Management of the Early-Stage Prostate Cancer
January 4, 2023 - read ≈ 72 min
Julian Hanske, M.D.
Graduated Research fellow and Resident. Division of Urological Surgery and Center for Surgery and Public Health, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA; Department for Urology, Stiftungsklinikum PROSELIS, Recklinghausen, Germany
Muhieddine Labban, M.D.
Research Fellow. Division of Urological Surgery and Center for Surgery and Public Health, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
Neil E. Martin, M.D., M.P.H.
Assistant Professor of Medicine. Department of Radiation Oncology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
Lauren C. Harshman, M.D.
Assistant Professor of Medicine. Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA, Surface Oncology, Cambridge, MA, USA
Quoc-Dien Trinh, M.D.
Assistant Professor of Surgery. Division of Urological Surgery and Center for Surgery and Public Health, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
Conflict of Interest
LCH reports previous employment at Dana-Farber Cancer Institute and grants to institution from Bayer, Sotio, Bristol-Myers Squib, Merck, Takeda, Dendreon/Valient, Jannsen, Medivation/Astellas, Genentech, Pfizer, and Endocyte (Novartis), Advisory or consulting services for Bayer, Genentech, Pfizer, Medivation/Astellas, Corvus, Merck, Exelixis, Novartis, Advanced Accelerator Applications, Jounce, Bristol-Myers Squibb, EMD Serrano, Michael J Hennessy Associates (Healthcare Communications Company and several brands such as OncLive and PER), ASIM CME, and Ology Medical Education during the conduct of the study, as well as current employment (including stock options) at Surface Oncology and travel support form Bayer and Genentech outside the submitted work. QDT reports personal fees from Astellas, Bayer and Janssen, outside the submitted work. QDT reports research funding from the American Cancer Society, the Defense Health Agency, Pfizer Global Medical Grants. All other authors report no conflict of interest.
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. 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. 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.
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. 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.
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. 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. 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. 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. 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. 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, 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. 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).
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. 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. 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).
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. 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. A study also showed that lycopene, a member of the carotenoid family with strong anti-oxidant attributes, does not affect PCa development. 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).
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). Another study evaluated the impact of nut consumption and the risk of being diagnosed with PCa, but found no significant correlation. 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).
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). 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). 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. On the other hand, one protective parameter against the development of PCa may be increased frequency of ejaculation. 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.
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. Nevertheless, a serum prostate-specific antigen test (PSA) could be combined with a DRE to screen for PCa in informed men.
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.
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. 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).
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. 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. 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. 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. 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.
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”. This led to a 28% decline in incidence of PCa in the year following the USPSTF recommendation. 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. 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). 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]
Table 3. Recommendations against / for PSA based-PCa screening
|United States Preventive Services Task Force (USPSTF)||Grade ‘C’ screening for men between 55 and 69 years who choose to undergo screening after being informed about the risks and benefits of screening|
|American Cancer Society (ACS)|
European Urological Association (EAU)
1. men at the age of 50 who are at average risk of PCa with a life expectancy ≥10 years
2. men at the age of 45 that are at high risk to suffer from PCa (Africans Americans or first-degree relative [father, son, brother] diagnosed with PCa at the age <65 years)
3. men at the age of 40 with higher risk to develop PCa (defined as more than one first-degree relative who experienced PCa at an early age) or harboring a BRACA 2 mutation
|American Urological Association (AUA)||Shared decision-making for men between the age of 55 to 69 years|
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. 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. A multi-center study showed a two-fold higher specificity of PHI compared to free-to-total PSA. A higher PHI portends higher odds of ≥ Gleason 7 PCa.
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). 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.
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]
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]
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. 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.
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. 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.
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. However, the transperineal route is associated with lower risk for urinary tract infections. 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.
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). 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. 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) and single dose of cephazolin should be considered in transrectal and transperineal biopsy, respectively to decrease the incidence of post-biopsy infectious complications, such as prostatitis. 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.
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. 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. 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]
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. 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.
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. 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.
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. 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.
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). Effectively, the American Society of Clinical Oncology asserts that tissue-based molecular biomarkers (Decipher included) may improve risk stratification when consolidated by clinical parameters. Since prospective studies are still lacking, their use should be limited to settings where the results would impact decision making.
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. 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.
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]. 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.
Table 1. American Joint Committee on Cancer TNM criteria
|Clinical T category (cT)|
|TX||Primary tumor cannot be assessed|
|T0||No evidence of primary tumor|
|T1||Clinically inapparent tumor not palpable nor visible by imaging|
|T1a||Tumor incidental histologic finding in ≤5% of tissue resected|
|T1b||Tumor incidental histologic finding in >5% of tissue resected|
|T1c||Tumor identified by needle biopsy (e.g., because of elevated PSA)|
|T2||Palpable tumor confined within prostate*|
|T2a||Tumor involves one half of one lobe or less|
|T2b||Tumor involves more than one half of one lobe but not both lobes|
|T2c||Tumor involves both lobes|
|T3||Tumor extends through the prostatic capsule†|
|T3a||Extracapsular extension (unilateral or bilateral)|
|T3b||Tumor invades seminal vesicle(s)|
|T4||Tumor is fixed or invades adjacent structures other than seminal vesicles such as external sphincter, rectum bladder, levator muscles, and/or pelvic wall|
|Pathologic T Category (pT) ‡|
|pT3a||Extraprostatic extension or microscopic invasion of the bladder neck**|
|pT3b||Seminal vesicle invasion|
|pT4||Invasion of bladder, rectum, levator muscles, or pelvic wall|
|NX||Regional lymph nodes were not assessed|
|N0||No regional lymph node metastasis|
|N1||Metastasis in regional lymph node(s)|
|M0||No distant metastasis|
|M1a||Nonregional lymph node(s)|
|M1c||Other site(s) with or without bone disease|
*A tumor that is found in one or both lobes by needle biopsy but is not palpable or reliably visible by imaging is classified as T1c.
** Positive surgical margin should be indicated by an R1 descriptor (residual microscopic disease).
†Invasion into the prostate apex or into (but not beyond) the prostatic capsule is classified not as T3 but as T2.
‡There is no pathologic T1 classification.
§When more than one site of metastasis is present, the most advanced category is used. pM1c is most advanced
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. 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). 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.
Table 2. Combined-Modality Staging Approach according to the D´Amico Risk Group Classification
|Risk||5-Year PSA Failure-Free Survival (%)*||5-Year Rate of Local Recurrence-Free Survival (%)*||Characteristics|
|Low||90||98||T1c-T2a and PSA ≤ 10 ng/mL and Gleason score < 7|
|Intermediate||78||96||T2b or PSA 10-20 ng/mL or Gleason score ≤ 7|
|High||68||94||T2c-3a or PSA > 20 ng/mL or Gleason score > 7|
*after radical prostatectomy
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. 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.
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%). Furthermore, anxiety was associated with depressive symptoms (p=0.024). 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.
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. 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. 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.
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 (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. 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. 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). 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.
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. Similar concerns were elucidated in another recently published study using data from the Veterans Affairs Central Cancer Registry. 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). 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. 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. 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).
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. 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.
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. 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.
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. 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.
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. 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. 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).
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). 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).
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. 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).
These findings corroborate another study in which RT affected erectile function to a lesser degree than definitive surgery. 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.
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. 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).
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). 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.
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. Current guidelines recommend offering cryotherapy only within a clinical trial setting or a well-designed prospective cohort study.
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. Another study reported BCR-free survival rate for low-risk PCa patients of 86% and 76% at a 5 and 8 years, respectively.
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. HIFU is associated with less treatment toxicities as 98% (n=247) achieved pad-free urinary continence.
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). 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.
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. Hormone therapy (with or without RT) can also be administered after RP in men with pN+. 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.
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). 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]
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. A recently published study demonstrated the positive effect of multidisciplinary management on final decision-making, specifically with regard to adequate staging and treatment. 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.
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.
RP was traditionally the most commonly performed treatment for prostate cancer. 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. 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. 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. 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.
- 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.
- Active surveillance is gaining acceptance as a standard of care treatment option for localized low-risk prostate cancer.
- Recent randomized trials for prostate cancer treatments has advanced our knowledge regarding the differences in quality of life and survival following treatment.
- MRIs are increasingly being used in the diagnostic and active surveillance settings.
- Novel treatment approaches focusing on the index lesion seen on imaging have emerged as alternatives to standard of care definitive therapy.
- The management of high-risk prostate cancer has evolved towards a multimodal approach, supported by high-level evidence.
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).
- Institute NC. Surveillance, Epidemiology, and End Results Program. https://seer.cancer.gov/statfacts/html/prost.html. Published 2016. Accessed.
- Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, et al. Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. Eur J Cancer. 2013;49(6):1374-1403.
- Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer Statistics, 2021. CA: A Cancer Journal for Clinicians. 2021;71(1):7-33.
- Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65(1):5-29.
- Hemminki K. Familial risk and familial survival in prostate cancer. World journal of urology. 2012;30(2):143-148.
- Stewart RW, Lizama S, Peairs K, Sateia HF, Choi Y. Screening for prostate cancer. Semin Oncol. 2017;44(1):47-56.
- Leitzmann MF, Rohrmann S. Risk factors for the onset of prostatic cancer: age, location, and behavioral correlates. Clin Epidemiol. 2012;4:1-11.
- Kheirandish P, Chinegwundoh F. Ethnic differences in prostate cancer. British journal of cancer. 2011;105(4):481-485.
- Esposito K, Chiodini P, Capuano A, et al. Effect of metabolic syndrome and its components on prostate cancer risk: meta-analysis. J Endocrinol Invest. 2013;36(2):132-139.
- Schlaberg R, Choe DJ, Brown KR, Thaker HM, Singh IR. XMRV is present in malignant prostatic epithelium and is associated with prostate cancer, especially high-grade tumors. Proceedings of the National Academy of Sciences of the United States of America. 2009;106(38):16351-16356.
- Khodabandehloo M, Hosseini W, Rahmani MR, et al. No detection of xenotropic murine leukemia virus-related viruses in prostate cancer in Sanandaj, west of Iran. Asian Pacific journal of cancer prevention : APJCP. 2013;14(11):6929-6933.
- Rezaei SD, Hearps AC, Mills J, Pedersen J, Tachedjian G. No association between XMRV or related gammaretroviruses in Australian prostate cancer patients. Virology journal. 2013;10:20.
- Lynch HT, Kosoko-Lasaki O, Leslie SW, et al. Screening for familial and hereditary prostate cancer. Int J Cancer. 2016;138(11):2579-2591.
- Nicolosi P, Ledet E, Yang S, et al. Prevalence of Germline Variants in Prostate Cancer and Implications for Current Genetic Testing Guidelines. JAMA Oncology. 2019;5(4):523-528.
- Page EC, Bancroft EK, Brook MN, et al. Interim Results from the IMPACT Study: Evidence for Prostate-specific Antigen Screening in BRCA2 Mutation Carriers. Eur Urol. 2019;76(6):831-842.
- Cropp CD, Robbins CM, Sheng X, et al. 8q24 risk alleles and prostate cancer in African-Barbadian men. The Prostate. 2014;74(16):1579-1588.
- Zhao CX, Liu M, Wang JY, et al. Association of 8 loci on chromosome 8q24 with prostate carcinoma risk in northern Chinese men. Asian Pacific journal of cancer prevention : APJCP. 2014;14(11):6733-6738.
- Meyer MS, Penney KL, Stark JR, et al. Genetic variation in RNASEL associated with prostate cancer risk and progression. Carcinogenesis. 2010;31(9):1597-1603.
- Miar A, Hevia D, Munoz-Cimadevilla H, et al. Manganese superoxide dismutase (SOD2/MnSOD)/catalase and SOD2/GPx1 ratios as biomarkers for tumor progression and metastasis in prostate, colon, and lung cancer. Free radical biology & medicine. 2015;85:45-55.
- Pettersson A, Graff RE, Bauer SR, et al. The TMPRSS2:ERG rearrangement, ERG expression, and prostate cancer outcomes: a cohort study and meta-analysis. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2012;21(9):1497-1509.
- Concato J, Jain D, Uchio E, Risch H, Li WW, Wells CK. Molecular markers and death from prostate cancer. Annals of internal medicine. 2009;150(9):595-603.
- Bookstein R, MacGrogan D, Hilsenbeck SG, Sharkey F, Allred DC. p53 is mutated in a subset of advanced-stage prostate cancers. Cancer research. 1993;53(14):3369-3373.
- Lippman SM, Klein EA, Goodman PJ, et al. Effect of selenium and vitamin E on risk of prostate cancer and other cancers: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). Jama. 2009;301(1):39-51.
- Ilic D, Misso M. Lycopene for the prevention and treatment of benign prostatic hyperplasia and prostate cancer: a systematic review. Maturitas. 2012;72(4):269-276.
- Richman EL, Kenfield SA, Stampfer MJ, Giovannucci EL, Chan JM. Egg, red meat, and poultry intake and risk of lethal prostate cancer in the prostate-specific antigen-era: incidence and survival. Cancer prevention research. 2011;4(12):2110-2121.
- Yang M, Kenfield SA, Van Blarigan EL, et al. Dietary patterns after prostate cancer diagnosis in relation to disease-specific and total mortality. Cancer prevention research. 2015;8(6):545-551.
- Wang W, Yang M, Kenfield SA, et al. Nut consumption and prostate cancer risk and mortality. British journal of cancer. 2016;115(3):371-374.
- Wilson KM, Balter K, Moller E, et al. Coffee and risk of prostate cancer incidence and mortality in the Cancer of the Prostate in Sweden Study. Cancer causes & control : CCC. 2013;24(8):1575-1581.
- Dickerman BA, Markt SC, Koskenvuo M, Pukkala E, Mucci LA, Kaprio J. Alcohol intake, drinking patterns, and prostate cancer risk and mortality: a 30-year prospective cohort study of Finnish twins. Cancer causes & control : CCC. 2016.
- Markt SC, Grotta A, Nyren O, et al. Insufficient Sleep and Risk of Prostate Cancer in a Large Swedish Cohort. Sleep. 2015;38(9):1405-1410.
- Rider JR, Wilson KM, Sinnott JA, Kelly RS, Mucci LA, Giovannucci EL. Ejaculation Frequency and Risk of Prostate Cancer: Updated Results with an Additional Decade of Follow-up. Eur Urol. 2016.
- Naji L, Randhawa H, Sohani Z, et al. Digital Rectal Examination for Prostate Cancer Screening in Primary Care: A Systematic Review and Meta-Analysis. Ann Fam Med. 2018;16(2):149-154.
- Mottet N, van den Bergh RCN, Briers E, et al. EAU-EANM-ESTRO-ESUR-SIOG Guidelines on Prostate Cancer-2020 Update. Part 1: Screening, Diagnosis, and Local Treatment with Curative Intent. Eur Urol. 2021;79(2):243-262.
- Force USPST. Screening for prostate cancer: U.S. Preventive Services Task Force recommendation statement. Annals of internal medicine. 2008;149(3):185-191.
- Drazer MW, Huo D, Eggener SE. National Prostate Cancer Screening Rates After the 2012 US Preventive Services Task Force Recommendation Discouraging Prostate-Specific Antigen-Based Screening. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2015;33(22):2416-2423.
- Schroder FH, Hugosson J, Roobol MJ, et al. Screening and prostate-cancer mortality in a randomized European study. The New England journal of medicine. 2009;360(13):1320-1328.
- Andriole GL, Crawford ED, Grubb RL, 3rd, et al. Prostate cancer screening in the randomized Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial: mortality results after 13 years of follow-up. Journal of the National Cancer Institute. 2012;104(2):125-132.
- Schroder FH, Hugosson J, Roobol MJ, 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(9959):2027-2035.
- Shoag JE, Mittal S, Hu JC. Reevaluating PSA Testing Rates in the PLCO Trial. The New England journal of medicine. 2016;374(18):1795-1796.
- Moyer VA. Screening for prostate cancer: U.S. Preventive Services Task Force recommendation statement. Annals of internal medicine. 2012;157(2):120-134.
- Barocas DA, Mallin K, Graves AJ, et al. The effect of the United States Preventive Services Task Force grade D recommendation against screening for prostate cancer on incident prostate cancer diagnoses in the US. The Journal of urology. 2015.
- Force USPST. Prostate Cancer: Screening. https://www.uspreventiveservicestaskforce.org/uspstf/recommendation/prostate-cancer-screening#citation1. Published 2018. Accessed April 9, 2021.
- Carter HB, Albertsen PC, Barry MJ, et al. Early detection of prostate cancer: AUA Guideline. The Journal of urology. 2013;190(2):419-426.
- Society AC. American Cancer Society recommendations for prostate cancer early detection. http://www.cancer.org/cancer/prostatecancer/moreinformation/prostatecancerearlydetection/prostate-cancer-early-detection-acs-recommendations. Published 2015. Accessed.
- Vickers AJ. Markers for the early detection of prostate cancer: some principles for statistical reporting and interpretation. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2014;32(36):4033-4034.
- Filella X, Gimenez N. Evaluation of [-2] proPSA and Prostate Health Index (phi) for the detection of prostate cancer: a systematic review and meta-analysis. Clinical chemistry and laboratory medicine : CCLM / FESCC. 2013;51(4):729-739.
- Catalona WJ, Partin AW, Sanda MG, 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. The Journal of urology. 2011;185(5):1650-1655.
- Parekh DJ, Punnen S, Sjoberg DD, et al. A Multi-institutional Prospective Trial in the USA Confirms that the 4Kscore Accurately Identifies Men with High-grade Prostate Cancer. Eur Urol. 2014.
- Network NCC. NCCN Guidelines Version 2.2015 – Prostate Cancer Early Detection. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Published 2015. Accessed.
- Stephan C, Klaas M, Muller C, Schnorr D, Loening SA, Jung K. Interchangeability of measurements of total and free prostate-specific antigen in serum with 5 frequently used assay combinations: an update. Clinical chemistry. 2006;52(1):59-64.
- Eastham JA, Riedel E, Scardino PT, et al. Variation of serum prostate-specific antigen levels: an evaluation of year-to-year fluctuations. Jama. 2003;289(20):2695-2700.
- Louie KS, Seigneurin A, Cathcart P, Sasieni P. Do prostate cancer risk models improve the predictive accuracy of PSA screening? A meta-analysis. Ann Oncol. 2015;26(5):848-864.
- van der Leest M, Cornel E, Israël B, et al. Head-to-head Comparison of Transrectal Ultrasound-guided Prostate Biopsy Versus Multiparametric Prostate Resonance Imaging with Subsequent Magnetic Resonance-guided Biopsy in Biopsy-naïve Men with Elevated Prostate-specific Antigen: A Large Prospective Multicenter Clinical Study. Eur Urol. 2019;75(4):570-578.
- Kasivisvanathan V, Rannikko AS, Borghi M, et al. MRI-Targeted or Standard Biopsy for Prostate-Cancer Diagnosis. New England Journal of Medicine. 2018;378(19):1767-1777.
- Rouvière O, Puech P, Renard-Penna R, et al. Use of prostate systematic and targeted biopsy on the basis of multiparametric MRI in biopsy-naive patients (MRI-FIRST): a prospective, multicentre, paired diagnostic study. Lancet Oncol. 2019;20(1):100-109.
- Drost FH, Osses DF, Nieboer D, et al. Prostate MRI, with or without MRI-targeted biopsy, and systematic biopsy for detecting prostate cancer. Cochrane Database Syst Rev. 2019;4(4):Cd012663.
- Washino S, Okochi T, Saito K, et al. Combination of prostate imaging reporting and data system (PI-RADS) score and prostate-specific antigen (PSA) density predicts biopsy outcome in prostate biopsy naïve patients. BJU Int. 2017;119(2):225-233.
- Xue J, Qin Z, Cai H, et al. Comparison between transrectal and transperineal prostate biopsy for detection of prostate cancer: a meta-analysis and trial sequential analysis. Oncotarget. 2017;8(14):23322-23336.
- Xiang J, Yan H, Li J, Wang X, Chen H, Zheng X. Transperineal versus transrectal prostate biopsy in the diagnosis of prostate cancer: a systematic review and meta-analysis. World J Surg Oncol. 2019;17(1):31.
- Eichler K, Hempel S, Wilby J, Myers L, Bachmann LM, Kleijnen J. Diagnostic value of systematic biopsy methods in the investigation of prostate cancer: a systematic review. The Journal of urology. 2006;175(5):1605-1612.
- Donovan J, Hamdy F, Neal D, et al. Prostate Testing for Cancer and Treatment (ProtecT) feasibility study. Health Technol Assess. 2003;7(14):1-88.
- Campos-Fernandes JL, Bastien L, Nicolaiew N, et al. Prostate cancer detection rate in patients with repeated extended 21-sample needle biopsy. Eur Urol. 2009;55(3):600-606.
- Rabets JC, Jones JS, Patel A, Zippe CD. Prostate cancer detection with office based saturation biopsy in a repeat biopsy population. The Journal of urology. 2004;172(1):94-97.
- Stewart CS, Leibovich BC, Weaver AL, Lieber MM. Prostate cancer diagnosis using a saturation needle biopsy technique after previous negative sextant biopsies. The Journal of urology. 2001;166(1):86-91; discussion 91-82.
- Merrimen JL, Jones G, Walker D, Leung CS, Kapusta LR, Srigley JR. Multifocal high grade prostatic intraepithelial neoplasia is a significant risk factor for prostatic adenocarcinoma. The Journal of urology. 2009;182(2):485-490; discussion 490.
- Epstein JI, Herawi M. Prostate needle biopsies containing prostatic intraepithelial neoplasia or atypical foci suspicious for carcinoma: implications for patient care. The Journal of urology. 2006;175(3 Pt 1):820-834.
- Siddiqui MM, Rais-Bahrami S, Turkbey B, et al. Comparison of MR/ultrasound fusion-guided biopsy with ultrasound-guided biopsy for the diagnosis of prostate cancer. Jama. 2015;313(4):390-397.
- Brock M, Roghmann F, Sonntag C, et al. Fusion of Magnetic Resonance Imaging and Real-Time Elastography to Visualize Prostate Cancer: A Prospective Analysis using Whole Mount Sections after Radical Prostatectomy. Ultraschall Med. 2014.
- Eklund M, Jäderling F, Discacciati A, et al. MRI-Targeted or Standard Biopsy in Prostate Cancer Screening. New England Journal of Medicine. 2021;385(10):908-920.
- Schwartz LH, Basch E. MR/ultrasound fusion-guided biopsy in prostate cancer: what is the evidentiary standard? Jama. 2015;313(4):367-368.
- Pahwa S, Schiltz NK, Ponsky LE, Lu Z, Griswold MA, Gulani V. Cost-effectiveness of MR Imaging-guided Strategies for Detection of Prostate Cancer in Biopsy-Naive Men. Radiology. 2017;285(1):157-166.
- Lotan Y, Haddad AQ, Costa DN, Pedrosa I, Rofsky NM, Roehrborn CG. Decision analysis model comparing cost of multiparametric magnetic resonance imaging vs. repeat biopsy for detection of prostate cancer in men with prior negative findings on biopsy. Urol Oncol. 2015;33(6):266.e269-216.
- Aron M, Rajeev TP, Gupta NP. Antibiotic prophylaxis for transrectal needle biopsy of the prostate: a randomized controlled study. BJU Int. 2000;85(6):682-685.
- Pepdjonovic L, Tan GH, Huang S, et al. Zero hospital admissions for infection after 577 transperineal prostate biopsies using single-dose cephazolin prophylaxis. World journal of urology. 2017;35(8):1199-1203.
- Loeb S, Vellekoop A, Ahmed HU, et al. Systematic review of complications of prostate biopsy. Eur Urol. 2013;64(6):876-892.
- Cook I, Angel JB, Vera PL, Demos J, Preston D. Rectal swab testing before prostate biopsy: experience in a VA Medical Center urology practice. Prostate cancer and prostatic diseases. 2015;18(4):365-369.
- Moran BJ, Braccioforte MH, Conterato DJ. Re-biopsy of the prostate using a stereotactic transperineal technique. The Journal of urology. 2006;176(4 Pt 1):1376-1381; discussion 1381.
- Zisman A, Leibovici D, Kleinmann J, Siegel YI, Lindner A. The impact of prostate biopsy on patient well-being: a prospective study of pain, anxiety and erectile dysfunction. The Journal of urology. 2001;165(2):445-454.
- Chiu L-P, Tung H-H, Lin K-C, et al. Effectiveness of stress management in patients undergoing transrectal ultrasound-guided biopsy of the prostate. Patient Prefer Adherence. 2016;10:147-152.
- Sartori DA, Chan DW. Biomarkers in prostate cancer: what’s new? Current opinion in oncology. 2014;26(3):259-264.
- Network NCC. NCCN Guidelines Prostate Cancer. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed.
- Knezevic D, Goddard AD, Natraj N, et al. Analytical validation of the Oncotype DX prostate cancer assay – a clinical RT-PCR assay optimized for prostate needle biopsies. BMC genomics. 2013;14:690.
- Nguyen HG, Welty CJ, Cooperberg MR. Diagnostic associations of gene expression signatures in prostate cancer tissue. Current opinion in urology. 2015;25(1):65-70.
- Jairath NK, Dal Pra A, Vince R, Jr., et al. A Systematic Review of the Evidence for the Decipher Genomic Classifier in Prostate Cancer. Eur Urol. 2021;79(3):374-383.
- Eggener SE, Rumble RB, Armstrong AJ, et al. Molecular Biomarkers in Localized Prostate Cancer: ASCO Guideline. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2020;38(13):1474-1494.
- Epstein JI, Zelefsky MJ, Sjoberg DD, et al. A Contemporary Prostate Cancer Grading System: A Validated Alternative to the Gleason Score. Eur Urol. 2016;69(3):428-435.
- Epstein JI, Egevad L, Amin MB, Delahunt B, Srigley JR, Humphrey PA. The 2014 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason Grading of Prostatic Carcinoma: Definition of Grading Patterns and Proposal for a New Grading System. Am J Surg Pathol. 2016;40(2):244-252.
- Buyyounouski MK, Choyke PL, McKenney JK, et al. Prostate cancer – major changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA: A Cancer Journal for Clinicians. 2017;67(3):245-253.
- Brierley J.D. GM, Wittekind C. TNM classification of malignant tumors. 8 ed: Wiley-Blackwell; 2017.
- D’Amico AV, Whittington R, Malkowicz SB, et al. Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. Jama. 1998;280(11):969-974.
- Hamdy FC, Donovan JL, Lane JA, et al. 10-Year Outcomes after Monitoring, Surgery, or Radiotherapy for Localized Prostate Cancer. The New England journal of medicine. 2016;375(15):1415-1424.
- Watts S, Leydon G, Eyles C, et al. A quantitative analysis of the prevalence of clinical depression and anxiety in patients with prostate cancer undergoing active surveillance. BMJ open. 2015;5(5):e006674.
- Tan HJ, Marks LS, Hoyt MA, et al. The Relationship between Intolerance of Uncertainty and Anxiety in Men on Active Surveillance for Prostate Cancer. The Journal of urology. 2016;195(6):1724-1730.
- Margel D, Yap SA, Lawrentschuk N, et al. Impact of multiparametric endorectal coil prostate magnetic resonance imaging on disease reclassification among active surveillance candidates: a prospective cohort study. The Journal of urology. 2012;187(4):1247-1252.
- Martin NE. A Phase II, Prospective Study of MRI in the Reclassification of Men Considering Active Surveillance in Prostate Cancer. https://clinicaltrials.gov/ct2/show/study/NCT01858688. Published 2013. Updated January 19, 2016. Accessed.
- Bill-Axelson A, Holmberg L, Ruutu M, et al. Radical prostatectomy versus watchful waiting in early prostate cancer. The New England journal of medicine. 2011;364(18):1708-1717.
- Wilt TJ, Brawer MK, Jones KM, et al. Radical prostatectomy versus observation for localized prostate cancer. The New England journal of medicine. 2012;367(3):203-213.
- Bill-Axelson A, Holmberg L, Ruutu M, et al. Radical prostatectomy versus watchful waiting in early prostate cancer. The New England journal of medicine. 2011;364(18):1708-1717.
- Dalela D, Karabon P, Sammon J, et al. Generalizability of the Prostate Cancer Intervention Versus Observation Trial (PIVOT) Results to Contemporary North American Men with Prostate Cancer. Eur Urol. 2016.
- Barbosa PV, Thomas IC, Srinivas S, et al. Overall Survival in Patients with Localized Prostate Cancer in the US Veterans Health Administration: Is PIVOT Generalizable? Eur Urol. 2016;70(2):227-230.
- Bill-Axelson A, Holmberg L, Garmo H, et al. Radical Prostatectomy or Watchful Waiting in Early Prostate Cancer. New England Journal of Medicine. 2014;370(10):932-942.
- Steuber T, Graefen M, Haese A, et al. Validation of a nomogram for prediction of side specific extracapsular extension at radical prostatectomy. The Journal of urology. 2006;175(3 Pt 1):939-944; discussion 944.
- de Rooij M, Hamoen EH, Witjes JA, Barentsz JO, Rovers MM. Accuracy of Magnetic Resonance Imaging for Local Staging of Prostate Cancer: A Diagnostic Meta-analysis. Eur Urol. 2016;70(2):233-245.
- Cagiannos I, Karakiewicz P, Eastham JA, et al. A preoperative nomogram identifying decreased risk of positive pelvic lymph nodes in patients with prostate cancer. The Journal of urology. 2003;170(5):1798-1803.
- Godoy G, Chong KT, Cronin A, et al. Extent of pelvic lymph node dissection and the impact of standard template dissection on nomogram prediction of lymph node involvement. Eur Urol. 2011;60(2):195-201.
- Briganti A, Larcher A, Abdollah F, et al. Updated nomogram predicting lymph node invasion in patients with prostate cancer undergoing extended pelvic lymph node dissection: the essential importance of percentage of positive cores. Eur Urol. 2012;61(3):480-487.
- Merhe A, Labban M, Hout M, et al. Development of a novel nomogram incorporating platelet-to-lymphocyte ratio for the prediction of lymph node involvement in prostate carcinoma. Urol Oncol. 2020;38(12):930.e931-930.e936.
- Gandaglia G, Martini A, Ploussard G, et al. External Validation of the 2019 Briganti Nomogram for the Identification of Prostate Cancer Patients Who Should Be Considered for an Extended Pelvic Lymph Node Dissection. Eur Urol. 2020;78(2):138-142.
- Hsu CY, Joniau S, Oyen R, Roskams T, Van Poppel H. Outcome of surgery for clinical unilateral T3a prostate cancer: a single-institution experience. Eur Urol. 2007;51(1):121-128; discussion 128-129.
- Ward JF, Slezak JM, Blute ML, Bergstralh EJ, Zincke H. Radical prostatectomy for clinically advanced (cT3) prostate cancer since the advent of prostate-specific antigen testing: 15-year outcome. BJU Int. 2005;95(6):751-756.
- Briganti A, Karnes RJ, Da Pozzo LF, et al. Combination of adjuvant hormonal and radiation therapy significantly prolongs survival of patients with pT2-4 pN+ prostate cancer: results of a matched analysis. Eur Urol. 2011;59(5):832-840.
- Labban M, Briggs L, Cole AP, Trinh Q-D. Measuring What Matters: Patient-Reported Outcome and Experience Measures for Men Undergoing Radical Prostatectomy. European Urology Focus. 2021.
- Sanda MG, Dunn RL, Michalski J, et al. Quality of life and satisfaction with outcome among prostate-cancer survivors. The New England journal of medicine. 2008;358(12):1250-1261.
- Trinh QD, Sammon J, Sun M, et al. Perioperative outcomes of robot-assisted radical prostatectomy compared with open radical prostatectomy: results from the nationwide inpatient sample. Eur Urol. 2012;61(4):679-685.
- Gandaglia G, Abdollah F, Hu J, et al. Is robot-assisted radical prostatectomy safe in men with high-risk prostate cancer? Assessment of perioperative outcomes, positive surgical margins, and use of additional cancer treatments. Journal of endourology / Endourological Society. 2014;28(7):784-791.
- Gandaglia G, Sammon JD, Chang SL, et al. Comparative effectiveness of robot-assisted and open radical prostatectomy in the postdissemination era. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2014;32(14):1419-1426.
- Sammon JD, Karakiewicz PI, Sun M, et al. Robot-assisted versus open radical prostatectomy: the differential effect of regionalization, procedure volume and operative approach. The Journal of urology. 2013;189(4):1289-1294.
- Ramsay C, Pickard R, Robertson C, et al. Systematic review and economic modelling of the relative clinical benefit and cost-effectiveness of laparoscopic surgery and robotic surgery for removal of the prostate in men with localised prostate cancer. Health Technol Assess. 2012;16(41):1-313.
- Sheets NC, Goldin GH, Meyer AM, et al. Intensity-modulated radiation therapy, proton therapy, or conformal radiation therapy and morbidity and disease control in localized prostate cancer. Jama. 2012;307(15):1611-1620.
- King CR, Collins S, Fuller D, et al. Health-related quality of life after stereotactic body radiation therapy for localized prostate cancer: results from a multi-institutional consortium of prospective trials. International journal of radiation oncology, biology, physics. 2013;87(5):939-945.
- Ash D, Flynn A, Battermann J, de Reijke T, Lavagnini P, Blank L. ESTRO/EAU/EORTC recommendations on permanent seed implantation for localized prostate cancer. Radiother Oncol. 2000;57(3):315-321.
- Morris WJ, Tyldesley S, Pai HH, et al. ASCENDE-RT*: A multicenter, randomized trial of dose-escalated external beam radiation therapy (EBRT-B) versus low-dose-rate brachytherapy (LDR-B) for men with unfavorable-risk localized prostate cancer. Journal of Clinical Oncology. 2015;33(7).
- Muralidhar V, Xiang M, Orio PF, 3rd, et al. Brachytherapy boost and cancer-specific mortality in favorable high-risk versus other high-risk prostate cancer. Journal of contemporary brachytherapy. 2016;8(1):1-6.
- Buckstein M, Carpenter TJ, Stone NN, Stock RG. Long-term outcomes and toxicity in patients treated with brachytherapy for prostate adenocarcinoma younger than 60 years of age at treatment with minimum 10 years of follow-up. Urology. 2013;81(2):364-368.
- Robinson JW, Moritz S, Fung T. Meta-analysis of rates of erectile function after treatment of localized prostate carcinoma. International journal of radiation oncology, biology, physics. 2002;54(4):1063-1068.
- Fowler FJ, Jr., Barry MJ, Lu-Yao G, Wasson JH, Bin L. Outcomes of external-beam radiation therapy for prostate cancer: a study of Medicare beneficiaries in three surveillance, epidemiology, and end results areas. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 1996;14(8):2258-2265.
- Urology EAo. Guidelines on Prostate Cancer http://uroweb.org/wp-content/uploads/09-Prostate-Cancer_LR.pdf. Published 2015. Accessed.
- Bahn DK, Lee F, Badalament R, Kumar A, Greski J, Chernick M. Targeted cryoablation of the prostate: 7-year outcomes in the primary treatment of prostate cancer. Urology. 2002;60(2 Suppl 1):3-11.
- Donnelly BJ, Saliken JC, Brasher PM, et al. A randomized trial of external beam radiotherapy versus cryoablation in patients with localized prostate cancer. Cancer. 2010;116(2):323-330.
- De La Taille A, Benson MC, Bagiella E, et al. Cryoablation for clinically localized prostate cancer using an argon-based system: complication rates and biochemical recurrence. BJU Int. 2000;85(3):281-286.
- Aus G. Current status of HIFU and cryotherapy in prostate cancer–a review. Eur Urol. 2006;50(5):927-934; discussion 934.
- Crouzet S, Chapelon JY, Rouviere O, et al. Whole-gland ablation of localized prostate cancer with high-intensity focused ultrasound: oncologic outcomes and morbidity in 1002 patients. Eur Urol. 2014;65(5):907-914.
- Guillaumier S, Peters M, Arya M, et al. A Multicentre Study of 5-year Outcomes Following Focal Therapy in Treating Clinically Significant Nonmetastatic Prostate Cancer. Eur Urol. 2018;74(4):422-429.
- Liu YY, Chiang PH. Comparisons of Oncological and Functional Outcomes Between Primary Whole-Gland Cryoablation and High-Intensity Focused Ultrasound for Localized Prostate Cancer. Annals of surgical oncology. 2015.
- Bolla M, de Reijke TM, Van Tienhoven G, et al. Duration of androgen suppression in the treatment of prostate cancer. The New England journal of medicine. 2009;360(24):2516-2527.
- Jones CU, Hunt D, McGowan DG, et al. Radiotherapy and short-term androgen deprivation for localized prostate cancer. The New England journal of medicine. 2011;365(2):107-118.
- Lu-Yao GL, Albertsen PC, Moore DF, et al. Fifteen-year survival outcomes following primary androgen-deprivation therapy for localized prostate cancer. JAMA internal medicine. 2014;174(9):1460-1467.
- Aizer AA, Paly JJ, Efstathiou JA. Multidisciplinary care and management selection in prostate cancer. Seminars in radiation oncology. 2013;23(3):157-164.
- Pillay B, Wootten AC, Crowe H, et al. The impact of multidisciplinary team meetings on patient assessment, management and outcomes in oncology settings: A systematic review of the literature. Cancer treatment reviews. 2016;42:56-72.
- Heidenreich A, Bastian PJ, Bellmunt J, et al. EAU guidelines on prostate cancer. part 1: screening, diagnosis, and local treatment with curative intent-update 2013. Eur Urol. 2014;65(1):124-137.
- Mitchell JM. Urologists’ use of intensity-modulated radiation therapy for prostate cancer. The New England journal of medicine. 2013;369(17):1629-1637.
- Leow JJ, Chang SL, Meyer CP, et al. Robot-assisted Versus Open Radical Prostatectomy: A Contemporary Analysis of an All-payer Discharge Database. Eur Urol. 2016;70(5):837-845.
- Aizer AA, Gu X, Chen MH, et al. Cost implications and complications of overtreatment of low-risk prostate cancer in the United States. Journal of the National Comprehensive Cancer Network : JNCCN. 2015;13(1):61-68.
- Jacobs BL, Zhang Y, Schroeck FR, et al. Use of advanced treatment technologies among men at low risk of dying from prostate cancer. Jama. 2013;309(24):2587-2595.
- Cooperberg MR, Carroll PR. Trends in Management for Patients With Localized Prostate Cancer, 1990-2013. Jama. 2015;314(1):80-82.