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Advanced Prostate Cancer COE

  • A Look at the Prostate Cancer Foundation Its History and Contributions to Medical Progress: Interview with Stuart Holden

    Stuart Holden, MD, is the Medical Director of the Prostate Cancer Foundation’s since the inception in 1993. Dr. Holden directs the medical and scientific strategy of PCF and oversees its grant award programs, consortia activities and scientific meetings. Separately, Dr. Holden is a Health Sciences Clinical Professor in the Department of Urology at the David Geffen School of Medicine at UCLA, and Associate Director of the UCLA Institute of Urologic Oncology. 
    Published May 23, 2017
  • Androgen deprivation therapy for prostate cancer and dementia risk: a systematic review and meta-analysis

    BACKGROUND: Androgen deprivation therapy (ADT) to treat prostate cancer may be associated with an increased risk of dementia, but existing studies have shown conflicting results. Here we synthesize the literature on the association of ADT for the treatment of prostate cancer with dementia risk.
    Published July 1, 2017
  • ASCO 2017: Results of LATITUDE: ADT with Abiraterone Acetate Plus Prednisone in High-Risk Metastatic Hormone-Naive Prostate Cancer

    Chicago, IL (UroToday.com) Dr. Karim Fizazi and colleagues presented their much-anticipated results from the LATITUDE trial at the 2017 ASCO annual meeting’s plenary session. In a phase III, double-blind, randomized setting, LATITUDE tested androgen deprivation therapy (ADT) with abiraterone acetate (AA) plus prednisone vs ADT + placebo in newly diagnosed high-risk metastatic hormone-naïve prostate cancer patients.
    Published June 5, 2017
  • ASCO GU 2019: Biologic Basis for Sequencing Novel Treatments for Metastatic Prostate Cancer

    San Francisco, CA (UroToday.com) Dr. Beltran presented a summary of the biologic basis for sequencing novel treatments for metastatic prostate cancer.

    There is an increasing need for biomarkers in advanced prostate cancer management – as there is a plethora of treatment options without much guidance about selection or sequencing. Some of the areas that require work are:
    Published February 15, 2019
  • ASCO GU 2019: Intensification Versus Deintensification in High-Risk Prostate Cancer

    San Francisco, CA (UroToday.com) During the general session on optimizing diagnosis and treatment of clinically significant nonmetastatic prostate cancer at the Annual ASCO GU 2019 meeting in San Francisco, CA, Drs. Sridhar, Briganti, and Payne presented on the treatment of high-risk localized prostate cancer,   and issues related to intensification and deintensification of treatment from medical oncology, urology, and radiation oncology perspective.
    Published February 15, 2019
  • Assessment of Cardiovascular Risk With the Use of Androgen Deprivation Therapy for Prostate Cancer

    Published in Everyday Urology - Oncology Insights: Volume 2, Issue 1
    Heart disease and cancer are the leading causes of death in the United States.1 Prostate cancer (PC) is the most common cancer in American men, and PC is most frequently diagnosed among men aged 65 to 74 years.2 The American Cancer Society’s estimates for PC in the United States for 2017 are about 161,360 new cases. Of these, about 26,730 are expected to die of the disease.1 
    Published June 9, 2017
  • Cardiovascular status and events in patients with prostate cancer treated with a luteinising hormone-releasing hormone agonist or degarelix: A comparison of USA/Canada vs Europe

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    Published October 16, 2015
  • Crashing into progress: New findings meet old habits

    In the last few weeks I have talked with numerous colleagues about the findings from LATITUDE and STAMPEDE presented recently at the ASCO Annual Meeting and published in the New England Journal of Medicine in June 2017.  We find ourselves in the process of integrating the findings into a treatment landscape that is still grappling with the findings of CHAARTED, data demonstrating a survival benefit from the use of chemohormonal therapy in a similar high risk population of men with metastatic hormone sensitive prostate cancer (mHSPC) first presented only a few years ago. 
    Published July 27, 2017
  • Degarelix therapy for prostate cancer in a real-world setting: experience from the German IQUO (Association for Uro-Oncological Quality Assurance) Firmagon® registry.

    We investigated the use of the gonadotropin-releasing hormone (GnRH) antagonist degarelix in everyday clinical practice using registry data from uro-oncology practices in Germany.

    Data were analysed retrospectively from the IQUO (Association for uro-oncological quality assurance) patient registry.

    Published December 20, 2015
  • Diagnosing and Staging of Prostate Cancer

    Secondary to the introduction of prostate specific antigen (PSA) screening in the 1980’s/1990’s, symptomatic presentation of prostate cancer has become less frequent. Symptoms of locally advanced prostate cancer may include obstructive urinary symptoms, gross hematuria, and/or upper tract urinary obstruction leading to renal failure. Once the diagnosis of prostate cancer is made, staging is important, which may include imaging studies in cases of high-risk disease. This article will focus on contemporary diagnosis/screening modalities in addition to the staging of localized prostate cancer.

    Diagnosis

    Screening

    The goal of screening for any malignancy is early detection with the hopes of intervening with treatment at an earlier time period in order to reduce cancer-specific mortality. Screening for prostate cancer involves a digital rectal examination (DRE) and a serum PSA blood test. Screening in certain instances may lead to over treatment of clinically insignificant disease, for which urologists have been criticized with regards to prostate cancer over treatment.1, 2 Notwithstanding, during the PSA screening era for prostate cancer, disease mortality has declined by ~40% with a substantial decrease in men presenting with advanced malignancy.3

    Two randomized control trials (RCTs) were initiated in 1993 to compare prostate cancer-specific mortality between prostate cancer screened and unscreened men.4, 5 The European Randomized Study of Screening for Prostate Cancer (ERSPC) trial identified 182,000 men (ages 50-74 years) who were randomly assigned to a group that was offered PSA screening once every four years or to a control group that did not receive screening4. During a median follow-up of 9 years, the cumulative incidence of prostate cancer was 8.2% in the screening group and 4.8% in the control group. The rate ratio (RR) for death from prostate cancer in the screening vs control group, was 0.80 (95%CI 0.65-0.98). This correlated to 1410 men needing to be screened and 48 additional cases of prostate cancer treated to prevent one death from prostate cancer. The Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial randomly assigned men in the US to receive either annual screening (n=38,343) or usual care (n=38,350).5 Importantly, in this trial “usual care” occasionally included screening; rates of screening in the control group increased from 40% in the first year to 52% in the sixth year for PSA testing. After seven years of follow-up, the incidence of prostate cancer per 10,000 person-years was 116 in the screening group and 95 in the control group (RR 1.22; 95CI 1.16-1.29). The incidence of death per 10,000 person-years was 2.0 in the screening group and 1.7 in the control group (RR 1.13; 95%CI 0.75-1.70), thus the results of the study suggested that prostate cancer screening did not reduce cancer-specific mortality.

    Since the initial reporting of these two RCTs nearly a decade ago, several follow-up iterations have been published for the ERSPC6, 7 and PLCO8, 9 trials, confirming initial results: a screening benefit in the ERSPC trial and no benefit in the PLCO trial. These trials have been thoroughly analyzed as to potential reasons for differing results. The PLCO trial had (i) a shorter screening interval, (ii) higher threshold for prostate biopsy, (iii) halted regular screening after six rounds, and had (iv) “contamination” in the control group, considering that these men often received screening. As such, the PLCO has been described as organized screening vs opportunistic screening, rather than screening vs no screening.8, 9 

    Recommendations for Screening

    The United States Preventative Services Task Force (USPSTF) has been highly critical of PSA screening and relied heavily on results of the PLCO trial for their recommendations against routine screening for prostate cancer.2, 10 The American Urological Association (AUA) guidelines for prostate cancer screening were most recently released in 2013 and revalidated in 2018,11 suggesting shared decision making for men 55-69 years of age who are considering PSA-based screening. These recommendations were based on the benefits outweighing the harms of screening in this age group. Other organizations, such as the European Association of Urology (EAU), recommend a baseline PSA test at age 40-45, which is then used to guide a subsequent screening interval.12 Most recently, the USPSTF changed their recommendation against PSA screening for men aged 55-69 (Grade D) to a Grade C recommendation for prostate cancer screening: clinicians should not screen men who do not express a preference for screening.13

    Triggers for Biopsy

    Various “triggers” for prostate biopsy have been proposed with no consensus agreement. Generally, urologists agree that a positive DRE finding should be followed by a prostate biopsy. When the DRE is unremarkable, PSA thresholds are primarily used to guide recommendations for consideration of a prostate biopsy. The upper limit of a normal PSA has historically been set at 4 ng/mL, however the ERSPC has suggested this level should be lowered to 2.5-3.0 ng/mL. A recent study suggested that men <50 years of age with a PSA >1.5 ng/mL should consider a prostate biopsy, as more than half of these patients diagnosed with prostate cancer exceed the Epstein criteria for active surveillance.14 Furthermore, in an ad hoc analysis of the placebo arm of the Prostate Cancer Prevention Trial (PCPT), Thompson et al.15 showed a continuum of prostate cancer risk at all PSA values: PSA cutoff values of 1.1, 2.1, 3.1, and 4.1 ng/mL yielded sensitivities of 83.4%, 52.6%, 32.2%, and 20.5%, and specificities of 38.9%, 72.5%, 86.7%, and 93.8%, respectively, for detecting any prostate cancer. Undoubtedly, there is no perfect trigger for deciding whether to perform a prostate biopsy, as all factors must be taken into account, including age, race, family history, PSA trend, etc.

    Staging


    The clinical staging of prostate cancer relies on factors prior to treatment, such as PSA, DRE, prostate biopsy results, and imaging findings. Pathologic staging of prostate cancer relies on the stage of disease after surgical extirpation of the prostate. The following discussion will primarily focus on clinical staging.

    Prostate Biopsy and Gleason Classification

    At the time of prostate biopsy, a “systematic sampling” of the prostate is undertaken, typically consisting of 10-12 biopsy cores of tissue. Positive samples are then scored a primary and secondary Gleason score: 3+3, 3+4, 4+3, 4+4, 4+5, 5+4, or 5+5. Over the last 20 years, the D’Amico risk stratification has been commonly used to guide treatment16 Low-risk disease (cT1-2a, PSA ≤10 ng/mL, and Gleason ≤6), intermediate-risk disease (T2b or PSA >10 ng/ml but <20 ng/ML, or Gleason score 7), and high-risk disease (T2c, or PSA >20 ng/mL or Gleason 8-10), conferred freedom of disease 10-years after radical prostatectomy rates of 83%, 46%, and 29%, respectively.16

    Several years ago, the Gleason Grade Group (GGG) was proposed to better reflect the true cancer biologic aggressiveness and better guide treatment: GGG 1 is Gleason 6, GGG 2 is 3+4=7, GGG 3 is Gleason 4+3=7, GGG 4 is Gleason 8, GGG 5 is Gleason 9-10.17 In a Swedish population-level database of 5,880 men diagnosed with prostate cancer, using the GGG schema demonstrated four-year biochemical recurrence-free survival rates of 89% (GGG 1), 82% (GGG 2), 74% (GGG 3), 77% (GGG 4), and 49% (GGG 5) on biopsy, and 92% (GGG 1), 85% (GGG 2), 73% (GGG 3), 63% (GGG 4), and 51% (GGG 5) based on prostatectomy data18 Generally, the GGG classification offers a simplified nomenclature with predictive accuracy comparable to previously used classification schemes.

    Classification

    table 1 diagnosing staging prostate cancer2x

    table 2 diagnosing staging prostate cancer2x

    Imaging

    Several imaging modalities have been used to radiographically stage prostate patients. Generally, staging studies have included a radionuclide bone scan (to assess for skeletal metastases) and a computed tomography (CT) scan of the abdomen and pelvis (to assess for lymphadenopathy). Selecting appropriate patients for imaging is a point of much debate. The general consensus is that there is no role for imaging patients with low-risk disease, whereas imaging is appropriate for patients with either PSA >20 ng/mL, GGG 4-5, cT3-T4 or clinical symptoms of bone metastases.11

    The improvement in multi-parametric MRI (mpMRI) technology has allowed, not only the ability to perform targeted prostate biopsies but also to stage patients for locoregional extent of disease. mpMRI comprises anatomic sequences (T1/T2) supplemented by functional imaging techniques such as diffusion-weighted and dynamic contrast-enhanced (DCE) imaging. When performed at high resolution, DCE facilitates detection of disease, as well as an assessment of extracapsular extension, urethral sphincter, and seminal vesicles involvement.20 Furthermore, mpMRI may provide accurate information for planning robotic prostatectomy. In a study assessing the ability of mpMRI to assist with planning neurovascular bundle preservation, mpMRI results changed preoperatively planning in 26% of cases based on the extent of disease.21

    Conclusions  

    Prostate cancer screening has been crucial to decreasing the burden of disease and improving mortality rates. However, early practices of over-screening and over-treatment have led to strong recommendations from non-urologic governing bodies recommending against prostate cancer screening, which has just recently changed to provide screening options for certain men (55-69 years of age). Prostate cancer screening should be based on a shared decision-making model, allowing patients to make educated decisions that best fit their healthcare needs. As prognostic tools continue to be refined and imaging technology improves, diagnosis and staging of prostate cancer will hopefully lead to an improved selection of men that need screening and ultimately those who may benefit from treatment.

     
    Written by: Zachary Klaassen, MD, MSc
    References:
    1. Barry MJ. Screening for prostate cancer--the controversy that refuses to die. N Engl J Med. 2009;360:1351-4.
    2. Moyer VA, Force USPST. Screening for prostate cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2012;157:120-34.
    3. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68:7-30.
    4. Schroder FH, Hugosson J, Roobol MJ, Tammela TL, Ciatto S, Nelen V, et al. Screening and prostate-cancer mortality in a randomized European study. N Engl J Med. 2009;360:1320-8.
    5. Andriole GL, Crawford ED, Grubb RL, 3rd, Buys SS, Chia D, Church TR, et al. Mortality results from a randomized prostate-cancer screening trial. N Engl J Med. 2009;360:1310-9.
    6. Schroder FH, Hugosson J, Roobol MJ, Tammela TL, Ciatto S, Nelen V, et al. Prostate-cancer mortality at 11 years of follow-up. N Engl J Med. 2012;366:981-90.
    7. Schroder FH, Hugosson J, Roobol MJ, Tammela TL, Zappa M, Nelen V, et al. Screening and prostate cancer mortality: results of the European Randomised Study of Screening for Prostate Cancer (ERSPC) at 13 years of follow-up. Lancet. 2014;384:2027-35.
    8. Andriole GL, Crawford ED, Grubb RL, 3rd, Buys SS, Chia D, Church TR, et al. Prostate cancer screening in the randomized Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial: mortality results after 13 years of follow-up. J Natl Cancer Inst. 2012;104:125-32.
    9. Pinsky PF, Prorok PC, Yu K, Kramer BS, Black A, Gohagan JK, et al. Extended mortality results for prostate cancer screening in the PLCO trial with median follow-up of 15 years. Cancer. 2017;123:592-9.
    10. Force USPST. Screening for prostate cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2008;149:185-91.
    11. Carter HB, Albertsen PC, Barry MJ, Etzioni R, Freedland SJ, Greene KL, et al. Early detection of prostate cancer: AUA Guideline. J Urol. 2013;190:419-26.
    12. Heidenreich A, Bastian PJ, Bellmunt J, Bolla M, Joniau S, van der Kwast T, et al. EAU guidelines on prostate cancer. part 1: screening, diagnosis, and local treatment with curative intent-update 2013. Eur Urol. 2014;65:124-37.
    13. Force USPST, Grossman DC, Curry SJ, Owens DK, Bibbins-Domingo K, Caughey AB, et al. Screening for Prostate Cancer: US Preventive Services Task Force Recommendation Statement. JAMA. 2018;319:1901-13.
    14. Goldberg H, Klaassen Z, Chandrasekar T, Wallis CJD, Toi A, Sayyid R, et al. Evaluation of an Aggressive Prostate Biopsy Strategy in Men Younger than 50 Years of Age. J Urol. 2018.
    15. Thompson IM, Ankerst DP, Chi C, Lucia MS, Goodman PJ, Crowley JJ, et al. Operating characteristics of prostate-specific antigen in men with an initial PSA level of 3.0 ng/ml or lower. JAMA. 2005;294:66-70.
    16. D'Amico AV, Whittington R, Malkowicz SB, Schultz D, Blank K, Broderick GA, et al. Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA. 1998;280:969-74.
    17. Carter HB, Partin AW, Walsh PC, Trock BJ, Veltri RW, Nelson WG, et al. Gleason score 6 adenocarcinoma: should it be labeled as cancer? J Clin Oncol. 2012;30:4294-6.
    18. Loeb S, Folkvaljon Y, Robinson D, Lissbrant IF, Egevad L, Stattin P. Evaluation of the 2015 Gleason Grade Groups in a Nationwide Population-based Cohort. Eur Urol. 2016;69:1135-41.
    19. Buyyounouski MK, Choyke PL, McKenney JK, Sartor O, Sandler HM, Amin MB, et al. Prostate cancer - major changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J Clin. 2017;67:245-53.
    20. Appayya MB, Johnston EW, Punwani S. The role of multi-parametric MRI in loco-regional staging of men diagnosed with early prostate cancer. Curr Opin Urol. 2015;25:510-7.
    21. Park BH, Jeon HG, Jeong BC, Seo SI, Lee HM, Choi HY, et al. Influence of magnetic resonance imaging in the decision to preserve or resect neurovascular bundles at robotic assisted laparoscopic radical prostatectomy. J Urol. 2014;192:82-8.

    Published April 16, 2019
  • EAU 2018: Complications of Hormonal Treatment in Prostate Cancer

    Copenhagen, Denmark (UroToday.com)  Dr. Sommer gave an overview of the complications associated with the treatment for advanced prostate cancer. The first topic discussed was the acute side effects of androgen deprivation therapy (ADT). These include decreased libido, erectile dysfunction, hot flashes, and fatigue. The chronic side effects include anemia, osteoporosis/fractures, obesity, sarcopenia, lipid alterations, insulin resistance and diabetes. ADT is also associated with other problems, including cardiovascular disease, thromboembolism, colorectal cancer, depression, dementia, and renal failure.
    Published March 17, 2018
  • EAU 2019: Challenging Paradigms in Advanced Prostate Cancer: A New Era

    Barcelona, Spain (UroToday.com) Dr. Maria Ribal from Barcelona started the urogenital cancer treatment at a glance session by giving an overview of challenging paradigms in advanced prostate cancer. Dr. Ribal notes that not only is the incidence of prostate cancer the highest among male malignancies, but there is also expected to be a 188% increase in men >65 years of age during the next few years. Regarding advanced prostate cancer, the incidence of metastatic prostate cancer varies greatly:
    Published March 20, 2019
  • Epidemiology and Etiology of Prostate Cancer

    In 2018 in the United States, there will be an estimated 164,690 new cases of prostate cancer (19% of all male cancer incident cases, 1st) and an estimated 29,430 prostate cancer mortalities (9% of all male cancer deaths, 2nd only to lung/bronchus cancer).1 Over the last four decades, there was a spike in prostate cancer incidence in the late 1980’s/early 1990’s secondary to the widespread adoption of prostate-specific antigen (PSA) testing for the asymptomatic detection of prostate cancer.2 Since 1991, prostate cancer mortality has decreased by more than 40% due to a combination of increased PSA screening and improvement in treatment.3 This article will discuss the epidemiology of prostate cancer, as well as focus on several important etiologic risk factors associated with the disease.

    Epidemiology

    Incidence
    For the last 30+ years, prostate cancer has been the most common noncutaneous malignancy among men in the United States, with 1 in 7 men being diagnosed with the disease.4 Similar to the United States, prostate cancer is the second most commonly diagnosed malignancy among men worldwide, with 1.1 million new cases diagnosed per year.5 In developed countries, the age-standardized rate (ASR) of prostate cancer incidence is 69.5 per 100,000 compared to 14.5 per 100,000 in developing countries.5 Crude differences in incidence between developed and developing countries are likely secondary to poor use of screening6 and lower life expectancies in developing countries.

    Mortality
    Among all men in the United States, 1 in 38 men will die from prostate cancer.4 Prostate cancer ranks as the leading cause of cancer death globally, with the highest mortality rates noted in the Caribbean and Southern/Middle Africa.5 Furthermore, the ASR for mortality in developed countries is 10.0 per 100,000 compared to 6.6 per 100,000 in developing countries.5 Many hypotheses have been considered as to the decline in mortality seen in the United States after 1991, with the most commonly accepted (in addition to utilization of screening) being an increase in aggressive curative treatment of prostate cancer diagnosed in the 1980s.7,8

    A Global Perspective
    The incidence and epidemiology from a global perspective is much different than what may typically be seen in the United States and Europe. For example, in India the incidence of prostate cancer is a fraction (1.7-5.3 per 100,000) of other first world countries (North America: 83.2-173.7 per 100,000),6 but secondary to the sheer size of the population (1.2 billion) the crude prevalence of prostate cancer is on par with countries such as the United States, UK, France, and Italy. Despite greater awareness of prostate cancer screening, data from India suggest that 4% of patients <50 years of age present with metastatic disease. Among worldwide prostate cancer incidence, 14% of cases are diagnosed within the Asia-Pacific region, with a wide variation of incidence rates across the Asian-Pacific countries. In Latin American countries, prostate cancer represents 28% of all incidence cancers (highest) and 13% of all cancer mortalities (second after lung cancer). Specifically, in Trinidad and Tobago, Guyana and Barbados, the incidence is 3-4x that of the United States. Particularly in Cuba, the mortality rates continue to increase, despite greater adoption of screening.  The incidence of prostate cancer in the Middle East is higher than the Asian countries, specifically in Lebanon (37.2 per 100,000), Jordan (15.3 per 100,000), and Palestine (15.2 per 100,000). A closer look at the demographics at presentation among Middle Eastern men shows that 25% present with metastatic disease, with rates as high as 58% among men from Iraq. There are several hypotheses for the shift in incidence and prevalence of prostate cancer among non-North America/European countries, including (1) an increased awareness of prostate cancer leading to greater utilization of PSA testing, and (2) adoption of a more “Western” diet/lifestyle and less the traditional Indian/Asian/Mediterranean diet, particularly in the urban centers.

    Unfortunately, a greater burden of disease among non-North American/European regions has presented several problems:

    1. A wide variation in incidence/prevalence across countries in these regions, particularly in Asia-Pacific and Latin America
    2. Huge discrepancies in quality and access to care between the private and public sector
    3. Poor access to newer standards of care, leading to high rates of surgical castration and limited access to radiation therapy (ie. for treatment of bone metastases)
    4. Limited organized cancer registries, thus grossly underestimating the true incidence and prevalence of prostate cancer
    Age and Family History
    Age is an established risk factor for prostate cancer, as men <40 years of age are highly unlikely to be diagnosed with prostate cancer, whereas men >70 years of age have a 1 in 8 chance of prostate cancer diagnosis.1 In a population-based analysis of more than 200,000 patients, increasing age was associated with higher 15-year cancer-specific mortality (CSM) rates: 2.3% for men diagnosed ≤50 years of age, 3.4% for men 51-60 years of age, 4.6% for men 61-70 years of age, and 6.3% for men ≥71 years of age.9

    A family history of prostate cancer is also strongly predictive of a prostate cancer diagnosis. To be considered hereditary prostate cancer, a family must have three affected generations, three first-degree relatives affected, or two relatives diagnosed prior to age 55.10 Men with one first-degree relative previously diagnosed with prostate cancer have a risk of a prostate cancer diagnosis that is 2-3x that of individuals with no family history.11 Data on 65,179 white men from the PLCO cancer screening trial showed that men with a family history of prostate cancer had a significantly higher incidence of prostate cancer (16.9% vs 10.8%, p<0.01) and higher cancer-specific mortality (0.56% vs 0.37%, p<0.01).12

    Race
    Both prostate cancer incidence and mortality have been shown to be significantly related to race. African-Americans and Jamaicans of African descent have the highest incidence of prostate cancer in the world.1 Despite decreases in mortality since the 1990s among all races, death rates of African Americans are still 2.4x higher than Caucasian patients.13 Several studies have assessed possible reasons for this discrepancy. In an ad hoc analysis of the REDUCE trial, African American men had greater non-compliance with study-mandated2 and 4-year prostate biopsies, despite having greater prostate cancer risk (at 2-year biopsy),14 suggesting that population-level estimates of the excess prostate cancer burden in African American men may underestimate the degree of prostate cancer disparity. Gene expression assessment of prostate cancer specimens has noted numerous differentially expressed genes between African American and white patients, suggesting that there may be racial differences in androgen biosynthesis and metabolism.15 However, studies in mCRPC patients assessing clinical response to the potent anti-androgen abiraterone have not demonstrated racial differences when prospectively evaluated.16

    The incidence of prostate cancer among races other than African-American and Caucasians is lower, including men of Asian descent living in the United States, although their incidence of prostate cancer is higher than those living within continental Asia.17 Interestingly, men moving from developing countries to high prostate cancer incidence countries demonstrate a shift in prostate cancer risk similar to that of their new country of residence.18 Ultimately, the relative components of genetics, socioeconomic factors, cultural, and environmental factors associated with racial differences observed are poorly understood.   

    Trends
    There has been a significant drop in prostate cancer incidence in the last decade (~10% annually per year from 2010-2014), likely secondary to a decrease in PSA testing after the US Preventative Services Task Force (USPSTF) Grade D recommendation for screening of men older than 75 years of age (2008) and subsequently all men (2012) due to concern for overdiagnosis and overtreatment.13,19 Following the USPSTF recommendations, an analysis of the National Cancer Database suggested that in the month after the recommendation, incident prostate cancer diagnoses decreased by 1,363 cases, followed by a drop of 164 cases per month thereafter for the first year (28% decrease in incident cases).20 There has been considerable debate as to whether patients present with the more advanced disease since the USPSTF recommendations with no general consensus.21 Recently, the USPSTF changed their recommendation for PSA screening among men aged 55-69 years of age to a Grade C, suggesting that men in this age bracket should undergo periodic PSA-based screening for prostate cancer based on a decision after discussion regarding the potential benefits and harms of screening with their clinician.22

    Etiology and Risk Factors

    Diet and Obesity
    Initial evidence that diet and lifestyle may have a role in prostate cancer epidemiological outcomes was provided by ecological studies which demonstrated that men in Western countries had higher rates of prostate cancer than developing/non-Western countries.6 To strengthen this possible association, subsequent studies demonstrated that men from non-Western countries migrating to Western countries adopted similar lifestyle and prostate cancer risk as those in Western countries.23 Nonetheless, several prospective studies since these ecologic descriptions assessing self-reported dietary patterns of healthy foods and the risk of prostate cancer have failed to show an association with diet and risk of prostate cancer.24,25 Epidemiological evidence suggesting that statins reduce the risk of advanced stage prostate cancer suggests a possible role of cholesterol and prostate cancer risk.26 Regardless, the complexity of the Western diet and the association/interaction with healthier lifestyles are limitations to understanding how diet influences prostate cancer risk.  

    Obesity has become an epidemic in the United States, and observational studies have suggested a modest increase in the risk of prostate cancer among obese individuals.27,28 The pathophysiology between obesity and prostate cancer is likely secondary to higher levels of estradiol, insulin, and free IGF-1 levels, as well as lower free testosterone and adiponectin levels.29 However, a clear pathophysiological explanation between obesity and prostate cancer is still uncertain and may be associated with lower serum PSA and larger prostates leading to fewer prostate biopsies.30   

    Inflammation
    Chronic inflammation has been implicated in the development of several cancers and may also be associated with prostate cancer. Possible etiologic factors suggested include: infectious agents, dietary carcinogens, hormonal imbalances, as well as physical and chronic trauma.31 As a result, intra-prostatic inflammation may lead to DNA damage, epithelial proliferation, cellular turnover, and angiogenesis.31 In men part of the placebo arm of the Prostate Cancer Prevention Trial (PCPT), those with at least one biopsy core of inflammation had an odds ratio (OR) of 1.78 (95%CI 1.04-3.06) for prostate cancer compared to men with no cores of inflammation.32 Furthermore, this association was even higher when considering a high-grade prostate cancer diagnosis (OR 2.24, 95%CI 1.06-4.71).32

    Medications
    As mentioned, there has been emerging evidence that HMG-CoA reductase inhibitors (statins) may be associated with a lower risk of prostate cancer mortality following diagnosis.33 Although there have been disparate results for the beneficial nature of statins and prostate cancer, a recent meta-analysis from observational studies of nearly 1 million patients noted that both post- and pre-diagnosis use of statins are beneficial for both overall survival (HR 0.81, 95%CI 0.72-0.91) and cancer-specific survival (HR 0.77, 95%CI 0.66-0.85).34 Nonetheless, the exact role statins play in prostate carcinogenesis/protection is still widely debated.

    Similar optimism with statins has been associated with metformin use and prostate cancer outcomes. Among patients with diabetes, metformin has been associated with a significant dose-dependent benefit for both prostate cancer-specific (HR 0.76, 95%CI 0.64-0.89 for each additional six months of metformin use) and all-cause mortality.35 In a systematic review and meta-analysis of observational studies assessing clinical outcomes of patients with prostate cancer and metformin, medication use was marginally associated with a reduction in risk of biochemical recurrence (HR 0.82, 95%CI 0.67-1.01), but not associated with metastasis, prostate-cancer mortality or all-cause mortality.36

    Genetics
    Prostate cancer is known to have an extraordinarily complex genetic makeup, including somatic copy number alterations, point mutations, structural rearrangements, and changes in chromosomal number.37 It is estimated that 5-10% of all prostate cancers may be caused by dominantly inherited genetic factors.11 These include, but are not limited to HPC1, HPC2, HPC20, HPCX, PCAP, and CAPB.38 More famously are the mutations associated with BRCA1 and BRCA2 and the associated increase in the risk of clinically significant prostate cancer, and prostate cancer-specific mortality among men with screen-detected prostate cancer.39-41 Recent research has evaluated epigenetic markers for prostate cancer such as miRNA. The first report of miRNA and prostate cancer was reported in 2007,42 and since then many reports have implicated over 30 unique miRNAs and prostate carcinogenesis.

    Conclusions

    The epidemiology and etiology of prostate cancer are complex and multi-factorial. Prostate cancer remains a malignancy spanning the spectrum of localized/indolent disease to de novo advanced disease that is ultimately fatal. Although there are accepted differences in race and geography, the ultimate interplay between sociodemographic factors, environmental/lifestyle factors, and genetic differences remains to be fully elucidated.
    Written by: Zachary Klaassen, MD, MSc
    References:
    1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68(1):7-30.
    2. Potosky AL, Miller BA, Albertsen PC, Kramer BS. The role of increasing detection in the rising incidence of prostate cancer. JAMA. 1995;273(7):548-552.
    3. Etzioni R, Gulati R, Tsodikov A, et al. The prostate cancer conundrum revisited: treatment changes and prostate cancer mortality declines. Cancer. 2012;118(23):5955-5963.
    4. Brawley OW. Trends in prostate cancer in the United States. J Natl Cancer Inst Monogr. 2012;2012(45):152-156.
    5. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87-108.
    6. Center MM, Jemal A, Lortet-Tieulent J, et al. International variation in prostate cancer incidence and mortality rates. Eur Urol. 2012;61(6):1079-1092.
    7. Walsh PC. Cancer surveillance series: interpreting trends in prostate cancer--part I: evidence of the effects of screening in recent prostate cancer incidence, mortality, and survival rates. J Urol. 2000;163(1):364-365.
    8. Etzioni R, Tsodikov A, Mariotto A, et al. Quantifying the role of PSA screening in the US prostate cancer mortality decline. Cancer Causes Control. 2008;19(2):175-181.
    9. Gandaglia G, Karakiewicz PI, Abdollah F, et al. The effect of age at diagnosis on prostate cancer mortality: a grade-for-grade and stage-for-stage analysis. Eur J Surg Oncol. 2014;40(12):1706-1715.
    10. Potter SR, Partin AW. Hereditary and familial prostate cancer: biologic aggressiveness and recurrence. Rev Urol. 2000;2(1):35-36.
    11. Bratt O. Hereditary prostate cancer: clinical aspects. J Urol. 2002;168(3):906-913.
    12. Liss MA, Chen H, Hemal S, et al. Impact of family history on prostate cancer mortality in white men undergoing prostate specific antigen based screening. J Urol. 2015;193(1):75-79.
    13. Jemal A, Fedewa SA, Ma J, et al. Prostate Cancer Incidence and PSA Testing Patterns in Relation to USPSTF Screening Recommendations. JAMA. 2015;314(19):2054-2061.
    14. Freedland A, Howard LE, Vidal A, et al. Black Race Predicts Poor Compliance but Higher Prostate Cancer Risk: Results from the REDUCE Trial. AUA 2018. 2018.
    15. Wang BD, Yang Q, Ceniccola K, et al. Androgen receptor-target genes in african american prostate cancer disparities. Prostate Cancer. 2013;2013:763569.
    16. George DJ, Heath EI, Sartor O, et al. Abi Race: A prospective, multicenter study of black (B) and white (W) patients (pts) with metastatic castrate resistant prostate cancer (mCRPC) treated with abiraterone acetate and prednisone (AAP). J Clin Oncol. 2018;36(Suppl; abstr LBA5009).
    17. Yu H, Harris RE, Gao YT, Gao R, Wynder EL. Comparative epidemiology of cancers of the colon, rectum, prostate and breast in Shanghai, China versus the United States. Int J Epidemiol. 1991;20(1):76-81.
    18. Gronberg H. Prostate cancer epidemiology. Lancet. 2003;361(9360):859-864.
    19. Moyer VA, Force USPST. Screening for prostate cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2012;157(2):120-134.
    20. Barocas DA, Mallin K, Graves AJ, et al. Effect of the USPSTF Grade D Recommendation against Screening for Prostate Cancer on Incident Prostate Cancer Diagnoses in the United States. J Urol. 2015;194(6):1587-1593.
    21. Barry MJ, Nelson JB. Patients Present with More Advanced Prostate Cancer since the USPSTF Screening Recommendations. J Urol. 2015;194(6):1534-1536.
    22. Force USPST, Grossman DC, Curry SJ, et al. Screening for Prostate Cancer: US Preventive Services Task Force Recommendation Statement. JAMA. 2018;319(18):1901-1913.
    23. Yatani R, Shiraishi T, Nakakuki K, et al. Trends in frequency of latent prostate carcinoma in Japan from 1965-1979 to 1982-1986. J Natl Cancer Inst. 1988;80(9):683-687.
    24. Wu K, Hu FB, Willett WC, Giovannucci E. Dietary patterns and risk of prostate cancer in U.S. men. Cancer Epidemiol Biomarkers Prev. 2006;15(1):167-171.
    25. Key TJ, Allen N, Appleby P, et al. Fruits and vegetables and prostate cancer: no association among 1104 cases in a prospective study of 130544 men in the European Prospective Investigation into Cancer and Nutrition (EPIC). Int J Cancer. 2004;109(1):119-124.
    26. Jespersen CG, Norgaard M, Friis S, Skriver C, Borre M. Statin use and risk of prostate cancer: a Danish population-based case-control study, 1997-2010. Cancer Epidemiol. 2014;38(1):42-47.
    27. MacInnis RJ, English DR. Body size and composition and prostate cancer risk: systematic review and meta-regression analysis. Cancer Causes Control. 2006;17(8):989-1003.
    28. Renehan AG, Tyson M, Egger M, Heller RF, Zwahlen M. Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet. 2008;371(9612):569-578.
    29. Buschemeyer WC, 3rd, Freedland SJ. Obesity and prostate cancer: epidemiology and clinical implications. Eur Urol. 2007;52(2):331-343.
    30. Freedland SJ, Platz EA, Presti JC, Jr., et al. Obesity, serum prostate specific antigen and prostate size: implications for prostate cancer detection. J Urol. 2006;175(2):500-504; discussion 504.
    31. De Marzo AM, Platz EA, Sutcliffe S, et al. Inflammation in prostate carcinogenesis. Nat Rev Cancer. 2007;7(4):256-269.
    32. Gurel B, Lucia MS, Thompson IM, Jr., et al. Chronic inflammation in benign prostate tissue is associated with high-grade prostate cancer in the placebo arm of the prostate cancer prevention trial. Cancer Epidemiol Biomarkers Prev. 2014;23(5):847-856.
    33. Stopsack KH, Greenberg AJ, Mucci LA. Common medications and prostate cancer mortality: a review. World J Urol. 2017;35(6):875-882.
    34. Zhong S, Zhang X, Chen L, Ma T, Tang J, Zhao J. Statin use and mortality in cancer patients: Systematic review and meta-analysis of observational studies. Cancer Treat Rev. 2015;41(6):554-567.
    35. Margel D, Urbach DR, Lipscombe LL, et al. Metformin use and all-cause and prostate cancer-specific mortality among men with diabetes. J Clin Oncol. 2013;31(25):3069-3075.
    36. Raval AD, Thakker D, Vyas A, Salkini M, Madhavan S, Sambamoorthi U. Impact of metformin on clinical outcomes among men with prostate cancer: a systematic review and meta-analysis. Prostate Cancer Prostatic Dis. 2015;18(2):110-121.
    37. Schoenborn JR, Nelson P, Fang M. Genomic profiling defines subtypes of prostate cancer with the potential for therapeutic stratification. Clin Cancer Res. 2013;19(15):4058-4066.
    38. Gronberg H, Isaacs SD, Smith JR, et al. Characteristics of prostate cancer in families potentially linked to the hereditary prostate cancer 1 (HPC1) locus. JAMA. 1997;278(15):1251-1255.
    39. Mitra AV, Bancroft EK, Barbachano Y, et al. Targeted prostate cancer screening in men with mutations in BRCA1 and BRCA2 detects aggressive prostate cancer: preliminary analysis of the results of the IMPACT study. BJU Int. 2011;107(1):28-39.
    40. Akbari MR, Wallis CJ, Toi A, et al. The impact of a BRCA2 mutation on mortality from screen-detected prostate cancer. Br J Cancer. 2014;111(6):1238-1240.
    41. Castro E, Goh C, Olmos D, et al. Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. J Clin Oncol. 2013;31(14):1748-1757.
    42. Porkka KP, Pfeiffer MJ, Waltering KK, Vessella RL, Tammela TL, Visakorpi T. MicroRNA expression profiling in prostate cancer. Cancer Res. 2007;67(13):6130-6135.
    Published April 16, 2019
  • FOIU 2018: Epidemiology: The RADICAL PC Trial

    Tel-Aviv, Israel (UroToday.com) Jehonathan Pinthus, MD presented the RADICAL PC trial and elaborated on the correlation of prostate cancer (PC) to cardiovascular disease (CVD). It is known that PC patients are at risk for CVD.1 Patients are deemed to be high-risk if they have a global risk estimate for severe CVD events with a rate of more than 2% per year. This risk increases significantly if patients are treated with hormonal therapy (Table 1).1
    Published July 6, 2018
  • FOIU 2018: Intermittent vs. Continuous ADT

    Tel-Aviv, Israel (UroToday.com) Laurence Klotz, MD gave a presentation on intermittent androgen deprivation therapy (IADT) and its association with cardiovascular disease (CVD). He began stating the many advantages of IADT:
    Published July 6, 2018
  • Hypofractionated Radiation Therapy for Localized Prostate Cancer: An ASTRO, ASCO, and AUA Evidence-Based Guideline - Beyond the Abstract

    Compared to most other solid tumors, prostate cancer appears to exhibit a greater sensitivity to radiation fraction size. This observation has spurred investigation of hypofractionated external beam radiation therapy (EBRT) in the management of localized prostate cancer. Eight randomized trials comparing moderately hypofractionated EBRT (defined as a daily fraction size between 240 cGy and 340 cGy) and conventionally fractionated EBRT (180-200 cGy daily) have been completed and, among these, the four largest trials reported efficacy results in 2016 and 2017.
    Published October 29, 2018
  • Many vs. Cancer: First Major Global Crowd funding Effort to Defeat Prostate Cancer

    Many vs. Cancer, the first major global Crowdfunding Initiative to Defeat Prostate Cancer, launched May 17, 2017, with an ambitious program, and a goal to greatly accelerate research into the search for cure. Its strategies are of the moment-- including global crowd funding, through innovative community engagement tools and campaigns. All money raised by any Many vs. Cancer goes directly to the PCF
    Published May 31, 2017
  • Optimizing subcutaneous injection of the gonadotropin-releasing hormone receptor antagonist degarelix.

    The gonadotropin-releasing hormone (GnRH) receptor antagonist degarelix has several unique characteristics compared to luteinizing hormone-releasing hormone (LHRH) analogs used in the management of prostate cancer.

    Published February 21, 2016
  • PET imaging of prostate-specific membrane antigen in prostate cancer: current state of the art and future challenges

    BACKGROUND:Prostate-specific membrane antigen (PSMA) is a cell surface enzyme that is highly expressed in prostate cancer (PCa) and is currently being extensively explored as a promising target for molecular imaging in a variety of clinical contexts. Novel antibody and small-molecule PSMA radiotracers labeled with a variety of radionuclides for positron emission tomography (PET) imaging applications have been developed and explored in recent studies.
    Published August 16, 2017
  • Prostate Cancer and Tumor Markers

    The discovery of prostate-specific antigen (PSA) in the late 1970s and its widespread application and adoption in the 1980s and 1990s ushered in the prostate cancer screening and disease monitoring era. As the first tumor marker for prostate cancer, it is organ specific but not cancer specific.1 thus providing the opportunity for further tumor marker investigation. A potential biomarker must go through a rigorous vetting process from discovery → differentiation of case from control → ability to detect preclinical disease (defining a positive test) → indications for application and validation → cancer control studies.2 Secondary to the cost and time involved, biomarkers are rarely tested in large randomized controlled trials (RCTs). However, the development of the Prospective Randomized Open, Blinded Endpoint (PROBE) initiative for biomarker studies was designed to overcome spectrum and ascertainment bias and give guidance for validation studies.3 Biomarkers are typically evaluated based on their positive predictive value (probability that a positive test indicates the presence of disease) and negative predictive value (probability that a negative test indicates the absence of disease), entities that rely on the test’s specificity, sensitivity, and prevalence of the disease. This article will focus on briefly reviewing the clinical utility of several commonly used tumor markers associated with prostate cancer detection.

    Blood

    PSA
    PSA is part of the kallikrein gene family located on chromosome 19 and functions as a serine protease, predominantly produced by prostate luminal cells. PSA in the serum is typically bound to proteins (~80% of PSA; complexed) or unbound (free PSA). The production of PSA is androgen dependent4 and in the absence of cancer varies with age,5 race,6, 7 and prostate volume.8 African-American men without prostate cancer have a higher PSA level compared to similar Caucasian men when assessed on a volume-to-volume ratio.9 Additionally, many studies have suggested that PSA in men with higher body mass index (BMI) have lower PSAs, a concept referred to as “hemodilution”:10 a greater plasma volume leading to lower hematocrit and PSA. Recent studies have provided further support for the hemodilution theory, in that only a fraction of lower PSA values in obese men are attributed to testosterone and dihydrotestosterone levels, with the remaining lower PSA explained presumably by hemodilution.11 The greatest contributor to elevated PSA is prostatic diseases, namely prostatitis, BPH and prostate cancer. Without question, the decrease in specificity associated with PSA and prostate cancer is an elevated PSA in men with prostatitis and/or BPH.

    Free PSA (fPSA)
    fPSA is PSA that is enzymatically inactive and non-complexed, making up 4-45% of total PSA;12 men with PSA from prostate cancer cells have a lower percentage of total PSA that is free, compared to those without prostate cancer.13 fPSA has FDA approval for men with a negative digital rectal examination (DRE) and total PSA level of 4-10 ng/mL, largely on the basis of a prospective study of men demonstrating a %fPSA (fPSA/total PSA) cutoff of 25% detecting 95% of prostate cancers, while avoiding 20% of biopsies.14 A generally acceptable cut-point ranges from 15-25%. Twenty years later, %fPSA is still used for clinically appropriate men, most commonly used in those with an elevated PSA and a negative prostate biopsy. In these men, studies have reported a 5% cancer under-detection rate and 21% cutoff for repeating prostate biopsy.15

    Kallikreins
    PSA, also known as human kallikrein 3 (hK3), is the most famous of the kallikreins, however, there are other kallikreins that have recently been explored as prostate cancer tumor markers. hK2 shares 80% amino acid homology with PSA, however, is weakly expressed in benign tissue and intensely expressed in prostate cancer tissue.16 Low-grade disease generally has low expression of hK2, whereas aggressive disease has high levels of expression.16 Recently, the hK2 kallikrein has been incorporated into a panel of kallikrein markers (total PSA, free PSA, intact PSA, and hK2, along with clinical information), commercially available as the 4KScore Test, used for calculating a patient’s percent risk for aggressive prostate cancer. First described in 2008, Vickers et al.17 tested the utility of the kallikrein panel in 740 men in the Swedish arm of the ERSPC screening trial. They found that adding free and intact PSA with hK2 to total PSA improved the clinical area under the curve (AUC) from 0.72 to 0.84. When the authors applied a 20% risk of prostate cancer as the threshold for biopsy, 424 (57%) of biopsies would have been avoided, missing 31 of 152 low-grade and 3 of 40 high-grade cancers.17 Since this study a decade ago, many studies have validated these findings, including among 6,129 men participating in the ProtecT study:18 the AUC for the four kallikreins was 0.719 (95%CI 0.704-0.734) vs 0.634 (95%CI 0.617-0.651, p<0.001) for PSA and age alone for any-grade cancer, and 0.820 (95%CI 0.802-0.838) vs 0.738 (95%CI 0.716-0.761) for high-grade prostate cancer. 

    Prostate Health Index (phi)
    The phi test combines total, free and [-2]proPSA into a single score for improving the accuracy of prostate cancer detection. In the seminal study leading to FDA approval, Catalona et al.19 assessed phi scores among 892 patients without prostate cancer and a PSA between 2-10 ng/mL. They found that an increasing phi score was associated with a 4.7-fold increased risk of prostate cancer and a 1.6-fold increased risk of Gleason score ≥ 4+3 disease at prostate biopsy. Furthermore, the phi score AUC exceeded that of %fPSA (0.72 vs 0.67) to discriminate high vs low-grade disease or negative biopsy. In a subsequent study, Loeb et al.20 confirmed the phi score’s ability to outperform total, free and [-2]proPSA for identifying clinically significant prostate cancer.

    Urine

    Prostate Cancer Antigen 3 (PCA3)
    PCA3 is a long noncoding RNA shed into the urine that is not expressed outside the prostate and is associated with much higher expression in malignant than benign prostate tissue.21 Prior to collecting urine for a PCA3 test, a “rigorous” DRE is performed in order to enhance the sensitivity of the test. The commercial PCA3 score is reported as a ratio of urine PCA3 mRNA to urine PSA mRNA x 1000. The optimal cutoff is still debated, however in a contemporary comparative effectiveness review, Bradley et al.22 showed that a PCA3 threshold of 25 resulted in a sensitivity of 74% and specificity of 57% for a positive biopsy. This threshold led to FDA approval of the PCA3 test in 2012 among men with a prior negative prostate biopsy.

    Since then, several groups have reported results of PCA3 in biopsy naïve men. In a retrospective review of 3,073 men undergoing initial biopsy, Chevli et al.23 found that the mean PCA3 was 27.2 for those without, and 52.5 for patients with prostate cancer. Prostate cancer was identified in 1,341 (43.6%) men; on multivariable analysis, PCA3 was associated with any (OR 3.0, 95%CI 2.5-3.6) and high-grade (OR 2.4, 95%CI 1.9-3.1) prostate cancer after adjusting for clinicopathologic variables. Furthermore, PCA3 outperformed PSA in the prediction of prostate cancer (AUC 0.697 vs 0.599, p<0.01) but did not for high-grade disease (AUC 0.682 vs 0.679, p=0.702).23

    microRNAs (miRNAs)
    miRNAs are small, noncoding single-stranded RNAs involved in the regulation of mRNA. Due to their short sequence (typically 19-22 nucleotides), miRNAs are highly stable in most body fluids (including urine) as they are resistant to RNase degradation.24 Several miRNAs have been implicated as potential biomarkers in prostate cancer diagnosis and management, including miRNA-141, miRNA-375, miRNA-221, miRNA-21, miRNA-182 and miRNA-187.25, 26 miR-187 detected in urine has been suggested as a candidate for improving the predictive value for a positive biopsy; a prediction model including serum PSA, urine PCA3, and miR-187 provided 88.6% sensitivity and 50% specificity (AUC 0.711, p = 0.001) for a positive biopsy.26 Ultimately, these miRNAs need to be further validated in terms of their ability to regulate various pathways important for prostate cancer management and their potential role as tumor markers.

    Combining Tumor Markers

    In an effort to improve the predictive accuracy of a positive biopsy, the last several years have seen a plethora of studies combining biomarkers to not only improve predictive accuracy above that offered by PSA, but also individual, newer biomarkers. As previously mentioned, the decrease in specificity associated with PSA and prostate cancer is secondary to an elevated PSA in men with prostatitis and/or BPH. The “perfect” biomarker (or combination) would delineate prostate cancer (and ultimately high-grade prostate cancer) from other benign entities.

    Vedder et al.27 assessed the added value of %fPSA, PCA3, and 4KScore Test to the ERSPC prediction models among men in the Dutch arm of the ERSPC screening trial. Prostate cancer was detected in 119 of 708 men – adding %fPSA did not improve the predictive value of the risk calculators, however, the 4KScore discriminated better than PCA3 in univariate models (AUC 0.78 vs. 0.62; p=0.01). In the overall population, there was no statistically significant difference between the multivariable model with PCA3 (AUC 0.73) versus the model with the 4KScore (AUC 0.71; p=0.18). Among 127 men with a previous negative biopsy, Auprich et al.28 compared the performance of total PSA, %fPSA, PSA velocity (PSAV), and PCA3 at first, second and ≥ third repeat biopsy. At first repeat biopsy, PCA3 predicted prostate cancer best (AUC 0.80) compared with total PSA. A second repeat biopsy, %fPSA demonstrated the highest accuracy (AUC 0.82), and again at ≥ third repeat biopsy %fPSA demonstrated the highest accuracy (AUC 0.70).28 

    This sampling of studies demonstrates that many combinations of biomarkers are being studied in an effort to improve detection of high-grade cancer and decrease the number of unnecessary biopsies. The next generation of biomarker combinations has and will continue to incorporate multi-parametric prostate MRI into predictive algorithms for clinically significant prostate cancer.29-31

    Conclusions

    For over four decades, research efforts have been directed towards improving the detection of prostate cancer and attempting to build on the predictive accuracy of the first prostate cancer tumor marker, PSA. With the United States Preventative Services Task Force’s 2012 recommendation for the urgent need to identify new screening efforts to better identify indolent versus aggressive disease, the last several years have seen a dramatic increase in prostate cancer biomarker options. As briefly highlighted, biomarker combinations studies have demonstrated improved predictive accuracy of positive biopsies; however, these combinations are far from perfect, are expensive and much work remains to be done. Furthermore, the specific indication (pre-biopsy, post-negative biopsy, active surveillance, etc) and a combination of tumor markers remain to be fully elucidated.
    Written by: Zachary Klaassen, MD, MSc
    References: 1. Partin AW, Carter HB, Chan DW, Epstein JI, Oesterling JE, Rock RC, et al. Prostate specific antigen in the staging of localized prostate cancer: influence of tumor differentiation, tumor volume and benign hyperplasia. J Urol. 1990;143:747-52.
    2. Srivastava S. The early detection research network: 10-year outlook. Clin Chem. 2013;59:60-7.
    3. Pepe MS, Feng Z, Janes H, Bossuyt PM, Potter JD. Pivotal evaluation of the accuracy of a biomarker used for classification or prediction: standards for study design. J Natl Cancer Inst. 2008;100:1432-8.
    4. Henttu P, Liao SS, Vihko P. Androgens up-regulate the human prostate-specific antigen messenger ribonucleic acid (mRNA), but down-regulate the prostatic acid phosphatase mRNA in the LNCaP cell line. Endocrinology. 1992;130:766-72.
    5. Partin AW, Criley SR, Subong EN, Zincke H, Walsh PC, Oesterling JE. Standard versus age-specific prostate specific antigen reference ranges among men with clinically localized prostate cancer: A pathological analysis. J Urol. 1996;155:1336-9.
    6. Smith DS, Carvalhal GF, Mager DE, Bullock AD, Catalona WJ. Use of lower prostate specific antigen cutoffs for prostate cancer screening in black and white men. J Urol. 1998;160:1734-8.
    7. Espaldon R, Kirby KA, Fung KZ, Hoffman RM, Powell AA, Freedland SJ, et al. Probability of an abnormal screening prostate-specific antigen result based on age, race, and prostate-specific antigen threshold. Urology. 2014;83:599-605.
    8. Naya Y, Stamey TA, Cheli CD, Partin AW, Sokoll LJ, Chan DW, et al. Can volume measurement of the prostate enhance the performance of complexed prostate-specific antigen? Urology. 2002;60:36-41.
    9. Fowler JE, Jr., Bigler SA, Kilambi NK, Land SA. Relationships between prostate-specific antigen and prostate volume in black and white men with benign prostate biopsies. Urology. 1999;53:1175-8.
    10. Ohwaki K, Endo F, Muraishi O, Hiramatsu S, Yano E. Relationship between prostate-specific antigen and hematocrit: does hemodilution lead to lower PSA concentrations in men with a higher body mass index? Urology. 2010;75:648-52.
    11. Klaassen Z, Howard LE, Moreira DM, Andriole GL, Jr., Terris MK, Freedland SJ. Association of Obesity-Related Hemodilution of Prostate-Specific Antigen, Dihydrotestosterone, and Testosterone. Prostate. 2017;77:466-70.
    12. McCormack RT, Rittenhouse HG, Finlay JA, Sokoloff RL, Wang TJ, Wolfert RL, et al. Molecular forms of prostate-specific antigen and the human kallikrein gene family: a new era. Urology. 1995;45:729-44.
    13. Catalona WJ, Beiser JA, Smith DS. Serum free prostate specific antigen and prostate specific antigen density measurements for predicting cancer in men with prior negative prostatic biopsies. J Urol. 1997;158:2162-7.
    14. Catalona WJ, Partin AW, Slawin KM, Brawer MK, Flanigan RC, Patel A, et al. Use of the percentage of free prostate-specific antigen to enhance differentiation of prostate cancer from benign prostatic disease: a prospective multicenter clinical trial. JAMA. 1998;279:1542-7.
    15. Stephan C, Lein M, Jung K, Schnorr D, Loening SA. Re: Editorial: can prostate specific antigen derivatives reduce the frequency of unnecessary prostate biopsies? J Urol. 1997;157:1371.
    16. Darson MF, Pacelli A, Roche P, Rittenhouse HG, Wolfert RL, Saeid MS, et al. Human glandular kallikrein 2 expression in prostate adenocarcinoma and lymph node metastases. Urology. 1999;53:939-44.
    17. Vickers AJ, Cronin AM, Aus G, Pihl CG, Becker C, Pettersson K, et al. A panel of kallikrein markers can reduce unnecessary biopsy for prostate cancer: data from the European Randomized Study of Prostate Cancer Screening in Goteborg, Sweden. BMC Med. 2008;6:19.
    18. Bryant RJ, Sjoberg DD, Vickers AJ, Robinson MC, Kumar R, Marsden L, et al. Predicting high-grade cancer at ten-core prostate biopsy using four kallikrein markers measured in blood in the ProtecT study. J Natl Cancer Inst. 2015;107.
    19. Catalona WJ, Partin AW, Sanda MG, Wei JT, Klee GG, Bangma CH, et al. A multicenter study of [-2]pro-prostate specific antigen combined with prostate specific antigen and free prostate specific antigen for prostate cancer detection in the 2.0 to 10.0 ng/ml prostate specific antigen range. J Urol. 2011;185:1650-5.
    20. Loeb S, Sanda MG, Broyles DL, Shin SS, Bangma CH, Wei JT, et al. The prostate health index selectively identifies clinically significant prostate cancer. J Urol. 2015;193:1163-9.
    21. de Kok JB, Verhaegh GW, Roelofs RW, Hessels D, Kiemeney LA, Aalders TW, et al. DD3(PCA3), a very sensitive and specific marker to detect prostate tumors. Cancer Res. 2002;62:2695-8.
    22. Bradley LA, Palomaki GE, Gutman S, Samson D, Aronson N. Comparative effectiveness review: prostate cancer antigen 3 testing for the diagnosis and management of prostate cancer. J Urol. 2013;190:389-98.
    23. Chevli KK, Duff M, Walter P, Yu C, Capuder B, Elshafei A, et al. Urinary PCA3 as a predictor of prostate cancer in a cohort of 3,073 men undergoing initial prostate biopsy. J Urol. 2014;191:1743-8.
    24. Schwarzenbach H, Nishida N, Calin GA, Pantel K. Clinical relevance of circulating cell-free microRNAs in cancer. Nat Rev Clin Oncol. 2014;11:145-56.
    25. Sharma N, Baruah MM. The microRNA signatures: aberrantly expressed miRNAs in prostate cancer. Clin Transl Oncol. 2018.
    26. Casanova-Salas I, Rubio-Briones J, Calatrava A, Mancarella C, Masia E, Casanova J, et al. Identification of miR-187 and miR-182 as biomarkers of early diagnosis and prognosis in patients with prostate cancer treated with radical prostatectomy. J Urol. 2014;192:252-9.
    27. Vedder MM, de Bekker-Grob EW, Lilja HG, Vickers AJ, van Leenders GJ, Steyerberg EW, et al. The added value of percentage of free to total prostate-specific antigen, PCA3, and a kallikrein panel to the ERSPC risk calculator for prostate cancer in prescreened men. Eur Urol. 2014;66:1109-15.
    28. Auprich M, Augustin H, Budaus L, Kluth L, Mannweiler S, Shariat SF, et al. A comparative performance analysis of total prostate-specific antigen, percentage free prostate-specific antigen, prostate-specific antigen velocity and urinary prostate cancer gene 3 in the first, second and third repeat prostate biopsy. BJU Int. 2012;109:1627-35.
    29. Johnston E, Pye H, Bonet-Carne E, Panagiotaki E, Patel D, Galazi M, et al. INNOVATE: A prospective cohort study combining serum and urinary biomarkers with novel diffusion-weighted magnetic resonance imaging for the prediction and characterization of prostate cancer. BMC Cancer. 2016;16:816.
    30. Sciarra A, Panebianco V, Cattarino S, Busetto GM, De Berardinis E, Ciccariello M, et al. Multiparametric magnetic resonance imaging of the prostate can improve the predictive value of the urinary prostate cancer antigen 3 test in patients with elevated prostate-specific antigen levels and a previous negative biopsy. BJU Int. 2012;110:1661-5.
    31. Perlis N, Al-Kasab T, Ahmad A, Goldberg E, Fadak K, Sayid R, et al. Defining a Cohort that May Not Require Repeat Prostate Biopsy Based on PCA3 Score and Magnetic Resonance Imaging: The Dual Negative Effect. J Urol. 2018;199:1182-7.
    Published April 16, 2019
  • Prostate Cancer and Utilization of Multi-Parametric MRI

    Over the last decade, imaging for prostate cancer has improved immensely. Specifically, prostate multiparametric MRI (mpMRI) has improved primarily as a result of an increase in magnet strength from 1 to 3-tesla. mpMRI consists of anatomic and functional imaging techniques: anatomic imaging includes T1- and T2-weighted images, and functional imaging includes diffusion-weighted imaging (DWI) and dynamic contrast-enhanced (DCE) sequences. Currently, the recommendation is for a 1.5 tesla MRI with an endorectal coil or a 3-tesla MRI with no endorectal coil.1 

    Initial T1-weighted images are performed first to determine if hemorrhage is present in the prostate. As such, most experts recommend waiting 3-8 weeks after a prostate biopsy to decrease artifact associated with hemorrhage from the biopsy.2 Subsequently, T2-weighted images provide anatomic configuration of the prostate gland: the normal peripheral zone appears as areas of high signal intensity, whereas areas of low signal intensity may represent prostate cancer, prostatitis, BPH, etc. T2-weighted images also provide information regarding extraprostatic extension (EPE) or seminal vesical invasion (SVI), which are represented by areas of low signal intensity. DWI assess the diffusion of water within the magnetic field—the closer the cells are together (ie. for a prostate cancer nodule), the lower the motion of water, which leads to a high signal intensity in this phase. The DCE phase is a T1-weighed image with gadolinium-based contrast, which assesses vascular permeability of the prostate over a period of typically 5-10 minutes. Importantly, the combination of T2, DCE, and DWI phases yields both a NPV and PPV of >90%.3


    table-1-prostate-cancer-utilization@2x.jpg


    The objective of this article is to focus on indications for mpMRI use in the localized prostate cancer setting, specifically exploring its use before prostate biopsy, after a negative biopsy, on active surveillance, and prior to radical prostatectomy for surgical planning purposes.

    Before Prostate Biopsy

    Until recently, the utilization of mpMRI as a “triage test” prior to transrectal ultrasound (TRUS)-guided prostate biopsy was a contentious topic, relying on single centers suggesting that such an approach may decrease unnecessary biopsies.5,6 However, in 2017, the PROMIS trial provided level 1b evidence for utilizing mpMRI prior to TRUS-guided biopsy among men with elevated PSA.7 PROMIS was a multi-center, paired-cohort study to assess the diagnostic accuracy of mpMRI and TRUS biopsy against a gold-standard reference template mapping biopsy. Men were included (n=576) if they had a PSA <15 ng/ml and no history of the previous biopsy. On mapping biopsy, 71% of men had cancer, including 40% with clinically significant prostate cancer (Gleason score ≥4+3 or maximum cancer length ≥6 mm). For clinically significant disease, mpMRI was more sensitive (93%) than TRUS-biopsy (48%), albeit less specific (41% for mpMRI; 96% for TRUS-biopsy). Based on these data, a triage mpMRI would allow 25% of men to safely avoid a prostate biopsy, while at the same time reducing detection of clinically insignificant prostate cancer. Importantly, secondary to the poor specificity and positive predictive value, this study does not suggest that mpMRI should replace prostate biopsy and that men with suspicious lesions should still have histologic confirmation of prostate cancer.

    Shortly after PROMIS was published, PRECISION reported results of their trial which assigned 500 men with a clinical suspicion of prostate cancer who had not previously undergone a prostate biopsy to undergo MRI with or without a targeted biopsy vs standard TRUS-guided biopsy.8 Men in the MRI group underwent a targeted biopsy if there was a suspicion of prostate cancer on imaging and did not undergo a biopsy if the MRI was negative. The primary outcome for this randomized clinical trial was a diagnosis of clinically significant prostate cancer. In the MRI-targeted biopsy group, 28% had a negative MRI and thus no biopsy. Among men undergoing targeted biopsy, 38% had clinically significant cancer, compared to 26% in the TRUS-guided biopsy group (p=0.005). Furthermore, fewer men in the MRI-targeted biopsy group had clinically insignificant prostate cancer compared to the TRUS-guided biopsy group.

    Since the publication of these two trials, debate regarding the implementation of mpMRI prior to biopsy has ensued. Detractors have mentioned that the negative predictive value of mpMRI in PROMIS for detecting Gleason grade group ≥2 was only 76%, albeit no grade group ≥3 were missed on mpMRI.7 mpMRI prior to prostate biopsy has already been widely accepted in the UK and Australia where mpMRI is reimbursed in this setting.9 There is evidence to suggest that men with a negative mpMRI should not be biopsied unless caveats such as a strong family history, abnormal digital rectal exam, or BRCA mutation are present. At present, experts have pressed for a new paradigm for prostate cancer detection in which an abnormal mpMRI should have a targeted biopsy performed; if the mpMRI is negative then a routine follow-up protocol should be employed.9 It is noteworthy to mention that widespread dissemination will undoubtedly rely on (i) affordability/reimbursement of mpMRI, (ii) quality of the mpMRI, and (iii) skill of the radiologist.

    After Negative Prostate Biopsy

    It is generally accepted that men with a history of negative TRUS-guided biopsy and persistently elevated or increasing PSA should undergo a mpMRI prior to consideration of a second (or in some cases third or fourth) prostate biopsy. In a study of 265 patients with a PSA >4.0 ng/ml and one negative TRUS-biopsy mpMRI detected prostate cancer in 41% of men, including 87% with clinically significant prostate cancer.10 

    mpMRI has been shown in the previous negative biopsy setting to detect tumors in up to 40% of cases, often in the anterior region of the prostate.11-14 An advantage of mpMRI fusion biopsy in patients with prior negative biopsy is the ability of MRI to identify suspicious lesions in areas not normally sampled by standard TRUS-guided biopsy, specifically the anterior and apical parts of the prostate. Thus, the benefit of fusion biopsy is particularly accentuated in the prior negative biopsy cohort. Furthermore, a study by Kongnyuy et al.15 suggested that there may be racial differences with regards to anterior tumors. In a cohort of 195 African-American men matched 1:1 to white men undergoing mpMRI, 47.7% of African-American men had anterior prostate lesions. Amongst these men, a history of prior negative biopsy was significantly associated with an anterior prostate lesion (OR 1.81, 95%CI 1.03-3.20). Despite an overall higher cancer detection rate among African American than white men, the presence of anterior prostate lesions and lesions harboring clinically significant cancer were not different between races.

    On Active Surveillance

    Over the last decade, adoption of active surveillance as a management strategy for men with clinically low-risk prostate cancer has appropriately continued to increase. However, until recently, the utilization of mpMRI in active surveillance management has been somewhat discretionary and clinician dependent.16

    Earlier this year the European Association of Urology (EAU) released a position statement for active surveillance, which included 10 recommendation statements;17 the 3rd statement assessed “use and timing of MRI in active surveillance.” mpMRI can be used to increase clinically significant cancer detection, thus ensuring men are appropriately included in surveillance regimens and those with potentially threatening disease can have appropriate and timely intervention. The statement recommends that mpMRI can be performed at several time points during active surveillance:

    1. At the time of initial diagnosis – the EAU statement recommends that men diagnosed with a low-risk disease without a prior mpMRI should under a mpMRI prior to enrolment to ensure no significant disease was missed on initial biopsy. In cases of initial targeted mpMRI biopsy, both targeted and systematic biopsies should be performed.17 In addition to the excitement generated by PROMIS 7 and PRECISION,8 a recent systematic review assessed the role of mpMRI among active surveillance patients, noting that a lesion suspicious for prostate cancer was found in nearly two-thirds of men otherwise suitable for surveillance.18
    2. Before confirmatory biopsy – the EAU statement recommends that a mpMRI be performed before the confirmatory biopsy, within 12 months from initial diagnosis, and to include targeted and systematic biopsies.17 The rate of reclassification after targeted biopsies among men on active surveillance without a prior mpMRI may be as high as 22%.18-20 A recent publication assessed the value of serial mpMRI imaging among 111 men on active surveillance with > 1-year of follow-up, noting that among 33 reclassifications after one year, 55% were reclassified on only TRUS-guided biopsy.21 As such, the value of serial mpMRI in active surveillance algorithms remains unclear.
    3. During follow-up – the EAU statement does not support the use of solely using mpMRI instead of repeat biopsy in active surveillance follow-up.17 As mentioned, the use of serial mpMRIs over long-term follow-up is not currently recommended, however it may be used in situations where a targeted lesion is being followed. This is an area of great research interest considering that institutional studies with vast experience with mpMRI suggest that mpMRI supplanting follow-up biopsies is safe and feasible.22  
    Last month, the ASIST trial published results of the randomized, multicenter, prospective trial assessing if mpMRI with targeted biopsy could identify a greater proportion of men with grade group ≥2 cancer on confirmatory biopsy compared with systematic biopsies.23 Among 273 men included in the study, 64% in the MRI group had a suspicious region of interest. Unfortunately, no difference was observed in the rate of grade group ≥2 upgrading in the intention to treat or per protocol cohort, grade group ≥2 upgrading within each stratum separately, or grade group ≥3. This trial confirms that there is still a role for TRUS-guided biopsy among active surveillance patients, in addition to tempering the current role for targeted biopsies in this setting.

    Before Radical Prostatectomy

    With improved mpMRI technology has come an interest in more precise clinical staging of localized prostate cancer, particularly before performing radical prostatectomy. Ultimately, the patient and urologist are concerned about the risk of EPE preoperatively, which dictates the degree of nerve-sparing performed at the time of radical prostatectomy. Somford et al.24 assessed mpMRI images among 183 men to determine the positive and negative predictive values of mpMRI for EPE at radical prostatectomy for different prostate cancer risk groups. The overall prevalence of EPE at radical prostatectomy was 49.7% (24.7% low-risk; 77.1% high-risk) – the overall staging sensitivity was 58.2%, specificity was 89.1%, positive predictive value was 84.1% and a negative predictive value was 68.3%. The positive predictive value was best in the high-risk cohort (88.8%) and a negative predictive value was best in the low-risk cohort (87.7%).

    Data regarding whether preoperative imaging influences surgical planning is limited. However, Schiavina et al.25 assessed the impact of mpMRI on preoperative decision making among 137 patients planned for radical prostatectomy who underwent mpMRI. They found that mpMRI changes robotic surgeon’s initial surgical plan with regards to the degree of nerve-sparing in nearly half of patients. Interestingly, there was an equal alteration in surgical planning when considering a more aggressive (to less aggressive) and less aggressive (to more aggressive) preliminary plan. Although the above results for EPE prediction and tailored surgical planning are encouraging, this degree of advanced mpMRI interpretation should be reserved for expert radiologists where sensitivities and specificities for predicting EPE are typically both >80%.26

    Conclusions

    The improvement of MRI technology and development of mpMRI for prostate imaging is one of the most important technologic advancements in urologic oncology over the past decade. The PROMIS and PRECISION trials have delineated the utility of mpMRI among men considering a prostate biopsy. Likely the most accepted and concrete indication for utilization of mpMRI is in men with a negative prostate biopsy and persistent/increasingly elevated PSA, specifically to enhance the ability to detect previously unsampled (often anterior) tumors. The recent EAU statement on active surveillance has provided much-needed guidance as to when to include mpMRI in the surveillance algorithm; work is still necessary to delineate who benefits from serial mpMRI, particularly after 1 year on active surveillance. Finally, there is increased utilization of mpMRI among patients planned for radical prostatectomy to assess the degree of acceptable nerve sparing without compromising oncologic efficacy, however the high-level of mpMRI interpretation to accurately assess EPE in these instances requires expert radiologic experience.
    Written by: Zachary Klaassen, MD, MSc
    References: 1. Muller BG, Futterer JJ, Gupta RT, Katz A, Kirkham A, Kurhanewicz J, et al. The role of magnetic resonance imaging (MRI) in focal therapy for prostate cancer: recommendations from a consensus panel. BJU Int. 2014;113:218-27.
    2. Rosenkrantz AB, Kopec M, Kong X, Melamed J, Dakwar G, Babb JS, et al. Prostate cancer vs. post-biopsy hemorrhage: diagnosis with T2- and diffusion-weighted imaging. J Magn Reson Imaging. 2010;31:1387-94.
    3. Abd-Alazeez M, Kirkham A, Ahmed HU, Arya M, Anastasiadis E, Charman SC, et al. Performance of multiparametric MRI in men at risk of prostate cancer before the first biopsy: a paired validating cohort study using template prostate mapping biopsies as the reference standard. Prostate Cancer Prostatic Dis. 2014;17:40-6.
    4. Barentsz JO, Weinreb JC, Verma S, Thoeny HC, Tempany CM, Shtern F, et al. Synopsis of the PI-RADS v2 Guidelines for Multiparametric Prostate Magnetic Resonance Imaging and Recommendations for Use. Eur Urol. 2016;69:41-9.
    5. Thompson JE, Moses D, Shnier R, Brenner P, Delprado W, Ponsky L, et al. Multiparametric magnetic resonance imaging guided diagnostic biopsy detects significant prostate cancer and could reduce unnecessary biopsies and over detection: a prospective study. J Urol. 2014;192:67-74.
    6. Thompson JE, van Leeuwen PJ, Moses D, Shnier R, Brenner P, Delprado W, et al. The Diagnostic Performance of Multiparametric Magnetic Resonance Imaging to Detect Significant Prostate Cancer. J Urol. 2016;195:1428-35.
    7. Ahmed HU, El-Shater Bosaily A, Brown LC, Gabe R, Kaplan R, Parmar MK, et al. Diagnostic accuracy of multi-parametric MRI and TRUS biopsy in prostate cancer (PROMIS): a paired validating confirmatory study. Lancet. 2017;389:815-22.
    8. Kasivisvanathan V, Rannikko AS, Borghi M, Panebianco V, Mynderse LA, Vaarala MH, et al. MRI-Targeted or Standard Biopsy for Prostate-Cancer Diagnosis. N Engl J Med. 2018;378:1767-77.
    9. Nzenza T, Murphy DG. PRECISION delivers on the PROMIS of mpMRI in early detection. Nat Rev Urol. 2018.
    10. Hoeks CM, Schouten MG, Bomers JG, Hoogendoorn SP, Hulsbergen-van de Kaa CA, Hambrock T, et al. Three-Tesla magnetic resonance-guided prostate biopsy in men with increased prostate-specific antigen and repeated, negative, random, systematic, transrectal ultrasound biopsies: detection of clinically significant prostate cancers. Eur Urol. 2012;62:902-9.
    11. Kirkham AP, Haslam P, Keanie JY, McCafferty I, Padhani AR, Punwani S, et al. Prostate MRI: who, when, and how? Report from a UK consensus meeting. Clin Radiol. 2013;68:1016-23.
    12. Lawrentschuk N, Fleshner N. The role of magnetic resonance imaging in targeting prostate cancer in patients with previous negative biopsies and elevated prostate-specific antigen levels. BJU Int. 2009;103:730-3.
    13. Hambrock T, Somford DM, Hoeks C, Bouwense SA, Huisman H, Yakar D, et al. Magnetic resonance imaging guided prostate biopsy in men with repeat negative biopsies and increased prostate specific antigen. J Urol. 2010;183:520-7.
    14. Zugor V, Kuhn R, Engelhard K, Poth S, Bernat MM, Porres D, et al. The Value of Endorectal Magnetic Resonance Imaging of the Prostate in Improving the Detection of Anterior Prostate Cancer. Anticancer Res. 2016;36:4279-83.
    15. Kongnyuy M, Sidana A, George AK, Muthigi A, Iyer A, Fascelli M, et al. The significance of anterior prostate lesions on multiparametric magnetic resonance imaging in African-American men. Urol Oncol. 2016;34:254 e15-21.
    16. Scarpato KR, Barocas DA. Use of mpMRI in active surveillance for localized prostate cancer. Urol Oncol. 2016;34:320-5.
    17. Briganti A, Fossati N, Catto JWF, Cornford P, Montorsi F, Mottet N, et al. Active Surveillance for Low-risk Prostate Cancer: The European Association of Urology Position in 2018. Eur Urol. 2018;74:357-68.
    18. Schoots IG, Petrides N, Giganti F, Bokhorst LP, Rannikko A, Klotz L, et al. Magnetic resonance imaging in active surveillance of prostate cancer: a systematic review. Eur Urol. 2015;67:627-36.
    19. Recabal P, Assel M, Sjoberg DD, Lee D, Laudone VP, Touijer K, et al. The Efficacy of Multiparametric Magnetic Resonance Imaging and Magnetic Resonance Imaging Targeted Biopsy in Risk Classification for Patients with Prostate Cancer on Active Surveillance. J Urol. 2016;196:374-81.
    20. Pessoa RR, Viana PC, Mattedi RL, Guglielmetti GB, Cordeiro MD, Coelho RF, et al. Value of 3-Tesla multiparametric magnetic resonance imaging and targeted biopsy for improved risk stratification in patients considered for active surveillance. BJU Int. 2017;119:535-42.
    21. Hamoen EHJ, Hoeks CMA, Somford DM, van Oort IM, Vergunst H, Oddens JR, et al. Value of Serial Multiparametric Magnetic Resonance Imaging and Magnetic Resonance Imaging-guided Biopsies in Men with Low-risk Prostate Cancer on Active Surveillance After 1 Yr Follow-up. Eur Urol Focus. 2018.
    22. Walton Diaz A, Shakir NA, George AK, Rais-Bahrami S, Turkbey B, Rothwax JT, et al. Use of serial multiparametric magnetic resonance imaging in the management of patients with prostate cancer on active surveillance. Urol Oncol. 2015;33:202 e1- e7.
    23. Klotz L, Loblaw A, Sugar L, Moussa M, Berman DM, Van der Kwast T, et al. Active Surveillance Magnetic Resonance Imaging Study (ASIST): Results of a Randomized Multicenter Prospective Trial. Eur Urol. 2018.
    24. Somford DM, Hamoen EH, Futterer JJ, van Basten JP, Hulsbergen-van de Kaa CA, Vreuls W, et al. The predictive value of endorectal 3 Tesla multiparametric magnetic resonance imaging for extraprostatic extension in patients with low, intermediate and high risk prostate cancer. J Urol. 2013;190:1728-34.
    25. Schiavina R, Bianchi L, Borghesi M, Dababneh H, Chessa F, Pultrone CV, et al. MRI Displays the Prostatic Cancer Anatomy and Improves the Bundles Management Before Robot-Assisted Radical Prostatectomy. J Endourol. 2018;32:315-21.
    26. Tay KJ, Gupta RT, Brown AF, Silverman RK, Polascik TJ. Defining the Incremental Utility of Prostate Multiparametric Magnetic Resonance Imaging at Standard and Specialized Read in Predicting Extracapsular Extension of Prostate Cancer. Eur Urol. 2016;70:211-3.
    Published April 16, 2019
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