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

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).

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, Medical Director of the Carolina Urologic Research Center, Atlantic Urology Clinics, Myrtle Beach, South Carolina, and Michael S. Cookson, MD, MMHC, Professor and Chairman, Department of Urology, Donald D. Albers Endowed Chair in Urology, Stephenson Cancer Center, University of Oklahoma College of Medicine, Oklahoma City, Oklahoma
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.

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).

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.

References: 1. Crawford ED, Koo PJ, Shore N, et al. A clinician’s guide to next generation imaging in patients with advanced prostate cancer (RADAR III). J Urol. 2019;201: 682–692.
2. Perez-Lopez R, Tiunariu N, Padhani AR, et al. Imaging diagnosis and follow-up of advanced prostate cancer: clinical perspectives and state of the art. Radiology. 2019;292:273–286.
3. Protecting Access to Medicare Act of 2014, Pub L No. 113-93, 128 Stat 1040 (2014).
4. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394–424.
5. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68:7–30.
6. Mullins JK, Feng Z, Trock BJ, Epstein JI, Walsh PC, Loeb S. The impact of anatomical radical retropubic prostatectomy on cancer control: the 30-year anniversary. J Urol. 2012;188:2219–2224.
7. Cookson MS, Aus G, Burnett AL, et al. Variation in the definition of biochemical recurrence in patients treated for localized prostate cancer update panel report and recommendations for standard in the reporting of surgical outcomes. J Urol. 2007;177:540–545.
8. Roach M, 3rd, Hanks G, Thames H Jr, et al. Defining biochemical failure following radiation therapy with or without hormonal therapy in men with clinically localized prostate cancer: recommendations of the RTOG-ASTRO Phoenix Consensus Conference. Int J Radiat Oncol Biol Phys. 2006;65:965– 974.
9. Freedland SJ, Humphreys EB, Mangold LA, et al. Risk of prostate cancerspecific mortality following biochemical recurrence after radical prostatectomy. JAMA. 2005;294:433–439.
10. Antonarakis ES, Feng Z, Trock BJ, et al. The natural history of metastatic progression in men with prostate-specific antigen recurrence after radical prostatectomy: long-term follow-up. BJU Int. 2012;109:32–39.
11. Stephenson AJ, Scardino PT, Kattan MW, et al. Predicting the outcome of salvage radiation therapy for recurrent prostate cancer after radical prostatectomy. J Clin Oncol. 2007;25:2035–2041.
12. Dalela D, Löppenberg B, Sood A, Sammon J, Abdollah F. Contemporary role of the Decipher® test in prostate cancer management: current practice and future perspectives. Rev Urol. 2016;18:1–9.
13. Xu MJ, Kornberg Z, Gadzinski AJ, et al. Genomic risk predicts molecular imaging-detected metastatic nodal disease in prostate cancer. Eur Urol Oncol. January 14, 2019 [Epub ahead of print].
14. Pollack A, Karrison TG, Balogh AG, et al. Short term androgen deprivation therapy without or with pelvic lymph node treatment added to prostate bed only salvage radiotherapy: The NRG Oncology/RTOG 0534 SPPORT trial. Int J Radiat Oncol Biol Phys. 2018;102:1605.
15. Jadvar H. Oligometastatic prostate cancer: molecular imaging and clinical management implications in the era of precision oncology. J Nucl Med. 2018;59:1338– 1339.
16. Muldermans JL, Romak LB, Kwon ED, Park SS, Olivier KR. Stereotactic body radiation therapy for oligometastatic prostate cancer. Int J Radiat Oncol Biol Phys. 2016;95:696–702.
17. Ost P, Jereczek-Fossa BA, As NV, et al. Progression-free survival following stereotactic body radiotherapy for oligometastatic prostate cancer treatment naive recurrence: a multi-institutional analysis. Eur Urol. 2016;69:9–12.
18. Brassetti A, Proietti F, Pansadoro V. Oligometastic prostate cancer and salvage lymph node dissection: systematic review. Minerva Chir. 2019;74:97–106.
19. Fitch K, Bernstein SJ, Aguilar MD, Burnand B. The RAND/UCLA Appropriateness Method User’s Manual. Santa Monica, CA: RAND; 2001.
20. Institute of Medicine of the National Academy. Clinical Practice Guidelines We Can Trust. Washington, DC: National Academies Press; 2011.
21. AQA Principles for Appropriateness Criteria. London, U.K.: Assessment and Qualifications Alliance; 2009.
22. Oyen RH, Van Poppel HP, Ameye FE, Van de Voorde WA, Baert AL, Baert LV. Lymph node staging of localized prostatic carcinoma with CT and CT-guided fine-needle aspiration biopsy: prospective study of 285 patients. Radiology. 1994;190:315–322.
23. Kane CJ, Amling CL, Johnstone PA, et al. Limited value of bone scintigraphy and computed tomography in assessing biochemical failure after radical prostatectomy. Urology. 2003;61:607–611.
24. Johnstone PA, Tarman GJ, Riffenburgh R, Rohde DC, Puckett ML, Kane CJ. Yield of imaging and scintigraphy assessing biochemical failure in prostate cancer patients. Urol Oncol. 1997;3:108–112.
25. Spencer JA, Golding SJ. Patterns of lymphatic metastases at recurrence of prostate cancer: CT findings. Clin Radiol. 1994;49:404–407.
26. Lamothe F, Kovi J, Heshmat MY, Green EJ. Dissemination of prostate carcinoma: an autopsy study. J Natl Med Assoc. 1986;78:1083–1086.
27. Suh CH, Shinagare AB, Westenfield AM, Ramaiya NH, Van den Abbeele AD, Kim KW. Yield of bone scintigraphy for the detection of metastatic disease in treatment-naive prostate cancer: a systematic review and meta-analysis. Clin Radiol. 2018;73:158–167.
28. Gomez P, Manoharan M, Kim SS, Soloway MS. Radionuclide bone scintigraphy in patients with biochemical recurrence after radical prostatectomy: when is it indicated? BJU Int. 2004;94:299–302.
29. Cher ML, Bianco FJ Jr, Lam JS, et al. Limited role of radionuclide bone scintigraphy in patients with prostate specific antigen elevations after radical prostatectomy. J Urol. 1998;160:1387–1391.
30. Vargas HA, Martin-Malburet AG, Takeda T, et al. Localizing sites of disease in patients with rising serum prostate-specific antigen up to 1 ng/ml following prostatectomy: how much information can conventional imaging provide? Urol Oncol. 2016;34:482.e5–482.e10.
31. Choueiri TK, Dreicer R, Paciorek A, Carroll PR, Konety B. A model that predicts the probability of positive imaging in prostate cancer cases with biochemical failure after initial definitive local therapy. J Urol. 2008;179:906–910.
32. Okotie OT, Aronson WJ, Wieder JA, et al. Predictors of metastatic disease in men with biochemical failure following radical prostatectomy. J Urol. 2004;171: 2260–2264.
33. Moreira DM, Cooperberg MR, Howard LE, et al. Predicting bone scan positivity after biochemical recurrence following radical prostatectomy in both hormone-naive men and patients receiving androgen-deprivation therapy: results from the SEARCH database. Prostate Cancer Prostatic Dis. 2014;17:91–96.
34. Dotan ZA, Bianco FJ Jr, Rabbani F, et al. Pattern of prostate-specific antigen (PSA) failure dictates the probability of a positive bone scan in patients with an increasing PSA after radical prostatectomy. J Clin Oncol. 2005;23:1962–1968.
35. Wondergem M, van der Zant FM, Knol RJJ, et al. 99mTc-HDP bone scintigraphy and 18F-sodium fluoride PET/CT in primary staging of patients with prostate cancer. World J Urol. 2018;36:27–34.
36. Apolo AB, Lindenberg L, Shih JH, et al. Prospective study evaluating Na18F PET/CT in predicting clinical outcomes and survival in advanced prostate cancer. J Nucl Med. 2016;57:886–892.
37. Schirrmeister H, Guhlmann A, Elsner K, et al. Sensitivity in detecting osseous lesions depends on anatomic localization: planar bone scintigraphy versus 18F PET. J Nucl Med. 1999;40:1623–1629.
38. Even-Sapir E, Metser U, Mishani E, Lievshitz G, Lerman H, Leibovitch I. The detection of bone metastases in patients with high-risk prostate cancer: 99mTcMDP planar bone scintigraphy, single- and multi-field-of-view SPECT, 18Ffluoride PET, and 18F-fluoride PET/CT. J Nucl Med. 2006;47:287–297.
39. Poulsen MH, Petersen H, Hoilund-Carlsen PF, et al. Spine metastases in prostate cancer: comparison of technetium-99m-MDP whole-body bone scintigraphy, [18F]choline positron emission tomography(PET)/computed tomography (CT) and [18F]NaF PET/CT. BJU Int. 2014;114:818–823.
40. Jambor I, Kuisma A, Ramadan S, et al. Prospective evaluation of planar bone scintigraphy, SPECT, SPECT/CT, 18F-NaF PET/CT and whole body 1.5T MRI, including DWI, for the detection of bone metastases in high risk breast and prostate cancer patients: SKELETA clinical trial. Acta Oncol. 2016;55:59–67.
41. Hillner BE, Siegel BA, Hanna L, et al. Impact of 18F-fluoride PET on intended management of patients with cancers other than prostate cancer: results from the National Oncologic PET Registry. J Nucl Med. 2014;55:1054–1061.
42. Sarikaya I, Sarikaya A, Elgazzar AH, et al. Prostate-specific antigen cutoff value for ordering sodium fluoride positron emission tomography/computed tomography bone scan in patients with prostate cancer. World J Nucl Med. 2018;17:281–285.
43. Beheshti M, Vali R, Waldenberger P, et al. Detection of bone metastases in patients with prostate cancer by 18F fluorocholine and 18F fluoride PET-CT: a comparative study. Eur J Nucl Med Mol Imaging. 2008;35:1766–1774.
44. Kjölhede H, Ahlgren G, Almquist H, et al. Combined 18F-fluorocholine and 18F-fluoride positron emission tomography/computed tomography imaging for staging of high-risk prostate cancer. BJU Int. 2012;110:1501–1506.
45. Langsteger W, Balogova S, Huchet V, et al. Fluorocholine (18F) and sodium fluoride (18F) PET/CT in the detection of prostate cancer: prospective comparison of diagnostic performance determined by masked reading. Q J Nucl Med Mol Imaging. 2011;55:448–457.
46. Jadvar H, Desai B, Ji L, et al. Prospective evaluation of 18F-NaF and 18F-FDG PET/CT in detection of occult metastatic disease in biochemical recurrence of prostate cancer. Clin Nucl Med. 2012;37:637–643.
47. Iagaru A, Mittra E, Dick DW, Gambhir SS. Prospective evaluation of 99mTc MDP scintigraphy, 18F NaF PET/CT, and 18F FDG PET/CT for detection of skeletal metastases. Mol Imaging Biol. 2012;14:252–259.
48. Damle NA, Bal C, Bandopadhyaya GP, et al. The role of 18F-fluoride PET-CT in the detection of bone metastases in patients with breast, lung and prostate carcinoma: a comparison with FDG PET/CT and 99mTc-MDP bone scan. Jpn J Radiol. 2013;31:262–269.
49. Uprimny C, Svirydenka A, Fritz J, et al. Comparison of [68Ga]Ga-PSMA-11 PET/CT with [18F]NaF PET/CT in the evaluation of bone metastases in metastatic prostate cancer patients prior to radionuclide therapy. Eur J Nucl Med Mol Imaging. 2018;45:1873–1883.
50. Zacho HD, Nielsen JB, Afshar-Oromieh A, et al. Prospective comparison of 68Ga-PSMA PET/CT, 18F-sodium fluoride PET/CT and diffusion weightedMRI at for the detection of bone metastases in biochemically recurrent prostate cancer. Eur J Nucl Med Mol Imaging. 2018;45:1884–1897.
51. Harmon SA, Bergvall E, Mena E, et al. A prospective comparison of 18Fsodium fluoride PET/CT and PSMA-targeted 18F-DCFBC PET/CT in metastatic prostate cancer. J Nucl Med. 2018;59:1665–1671.
52. Dyrberg E, Hendel HW, Huynh THV, et al. 68Ga-PSMA-PET/CT in comparison with 18F-fluoride-PET/CT and whole-body MRI for the detection of bone metastases in patients with prostate cancer: a prospective diagnostic accuracy study. Eur Radiol. 2019;29:1221–1230.
53. Jadvar H, Colletti PM. 18F-NaF/223RaCl2 theranostics in metastatic prostate cancer: treatment response assessment and prediction of outcome. Br J Radiol. 2018;91:20170948.
54. Oberlin DT, Casalino DD, Miller FH, Meeks JJ. Dramatic increase in the utilization of multiparametric magnetic resonance imaging for detection and management of prostate cancer. Abdom Radiol (NY). 2017;42:1255–1258.
55. Barchetti F, Stagnitti A, Megna V, et al. Unenhanced whole-body MRI versus PET-CT for the detection of prostate cancer metastases after primary treatment. Eur Rev Med Pharmacol Sci. 2016;20:3770–3776.
56. Couñago F, Sancho G, Catalá V, et al. Magnetic resonance imaging for prostate cancer before radical and salvage radiotherapy: what radiation oncologists need to know. World J Clin Oncol. 2017;8:305–319.
57. Hayman J, Hole KH, Seierstad T, et al. Local failure is a dominant mode of recurrence in locally advanced and clinical node positive prostate cancer patients treated with combined pelvic IMRT and androgen deprivation therapy. Urol Oncol. 2019;37:289.e19–289.e26.
58. Kitajima K, Murphy RC, Nathan MA, et al. Detection of recurrent prostate cancer after radical prostatectomy: comparison of 11C-choline PET/CT with pelvic multiparametric MR imaging with endorectal coil. J Nucl Med. 2014;55: 223–232.
59. Sobol I, Zaid HB, Haloi R, et al. Contemporary mapping of post-prostatectomy prostate cancer relapse with 11C-choline positron emission tomography and multiparametric magnetic resonance imaging. J Urol. 2017;197:129–134.
60. Giannarini G, Nguyen DP, Thalmann GN, Thoeny HC. Diffusion-weighted magnetic resonance imaging detects local recurrence after radical prostatectomy: initial experience. Eur Urol. 2012;61:616–620.
61. Thoeny HC, Froehlich JM, Triantafyllou M, et al. Metastases in normal-sized pelvic lymph nodes: detection with diffusion-weighted MR imaging. Radiology. 2014;273:125–135.
62. Sharma V, Nehra A, Colicchia M, et al. Multiparametric magnetic resonance imaging is an independent predictor of salvage radiotherapy outcomes after radical prostatectomy. Eur Urol. 2018;73:879–887.
63. Öztürk H, Karapolat I. 18F-fluorodeoxyglucose PET/CT for detection of disease in patients with prostate-specific antigen relapse following radical treatment of a local-stage prostate cancer. Oncol Lett. 2016;11:316–322.
64. Schöder H, Herrmann K, Gönen M, et al. 2-[18F]fluoro-2-deoxyglucose positron emission tomography for the detection of disease in patients with prostate-specific antigen relapse after radical prostatectomy. Clin Cancer Res. 2005;11:4761–4769.
65. Yu CY, Desai B, Ji L, Groshen SG, Jadvar H. Comparative performance of PET tracers in biochemical recurrence of prostate cancer: a critical analysis of literature. Am J Nucl Med Mol Imaging. 2014;4:580–601.
66. Fox JJ, Gavane SC, Blanc-Autran E, et al. Positron emission tomography/computed tomography-based assessments of androgen receptor expression and glycolytic activity as a prognostic biomarker for metastatic castration-resistant prostate cancer. JAMA Oncol. 2018;4:217–224.
67. Jadvar H, Desai B, Ji L, et al. Baseline 18F-FDG PET/CT parameters as imaging biomarkers of overall survival in castrate-resistant metastatic prostate cancer. J Nucl Med. 2013;54:1195–1201.
68. Vargas HA, Wassberg C, Fox JJ, et al. Bone metastases in castration-resistant prostate cancer: associations between morphologic CT patterns, glycolytic activity, and androgen receptor expression on PET and overall survival. Radiology. 2014;271:220–229.
69. Jadvar H, Velez EM, Desai B, Ji L, Colletti PM, Quinn DI. Prediction of time to hormonal treatment failure in metastatic castrate sensitive prostate cancer. J Nucl Med. 2019;60:1524–1530.
70. FDA approves 11C-choline for PET in prostate cancer. J Nucl Med. 2012;53:11N.
71. Rybalov M, Breeuwsma AJ, Leliveld AM, Pruim J, Dierckx RA, de Jong IJ. Impact of total PSA, PSA doubling time and PSA velocity on detection rates of 11C-Choline positron emission tomography in recurrent prostate cancer. World J Urol. 2013;31:319–323.
72. Ceci F, Herrmann K, Castellucci P, et al. Impact of 11C-choline PET/CT on clinical decision making in recurrent prostate cancer: results from a retrospective two-center trial. Eur J Nucl Med Mol Imaging. 2014;41:2222–2231.
73. Evangelista L, Zattoni F, Guttilla A, et al. Choline PET or PET/CT and biochemical relapse of prostate cancer: a systematic review and meta-analysis. Clin Nucl Med. 2013;38:305–314.
74. Fanti S, Minozzi S, Castellucci P, et al. PET/CT with 11C-choline for evaluation of prostate cancer patients with biochemical recurrence: meta-analysis and critical review of available data. Eur J Nucl Med Mol Imaging. 2016;43:55–69.
75. Treglia G, Ceriani L, Sadeghi R, Giovacchini G, Giovanella L. Relationship between prostate-specific antigen kinetics and detection rate of radiolabelled choline PET/CT in restaging prostate cancer patients: a meta-analysis. Clin Chem Lab Med. 2014;52:725–733.
76. Castellucci P, Ceci F, Graziani T, et al. Early biochemical relapse after radical prostatectomy: which prostate cancer patients may benefit from a restaging 11C-choline PET/CT scan before salvage radiation therapy? J Nucl Med. 2014;55:1424–1429.
77. FDA approves new diagnostic imaging agent to detect recurrent prostate cancer [news release]. U.S. Food and Drug Administration; May 27, 2016. https://www.fda. gov/newsevents/newsroom/pressannouncements/ucm503920.htm. Accessed March 27, 2019.
78. Nanni C, Zanoni L, Pultrone C, et al. 18F-FACBC (anti1-amino-3-18F-fluorocyclobutane1-carboxylic acid) versus 11C-choline PET/CT in prostate cancer relapse: results of a prospective trial. Eur J Nucl Med Mol Imaging. 2016;43:1601–1610.
79. Bach-Gansmo T, Nanni C, Nieh PT, et al. Multisite experience of the safety, detection rate and diagnostic performance of fluciclovine (18F) positron emission tomography/computerized tomography imaging in the staging of biochemically recurrent prostate cancer. J Urol. 2017;197:676–683.
80. England JR, Paluch J, Ballas LK, Jadvar H. 18F-fluciclovine PET/CT detection of recurrent prostate carcinoma in patients with serum PSA # 1 ng/mL after definitive primary treatment. Clin Nucl Med. 2019;44:e128–e132.
81. Andriole GL, Kostakoglu L, Chau A, et al. The impact of positron emission tomography with 18F-fluciclovine on the treatment of biochemical recurrence of prostate cancer: results from the LOCATE trial. J Urol. 2019;201:322–331.
82. Akin-Akintayo OO, Jani AB, Odewole O, et al. Change in salvage radiotherapy management based on guidance with FACBC (fluciclovine) PET/CT in postprostatectomy recurrent prostate cancer. Clin Nucl Med. 2017;42:e22–e28.
83. Drug Dictionary NCI. Indium In 111 capromab pendetide. National Cancer Institute website. https://www.cancer.gov/publications/dictionaries/cancer-drug/ def/indium-in-111-capromab-pendetide. Accessed September 11, 2019.
84. Capromab pendetide. https://www.pharmacodia.com/yaodu/html/v1/biologics/ b4f1ec9f4b5c8207f8fc29522efe783d.html. Accessed September 11, 2019.
85. Thomas CT, Bradshaw PT, Pollock BH, et al. Indium-111-capromab pendetide radioimmunoscintigraphy and prognosis for durable biochemical response to salvage radiation therapy in men after failed prostatectomy. J Clin Oncol. 2003;21:1715–1721.
86. Pucar D, Sella T, Schöder H. The role of imaging in the detection of prostate cancer local recurrence after radiation therapy and surgery. Curr Opin Urol. 2008;18:87–97.
87. Schuster DM, Nieh PT, Jani AB, et al. Anti-3-[18F]FACBC positron emission tomography-computerized tomography and 111In-capromab pendetide single photon emission computerized tomography-computerized tomography for recurrent prostate carcinoma: results of a prospective clinical trial. J Urol. 2014;191:1446–1453.
88. Schuster DM, Savir-Baruch B, Nieh PT, et al. Detection of recurrent prostate carcinoma with anti-1-amino-3-18F-fluorocyclobutane-1-carboxylic acid PETCT and 111In-capromab pendetide SPECT/CT. Radiology. 2011;259:852–861.
89. BlueCross BlueShield of Tennessee Medical Policy Manual. Radioimmunoscintigraphy imaging (monoclonal antibody imaging) with Indium-111 capromab pendetide for prostate cancer. https://www.bcbst.com/mpmanual/Radioimmunoscintigraphy_ Imaging_Monoclonal_Antibody_Imaging_with_Indium-111_Capromab_Pendetide_for_Prostate_Cancer_.htm. Published November 10, 2007. Reviewed October 11, 2018. Accessed September 11, 2019.
90. BlueCross BlueShield of North Carolina. Corporate medical policy: monoclonal antibody imaging for prostate cancer. https://www.bluecrossnc.com/sites/ default/files/document/attachment/services/public/pdfs/medicalpolicy/monoclonal_ antibody_imaging_for_prostate_cancer.pdf. Published May 2011. Reviewed April 2018. Accessed September 11, 2019.
91. Aytu BioScience discounting PROSTASCINT (Cpromab Pendetide) Kit [letter]. April 2018. http://www.radiopharmaceuticals.info/uploads/7/6/8/7/76874929/ prostascint_discontinue_letter_april_2018_final.pdf. Accessed September 11, 2019.
92. Afshar-Oromieh A, Babich JW, Kratochwil C, et al. The rise of PSMA ligands for diagnosis and therapy of prostate cancer. J Nucl Med. 2016;57:79S–89S.
93. Eiber M, Maurer T, Souvatzoglou M, et al. Evaluation of hybrid 68Ga-PSMA ligand PET/CT in 248 patients with biochemical recurrence after radical prostatectomy. J Nucl Med. 2015;56:668–674.
94. Hope TA, Goodman JZ, Allen IE, Calais J, Fendler WP, Carroll PR. Metaanalysis of 68Ga-PSMA-11 PET accuracy for the detection of prostate cancer validated by histopathology. J Nucl Med. 2019;60:786–793.
95. Perera M, Papa N, Christidis D, et al. Sensitivity, specificity, and predictors of positive 68Ga-prostate-specific membrane antigen positron emission tomography in advanced prostate cancer: a systematic review and meta-analysis. Eur Urol. 2016;70:926–937.
96. Morigi JJ, Stricker PD, van Leeuwen PJ, et al. Prospective comparison of 18Ffluoromethylcholine versus 68Ga-PSMA PET/CT in prostate cancer patients who have rising PSA after curative treatment and are being considered for targeted therapy. J Nucl Med. 2015;56:1185–1190.
97. Afshar-Oromieh A, Zechmann CM, Malcher A, et al. Comparison of PET imaging with a 68Ga-labelled PSMA ligand and 18F-choline-based PET/CT for the diagnosis of recurrent prostate cancer. Eur J Nucl Med Mol Imaging. 2014;41:11–20.
98. Calais J, Ceci F, Eiber M, et al. 18F-fluciclovine PET-CT and 68Ga-PSMA-11 PET/CT in patients with early biochemical recurrence after prostatectomy: a prospective, single-centre, single-arm, comparative imaging trial. Lancet Oncol. 2019;9:1286–1294.
99. Lawhn-Heath C, Flavell RR, Behr SC, et al. Single-center prospective evaluation of 68Ga-PSMA-11 PET in biochemical recurrence of prostate cancer. AJR. 2019;213:266–274.
100. Fendler WP, Calais J, Eiber M, et al. Assessment of 68Ga-PSMA-11 PET accuracy in localizing recurrent prostate cancer: a prospective single-arm clinical trial. JAMA Oncol. 2019;5:856–863.
101. Wu SY, Boreta L, Shinohara K, et al. Impact of staging 68Ga-PSMA-11 PET scans on radiation treatment plans in patients with prostate cancer. Urology. 2019;125:154–162.
102. Calais J, Fendler WP, Eiber M, et al. Impact of 68Ga-PSMA-11 PET/CT on the management of prostate cancer patients with biochemical recurrence. J Nucl Med. 2018;59:434–441.
103. Calais J, Czernin J, Cao M, et al. 68Ga-PSMA-11 PET/CT mapping of prostate cancer biochemical recurrence after radical prostatectomy in 270 patients with a PSA level of less than 1.0 ng/mL: impact on salvage radiotherapy planning. J Nucl Med. 2018;59:230–237.
104. Calais J, Czernin J, Fendler WP, Elashoff D, Nickols NG. Randomized prospective phase III trial of 68Ga-PSMA-11 PET/CT molecular imaging for prostate cancer salvage radiotherapy planning. BMC Cancer [PSMA-SRT]. 2019;19:18.
105. Sanchez-Crespo A. Comparison of gallium-68 and fluorine-18 imaging characteristics in positron emission tomography. Appl Radiat Isot. 2013;76:55– 62.
106. Gorin MA, Pomper MG, Rowe SP. PSMA-targeted imaging of prostate cancer: the best is yet to come. BJU Int. 2016;117:715–716.
107. Giesel FL, Knorr K, Spohn F, et al. Detection efficacy of 18F-PSMA-1007 PET/ CT in 251 patients with biochemical recurrence of prostate cancer after radical prostatectomy. J Nucl Med. 2019;60:362–368.
108. Rowe SP, Campbell SP, Mana-Ay M, et al. Prospective evaluation of PSMAtargeted 18F-DCFPyL PET/CT in men with biochemical failure after radical prostatectomy for prostate cancer. J Nucl Med. 2020;61:58–61.
109. Rousseau E, Wilson D, Lacroix-Poisson F, et al. A prospective study on 18FDCFPyL PSMA PET/CT imaging in biochemical recurrence of prostate cancer. J Nucl Med. 2019;60:1587–1593.
110. Vapiwala N, Hofman MS, Murphy DG, Williams S, Sweeney C. Strategies for evaluation of novel imaging in prostate cancer: putting the horse back before the cart. J Clin Oncol. 2019;37:765–769.

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.
24. Eiber, Matthias, Gregor Weirich, Konstantin Holzapfel, Michael Souvatzoglou, Bernhard Haller, Isabel Rauscher, Ambros J. Beer et al. "Simultaneous 68Ga-PSMA HBED-CC PET/MRI improves the localization of primary prostate cancer." European urology 70, no. 5 (2016): 829-836.
25. Zippel, Claus, Sarah C. Ronski, Sabine Bohnet-Joschko, Frederik L. Giesel, and Klaus Kopka. "Current Status of PSMA-Radiotracers for Prostate Cancer: Data Analysis of Prospective Trials Listed on ClinicalTrials. gov." Pharmaceuticals 13, no. 1 (2020): 12.
26. Klotz, Laurence, Greg Pond, Andrew Loblaw, Linda Sugar, Madeline Moussa, David Berman, Theo Van der Kwast et al. "Randomized Study of Systematic Biopsy Versus Magnetic Resonance Imaging and Targeted and Systematic Biopsy in Men on Active Surveillance (ASIST): 2-year Postbiopsy Follow-up." European urology (2019).