Active Surveillance in Prostate Cancer: The 2021 NCCN Controversy

Active Surveillance Background

Prostate cancer represents a public health dilemma: while prostate cancer is the second leading cause of death among men in the US1 and third in Canada,2 it is widely over-diagnosed and over-treated, leading to significant patient anxiety and morbidity.3 Much of the over-diagnosis of prostate cancer relates to the use of serum prostate-specific antigen (PSA) testing for prostate cancer screening, beginning in 1987.4
Written by: Christopher J.D. Wallis, MD, PhD, University of Toronto, Toronto, Ontario, Canada & Zachary Klaassen, MD, MSc, Medical College of Georgia, Augusta, Georgia, USA
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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.

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The Fight Against Increased Rates of Prostate Cancer

Over the nearly two years of navigating the COVID pandemic, urology practices were forced to increase their efficiency by focusing on streamlining patient visits without sacrificing care quality. However, postponed checkups were unavoidable as the public was encouraged to stay home. According to the Centers for Disease Control and Prevention (CDC), 40% of Americans in 2020 delayed or avoided medical care due to pandemic-related concerns. Although necessary, we are now facing the severe consequences of delayed diagnosis and prostate cancer seems to be leading the way.

Written by: David Crawford, MD

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).

Real-World Clinical Utility of Decipher Biopsy Testing in Localized Prostate Cancer

In prostate pre- and post-biopsy decision making, more precision is urgently needed. Whereas expert imaging and biomarker-based risk scores already enable the clinician in this respect, the dilemma remains for those patients that are diagnosed with apparent indolent cancer. Additional diagnostic tools that (de)select patients for active surveillance (AS) would provide a great benefit for the patient.

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.
3. March 17, Online, and 2020. “COVID-19: Guidance for Triage of Non-Emergent Surgical Procedures.” American College of Surgeons. Accessed April 10, 2020.
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).

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

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


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 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.
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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.
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