the active surveillance patient and the management of cancer, the development of new therapies for the aggressive disease, allowing clinicians to focus more on the types of cancers that need the treatment.

    Biographies:

    Sigrid Carlsson, MD, Ph.D., MPH, is the assistant attending epidemiologist at the Memorial Sloan Kettering Cancer Center. Dr. Carlsson’s research is focused on screening and early detection of prostate cancer. She is an investigator in the world’s largest randomized study of screening for prostate cancer, the European Randomized Study of Screening for Prostate Cancer. Dr. Carlsson’s research aims at finding a better balance between the harms and benefits of prostate-specific antigen (PSA) screening, through the use of multiplex testing and risk-stratified strategies that incorporate clinical information, biomarkers, and magnetic resonance imaging.

    Charles J. Ryan, MD is the B.J. Kennedy Chair in Clinical Medical Oncology at the University of Minnesota and Director of the Division of Hematology, Oncology and Transplantation.

    Read the Full Video Transcript

    Charles Ryan: Hello, I'm delighted to be joined today by Dr. Sigrid Carlsson, who is an Assistant Attending epidemiologist at Memorial Sloan Kettering Cancer Center in New York. Thank you for joining me. Eager to talk to you today about active surveillance. This is your area and we've had a few great conversations recently about active surveillance. I wonder if you could start by giving us a sense of the outcomes, the epidemiologic outcomes of men in the current era who are facing active surveillance?

    Sigrid Carlsson: Yes. Active surveillance, I would say, is a safe management strategy for carefully selected and carefully monitored patients on active surveillance in these days. We have now reported recently our outcomes of active surveillance at Memorial Sloan Kettering, so we have 17 years of follow-up. We have about 3000 patients on active surveillance that we have monitored. The median follow-up is, of course, shorter because most of these men have joined the program in recent years. The long-term outcomes are good, so we see a 1% risk of metastases over 10 years if they have Gleason 3+4 or Grade Group 2. If they have Gleason 6 the risk of metastases: 0.6% at 10 years.

    Charles Ryan: Are these patients who have metastases even though that's a very low number, are these patients who started out with active surveillance, had local therapy then recurred or are these patients who develop metastatic disease in the absence of local therapy?

    Sigrid Carlsson: It could be either-or. About 50% of men remain untreated on active surveillance after 10 years of follow-up, but, of course, they convert to treatment upon disease progression. Then, if they have a radical prostatectomy or radiotherapy some of them might have recurred and have pCR and then progressed.

    Charles Ryan: I'm assuming because you started out by asserting that metastasis was perhaps the worst outcome, that there have been no deaths from prostate cancer in this group?

    Sigrid Carlsson: That's correct. We had one death and there was a very unusual course of the disease, so, of course, there is no strategy that's perfectly safe. There's always someone that would slip through the net, but it's very rare because they are carefully monitored and carefully followed with repeated PSAs, digital rectal exams every six months, we do MRI every 18 months and then we do biopsy every two to three years or if anything indicates that you would need a biopsy earlier; so these men feel safe and secure, and we follow them closely.

    Charles Ryan: I see. In a patient who starts out on active surveillance, who is ultimately going to be treated, that 50%; when is that treatment occurring? Is it something that's occurring within the first year or two or is it later on? Give me a sense of that timeline.

    Sigrid Carlsson: Yeah, so it's a good question. If you look at the curve of treatment, a lot of them happened early, so either there's a reclassification on the first biopsy or the disease progression on the biopsy within the first three to five years, I would say. That's usually when that occurs or it could be over longer-term follow-up.

    Charles Ryan: Is there a single type of progression that occurs? Is it an increase in the Gleason score? Is it an increase in the T stage? What is the progression of that?

    Sigrid Carlsson: Could be both.

    Charles Ryan: Either, really.

    Sigrid Carlsson: It's usually is a Grade progression that triggers treatment.

    Charles Ryan: It's usually a Grade progression?

    Sigrid Carlsson: Yeah.

    Charles Ryan: I see.

    Sigrid Carlsson: There are some cases when the patient prefers treatment because dealing with the anxiety and uncertainty of living with untreated cancer could be, but we have programs in place for that too so that men can feel more secure so that we would ideally like it to be just the true biologic disease progression that triggers treatment.

    Charles Ryan: Are there patients who are lost to follow-up who are on active surveillance who just decide they're not even going to do that? I mean, I'm sure at your center they are followed-

    Sigrid Carlsson: Yeah.

    Charles Ryan:... but is that a risk that that is seen at your center, has been seen at others?

    Sigrid Carlsson: That's nothing that we've looked at specifically, so I can't give you an answer, but, of course, there are some patients who are lost to follow-up, so it's-

    Charles Ryan: But, I'm saying, I should say are there patients who start out in active surveillance who ultimately decide to stop doing active surveillance. Maybe they're not lost to follow-up, but they stopped doing the yearly biopsy and-

    Sigrid Carlsson: Yeah. We haven't looked exactly what proportion of men follow the protocol as we would like them to-

    Charles Ryan: I see.

    Sigrid Carlsson:... but, of course, we see that happening. You can understand that men are reluctant to have repeat biopsy and so on and so forth. We try to do everything to improve men's experience on active surveillance. For instance, the biopsy procedure, what can we do to reduce the pain, discomfort and the anxiety? Can we do a simple brief meditation exercise before the biopsy, can we change the way we do the local anesthesia, can we do transperineal instead of transrectal biopsies and so on and so forth so that men do not feel hesitant to be on a program that's uncomfortable long term?

    Charles Ryan: While we're on the topic of biopsies, I think you have been doing a lot of work on MRIs, and when the biopsy and the MRI, how they interact with one another. Tell us about your work on MRI.

    Sigrid Carlsson: This is more before the diagnosis. We're here now in Barcelona at the EAU and we had this debate the other day with a Dr. Caroline Moore from the UK. It was really interesting debates because it's becoming more and more common these days to do an MRI before the biopsy, so even before men are diagnosed. They come with an elevated PSA and then they want to have an imaging of the prostate before the diagnosis. Of course, again, it's patient experience. You don't want to have a biopsy if you don't have to. We've been looking in into that literature more and see if the MRI's negative, do you have to do the systematic biopsies, do you only do targeted biopsies if the MRI is positive or what's the pathway? That was the debate with Caroline Moore.

    There's more and more push to not do the systematic biopsy if the MRI is negative. But, the problem, so that the other side of the argument would be that the negative predictive value is not 100%, so there's definitely a miss rate by not doing the systematic biopsies. In one of these trials, the PROMIS study, the negative predictive value was 74%, so that means that you know there's the miss rate of up to 24% if you don't-

    Charles Ryan: 24% of individuals could have negative MRIs and if they underwent a systematic biopsy, they would have some tumor detected?

    Sigrid Carlsson: Exactly. That was clinically significant tumors. It's not safe to avoid the biopsies as of today. Also, depends on who does the MRI and who reads the MRI. What's the quality and the expertise of the radiologist, the machine you're using and what systems do we have in place to have sort of a quality assurance criteria? If you go to Caroline's center in the UK, you might have a beautiful, perfect MRI and it can be safe to say that there's nothing here, but at some other center elsewhere in the world that might not be true.

    Charles Ryan: One of the great challenges of logic and science is trying to prove when something isn't present, right? 

    Sigrid Carlsson: Exactly.

    Charles Ryan: You can only prove when it's there and that is a real challenge.

    Sigrid Carlsson: But, in this case, that's also a challenge because there are false positives, so even though you say there's a PI-RADS 3 to 4, even 5 we cannot even be sure that that's prostate cancer in that case.

    Charles Ryan: What are the factors that lead to a false positive on an MRI?

    Sigrid Carlsson: Well, there could be multiple reasons. I mean there are some rare cases where you would think it's prostate cancer, but it could be tuberculosis, so granulomatosis in the prostate that mimics prostate cancer. That could be one of those rare events or it could be just the interpretation by the radiologist. There's a learning curve in interpreting the images, and also if you do the targeted biopsies, there's a learning curve of targeting of the area. There are multiple factors for this concept to be successful. It's very interesting and very promising. 

    I think from a patient perspective, it would be ideal if we can find a pathway of men who have low risk of having clinically significant disease and a negative MRI who don't need a biopsy. That would be terrific if we could identify that, but then there are some challenges, so the question is how can we prove that. Can we add PSA density, for example, can we add biomarkers before the MRI? These are studies that we need to do and figure out what's the next.

    Charles Ryan: I look at this as there's two challenges that I think you face, right? One is improving the sensitivity of your technology at Memorial Sloan Kettering Cancer Center, a world-leading place on the development of this. Then, the next question is how can you export this technology, as you alluded to earlier, to other places that don't have the experience in radiology and don't have perhaps the same type of MRI scan, so how exportable it is there. That's going to provide some interesting and challenging work moving forward.

    Sigrid Carlsson: I think so too.

    Charles Ryan: I want to go back to active surveillance and ask you a question that I've wondered about. Active surveillance really started 17 years ago at your center as you said, but it seems, and in my conversations with other colleagues, that the envelope for active surveillance is being pushed and so we have patients who clearly would not have been offered active surveillance 10 years ago who now are on active surveillance. Do you see that migration in your study?

    Sigrid Carlsson: Yeah.

    Charles Ryan: I guess tying it to the MRI then, how is the MRI fitting into the active surveillance patient?

    Sigrid Carlsson: Yeah, that's a very good question. If you look at active surveillance, the evolution over time, Laurie Klotz started his series in Toronto and he was very inclusive. He included some Gleason score 7, 3+4, sometimes even 4+3. Then, on the other hand, you had Johns Hopkins, which just did very low-risk disease and very restrictive, so you had the full spectrum. Then, it converted back to, okay, maybe we should focus on Gleason score 6, but then again you want to expand your inclusion criteria to a larger population because otherwise, you become too restrictive. Now, we again see this pushing the envelope towards including at least 3+4 or low volume 3+4 so one or two cores.

    What we have recently published a paper from Memorial and my colleague Dr. Behfar Ehdaie Day showing that the tumor quantification is important, so the millimeters of pattern 4 in the biopsy is important. Maybe there is a limit there. Perhaps it's less than five millimeters of pattern 4 among the 3+4, that could also be one of the inclusion criteria. You have the 6s and the 3+4, but low volume. That could be one part of broadening the inclusion criteria because we still want to keep it safe, the strategy, so we will want to make sure that we have carefully selected and carefully monitored these patients.

    Charles Ryan: Again with the MRIs then, you are able to, the MRI is able to essentially, hopefully, identify where is the pattern 4, what is the central volume of the pattern 4 and then the urologist can make the decision about potentially recommending treatment based on that?

    Sigrid Carlsson: Yes, and the pathologist, the biopsy-

    Charles Ryan: The pathologist.

    Sigrid Carlsson:... information is, I would say, most important, but the MRI certainly helps. There are a lot of factors that you take into consideration, the PSA level, the Gleason score, the tumor stage, and then the MRI imaging and the age of and the race of the patient, also. But, definitely, if you do an MRI at the start of the active surveillance, that's the good way to start because you're going to have the initial risk stratification.

    Charles Ryan: With only 1% progressing to metastases, probably an unanswerable question at this point, but do you see risk factors in the biopsy samples on the active surveillance for the development of those metastases or the numbers just too small to really look at the factors associated with it?

    Sigrid Carlsson: Yeah, that's a good question. That's nothing that we've really looked at because like I said, those are rare events.

    Charles Ryan: Hopefully will remain rare, but I would imagine your data's only going to become enriched over time because as you said, the median follow-up is eight years or so?

    Sigrid Carlsson: It's around four or so.

    Charles Ryan: Oh, four years.

    Sigrid Carlsson: Because most of these patients have joined the cohort in recent years.

    Charles Ryan: You've got a lot of years of work ahead of you.

    Sigrid Carlsson: Yes, we do. There are other cohorts.

    Charles Ryan: I want to congratulate you for getting this far with this data set, and actually all of you who do research on active surveillance are really to be commended because, speaking now as an oncologist, it's quite amazing that we're identifying patients who a generation ago were told they had cancer and had to have immediate treatment, and in fact, they didn't. This, I think, is an important step in and the management of cancer as is the development of new therapies for the aggressive disease. It allows us to focus really on the types of cancers that need the treatment, but this is the type of work that is needed to be done, so congratulations on that. Thank you for joining me today.

    Sigrid Carlsson: Thank you.
    Published November 11, 2019
  • ESMO 2019: Adjuvant or Salvage Radiotherapy for the Treatment of Localized Prostate Cancer? A Prospectively Planned Aggregate Data Meta-analysis

    Barcelona, Spain (UroToday.com) There are three randomized trials, RADICALS (ISRCTN40814031),1 GETUG-AFU 17 (NCT00667069) and RAVES (NCT00860652); recently presented at ASTRO 2019, that have compared adjuvant radiotherapy with a policy of salvage radiotherapy for PSA failure after radical prostatectomy for men with localized prostate cancer. However, these trials have limited power for long-term outcomes. At the ESMO 2019 prostate cancer session, Claire Vale presented initial results of a pre-planned meta-analysis of the above trials. The ARTISTIC collaboration prospectively planned a series of meta-analyses for each outcome.

    Initial discussions for a meta-analysis occurred in 2011 with the RADICALS-RT and RAVES group. In 2014, the ARTISTIC collaboration was officially launched. The authors used a framework for adaptive meta-analysis (FAME), prospectively defining their methods, including a consistent definition of PSA-driven event-free survival, prior to knowledge of trial results (CRD42019132669). Event-free survival was defined as time from randomization to any of (i) PSA >=0.4 ng/mL and rising after completion of radiotherapy, (ii) clinical/radiological progression, (iii) initiation of non-trial treatment, (iv) death from prostate cancer following completion of radiotherapy, or (v) PSA level >= 2.0 ng/mL at any time after randomization. They anticipated 240 events across all trials by Fall 2019, giving 90% power to detect a 5% absolute difference in 5-year event-free survival.

    Across the 3 trials, 1,074 men were randomized to adjuvant radiotherapy and 1,077 to salvage radiotherapy. The trials are comparable, but with subtleties noted below:

    ESMO2019_trial_characteristics.png

    To date, 395 men (37%) had commenced salvage radiotherapy. Patient characteristics were balanced within trials and overall. Men had a median age of 65 years and most (77%) had a Gleason sum score of 7. Median follow-up ranged from 47 to 61 months. In August 2019, RADICALS and GETUG-AFU 17 provided event-free survival results for the meta-analysis (interim for GETUG-AFU 17). RAVES currently could only supply freedom from biochemical failure results. However, as the vast majority of first events across all trials are biochemical failures, these results were pooled in a preliminary meta-analysis of event-free survival. Based on 245 events, the meta-analysis shows no evidence that event-free survival is improved with adjuvant radiotherapy compared to salvage radiotherapy (HR 1.09, 95% CI 0.86-1.39, p = 0.47).

    ESMO2019_PSA-driven.png

    Professor Vale concluded that this collaborative, prospective and early meta-analysis of all men from three randomized trials, suggests that salvage and adjuvant radiotherapy offer similar outcomes for event-free survival. Importantly, salvage radiotherapy spares many men from receiving radiotherapy, and associated side-effects. Final data from GETUG-AFU 17 and RAVES may help establish whether some subgroups of men might benefit from either treatment. Finally, longer follow-up is needed for a meta-analysis of metastasis-free survival. The plan for the current analysis is to publish the results simultaneously to the three trials.

    Clinical trial identification

    ISRCTN40814031; NCT00667069; NCT00860652


    Presented by: Claire Vale, Ph.D., MRC Clinical Trials Unit, University College London, Institute of Clinical Trials and Methodology-UCL, United Kingdom

    Co-authors: M. Brihoum,2 S. Chabaud,3 A. Cook,1 D. Fisher,1 S. Forcat,4 C. Fraser-Browne,5 A. Herschtal,6 A. Kneebone,7 S. Nénan,2 C. Parker,8 M. Parmar,9 M. Pearse,5 P. Richaud,10 E. Rogozińska,4 P. Sargos,11 M. Sydes,9 J. Tierney1 

    1. Institute of Clinical Trials and Methodology-UCL, London, UK
    2. Unicancer, Paris, FR
    3. Centre Léon Bérard, Lyon, FR
    4. Institute of Clinical Trials and Methodology, UCL, London, UK
    5. Auckland City Hospital, Auckland, NZ
    6. Peter MacCallum Cancer Centre, Melbourne, AU
    7. Northern Sydney Cancer Centre, Sydney, AU
    8. The Institute of Cancer Research/Royal Marsden NHS Foundation Trust, Sutton, UK
    9. MRC Clinical Trials Unit at UCL, London, UK
    10. Institut Bergonie, Bordeaux, FR
    11. Institute Bergonié, Bordeaux, FR

    Written by: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia Twitter: @zklaassen_md at the 2019 European Society for Medical Oncology annual meeting, ESMO 2019 #ESMO19, 27 Sept - 1 Oct 2019 in Barcelona, Spain 

    References:
    1. Parker C, et al. Timing of Radiotherapy After Radical Prostatectomy: First Results from the RADICALS RT Randomized Controlled Trial. ESMO 2019.

    Published September 27, 2019
  • ESMO 2019: Timing of Radiotherapy after Radical Prostatectomy: First Results from the RADICALS Radiation Therapy Randomised Controlled Trial

    Barcelona, Spain (UroToday.com) Men who undergo surgery as definitive therapy for their localized prostate cancer generally only receive subsequent radiation therapy if their surgical pathology shows certain adverse pathologic features (adjuvant radiotherapy or aRT) or if they experience biochemical recurrence (early salvage radiotherapy or eSRT). Two prior trials randomizing men with high-risk prostatectomy features to adjuvant versus salvage therapy reached differing conclusions regarding overall survival benefit, with SWOG 8794 showing a benefit in pathologic stage T3 disease, but the larger EORTC 22911 trial showed no survival benefit. 
    Published September 27, 2019
  • ESOU 2019: Risk Stratification for Active Surveillance

    Prague, Czech Republic (UroToday.com) It is good news for both patients and physicians that there has been wider adoption of appropriate utilization of active surveillance (AS) among patients with prostate cancer. Dr. Nicolas Mottet presented risk stratification for active surveillance.
    Published January 21, 2019
  • ESOU 2019: Treatment of Gleason 3+4 in a Multidisciplinary Scenario: Active Surveillance

    Prague, Czech Republic (UroToday.com) As part of the ESOU 2019 prostate cancer session there was a discussion regarding the appropriate treatment of Gleason 3+4 disease. Dr. Monique Roobol discussed the possible utilization of active surveillance for these patients.
    Published January 21, 2019
  • Improving Prostate Cancer Early Detection with Biomarkers in Primary Care

    The COVID-19 pandemic has resulted in numerous physical and psychological adjustments for clinicians, patients, and their families—wearing personal protective equipment, adopting telemedicine, adjusting clinic workflow, etc. The ensuing uncertainty and attendant anxiety from the fluidity of information and healthcare policy debate has augmented the need for enhanced communication and thoughtfulness for healthcare providers.  For urologic patient care, we strive to surmount the ever-evolving challenges of the COVID-19 pandemic by incorporating strategies to avoid the infection while protecting and prioritizing patient care. Specifically, as we assess the optimization of prostate cancer detection and diagnosis, we should identify men at risk for clinically significant cancer who mainly first present within the primary care setting.
    Written by: Neal D. Shore, MD, FACS, and Michael S. Cookson, MD, MMHC
    Published October 12, 2020
  • Localized Prostate Cancer Management in the Time of COVID-19

    The rapid spread of Coronavirus Disease 2019 (COVID-19) throughout the world, caused by the betacoronavirus SARS-CoV-2, has had dramatic effects on health care systems with impacts far beyond the patients actually infected with COVID-19. Patients who manifest severe forms of COVID-19 requiring respiratory support typically require this for prolonged durations, with a mean of 13 days of respiratory support reported by the China Medical Treatment Expert Group for COVID-19.1 This lengthy requirement for ventilator support and ICU resources, exacerbated by relatively little excess health system capacity to accommodate epidemics, means that health care systems can (and have in the case of many hospitals in Italy) become overwhelmed relatively quickly.
    Written by: Christopher J.D. Wallis, MD, PhD and Zachary Klaassen, MD, MSc
    References: 1. Guan, Wei-jie, Zheng-yi Ni, Yu Hu, Wen-hua Liang, Chun-quan Ou, Jian-xing He, Lei Liu et al. "Clinical characteristics of coronavirus disease 2019 in China." New England Journal of Medicine (2020).
    2. March 13, Online, and 2020. “COVID-19: Recommendations for Management of Elective Surgical Procedures.” American College of Surgeons. Accessed April 10, 2020. https://www.facs.org/covid-19/clinical-guidance/elective-surgery.
    3. March 17, Online, and 2020. “COVID-19: Guidance for Triage of Non-Emergent Surgical Procedures.” American College of Surgeons. Accessed April 10, 2020. https://www.facs.org/covid-19/clinical-guidance/triage.
    4. Liang, Wenhua, Weijie Guan, Ruchong Chen, Wei Wang, Jianfu Li, Ke Xu, Caichen Li et al. "Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China." The Lancet Oncology 21, no. 3 (2020): 335-337.
    5. Choo, Richard, Laurence Klotz, Cyril Danjoux, Gerard C. Morton, Gerrit DeBoer, Ewa Szumacher, Neil Fleshner, Peter Bunting, and George Hruby. "Feasibility study: watchful waiting for localized low to intermediate grade prostate carcinoma with selective delayed intervention based on prostate specific antigen, histological and/or clinical progression." The Journal of urology 167, no. 4 (2002): 1664-1669.
    6. Klotz, Laurence, Danny Vesprini, Perakaa Sethukavalan, Vibhuti Jethava, Liying Zhang, Suneil Jain, Toshihiro Yamamoto, Alexandre Mamedov, and Andrew Loblaw. "Long-term follow-up of a large active surveillance cohort of patients with prostate cancer." Journal of Clinical Oncology 33, no. 3 (2015): 272-277.
    7. Musunuru, Hima Bindu, Toshihiro Yamamoto, Laurence Klotz, Gabriella Ghanem, Alexandre Mamedov, Peraka Sethukavalan, Vibhuti Jethava et al. "Active surveillance for intermediate risk prostate cancer: survival outcomes in the Sunnybrook experience." The Journal of urology 196, no. 6 (2016): 1651-1658.
    8. Wilt, Timothy J., Tien N. Vo, Lisa Langsetmo, Philipp Dahm, Thomas Wheeler, William J. Aronson, Matthew R. Cooperberg, Brent C. Taylor, and Michael K. Brawer. "Radical Prostatectomy or Observation for Clinically Localized Prostate Cancer: Extended Follow-up of the Prostate Cancer Intervention Versus Observation Trial (PIVOT)." European urology (2020).
    9. Bourgade, Vincent, Sarah J. Drouin, David R. Yates, Jerôme Parra, Marc-Olivier Bitker, Olivier Cussenot, and Morgan Rouprêt. "Impact of the length of time between diagnosis and surgical removal of urologic neoplasms on survival." World journal of urology 32, no. 2 (2014): 475-479.
    10. Vickers, Andrew J., Fernando J. Bianco Jr, Stephen Boorjian, Peter T. Scardino, and James A. Eastham. "Does a delay between diagnosis and radical prostatectomy increase the risk of disease recurrence?." Cancer: Interdisciplinary International Journal of the American Cancer Society 106, no. 3 (2006): 56-580.
    11. Korets, Ruslan, Catherine M. Seager, Max S. Pitman, Gregory W. Hruby, Mitchell C. Benson, and James M. McKiernan. "Effect of delaying surgery on radical prostatectomy outcomes: a contemporary analysis." BJU international 110, no. 2 (2012): 211-216.
    12. van den Bergh, Roderick CN, Ewout W. Steyerberg, Ali Khatami, Gunnar Aus, Carl Gustaf Pihl, Tineke Wolters, Pim J. van Leeuwen, Monique J. Roobol, Fritz H. Schröder, and Jonas Hugosson. "Is delayed radical prostatectomy in men with low‐risk screen‐detected prostate cancer associated with a higher risk of unfavorable outcomes?." Cancer: Interdisciplinary International Journal of the American Cancer Society 116, no. 5 (2010): 1281-1290.
    13. van den Bergh, Roderick CN, Peter C. Albertsen, Chris H. Bangma, Stephen J. Freedland, Markus Graefen, Andrew Vickers, and Henk G. van der Poel. "Timing of curative treatment for prostate cancer: a systematic review." European urology 64, no. 2 (2013): 204-215.
    14. Cooperberg, Matthew R., and Peter R. Carroll. "Trends in management for patients with localized prostate cancer, 1990-2013." Jama 314, no. 1 (2015): 80-82.
    15. Gupta, Natasha, Trinity J. Bivalacqua, Misop Han, Michael A. Gorin, Ben J. Challacombe, Alan W. Partin, and Mufaddal K. Mamawala. "Evaluating the impact of length of time from diagnosis to surgery in patients with unfavourable intermediate‐risk to very‐high‐risk clinically localised prostate cancer." BJU international 124, no. 2 (2019): 268-274.
    16. Patel, Premal, Ryan Sun, Benjamin Shiff, Kiril Trpkov, and Geoffrey Thomas Gotto. "The effect of time from biopsy to radical prostatectomy on adverse pathologic outcomes." Research and reports in urology 11 (2019): 53.
    17. Aas, Kirsti, Sophie Dorothea Fosså, Rune Kvåle, Bjørn Møller, Tor Åge Myklebust, Ljiljana Vlatkovic, Stig Müller, and Viktor Berge. "Is time from diagnosis to radical prostatectomy associated with oncological outcomes?." World journal of urology 37, no. 8 (2019): 1571-1580.
    18. Fossati, Nicola, Martina Sofia Rossi, Vito Cucchiara, Giorgio Gandaglia, Paolo Dell’Oglio, Marco Moschini, Nazareno Suardi et al. "Evaluating the effect of time from prostate cancer diagnosis to radical prostatectomy on cancer control: can surgery be postponed safely?." In Urologic Oncology: Seminars and Original Investigations, vol. 35, no. 4, pp. 150-e9. Elsevier, 2017.
    19. Berg, William T., Matthew R. Danzig, Jamie S. Pak, Ruslan Korets, Arindam RoyChoudhury, Gregory Hruby, Mitchell C. Benson, James M. McKiernan, and Ketan K. Badani. "Delay from biopsy to radical prostatectomy influences the rate of adverse pathologic outcomes." The Prostate 75, no. 10 (2015): 1085-1091.
    20. Meunier, M. E., Y. Neuzillet, C. Radulescu, C. Cherbonnier, J. M. Hervé, M. Rouanne, V. Molinié, and T. Lebret. "Does the delay from prostate biopsy to radical prostatectomy influence the risk of biochemical recurrence?." Progres en urologie: journal de l'Association francaise d'urologie et de la Societe francaise d'urologie 28, no. 10 (2018): 475-481.
    21. Zanaty, Marc, Mansour Alnazari, Kelsey Lawson, Mounsif Azizi, Emad Rajih, Abdullah Alenizi, Pierre-Alain Hueber et al. "Does surgical delay for radical prostatectomy affect patient pathological outcome? A retrospective analysis from a Canadian cohort." Canadian Urological Association Journal 11, no. 8 (2017): 265.
    22. Zanaty, Marc, Mansour Alnazari, Khaled Ajib, Kelsey Lawson, Mounsif Azizi, Emad Rajih, Abdullah Alenizi et al. "Does surgical delay for radical prostatectomy affect biochemical recurrence? A retrospective analysis from a Canadian cohort." World journal of urology 36, no. 1 (2018): 1-6.
    23. Westerman, Mary E., Vidit Sharma, George C. Bailey, Stephen A. Boorjian, Igor Frank, Matthew T. Gettman, R. Houston Thompson, Matthew K. Tollefson, and Robert Jeffrey Karnes. "Impact of time from biopsy to surgery on complications, functional and oncologic outcomes following radical prostatectomy." International braz j urol 45, no. 3 (2019): 468-477.
    24. Martin, George L., Rafael N. Nunez, Mitchell D. Humphreys, Aaron D. Martin, Robert G. Ferrigni, Paul E. Andrews, and Erik P. Castle. "Interval from prostate biopsy to robot‐assisted radical prostatectomy: effects on perioperative outcomes." BJU international 104, no. 11 (2009): 1734-1737.
    25. Schifano, N., P. Capogrosso, E. Pozzi, E. Ventimiglia, W. Cazzaniga, R. Matloob, G. Gandaglia et al. "Impact of time from diagnosis to treatment on erectile function outcomes after radical prostatectomy." Andrology 8, no. 2 (2020): 337-341.
    26. Radomski, Lenny, Johan Gani, Greg Trottier, and Antonio Finelli. "Active surveillance failure for prostate cancer: does the delay in treatment increase the risk of urinary incontinence?." The Canadian journal of urology 19, no. 3 (2012): 6287-6292.
    27. Kumar, Satish, Mike Shelley, Craig Harrison, Bernadette Coles, Timothy J. Wilt, and Malcolm Mason. "Neo‐adjuvant and adjuvant hormone therapy for localised and locally advanced prostate cancer." Cochrane Database of Systematic Reviews 4 (2006).
    Published April 17, 2020
  • Post-Operative Radiotherapy in Prostate Cancer – The State of the Data

    Published in Everyday Urology - Oncology Insights: Volume 5, Issue 4
    Published January 2021

    Contemporary treatment options for patients with clinically localized prostate cancer include radical prostatectomy, radiotherapy, and active surveillance. Surgery can be curative for approximately two-thirds of patients choosing radical prostatectomy.1 However, men with adverse pathologic findings at the time of radical prostatectomy, such as the presence of positive surgical margins, extraprostatic extension, or seminal vesicle invasion,2,3 experience up to a 60% risk of recurrence at 10 years and may require subsequent radiation therapy.2

    Published January 5, 2021
  • Prostate Cancer Early Detection During the COVID-19 Pandemic

    Currently, there is a global pandemic surrounding the spread of betacoronavirus SARS-CoV-2 leading to Coronavirus Disease 2019 (COVID-19). The rapid spread to all corners of the globe has had tremendous health and economic implications, including the appropriate allocation of healthcare resources. Considering that hospitals may be overwhelmed quickly given the need for a proportion of patients that require hospitalization with possible ventilator support, there is a necessity to decrease the use of items essential for the care of patients with COVID-19 including ICU beds, ventilators, personal protective equipment, and terminal cleaning supplies. This includes reassessing the priority and implications of treatments, including prostate cancer screening. 

    Written by: Zachary Klaassen, MD, MSc and Christopher J.D. Wallis, MD, PhD
    References: 1. Wilson, James Maxwell Glover, Gunnar Jungner, and World Health Organization. "Principles and practice of screening for disease." (1968).

    2. Sanda, Martin G., Jeffrey A. Cadeddu, Erin Kirkby, Ronald C. Chen, Tony Crispino, Joann Fontanarosa, Stephen J. Freedland et al. "Clinically localized prostate cancer: AUA/ASTRO/SUO guideline. Part I: risk stratification, shared decision making, and care options." The Journal of urology 199, no. 3 (2018): 683-690.

    3. Network NCC. NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer - Version 2.2019. In:2019.

    4. Reading, Stephanie R., Kimberly R. Porter, Jin-Wen Y. Hsu, Lauren P. Wallner, Ronald K. Loo, and Steven J. Jacobsen. "Racial and Ethnic Variation in Time to Prostate Biopsy After an Elevated Screening Level of Serum Prostate-specific Antigen." Urology 96 (2016): 121-127.

    5. Grummet, Jeremy P., Mahesha Weerakoon, Sean Huang, Nathan Lawrentschuk, Mark Frydenberg, Daniel A. Moon, Mary O'Reilly, and Declan Murphy. "Sepsis and ‘superbugs’: should we favour the transperineal over the transrectal approach for prostate biopsy?." BJU international 114, no. 3 (2014): 384-388.

    6. Liss, Michael A., MAS Behfar Ehdaie, Stacy Loeb, Maxwell V. Meng, Jay D. Raman, Vanessa Spears, CURN Sean P. Stroup et al. "THE PREVENTION AND TREATMENT OF THE MORE COMMON COMPLICATIONS RELATED TO PROSTATE BIOPSY UPDATE." (2016).

    7. Briganti, Alberto, Nicola Fossati, James WF Catto, Philip Cornford, Francesco Montorsi, Nicolas Mottet, Manfred Wirth, and Hendrik Van Poppel. "Active surveillance for low-risk prostate cancer: the European Association of Urology position in 2018." European urology 74, no. 3 (2018): 357-368.

    8. Klotz, Laurence, Danny Vesprini, Perakaa Sethukavalan, Vibhuti Jethava, Liying Zhang, Suneil Jain, Toshihiro Yamamoto, Alexandre Mamedov, and Andrew Loblaw. "Long-term follow-up of a large active surveillance cohort of patients with prostate cancer." Journal of Clinical Oncology 33, no. 3 (2015): 272-277.

    9. Fossati, Nicola, Martina Sofia Rossi, Vito Cucchiara, Giorgio Gandaglia, Paolo Dell’Oglio, Marco Moschini, Nazareno Suardi et al. "Evaluating the effect of time from prostate cancer diagnosis to radical prostatectomy on cancer control: can surgery be postponed safely?." In Urologic Oncology: Seminars and Original Investigations, vol. 35, no. 4, pp. 150-e9. Elsevier, 2017.

    10. Wilt, Timothy J., Tien N. Vo, Lisa Langsetmo, Philipp Dahm, Thomas Wheeler, William J. Aronson, Matthew R. Cooperberg, Brent C. Taylor, and Michael K. Brawer. "Radical Prostatectomy or Observation for Clinically Localized Prostate Cancer: Extended Follow-up of the Prostate Cancer Intervention Versus Observation Trial (PIVOT)." European urology (2020).

    11. Nacoti, Mirco, Andrea Ciocca, Angelo Giupponi, Pietro Brambillasca, Federico Lussana, Michele Pisano, Giuseppe Goisis et al. "At the epicenter of the Covid-19 pandemic and humanitarian crises in Italy: changing perspectives on preparation and mitigation." NEJM Catalyst Innovations in Care Delivery 1, no. 2 (2020).
    Published April 20, 2020
  • SIU 2019: Artificial Intelligence and Big Data

    Athens, Greece (Urotoday.com) In today’s medical environment of the growing number of patients, increasing complexity of patient problems, an ever-growing body of literature and available data, with limited time and increasing human error and bias, the need for artificial intelligence is at its peak. Human error is part of life in every field, including medicine, but in the medical field it can have a dire price and cost lives.
    Published October 22, 2019
  • SIU 2019: Focal Cryoablation for Prostate Cancer

    Athens, Greece (UroToday.com) Cryoablation involves freezing of the targeted prostate tissue in two cycles, reaching minus 40 degrees Celsius, with the following histological changes:

    1. Protein denaturation
    2. Direct rupture of cell membranes by crystal formation
    3. Vascular stasis and secondary microthrombi formation
    4. Ischemic cell death
    5. Coagulative necrosis
    Published October 20, 2019
  • SIU 2019: Use of Molecular Biomarkers in Localized Prostate Cancer Management

    Athens, Greece (Urotoday.com) In this talk, Dr. Tilki reviewed several prognostic biomarkers in the setting of localized prostate cancer management. 

    The currently available prognostic biomarkers include: 

    • Oncotype Dx (GPS) 
    • Prolaris 
    • Decipher 
    • Decipher Biopsy 
    Published October 22, 2019
  • SUO - AUA Summer Webcast: Focal Therapy for Prostate Cancer: SPARED Registry for Focal Therapy

    (UroToday.com) The Society of Urologic Oncology (SUO) held a virtual meeting on Saturday, July 18, 2020, in place of the usual meeting held at the American Urological Association (AUA) annual meeting. This virtual meeting was divided into sessions on bladder cancer, kidney cancer, and prostate cancer. In the session on prostate cancer, Jim Hu, MD, MPH, discussed the Study of Prostate Ablation Related Energy Devices (SPARED) Collaboration.
    Published July 19, 2020
  • SUO 2019: My Active Surveillance Trajectory: A Literary Bibliography - Laurence Klotz

    Washington, DC (UroToday.com) The recipient of this year’s Huggins Medal is Dr. Laurence Klotz from the University of Toronto and Sunnybrook Medical Centre. Dr. Klotz has 470 peer reviewed manuscripts and six books. His basic science research interests are in the role of micronutrients and diet in prostate cancer prevention and translational research. His research lab has been active for 30 years, producing several patents and a biotech company. Dr. Klotz’s clinical research interests have been in the areas of active surveillance, image-guided therapy, molecular biomarkers, and androgen receptor targeted therapy; additionally, he has lead numerous randomized trials in prostate cancer. His awards include the Queen’s Jubilee Medal in 2013 for meritorious public service, and in 2014 he received the Urologic Oncology Medal in 2014. He’s also received Canada’s highest civilian award, the Order of Canada, and the Harold Warwick Prize from the Canadian Cancer Society for international contributions to cancer control.

    Published December 6, 2019
  • SUO 2019: What Can We Learn from the Breast Experience?

    Washington, DC (UroToday.com) In the first prostate cancer session at the 2019 Society for Urologic Oncology meeting in Washington, DC, Dr. Matthew Cooperberg highlighted the similarities between breast cancer and prostate cancer and suggested some lessons that urologic oncologists can draw from the evolution of breast cancer treatment. He credited his colleague at UCSF, Dr. Laura Esserman, for her leadership in breast cancer research and her assistance with the preparation of his talk.

    Published December 6, 2019
  • The History of Imaging for Prostate Cancer

    Diagnosis and assessment of primary tumor – TRUS and mpMRI

    Historically, prostate cancer diagnosis was made on the basis of transrectal or transperineal needle biopsy guided by digital palpation per rectum (so-called, finger guided biopsies).1 These biopsies were typically directed at palpable abnormalities. A number of significant changes occurred to this approach beginning in the early 1990s. First, a systematic approach to prostate biopsy advocated by Hodge et al., as opposed to directed cores, was widely adopted.2

    Second, the use of transrectal ultrasound (TRUS) for prostate visualization and biopsy guidance became widespread. The use of TRUS allowed for direct visualization of the prostate, any of its anomalies, as well as the biopsy needle. Thus, TRUS-guided prostate biopsy became the gold standard approach to prostate cancer diagnosis.3 However, there are well-known limitations to TRUS-guided prostate biopsy including inherent random and systematic errors. Unless clear visible hypoechoic suspicious areas are seen in TRUS, sampling occurs by chance, and specific zones are under-sampled, including the anterior region and apex.4 Further, TRUS-guided systematic prostate biopsy can miss up to 20% of clinically significant prostate cancer, resulting in underdiagnosis and undertreatment.5 However, at the same time, TRUS-guided systematic prostate biopsy detects a relatively high percentage of clinically insignificant prostate cancer (Gleason grade group [GGG] 1), which may result in overtreatment.6

    Thus, thirdly, multiparametric magnetic resonance has recently been evaluated for the identification of prostate lesions likely to be cancerous, as well as the guidance of prostate biopsy.

    Initially, MRI was used as a staging test in patients with prostate cancer for assessment of direct extra-prostatic extension utilizing T2-weighted imaging. This approach was marked by significant variability in diagnostic performance, limited ability to detect microscopic disease and inability to localize the tumor within the gland itself.7 These factors limited the widespread adoption of MRI for local tumor staging. Indeed, to this data, TNM staging for prostate cancer relies on digital rectal examination rather than radiographic findings for local tumor staging.

    However, multiparametric MRI, particularly with the addition of diffusion-weighted imaging has allowed for increasingly informative studies, including the visualization of tumors within the prostate. This has allowed for the use of mpMRI to guide prostate biopsy, either directly with in-bore biopsy or more commonly using a fusion device platform.8 When performed in the evaluation of patients with elevated prostate-specific antigen (PSA) levels with previous negative prostate biopsy, multi-parametric magnetic resonance imaging has been shown to identify clinically significant prostate cancers which would have been otherwise missed by routine systematic biopsy.9 A recent systematic review and meta-analysis from Kasivisvanathan and colleagues suggested that multi-parametric magnetic resonance imaging targeted biopsy detects more clinically significant prostate cancer than standard TRUS-guided systematic biopsy alone and requires fewer prostate cores to do so; that the question of whether to include systematic biopsy along with multi-parametric magnetic resonance imaging targeted biopsy remains controversial; and that the omission of the systematic biopsy risks missing the diagnosis of clinically significant disease in approximately 13% of men while the inclusion of systematic biopsy increases the likelihood of diagnosing clinically insignificant prostate cancer.10

    The most recent European Association of Urology Prostate cancer guidelines conclude that, when at least one functional imaging technique is employed, mpMRI has good sensitivity for the detection and localization of clinically significant (Gleason Grade Group 2 or greater) prostate cancers6 with lower sensitivity for the detection of Gleason Grade Group 1 cancers, likely a beneficial characteristic. Potential limitations of the widespread use of a multi-parametric magnetic resonance imaging driven diagnostic pathway include only a moderate inter-reader reproducibility of multi-parametric magnetic resonance imaging, the lack of standardization of targeted biopsy, and cost-effectiveness concerns in certain jurisdictions.

    Even more recently, high-resolution micro-ultrasound has emerged as a novel imaging modality for prostate cancer. High-resolution micro-ultrasound has a very fine resolution (approximately 70 µm) which allows for visualization of alterations in ductal anatomy and cellular density consistent with prostate tumors.11 In early experiences, high-resolution micro-ultrasound has demonstrated an ability to detect clinically significant cancers that were not apparent on either traditional TRUS or mpMRI.12 In contrast to mpMRI, high-resolution micro-ultrasound has the advantage of providing real-time imaging results, a finding that authors from the Cleveland Clinic demonstrated was associated with a relative increase in prostate cancer detection of 26.7%.12 Aggregate data from early clinical experience at multiple centers suggests that high-resolution micro-ultrasound has comparable or increased sensitivity for clinically significant prostate cancer compared with mpMRI and comparable or slightly reduced specificity.11

    Distant staging – from radiographs to molecularly targeted imaging

    While mpMRI has revolutionized imaging of the prostate and substantially changed the diagnostic algorithm for prostate cancer, perhaps even greater changes have occurred in the imaging for distant disease.

    Initially, a radiographic diagnosis of bony prostate cancer metastasis was made on the basis of plain radiographs. However, bony metastases may be difficult to identify based on plain films as an extensive bone mineral loss (exceeding 30-50%) may be required before such changes are radiographically apparent.13 However, plain films remain useful for the immediate investigation of patients who present with bony pain and for the assessment of bony stability in those deemed at risk of pathologic fracture.

    Following plain projectional radiography, skeletal scintigraphy was the next imaging modality widely adopted for the assessment of bony metastases in patients with prostate cancer. To date, it remains widely utilized and is currently recommended, along with abdominal and pelvic computed tomography, for the staging of patients according to many guideline bodies. Skeletal scintigraphy, when performed in patients with known cancer in the absence of bony pain, has a sensitivity of 86% and specificity of 81% for the detection of metastatic lesions.13 As with any imaging modality, these characteristics differ somewhat on the basis of the patient population being tested (i.e. the pre-test probability or population-based disease prevalence). Among patients with prostate cancer, PSA levels are predictive of the likelihood of a positive bone scan. Across a number of different cancers, Yang et al. found that bone scintigraphy had a specificity of 81.4% and sensitivity of 86.0%, on a per-patient basis, for the detection of bony metastases.14

    Computed tomography has been utilized for the assessment of nodal metastatic disease, visceral disease, and bony metastasis. CT is highly sensitive for both osteoblastic tumors (such as prostate cancer) and osteolytic lesions in the cortical bone but is less sensitive in tumors that are restricted to the marrow space.13 As a result, CT is of relatively limited utility as a screening test for bony metastasis due to relatively low sensitivity (73%) despite excellent specificity (95%) – numbers based on a large scale meta-analysis from Yang and colleagues.14 For this reason, conventional staging recommendations for patients with prostate cancer include bony scintigraphy for the detection of bony lesions along with computed tomography for identification of nodal/visceral lesions and correlation of any bony lesions.15

    In addition to its role in the local staging of the prostate and guidance of prostate biopsy, mpMRI may also assist with evaluation for distant metastatic disease. Routine pelvic/prostate MRI typically allows for assessment of local/regional nodal involvement including obturator and external iliac nodal chains. However, the high soft-tissue contrast and high spatial resolution afforded by MRI call also allow for the identification of bony metastasis in marrow spaces much early than would be apparent based on CT scan.14 Further, use of T1-weighted sequences and STIR sequences can allow for adequate assessment for bony metastasis without the need for intravenous contrast agents; use of MRI for staging does not require the use of ionizing radiation. Thus, abdominal/pelvic or whole-body MRI may be considered for the identification of distant metastatic disease. Additionally, MRI with contrast has become the imaging modality of choice for the evaluation of liver metastases.16 Thus, this approach may be particularly valuable in patients at a high risk of visceral metastatic disease.

    Traditional positron emission tomography (PET) imaging utilizing fluorodeoxyglucose (FDG) is not typically effective in the initial diagnosis of prostate cancer metastasis owing to the relatively low metabolic activity associated with the disease. However, at least four other PET imaging approaches have been assessed and employed in patients with prostate cancer including 18F-NaF PET/CT, choline-based PET/CT, fluciclovine (Axumin®) PET/CT, and PSMA-targeted PET/CT.17 These modalities have been used in the staging of both primary and recurrent prostate cancer. While clearly improved compared to bony scintigraphy, the limitations are similar – namely, that sensitivity is highly dependent on PSA levels. However, choline-based PET/CT has demonstrated significantly higher sensitivity for the diagnosis of metastatic lesions at the time of biochemical recurrence compared to conventional imaging with a bone scan and computed tomography.17 However, compared to MRI, the benefits of choline-based PET/CT are less clear.18 MRI clearly outperformed choline-based PET/CT for the detection of local recurrence (36.1% vs 1.6%), while choline-PET/CT was superior for identification of lymph node metastasis and both were effective at identifying bony metastatic disease.19

    Choline-based PET/CT is not widely available in the United States. However, fluciclovine PET/CT (also known as Axumin® PET/CT) which utilizes the proliferation of tumor cells for localization, is much more available. Fluciclovine (18F-FACBC; 1-amino-3-fluorine 18F-flurocyclobutane-1-carboxylic acid) is a synthetic amino acid analog with the advantage of negligible renal uptake and no activity in the urinary tract.18 Nevertheless, non-specific prostate uptake limits its utility in the identification of primary prostate tumors due to an inability to distinguish from benign prostatic inflammation. Instead, fluciclovine-PET/CT has proven efficacy in the detection of recurrent prostate cancer with biochemical recurrence following local therapy, with a sensitivity of 90% and specificity of 40% (higher in distant, 97%, and nodal disease, 55%, than locally).20 Compared to choline-PET/CT, fluciclovine-PET/CT demonstrated lower false-negatives and false-positive rates in patients with biochemical recurrence.21, 22

    Finally, receptor-targeted PET imaging has recently been examined, most notably, PSMA-based PET/CT. PSMA is a transmembrane glycoprotein found on prostatic epithelium. The ratio of PSMA to its truncated isoform (PSM’) is proportional to tumor aggressivity. The most well examined PSMA based approach is 68Ga-PSMA-PET/CT. In patients with biochemical recurrence following radical prostatectomy, 68Ga-PSMA-PET/CT demonstrated superior detection rates of metastatic disease (56%) compared with fluciclovine-PET/CT (13%).23 This benefit was consistent in detecting pelvic nodal disease and extrapelvic disease. PSMA-based PET/CT demonstrated a particular benefit in the evaluation of patients with low absolute PSA levels. Further, 68Ga-PSMA-PET/CT appears to be superior to MRI in primary staging of patients prior to local therapy.24 Other radiotracers including 18F-DCFPyL and 177Lu-PSMA-617 have recently been examined in place of 68Ga-PSMA.25

    Recent work has also assessed the role of PET/MRI, rather than PET/CT. This approach leverages the advantages of the sensitivity of receptor-targeted imaging and the spatial resolution of MRI.24

    Conclusion

    The evolution of imaging in prostate cancer has allowed a more nuanced understanding of the disease. Assessing the local tumor, both mpMRI and high-resolution micro-ultrasound allow for a more informed prostate biopsy which may assist in more accurate initial disease characterization26 as well as local staging. Ongoing advances in receptor-targeted PET imaging continue to refine the identification of metastatic disease. This has important implications for what we understand to be M0 and M1 prostate cancer. Whether early detection of metastatic disease utilizing these modalities translates into improvements in patient outcomes, or simply lead-time bias, remains to be assessed.

    Published Date: March 19th, 2020
    Written by: Zachary Klaassen, MD, MSc and Christopher J.D. Wallis, MD, PhD
    References: 1. Shinohara, K., V. A. Master, T. Chi, and P. R. Carroll. "Prostate needle biopsy techniques and interpretation." Genitourinary Oncology. Philadelphia, Lippincott, Williams & Wilkins (2006): 111-119.
    2. Hodge, Kathryn K., John E. McNeal, Martha K. Terris, and Thomas A. Stamey. "Random systematic versus directed ultrasound guided transrectal core biopsies of the prostate." The Journal of urology 142, no. 1 (1989): 71-74.
    3. Heidenreich, Axel, Patrick J. Bastian, Joaquim Bellmunt, Michel Bolla, Steven Joniau, Theodor van der Kwast, Malcolm Mason et al. "EAU guidelines on prostate cancer. Part 1: screening, diagnosis, and local treatment with curative intent—update 2013." European urology 65, no. 1 (2014): 124-137.
    4. Kongnyuy, Michael, Abhinav Sidana, Arvin K. George, Akhil Muthigi, Amogh Iyer, Michele Fascelli, Meet Kadakia et al. "The significance of anterior prostate lesions on multiparametric magnetic resonance imaging in African-American men." In Urologic Oncology: Seminars and Original Investigations, vol. 34, no. 6, pp. 254-e15. Elsevier, 2016.
    5. Schouten, Martijn G., Marloes van der Leest, Morgan Pokorny, Martijn Hoogenboom, Jelle O. Barentsz, Les C. Thompson, and Jurgen J. Fütterer. "Why and where do we miss significant prostate cancer with multi-parametric magnetic resonance imaging followed by magnetic resonance-guided and transrectal ultrasound-guided biopsy in biopsy-naïve men?." European urology 71, no. 6 (2017): 896-903.
    6. Mottet, Nicolas, Joaquim Bellmunt, Michel Bolla, Erik Briers, Marcus G. Cumberbatch, Maria De Santis, Nicola Fossati et al. "EAU-ESTRO-SIOG guidelines on prostate cancer. Part 1: screening, diagnosis, and local treatment with curative intent." European urology 71, no. 4 (2017): 618-629.
    7. Rifkin, Matthew D., Elias A. Zerhouni, Constantine A. Gatsonis, Leslie E. Quint, David M. Paushter, Jonathan I. Epstein, Ulrike Hamper, Patrick C. Walsh, and Barbara J. McNeil. "Comparison of magnetic resonance imaging and ultrasonography in staging early prostate cancer: results of a multi-institutional cooperative trial." New England Journal of Medicine 323, no. 10 (1990): 621-626.
    8. Siddiqui, M. Minhaj, Soroush Rais-Bahrami, Baris Turkbey, Arvin K. George, Jason Rothwax, Nabeel Shakir, Chinonyerem Okoro et al. "Comparison of MR/ultrasound fusion–guided biopsy with ultrasound-guided biopsy for the diagnosis of prostate cancer." Jama 313, no. 4 (2015): 390-397.
    9. Vourganti, Srinivas, Ardeshir Rastinehad, Nitin K. Yerram, Jeffrey Nix, Dmitry Volkin, An Hoang, Baris Turkbey et al. "Multiparametric magnetic resonance imaging and ultrasound fusion biopsy detect prostate cancer in patients with prior negative transrectal ultrasound biopsies." The Journal of urology 188, no. 6 (2012): 2152-2157.
    10. Kasivisvanathan, Veeru, Armando Stabile, Joana B. Neves, Francesco Giganti, Massimo Valerio, Yaalini Shanmugabavan, Keiran D. Clement et al. "Magnetic resonance imaging-targeted biopsy versus systematic biopsy in the detection of prostate cancer: a systematic review and meta-analysis." European urology (2019).
    11. Klotz, CM Laurence. "Can high resolution micro-ultrasound replace MRI in the diagnosis of prostate cancer?." European urology focus (2019).
    12. Abouassaly, Robert, Eric A. Klein, Ahmed El-Shefai, and Andrew Stephenson. "Impact of using 29 MHz high-resolution micro-ultrasound in real-time targeting of transrectal prostate biopsies: initial experience." World journal of urology (2019): 1-6.
    13. Heindel, Walter, Raphael Gübitz, Volker Vieth, Matthias Weckesser, Otmar Schober, and Michael Schäfers. "The diagnostic imaging of bone metastases." Deutsches Ärzteblatt International 111, no. 44 (2014): 741.
    14. Yang, Hui-Lin, Tao Liu, Xi-Ming Wang, Yong Xu, and Sheng-Ming Deng. "Diagnosis of bone metastases: a meta-analysis comparing 18 FDG PET, CT, MRI and bone scintigraphy." European radiology 21, no. 12 (2011): 2604-2617.
    15. Network NCC. NCCN Clinical Practice Guideslines in Oncology: Prostate Cancer - Version 1.2019. 2019.
    16. Namasivayam, Saravanan, Diego R. Martin, and Sanjay Saini. "Imaging of liver metastases: MRI." Cancer Imaging 7, no. 1 (2007): 2.
    17. Li, Roger, Gregory C. Ravizzini, Michael A. Gorin, Tobias Maurer, Matthias Eiber, Matthew R. Cooperberg, Mehrdad Alemozzaffar, Matthew K. Tollefson, Scott E. Delacroix, and Brian F. Chapin. "The use of PET/CT in prostate cancer." Prostate cancer and prostatic diseases 21, no. 1 (2018): 4-21.
    18. Rayn, Kareem N., Youssef A. Elnabawi, and Niki Sheth. "Clinical implications of PET/CT in prostate cancer management." Translational andrology and urology 7, no. 5 (2018): 844.
    19. Reske, Sven N., Norbert M. Blumstein, and Gerhard Glatting. "[11 C] choline PET/CT imaging in occult local relapse of prostate cancer after radical prostatectomy." European journal of nuclear medicine and molecular imaging 35, no. 1 (2008): 9-17.
    20. Schuster, David M., Peter T. Nieh, Ashesh B. Jani, Rianot Amzat, F. DuBois Bowman, Raghuveer K. Halkar, Viraj A. Master 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." The Journal of urology 191, no. 5 (2014): 1446-1453.
    21. Wondergem, Maurits, Friso M. van der Zant, Tjeerd van der Ploeg, and Remco JJ Knol. "A literature review of 18F-fluoride PET/CT and 18F-choline or 11C-choline PET/CT for detection of bone metastases in patients with prostate cancer." Nuclear medicine communications 34, no. 10 (2013): 935-945.
    22. Nanni, Cristina, Lucia Zanoni, Cristian Pultrone, Riccardo Schiavina, Eugenio Brunocilla, Filippo Lodi, Claudio Malizia et al. "18 F-FACBC (anti1-amino-3-18 F-fluorocyclobutane-1-carboxylic acid) versus 11 C-choline PET/CT in prostate cancer relapse: results of a prospective trial." European journal of nuclear medicine and molecular imaging 43, no. 9 (2016): 1601-1610.
    23. Calais, Jeremie, Francesco Ceci, Matthias Eiber, Thomas A. Hope, Michael S. Hofman, Christoph Rischpler, Tore Bach-Gansmo 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." The Lancet Oncology 20, no. 9 (2019): 1286-1294.
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    Published March 19, 2020