Management of the Early-Stage Prostate Cancer

Introduction and Epidemiology

Prostate cancer (PCa) is the most common non-cutaneous malignancy among men in the Western hemisphere. In the United States (US), PCa accounts for approximately 11% of all new cancer diagnoses and 4% of all cancer deaths, accounting for 191,930 new cases and 33,330 deaths in 2020 ^[1-3]

In its early stage, PCa is mostly asymptomatic but it can be associated with lower urinary tract symptoms including nocturia, poor urinary stream, impotence, urinary retention, and hematuria among others. Symptoms will mainly correlate with the size and the location of the tumor. Since PCa most commonly metastasizes to bone (other than lymph nodes), bone pain could be seen in more advanced disease. 

The natural history of PCa is heterogeneous based on established prognostic factors. However, many patients experience a protracted disease course as evidenced by the discordance between the median age at diagnosis of 66 years and the median age of PCa-specific death of 80 years.^[1] Furthermore, early cancer detection and subsequent treatment have resulted in a favorable five-year survival rate of 97.5% among all PCa patients. Prognosis remains poor for approximately 7% of patients who present with distant metastases where the median overall survival drops to 30.6% at 5 years.^[1] Given the approximately 3.2 million men currently afflicted with the disease in the US, it is important for clinicians to have a thorough understanding of the epidemiology, risk factors, diagnosis, and treatment of PCa.^[1]

The incidence of PCa varies according to age, race, and heredity, as well as environmental factors. Based on data from the Surveillance, Epidemiology, and End Results (SEER) Program, the incidence rates for PCa range from 252.5 per 100,000 for men aged between 50 and 64 years to 622.1 per 100,000 for men aged ≥ 65years.^[1] Moreover, there is a wide variation in the incidence and mortality of PCa patients based on racial and ethnic background. For example, the incidence of PCa in non-Hispanic Black patients is 189.0 per 100,000, whereas it is 114.1per 100,000 in the non-Hispanic White population, 92.9 per 100,000 in the Hispanic population, 54.8 per 100,000 in the American Indian/Alaska Native population, and 64.8 per 100,000 in the Asian/Pacific Islander population.^[4]

Although there is no clearly identified single genetic risk factor, the hazard ratio (HR) for  PCa diagnosis in men with a first-degree relative affected by PCa ranges between 2.1 and 17.7.^[5] Men are at highest risk when they have a history of PCa in the father and one brother or a PCa history in two brothers.^[6] Additionally, first-degree relatives of men with high-grade PCa are at increased risk for high-grade PCa. While there is undoubtedly a genetic component to these findings, there are likely environmental causes as well.^[7] Specifically, studies show that geographic relocation, for example Japanese men moving to the US, eliminates much of the difference between races when it comes to PCa prevalence.^[8] This suggests that cultural and geographical factors such as diet, carcinogenic exposure, chronic inflammation, low exposure to ultraviolet radiation, and  exercise may play  major roles in PCa development.

The past 20 years have witnessed significant controversies regarding PCa screening given concerns about overdiagnosis and overtreatment in light of increasing recognition of treatment toxicities.

Etiology and Pathogenesis

Genetic factors are believed to be responsible for the development of some PCa.Generally, patients with a hereditary component (paternal or maternal) will develop PCa 6 to 7 years earlier than the overall population. In addition to the hereditary component, age, and African descent are well established risk factors.Similarly, lifestyle (for example diet, exercise pattern, region, socioeconomic status, and race) and metabolic syndrome may also contribute to this association.^[9] Although some studies identified the xenotropic marine leukemia virus-related virus as a possible cause due to its association with more aggressive forms of PCa,^[10] multiple studies now discredit this association.^[11,12]

Prostate cancer genomics

Many recent developments have contributed to our understanding of the genetic precursors of PCa growth. Germline mutations in BRCA 1, BRCA 2, HOXB13, and ATM genes have been linked to PCa development.^[13,14]

The prospective IMPACT study showed that BRCA 2 mutation carriers were associated with higher incidence of PCa, younger age at diagnosis, and clinically significant cancer.^[15] Other studies have shown that multiple variant regions of chromosome 8q24 have been linked with sporadic PCa in populations as distinct as African-Barbadian and Northern Chinese men.^[16,17] Another study found chromosome 1q25 variants, encoding ribonuclease L, were associated with increased risk for PCa (odds ratio = OR: 1.63, 95%CI: 1.18-2.25). Furthermore, 1q25 variants were also associated with high-grade tumors (OR: 1.90, 95%CI: 1.25-2.89).^[18]

The role of manganese-dependent superoxide dismutase (MnSOD) in PCa development has been a source of controversy. Increased levels of MnSOD have been described in cancerous tissue when compared to non-tumor samples.^[19] Other studies found that this association is highly dependent on circulating selenium levels and other genetic loci; therefore, it may not be practical for routine clinical use.

A more established genomic marker in PCa is the TMPRSS2:ERG translocation. This translocation is seen in 40% to 50% of primary tumors.^[20] The etiology of the translocation and its effect on cancerous growth in the prostate is still the subject of investigation. However, evidence demonstrated that this genetic variant is associated with a higher stage at diagnosis (≥ cT3 vs. cT2) (relative risk = RR: 1.23, 95%CI: 1.16-1.30) rather than development of biochemical recurrence (RR: 1.00, 95%CI: 0.86-1.17) or lethal disease (RR: 0.99, 95%CI: 0.47-2.09).^[20]

Several mutations are associated with the progression of PCa and these include methylation of Glutathione S-transferase P1 (GSTP1), deletion of phosphatase and tensin homologue (PTEN) from chromosome 10, and mutations in p53. Methylation of GSTP1 is present in over 90% of prostate cancer cases and, when functioning normally, detoxifies various substances in the body. PTEN deletion is common in all stages of PCa; however, this deletion has not been observed in familial PCa. Finally, alterations in the tumor suppressor gene TP53 gene lead to apoptosis and cell cycle arrest. This mutation is more common in metastatic disease.^[21,22] Research is ongoing to identify other genetic triggers. In addition genetic precursors are differentially relevant across populations.

Diet and lifestyle

Several studies found an association between daily food intake, vitamins, and the development of PCa or progression among genetic mutation carriers. In a meta-analysis, metabolic syndrome was associated with increased risk of PCa among European cohorts only (RR=1.30, p = 0.034). Nevertheless, these findings were not reflected in recent guidelines.^[9] In a large phase III randomized controlled trial (RCT) entitled Selenium and Vitamin E Cancer Prevention Trial (SELECT), Selenium and vitamin E supplementation were not associated with incidence of PCa.^[23] A study  also showed that lycopene, a member of the carotenoid family with strong anti-oxidant attributes, does not affect PCa development.^[24] Studies have also investigated the post-diagnosis intake of poultry and red meat and showed no impact on PCa progression; yet, men that consumed 2.5 or more eggs per week had an increased risk of developing lethal PCa compared to those whose weekly intake was fewer than 0.5 egg (HR: 1.81, 95%CI: 1.13-2.89).^[25]

In contrast, other groups have reported that a higher intake of red meat, high-fat dairy, and refined grains are associated with a higher risk of PCa-specific mortality (HR: 2.53, 95%CI: 1.00-6.42) and overall mortality (HR: 1.67, 95%CI: 1.16-2.42).^[26] Another study evaluated the impact of nut consumption and the risk of being diagnosed with PCa, but found no significant correlation.^[27] However, patients with known PCa and higher consumption of nuts (defined as five or more times during a week) had a 34% lower rate of overall mortality compared to those eating nuts less than once a month (HR: 0.66, 95%CI: 0.52-0.83).^[27]

Higher intake of coffee > 5 cups per day compared to a group with a daily intake of <1 cup per day may lower the risk of developing high-grade PCa (OR: 0.50, 95%CI: 0.26-0.98).^[28] Moreover, high alcohol intake may induce the opposite effect: one study has observed that heavy drinkers (>14 drinks per week) experienced a 1.46-fold increased risk (HR: 1.46, 95%CI: 1.12-1.91) of PCa than light drinkers (≤ 3 drinks/week).^[29] At this time, no specific micronutrient is recommended for the prevention of prostate cancer.

Furthermore, sleep or lack thereof do not appear to be significant risk factors. A study focusing on the effect of sleep duration of ≤ 5 hours per night, sleep disruption, difficulty maintaining sleep, sleep quality, and restorative power of sleep found no association with PCa.^[30] On the other hand, one protective parameter against the development of PCa may be increased frequency of ejaculation.^[31] Men between 40 and 49 who ejaculated ≥ 21 times per month were less likely to develop PCa (HR: 0.78, 95%CI: 0.69-0.89) compared to who ejaculated 4 to 7 times per month.^[31]

Screening and Diagnosis

Digital rectal examination (DRE)

The goal of PCa screening is to detect organ-confined PCa, which is potentially curable with definitive local therapy thereby decreasing the risk of PCa-specific mortality. Prior to the advent of PSA testing, DRE was the principal screening and diagnostic tool for PCa. DRE is often insufficient on its own (sensitivity and specificity <60%) for several reasons including: highly variable interpretation due to operator experience or bias, the fact that many cancers are not palpable, and many of the cancers detectable by DRE are not confined to the prostate and are therefore not curable.^[32] Nevertheless, a serum prostate-specific antigen test (PSA) could be combined with a DRE to screen for PCa in informed men.^[33]

Prostate specific antigen (PSA)

PSA-based screening for early detection of PCa is the subject of an ongoing debate and controversy. PSA is a protein produced by the prostate and secreted in the serum that was initially discovered by Richard J. Albin in 1970. It is a member of the kallikrein family and an androgen-regulated serine protease that is located on the chromosome 19q13.4. It is produced almost exclusively by epithelial cells of the prostate and its main function is to liquefy the semen coagulum. In 1987, Stamey and colleagues were the first to suggest the use of PSA as a potential marker for PCa. The greatest limitation of its use is that PSA is organ-specific, but not cancer-specific. Thus, other prostate conditions such as benign prostatic hypertrophy or prostatitis may also account for high levels of serum PSA. Nonetheless, several studies found PSA to be a reasonably accurate screening test for PCa when combined with DRE.^[33]

Given its lack of sensitivity and specificity, no PSA threshold can be used to definitively diagnosis or exclude PCa, though typically < 4.0 ng/mL is considered normal. However, in biopsy studies, the incidence of PCa among men with PSA levels less or equal to 4.0 ng/mL may be as high as 25%. Given that no one test is adequate to detect most cancers, PCa screening routinely combines a PSA test and DRE to capture both non-palpable early stage cancers and low PSA producing tumors.

In recent years, PSA-based PCa screening has become more controversial. While the goal of screening is to prevent prostate cancer deaths, the benefit may be mitigated by the risk of overdiagnosis of indolent cancers that would never lead to death and expose the patient to the risks of treatment toxicities. Given the unfavorable effects on quality of life (QoL) that can result from definitive treatment for PCa, and the absence of a survival benefit for men with a limited life expectancy, the United States Preventive Services Task Force (USPSTF) issued in 2012 a grade ‘D’ recommendation for PSA-based screening in men age 75 years or older.^[34] That being said, data have shown that this had a limited impact on the use of PSA testing in elderly men, as they continued to undergo PSA-based screening (up to 43.9% in the US in 2010).^[35]

At least two large studies have shown conflicting results regarding the benefit of PSA screening. These trials were initiated to evaluate the impact of PSA testing and DRE on PCa-specific-mortality. The European Randomized Study of Screening for Prostate Cancer trial randomized 72,952 men to screening versus no screening.^[36] After a 13-year follow-up, the authors found that PSA-based screening reduced PCa associated mortality by 20% (RR: 0.79; 95% CI, 0.69–0.91), but was associated with a high risk of overdiagnosis. Specifically, 1,410 men would need to be screened and 48 additional cases of PCa would need to be treated to prevent one death from PCa.^[36] The long-term follow-up of this study suggests that the numbers needed to screen and treat may continue to decrease, making PSA screening more appealing for younger men. Similarly, The US Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial randomized 38,340 men to systematic screening versus. no screening.^[37] The PLCO study revealed an overall low PCa associated mortality that was not improved with PCa screening. However, the interpretation of the initial results of this trial was limited by significant contamination of the control arm with approximately 50% of men undergoing PSA testing during the study.^[37.38] A recent study reported a proportion close to 90% of control participants that had at least one PSA test before or during the PLCO Screening Trial.^[39] Furthermore, the Health Status Questionnaire captured the rates of PSA testing during the study and found a higher proportion of PSA testing in the control arm compared to the intervention arm.^[39]

Based on the findings of the two randomized trials, in October 2012, the USPSTF issued a grade ‘D’ recommendation against PSA screening for all men, concluding that “there is moderate certainty that the benefits of PSA-based screening for prostate cancer outweigh the harms”.^[40] This led to a 28% decline in incidence of PCa in the year following the USPSTF recommendation.^[41] These findings align with recently released data from the SEER Program that show a decline of PCa incidence from 141.0 new cases per 100,000 members of the population in 2011 to 114.1 new cases per 100,000 members of the population in 2012.^[1] In 2017, the USPSTF updated their guidelines and now recommend screening for men between 55 and 69 years who choose to undergo screening after being informed about the risks and benefits of screening (grade C).^[42] Similarly, the American Urological Association (AUA) recommends a shared decision-making model for PSA based screening for men between the age of 55 to 69 years, while the American Cancer Society and the European Urological Association recommend shared decision-making for men starting at the age of 50 or 45 for men with a family history of PCa and men of African Descent. Men > 40 years of age harboring a BRCA2 mutation should also be screened. [see Table 3].^[33,43,44]

Other serum-based screening or diagnostic assays: PCA3

PCA3 is a noncoding, prostate tissue specific RNA (ribonucleic acid). This biomarker is overexpressed in PCa and measured in urine specimens after prostatic massage. Previous studies have shown that PCA3 is a valuable diagnostic tool to reduce the number of repeat biopsies. Integrating PCA3 testing prior to re-biopsy could reduce the number of re-biopsies by approximately 50%, but showed limited potential for biopsy naïve men.^[45] The US Food and Drug Administration (FDA) approved it as a tool to determine the need for re-biopsies in men 50 years or older with a history of one or more negative prostate biopsies.

Prostate Health Index

The Prostate Health Index (PHI) test is a blood test, which was recently approved by the FDA to aid decision-making in patients with PSA levels between 4 and 10 ng/mL. This assay measures three different forms of PSA (total PSA [tPSA], free PSA [fPSA], and proPSA [p2PSA]) and calculates a specific score.^[46] A multi-center study showed a two-fold higher specificity of PHI compared to free-to-total PSA.^[47] A higher PHI portends higher odds of ≥ Gleason 7 PCa.

4Kscore

The 4Kscore encompasses tPSA, fPSA, human kallikrein 2 (hK2), intact PSA as well as patient age, DRE results, and biopsy history. A multi-institutional prospective trial reported that this test provides excellent accuracy (area under the curve [AUC]: 0.82, 95%CI: 0.79-0.85) for detecting clinically significant PCa (csPCa).^[48] The National Comprehensive Cancer Network (NCCN) recommends considering this test for individuals pre-biopsy or after a negative biopsy in individuals with an increased risk of csPCa.^[49]

Prostate biopsy

A prostate biopsy is generally performed when cancer is suspected due to an elevated PSA, an abnormal DRE, or both. Age, life expectancy, comorbidities, and potential therapeutic consequences should all be considered and the decision to biopsy should be risk stratified to avoid unnecessary procedures. An initial elevated PSA level does not warrant an immediate biopsy. The result should be verified few weeks later through a second test under standardized conditions (in the same laboratory), and that no recent ejaculation, infection and/or manipulation of the lower urinary tract might have induced the false positive results.^[50,51]

Risk Calculator

In order to avoid unnecessary prostate biopsies, risk calculators could be used in asymptomatic men with a normal DRE and PSA level between 2 and 10 ng/mL. A meta-analysis revealed that Screening for Prostate Cancer Risk Calculator 3 (ERSPC RC3) and Prostataclass have the highest discriminative value (AUC = 0.79), equivalent to doubling the sensitivity of PSA testing without loss of specificity.^[33,52]

Imaging

Although multiparametric magnetic resonance imaging (mpMRI) should not be used as an initial screening tool, it can help with biopsy optimization as it has a sensitivity and specificity of 0.91 (95% CI: 0.83–0.95) and 0.37 (95% CI: 0.29–0.46) for International Society of Urological Pathology – ISUP grade ≥ 2 lesions and 0.95 (95% CI: 0.87–0.99) and 0.35 (95% CI: 0.26–0.46) for ISUP grade ≥3 lesions. In biopsy naïve patients, MRI targeted biopsy (MRI-TBx) had limited value over systematic biopsy (sBx) in the MRI-FIRST and M4 trials; but, in the PRECISION trial, MRI-TBx was superior to sBx (38% vs. 26%) in detecting csPCa.^[53-55]

It is strongly recommended to perform a mpMRI prior to biopsy in biopsy naïve patients. If a Prostate Imaging Reporting and Data System (PI-RADS) ≥ 3 (positive mpMRI finding) lesion is detected in a biopsy naive man, it is better to combine targeted and systematic biopsy.^[33] In men with prior negative biopsy, MRI-TBx increases the detection of ISUP ≥ 2 and ISUP ≥ 3 by 40% and 50%, respectively. The same meta-analysis also revealed that by performing biopsies for PI-RADS ≥ 3 only lesions, clinicians could avoid a third of biopsy procedures while missing on 11% of ISUP ≥ 2 cancers.^[56]

Thus, for men with a previous negative biopsy and strong clinical suspicion for PCa, a PI-RADS ≤ 2 lesion (negative mpMRI finding) reading could warrant sBx after shared decision making.^[33] The addition of PSA density (PSAD) to PI-RADS readings could help determine which patients should receive a biopsy. For PI-RADS 1 and PI-RADS 2 lesions and a PSAD < 0.15 ng/mL/cc, the chance of finding a clinically significant cancer on biopsy is ≤ 10%, but rises to 27-40% if PSAD is > 0.15-0.20 ng/mL/cc.^[57]

Ultrasound-guided biopsy

Ultrasound-guided biopsies may be done through either the transrectal approach (TRUS; transrectal ultrasonography) or the perineal approach based on personal preference. Both procedures have similar cancer detection rates and are considered standard of care.^[58] However, the transperineal route is associated with lower risk for urinary tract infections.^[59] Recent research recommend sampling as far posterior and lateral as possible on baseline biopsies and a minimum of eight cores. Ten cores results in a more conclusive test; however, procuring more than 12 cores does not significantly increase the accuracy of the first biopsy.^[60,61] A 12-core biopsy is now preferred given the higher detection rate; nevertheless, it does increase the odds of detecting csPCa in comparison to the sextant protocol.

Saturation biopsies (>12 cores) should be considered for select cases such as in men with large prostates. In the re-biopsy setting, studies have shown that a greater number of cores increases the PCa detection rate by 18-34%.^[62-64] Despite the broader sampling, the saturation technique can still miss cancer cases, highlighting the need to consider repeat biopsy and continue serial PSA monitoring. Indications for a repeat biopsy include: a rising PSA level, newly suspicious DRE, and atypical small acinar proliferation.^[65,66]

Targeted MRI/US fusion biopsy

Urologists and radiologists have recently started performing targeted prostate biopsies with magnetic resonance imaging (MRI) / ultrasound fusion-guidance. This approach incorporates MRI imaging into the ultrasound-guided technique. Initial prospective studies have shown an increase in the rate of detection for high-grade tumors and a reduction in the rate of detection for low-grade tumors ^[67,68] Recently, the STHLM3-MRI RCT was a population-based non-inferiority trial of PCa screening among men between 50 and 74 years with PSA ≥ 3ng/mL.^[69]

Men were randomized into either standard biopsy or MRI with targeted and standard biopsy if MRI results were suggestive of PCa. MRI with targeted and standard biopsy was non-inferior to standard biopsy to detect csPCa (3% percentage points; 95%CI, -1 to 7) and detected less clinically insignificant PCa (-8% percentage points; 95%CI, -11 to -5).^[69] The findings are promising due to the current concerns about overtreatment of low-grade PCa. Addtionally, improved grading/staging during the pretreatment phase could inform the decision for either active surveillance (AS) or definitive treatment based on the risk of progression and thereby reduce the incidence of overtreatment.^[70] There is also some evidence that MRI guided biopsy is cost effective in biopsy naïve patients and in men with prior negative results on biopsy.^[71,72] Nevertheless, due to its elevated cost, coverage might not be secured by all insurances.

Complications after prostate biopsy

Common side-effects following prostate biopsies include hematospermia and hematuria. The rate of severe rectal bleeding ranges from 1.3 to 45%, but overall this is an uncommon complication. Tailored antibiotic prophylaxis, usually a single dose of oral or intravenous quinolone (ciprofloxacin superior to ofloxacin)^[73] and single dose of cephazolin^[74] should be considered in transrectal and transperineal biopsy, respectively to decrease the incidence of post-biopsy infectious complications, such as prostatitis.^[75] Given the increasing rate of fluoroquinolone-resistant bacteria due to indwelling catheter, recent travel, hospitalization within the past 6 months, and urogenital infection, a rectal swab test may be warranted before transrectal ultrasound biopsy.or alternatively, a transperineal biopsy could be performed.^[74]

If the rectal swab test is positive, patients should be considered for targeted antibiotic prophylaxis according to the antibiogram taken from the test. One study revealed a significantly lower infection rate (0.41% compared to 2.65% in the control group; p < 0.05) with appropriate antibiotics.^[76] Finally, 0.2-1.7% of patients experience acute urinary retention after TRUS biopsy, with a higher rate (10%) of urinary retention reported in the re-biopsy setting.^[75,77] Prostate biopsy is associated with significant patient discomfort caused by the movement of the ultrasound probe in the rectum and the penetration of the biopsy needles into the prostate. In a meta-analysis pain was (RR: 1.83, 95% CI 1.27–2.65) higher in men who underwent transperineal biopsy.^[59] Furthermore, prostate biopsy could be anxiety provoking, and stress management using music therapy, one-on-one simulation education, and analgesic administration could decrease anxiety and pain during prostate biopsy.^[78,79]

Genomic testing

Prolaris Score

The Prolaris test is a molecular assay that quantifies the expression of cell cycle progression genes related to PCa. This information is synthesized to predict the risk of cancer progression.^[80] To perform the assay, paraffin-embedded tissue is required and can generally be obtained from prior TRUS-guided biopsies or prostate specimens. In retrospective cohorts followed conservately, lower scores have been associated with a lower risk of progression to lethal disease.^[81]

Oncotype DX Genomic Prostate Score

Oncotype DX is a multi-gene RT-PCR expression assay performed on prostate biopsy fixed paraffin-embedded tissue. It measures the expression of 12 cancer-related genes that represent four biological pathways relevant to PCa and 5 reference genes.^[82] This test aims to help decision-making in early-stage PCa following prostate biopsy using an algorithm that calculates the Genomic Prostate Score (GPS) where a higher score is associated with increased odds of pathologic upgrading at surgical resection. This test is most useful for patients contemplating AS versus. definitive treatment for low/intermediate-risk disease.

Decipher

The Decipher test is an mRNA expression-based test aimed at providing prognostic information following radical prostatectomy. It was developed to help predict the risk of metastatic disease in the hope of clarifying clinical decision-making following surgery, specifically the need for adjuvant treatments.^[83] A recent systematic review on the evidence for the Decipher Genomic Classifier found the tool to be predictive of adverse pathology, biochemical failure, metastasis, cancer-specific survival, and overall survival.^[84]

Based on the strength of the evidence, Decipher is most useful for intermediate-risk PCa and post-prostatectomy decision making (number needed to treat – NNT = 1.5-4).^[84] Effectively, the American Society of Clinical Oncology asserts that tissue-based molecular biomarkers (Decipher included) may improve risk stratification when consolidated by clinical parameters.^[85] Since prospective studies are still lacking, their use should be limited to settings where the results would impact decision making.^[85]

Pathological Findings and Histologic Grading

The majority of PCa cases are adenocarcinomas. Adenocarcinomas are often multifocal tumors that originate from the glandular epithelium of the prostate. Small cell or transitional cell carcinomas as well as sarcomas can also rarely occur. For histologic grading of adenocarcinomas, the Gleason score classifies the histologic appearance of the prostate tissue from 3 (defined as the lowest grade of malignancy) to 5 (defined as the highest grade of malignancy). The Gleason score combines the most prevalent and second most common Gleason grades. Current reporting guidelines also encourage the reporting of tertiary grades.

Nonetheless, the established Gleason scoring system has some weaknesses about a potential overtreatment of Gleason score 6 PCa or the accuracy of a Gleason score 7. Based on these considerations new approaches by the International Society of Urological Pathology (ISUP) in 2014 summarized the Gleason scoring system into five grade groups to further distinguish between clinically significant (Gleason > 6) and non-significant cancer as well as to highlight the difference between Gleason 7 (3+4) and Gleason 7 (4+3) disease.^[86] ISUP grade group 1 is for Gleason scores 2-6, ISUP 2 is for Gleason score 7 (3+4), ISUP 3 is for Gleason score 7 (4+3), ISUP 4 is for Gleason 8 (regardless of the combination), and ISUP 5 is for Gleason score 9 -10.^[87]

Clinical and Pathological Staging

The course of PCa is heterogeneous ranging from indolent, slow growing tumors with little risk for metastases, to very aggressive tumors with metastases present at diagnosis. While the most common sites of spread include bone and lymph nodes, visceral and brain metastases can also rarely occur. Prostate cancer is usually categorized according to the 2017 AJCC Tumor Node Metastasis (TNM) classification of malignant tumors [see Table 1].^[88] Clinical staging of prostate tumors distinguishes between localized (T1 and T2) tumors and locally advanced and metastatic (T3 and T4) tumors. T1a and T1b prostate tumors are detected incidentally at transurethral resection. Currently, most detected prostate cancers are non-palpable (T1c) cancers found on biopsy performed usually due to a elevated PSA level. Although T1c and T2 tumors generally behave in a similar fashion, their distinction from T3 and T4 tumors is critical given that T3 and T4 tumors are rarely cured by surgery or radiation therapy alone and require multimodal therapy.^[89]

Low-, Intermediate-, and High-Risk PCa

The risk stratification for localized PCa is based on PSA level, Gleason score, and clinical stage of the tumor.^[33] According to the D´Amico risk group classification, low-risk PCa is defined as a cT1c or cT2a tumor, PSA levels < 10 ng/mL, and a ISUP grade 1 (Gleason score < 7). Characteristics for intermediate-risk PCa include cT2b tumors, or PSA levels 10 to 20 ng/mL, or ISUP grade 2/3(Gleason score = 7).^[90] High-risk localized PCa is defined as a cT2c, or PSA levels > 20 ng/mL, or a ISUP grade 4/5 (Gleason score >7). High-risk locally advanced group is any PSA, any ISUP grade, cT3-4, or cN+. The rates of recurrence-free survival range from 90% for low-risk to 78% for intermediate-risk to 68% for high-risk PCa patients [see Table 2].

Further sub-stratification of these risk groups have been made over the past two decades and today there are widely considered to be at least two subcategories for each risk group based on features such as the number of positive cores and the greatest percent involvement of any core. This sub-stratification has helped refine treatment decisions with respect to appropriate choice of AS and use and duration of androgen deprivation therapy (ADT) in conjunction with radiation.

Treatment

Active Surveillance

Prostate cancer screening with DRE and PSA has resulted in a large number of diagnoses that might otherwise go undetected. Catching these cancers early results in earlier treatment among both younger patients with long life expectancy and older patients with comorbidities. Given the known short- and long-term toxicities of definitive local treatment of PCa, there have been strategies to delay or entirely avoid initial treatment. For patients with low-risk disease and a life expectancy > 10 years, AS is recommended; whereas, patients with a shorter life expectancy and any disease stage, palliative treatment (watchful waiting [WW]) should be considered. Active surveillance aims at avoiding treatment-related toxicity by offering the patient close and regular follow-up (using DRE, PSA, repeat biopsy, mpMRI) without compromising survival. As such, teatment is usually offered only when disease progression is identified.

A multicenter clinical trial (Prostate Testing for Cancer and Treatment [ProtecT]) randomized men to AS (545 men), surgery (553 men), or radiotherapy (545 men). The trial revealed no significant difference (p=0.48) in PCa-specific mortality at 10 years for either of the modalities; AS = 1.5 deaths per 1000 person-years; 95%CI, 0.4-2.2; surgery = 0.9 per 1000 person-years; 95% CI, 0.4-2.2; and radiotherapy = 0.7 per 1000 person-years; 95% CI, 0.3-2.0.^[92] However, AS was associated with higher rates of disease progression (22.9 events per 1000 person-years; 95% CI, 19.0- 27.5; p<0.001) and metastases (6.3 events per 1000 person-years; 95% CI, 4.5 to 8.8; p=0.004), compared to radical prostatectomy (RP) and radiotherapy.^[91]

Nonetheless, RCTs defining the ideal candidates for AS or the best surveillance strategy for men are lacking. The current evidence suggests that AS should only be recommended in low-risk patients, as delaying treatment in intermediate- or high-risk patients has proven to lead to worse patient outcomes. The optimal candidates for AS should have > 10 years life expectancy, stage cT1-2, PSA ≤10 ng/mL, Gleason score of ≤ 6, no more than 3 positive biopsies, and minimal biopsy core involvement (≤ 50% cancer per biopsy). The decision to shift from AS to WW is dependent upon the patient developing comorbidities. While there are less potential upfront side effects from AS, patient anxiety may compromise QoLand should be weighed in the decision-making. Recently published studies showed a nearly three-fold higher rates of anxiety in PCa patients managed with AS compared to the general population (23% vs. 8%).^[92] Furthermore, anxiety was associated with depressive symptoms (p=0.024).^[93] However, the ProtecT trial found no significant differences between definitive treatment and observation in measures of anxiety, depression, or general health-related or cancer-related QoL.^[91]

Patients who are younger or have higher volume Gleason 6 cancer should be monitored more carefully if placed on an AS. The standard AS protocol according to the NCCN includes a PSA test not more often than every 6 months, DRE not more often than every 12 months, and a repeat prostate biopsy not more often than every 12 months.^[81] However, physicians are encouraged to perform a PSA test, DRE, or prostate biopsy earlier if clinically indicated.

The role of mpMRI is also gaining traction as a less invasive alternative to biopsy. The elimination of complications combined with the possible upside of a more accurate assessment of disease progression, makes a compelling case for the inclusion of mpMRIs in the AS protocol. mpMRI has also been shown to be effective at predicting reclassification of cancerous growth during AS with positive and negative predictive values of 83% (95%CI: 73-93) and 81% (95%CI: 71-91), respectively.^[94] Another ongoing phase II prospective study is focusing on the sensitivity and specificity of mpMRI relative to 12-core TRUS biopsy for upgrading/upstaging in men on AS.^[95]

There are no RCT data to define optimal criteria for coming off surveillance. Today, the factors felt to be most reliable include Gleason upgrading (any pattern 4 or higher), increase in the number of cores involved, rising PSA density (PSAD) (measured by dividing the PSA by the prostate volume), or increased tumor involvement on any core. While PSA kinetics have been investigated retrospectively, they do not appear to be the most reliable predictors of disease progression. Patients placed on AS need to understand the uncertainties of outcomes associated with AS and that waiting for disease progression can upgrade their risk group at the time of definitive treatment.

Radical Prostatectomy

Radical prostatectomy (RP) includes removal of the entire prostate, the seminal vesicles, and enough surrounding tissue to minimize the risk of local/distant recurrence. The aim of the procedure is to resect the tumor while preserving, whenever possible, continence and potency. RP has been shown to be superior to WW with regard to cancer-specific survival.^[96] However, when such a procedure is performed on a patient with limited life expectancy, it is possible to do more harm than good.

For patients with low-grade cancer (cT1-T2a, Gleason score < 7, PSA ≤ 10 ng/mL), it is unclear if RP is superior to AS.^[97] Compared to WW, patients younger than 65 years who underwent RP had a significant reduction in PCa-specific mortality (RR: 0.49, 95%CI: 0.31-0.79), and metastases (RR: 0.47, 95%CI: 0.32-0.70).^[98] For the physician to make a recommendation for RP, the odds of clinical progression, as well as the surgery’s relative risks and benefits should be evaluated. Patients with a long-life expectancy and/or poorly differentiated tumors should be considered for local therapy such as surgical intervention.

Patients in the intermediate-risk group (cT2b, Gleason score = 7, PSA 10-20 ng/mL) are generally considered excellent candidates for RP. That being said, the Prostate Cancer Intervention versus Observation Trial (PIVOT) showed that there was no difference between RP and observation in all-cause mortality (HR: 0.88, 95%CI: 0.71-1.08) or prostate-cancer mortality (HR: 0.63, 95%CI: 0.36-1.09) among patients with low- or intermediate-risk PCa at 12-year follow-up.^[97]

Nonetheless, subgroup analysis of intermediate-risk disease revealed that RP resulted in a 31% relative reduction in all-cause mortality compared to observation (HR: 0.69, 95%CI: 0.49-0.98). Analyses performed with data from the National Cancer Database (NCDB) found significant differences in baseline patient characteristics where men in the NCDB were younger (60.3 vs. 67.0; p<0.001), healthier (Charlson-Deyo comorbidity index of 0: 93% vs. 56%; p < 0.001), and a higher proportion of men had low-risk PCa (42% vs. 32%) than the participants included in the PIVOT trial participants thereby jeopardizing the generalizability of the results.^[99] Similar concerns were elucidated in another recently published study using data from the Veterans Affairs Central Cancer Registry.^[100] The Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4), a randomized trial of RP versus WW in men with localized PCa showed decreased mortality for the intervention arm (RR 0.56; 95%CI 0.41-0.77).^[101] The benefit was mostly seen in men < 65 (RR 0.45) and men with intermediate disease risk (RR 0.38).

High-risk localized PCa (cT2c-cT3a, Gleason score > 7, PSA > 20 ng/mL) is a heterogeneous category and the prognosis varies greatly within this group. Surgery remains an option in this group; however, these patients may need adjuvant radiation and are at higher risk for micro-metastases. The optimal surgical candidate in this risk category would be a patient with low tumor volume, a tumor that is not fixed to the pelvic wall or in the urethral sphincter. Patients with cT2c or cT3 or any ISUP > 3 are at high-risk for extraprostatic extension (EPE); therefore, nerve sparing surgery is contraindicated in this population. Effectively, nomograms and mpMRI could predict EPE and guide decision for nerve sparing surgery.^[102,103] For high-risk patients, extended pelvic lymph node dissection (PLND) should be performed, as the estimated risk for lymph nodes involvement is 15-40%. Extended PLND (ePLND) remains the gold standard method for N staging and includes removal of the nodes at the level of the external iliac vessels, obturator fossa, medial and lateral to the internal iliac artery, and the common iliac vessels up to the ureters. Patients who receive ePLND should be carefully chosen given the added morbidity of the procedure. Nomograms have also been devised to predict LN involvement in PCa.^[104-108] Patients with locally advanced cancer (cT3a) have a high risk of biochemical recurrence (BCR) between 56-78% of cases.^[109,110]

As such, adjuvant or salvage radiation therapy with or without ADT should be strongly considered in men with adverse risk factors for recurrence including positive margins and ≥pT3 disease. While no RCT has compared RP and radiotherapy (RT) in high-risk patients, the outcomes of RP are similar to that of RT with concurrent ADT and surpass that of RT alone. If nodal involvement is found at surgery, adjuvant ADT or RT has been shown to provide superior oncological outcomes (overall survival and cancer-specific survival), especially when more than two nodes are involved.^[111] Furthermore, these patients benefit from immediate ADT initiation after surgical treatment in terms of overall survival (HR: 1.84, 95%CI, 1.01-3.35), PCa-specific survival (HR: 4.09; 95%CI, 1.76-9.49), and progression-free survival (HR: 3.42; 95%CI, 1.96-5.98) compared to patients with delayed adjuvant treatment.

Radical prostatectomy is associated with complications that impact the patients’ QoL, most commonly urinary continence and sexual function. Therefore, when counseling patients, it is necessary to consider these potential complications and compare them to those of other primary treatment options such as brachytherapy, external-beam radiation therapy (EBRT), and hormonal therapy. Urologists are also encouraged to collect patient-reported outcomes at baseline and at set time intervals (before or after clinic visit) to compare outcomes across time, treatments, and disease stages.^[112] A prospective study revealed that sexual function after RP was significantly associated with patient’s age (p=0.001), PSA score (p=0.01), and whether the surgery was nerve-sparing (p=0.008); whereas urinary incontinence was influenced by patients’ age (p=0.005) and black race (p=0.03).^[113]

The recent development of minimally invasive approaches such as laparoscopic and robot-assisted radical prostatectomy (LARP and RARP, respectively) have provided patients with alternatives to conventional open surgery. As of 2009, 61.1% of prostatectomies were RARP.^[114] The advantages of RARP include   decreased blood loss, fewer complications, shorter length of hospitalization, but equivalent cancer and functional outcomes in comparison to open RP.^[114-117] The costs of the robotic procedure are inherently higher than the open approach, and given the lack of oncological benefit (despite a lower positive margin rate), there is concern that this procedure provides limited economic value. Excess cost could be reduced by maintaining a high case volume.^[118]

Definitive Radiotherapy

Radiation is a standard first-line treatment approach for localized PCa and the most commonly used treatment for PCa in the US. External-beam radiation therapy (EBRT) is a treatment option for all risk groups of non-metastatic prostate cancer, whereas low-dose rate (LDR) brachytherapy is recommended for patients with low-risk PCa and certain subsets of intermediate risk disease.

Today, EBRT is most commonly delivered using intensity-modulated radiotherapy (IMRT), which provides more conformal coverage of the target volume and reduces dose to the nearby organs at risk including the rectum and bladder relative to 3-dimensional conformal radiation.^[33] Randomized trials comparing IMRT to traditional conformal radiation are lacking, but prospective data suggest that this technique may reduce bowel and bladder toxicities. IMRT is typically combined with daily image guidance in which implanted fiducial markers within the prostate are used for targeting prior to treatment. EBRT can be delivered using protons rather than x-rays and while a randomized trial comparing the two approaches is ongoing, it remains unclear if one modality is superior to the other.^[119]

In the past decade, the use of stereotactic radiation for prostate cancer has been reported from multiple centers. This approach uses image guidance and specialized immobilization to deliver significantly larger fraction sizes to the prostate. Rather than daily treatment for 8-9 weeks, stereotactic body radiation therapy (SBRT) can be delivered over a single week of treatment. Early disease control data suggests this approach is comparable to other definitive treatments such as surgery, brachytherapy or IMRT with a temporary decline in the health-related QoL, specifically urinary and bowel function within the first 3 months of treatment.^[120] A complete recovery from treatment-related toxicities appears to be possible within 6 months after SBRT with a stable health-related QoL exceeding 5 years.^[120]

Brachytherapy is a well-established treatment option in which radioactive seeds are placed within the prostate through the perineum. These provide a highly conformal dose to the prostate and allow for dose escalation relative to EBRT. This approach is viewed as being among the most cost-effective treatment strategies for localized (low risk and favorable intermediate risk) PCa.^[121] Further, given the significant urinary obstructive symptoms following brachytherapy, it is typically reserved for men with better baseline urinary function (International Prostate Symptom Score [IPSS] of ≤12).

In certain circumstances, combining EBRT and LDR brachytherapy with or without ADT has been demonstrated to be more effective than EBRT alone. These findings were taken from the ACSENDE-RT (Androgen Suppression Combined With Elective Nodal and Dose Escalated Radiation Therapy) trial that compared the different approaches of RT options for intermediate and high-risk disease.^[122] PCa patients were more likely to have higher rates of relapse-free survival after 5 years (89% vs. 77%), 7 years (86% vs. 71%), and 9 years (83% vs. 63%), if they received an Iodine-125 LDR boost instead of an EBRT boost (HR: 0.47; 95%CI: 0.29-0.76).^[122]

In patients with high-risk disease, EBRT and brachytherapy is associated with a lower rate of cancer-specific mortality compared to EBRT alone (3.9% vs. 5.3%; adjusted HR: 0.73; 95%CI: 0.55-0.95).^[123] Conversely, patients with intermediate-risk PCa may not need as the added brachytherapy and no  benefit from the combined  approach was observed (adjusted HR: 0.83; 95%CI: 0.59-1.16).^[123]

Treatment related side-effects of RT range from severe complications including gastrointestinal, genitourinary, and sexual toxicities that can greatly affect one’s QoL. Higher doses, while reducing the chance for BCR, also increase the odds for late toxicity complications. A recently published study showed that men < 60 years old who underwent brachytherapy for PCa reported minimal gastrointestinal and genitourinary toxicities within 10 years of follow-up.^[124] When comparing IMRT and three-dimensional conformal radiotherapy, IMRT reduced significantly the risk of gastrointestinal toxicities (13% to 5%, p<0.001). However, the odds of maintaining erectile function are highest after brachytherapy (0.80; 95%CI: 0.64-0.96), followed by EBRT (0.68; 95%CI: 0.41-0.95), and lowest with RP (with nerve sparing: 0.22; 95%CI: 0.0-0.53 and non-nerve sparing: 0.16; 95%CI: 0.0-0.37).^[125]

These findings corroborate another study in which RT affected erectile function to a lesser degree than definitive surgery.^[126] Radiation increases the likelihood of developing secondary solid malignancies, such as carcinomas of the bladder, rectum, lung, and sarcomas within the irradiated field (6%, p=0.02) relative to RP. The relative risk increases to 15% after 5 years and to 34% after 10 years. In other words, 1 out of 70 patients is likely to develop a radiation-associated second malignancy after 10 years.

Cryotherapy

Cyrotherapy is an alternative option for patients with PCa who are ineligible for surgery or RT. Patients should meet the following criteria to be candidates for cryoablation: Gleason score ≤ 7, a PSA level ≤ 20 ng/ml, and a prostate volume < 40 ml.^[127] Early results demonstrated a biochemical disease-free survival of 61% at 7 years after cryoablation for low-risk PCa patients(BCR threshold of 0.5 ng/ml).^[128]

In a RCT comparing EBRT to cryotherapy , there were no differences in overall or cancer-specific survival, nonetheless the rate of positive biopsies at 36 months was significant lower in the cryoablation group (7.7 vs. 28.9%, p=0.0004).^[129] Complications after cryoablation include (from most to least common) erectile dysfunction, incontinence, bladder outlet obstruction requiring subsequent transurethral resection of the prostate. Another study found rectal pain (26%), scrotal edema (12%), hematuria (6%), incontinence (6%), and urinary tract infection (3%) as complications following cryoablation.^[130]

A systematic review comparing outcomes across patients who received either cryotherapy vs. RP and EBRT revealed a worse disease specific survival for cryotherapy, but no difference in overall survival.^[118] Current guidelines recommend offering cryotherapy only within a clinical trial setting or a well-designed prospective cohort study.^[33]

High-intensity focused ultrasound

High-intensity focused ultrasound (HIFU) was FDA-approved in the late 2015, despite having been in use for over a decade in Canada and abroad. In a systematic review of HIFU outcomes, the progression-free survival ranges from 63-87% (depending on the PSA levels and/or biopsy data) with a median follow-up of 12 to 24 months.^[131] Another study reported BCR-free survival rate for low-risk PCa patients of 86% and 76% at a 5 and 8 years, respectively.^[132]

A more recent multicenter study of 5-year outcomes following HIFU which included 625 men with non-metastatic clinically significant PCa found 88% (95%CI 85-91%) 5-year BCR-free survival, 98% (95%CI 97-99%) 5-year metastasis-free survival, and 100% (95%CI 97-100%) PCa-specific survival.^[133] HIFU is associated with less treatment toxicities as 98% (n=247) achieved pad-free urinary continence.^[133]

In Another study including 1,002 patients, the rates of  grade 1 overall urinary stress incontinence, bladder outlet obstruction, and acute urinary retention were 18.7%, 16.6%, and 7.6%, respectively. Moreover, in comparison to cryoablation, patients who underwent HIFU experienced less scrotal edema (0% vs. 74.7%, p=0.008) and less erectile dysfunction after 12 months (65.6 vs. 88.0%, p=0.015).^[134] Patients also had significantly lower IPSS scores (5.70 ± 3.53 vs. 9.04 ± 6.30, p=0.030) with HIFU compared to those treated with cryoablation. Similarly to cryotherapy, HIFU is recommended only in well observed cohorts within the realm of clinical trials.^[33]

Androgen deprivation therapy

Prostate cancer is driven by androgen signaling. Over the past 30 years, multiple RCTs have investigated the combination of ADT and radiation. For men with unfavorable intermediate- and high-risk disease, the addition of ADT to EBRT improves disease control and overall survival. For men with high-risk disease, ADT (2-3 years) can be given in conjunction with EBRT and brachytherapy.^[33] Hormone therapy (with or without RT) can also be administered after RP in men with pN+.^[33] The duration of ADT has been extensively studied and for men with high-risk disease, 28-36 months is the current standard while for men with lower-risk disease, a 4-month regimen appears to be sufficient.^[135]

There is no proven benefit for lower risk PCa patients, as studies have shown no difference in overall survival (HR: 1.07; 95%CI: 0.83-1.39) or PCa-specific mortality (HR: 0.63; 95%CI: 0.21-1.92).^[136] ADT given alone did not improve 15-year overall or PCa-specific survival for men with localized disease, and as such multimodality therapy is required for these patients.^[127,137] However, ADT can be considered as a monotherapy in men unfit or refusing to undergo local treatment and with PSAD < 12 months and PSA > 50 ng/mL or in men with poorly differentiated tumors.^[33,137]

Multidisciplinary care

Several studies have revealed that multidisciplinary management results in higher patient satisfaction and improved outcomes.^[138,139] In most cases, urologists, radiation oncologists, and medical oncologists form a team within a multidisciplinary PCa clinic.^[138] A recently published study demonstrated the positive effect of multidisciplinary management on final decision-making, specifically with regard to adequate staging and treatment.^[139] Compared to individual practitioners the proportion of patients undergoing AS is nearly doubled in multidisciplinary clinics (22% vs. 43%, p<0.001). Furthermore, most of the patients that consult only one individual practitioner undergo RP (56% vs. 43%, p<0.001) as the first treatment option for PCa.^[138]

Taken all together the management of early stage PCa is challenging given the breadth of treatment approaches including surgical, radiation, systemic therapies and active surveillance. Decision-making requires in depth counseling of the patient about the different options and their potential toxicities and impact on QoL.

Treatment trends

RP was traditionally the most commonly performed treatment for prostate cancer.^[140] In recent years, radiation therapy, specifically IMRT, has gained popularity, to the point of raising concerns about physician ownership of technology and its impact on treatment patterns.^[141] Concurrently, on the surgical side, the robotic approach has gained tremendous traction, representing 85% of cases in the US as of 2013, despite concerns about limited benefits and excessive direct to consumer marketing.^[142] Indeed, the adoption of such novel technologies, namely IMRT and RARP, was seen in patients that may not even need treatment, e.g. men with limited life expectancy and/or low-risk disease.^[143,144]

Meanwhile, the use of AS for low-risk disease was low between 1990 to 2009 (6.7%, 95%CI: 5.8-7.6), but  increased significantly to 40% from 2010 to 2013 (40.4%, 95%CI: 34.9-45.9) in data from the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) registry. This shift reflects the field’s more contemporary concerns with respect to overtreatment of patients whose PCa might never be life threatening and aligns with the opposite trend of prescribing ADT in conjunction with RT only for intermediate- and high-risk tumors. Similar trends for high-risk disease are that of increased incorporation of multimodal management with local treatment such as RP in conjunction with adjunctive radiation or radiation with ADT over any one modality alone.^[145] The magnitude of these findings reflects a genuine shift in the treatment paradigm among prostate cancer physicians to optimize the balance between the degree of treatment needed to improve survival and impact on QoL.

Summary

• Prostate cancer is the most common non-skin malignancy among males in the Western hemisphere.
• The natural history of prostate cancer is generally indolent, but a significant number of men continue to die from prostate cancer every year.
• Prostate-specific antigen-based prostate cancer screening has come under intense scrutiny given valid concerns about the risk of overdiagnosis and overtreatment.
• The conflicting evidence on screening highlights the need for shared decision-making for prostate cancer screening.
• In recent years, new tools such magnetic resonance imaging have emerged to further advance prostate cancer diagnosis and treatment.
• Regarding treatment, standard of care treatment options for prostate cancer include active surveillance, radical prostatectomy and radiation therapy (including brachytherapy and external beam radiation therapy).
• Active surveillance has emerged as a leading option for low-risk prostate cancer, backed by recent high-level evidence. On the other hand, locally advanced prostate cancer is increasingly being managed with multimodal therapy.

Recommendations

1. Active surveillance is gaining acceptance as a standard of care treatment option for localized low-risk prostate cancer.
2. Recent randomized trials for prostate cancer treatments has advanced our knowledge regarding the differences in quality of life and survival following treatment.
3. MRIs are increasingly being used in the diagnostic and active surveillance settings.
4. Novel treatment approaches focusing on the index lesion seen on imaging have emerged as alternatives to standard of care definitive therapy.
5. The management of high-risk prostate cancer has evolved towards a multimodal approach, supported by high-level evidence.

Acknowledgement

The authors and editors gratefully acknowledge the contributions of the previous authors, Jonathan E. Rosenberg, MD, and Philip W. Kantoff, MD, to the development and writing of this chapter. The authors of previous contributions were not contacted. Quoc-Dien Trinh is supported by an unrestricted educational grant from the Vattikuti Urology Institute, a Clay Hamlin Young Investigator Award from the Prostate Cancer Foundation and a Genentech BioOncology Career Development Award from the Conquer Cancer Foundation of the American Society of Clinical Oncology. Lauren Harshman was supported by a 2013 Prostate Cancer Foundation Young Investigator Award and a Career Enhancement Award from the DF/HCC SPORE in Prostate Cancer (NIH/NCI P50CA090381-13).

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