Prostate Cancer


Article Author:
Stephen Leslie
Taylor Soon-Sutton


Article Editor:
Larry Siref


Editors In Chief:
Alexandra Caley
Sameh Boktor


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Trevor Nezwek
Radia Jamil
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes


Updated:
9/12/2019 7:35:34 PM

Introduction

Worldwide, prostate cancer is the most commonly diagnosed malignancy and the sixth leading cause of cancer death in men.[1]  In 2012, this amounted to 1,100,000 newly diagnosed cases and 307,000 deaths around the world from this disease.[2] 

Fortunately, the majority of prostate cancers tend to grow slowly and are low-grade with relatively low risk and limited aggressiveness.[3]

There are no initial or early symptoms in most cases, but late symptoms may include fatigue due to anemia, bone pain, and paralysis from spinal metastases, and renal failure from bilateral ureteral obstruction.

Diagnosis is primarily based on prostate-specific antigen (PSA) testing, and transrectal ultrasound-guided (TRUS) prostate tissue biopsies, although PSA testing for screening remains controversial.[4][5]

Newer diagnostic modalities include free and total PSA levels, PCA3 urine testing, Prostate Health Index scoring (PHI), the"4K" test, genomic analysis, MRI imaging, PIRADS scoring, and MRI-TRUS fusion guided biopsies.[6] 

When the cancer is limited to the prostate, it is considered localized and potentially curable.[7]

If the disease has spread to the bones or elsewhere outside the prostate, pain medications, bisphosphonates, rank ligand inhibitors, hormonal treatment, chemotherapy, radiopharmaceuticals, immunotherapy, focused radiation, and other targeted therapies can be used. Outcomes depend on age, associated health problems, tumor histology and the extent of cancer.[8]

Etiology

The primary known major risk factors are age, ethnicity, obesity, and family history.[9] 

The overall incidence increases as people get older; but fortunately, cancer aggressiveness decreases with age.[10]

Prostate cancer risk factors include male gender, older age, positive family history, increased height, obesity, hypertension, lack of exercise, persistently elevated testosterone levels, Agent Orange exposure, and ethnicity.[11][12][13]

5-Alpha-Reductase Inhibitors

These inhibitors such as finasteride and dutasteride may decrease low-grade cancer incidence but they do not appear to affect high-grade risk and thus, do not significantly improve survival. These medications will reduce PSA levels by about 50% which must be accounted for when comparing sequential PSA readings.[14][15][16][17]

Genetics

The cause of prostate cancer is unclear but genetics is certainly involved. Genetic background, ethnicity, and family history are all known to contribute to prostate cancer risk.[18]

  • Men with a first degree relative (father or brother) with prostate cancer have twice the risk of the general population.[19]
  • Risk increases with an affected brother more than an affected father.[20]
  • Men with two, first-degree relatives affected have a five-fold greater risk.
  • Patients with a strong family history of prostate cancer tend to present with cancer at a younger age (2.9 years) and with more locally advanced disease.[21] 
  • They also have a higher risk of biochemical recurrence after radical prostatectomy surgery.
  • In the United States, black men are more commonly affected than white or Hispanic men, and it is more deadly in blacks.
  • The incidence and mortality for Hispanic men are one third lower than for non-Hispanic whites.
  • No single gene is responsible for prostate cancer, although many genes have now been implicated.[22]
  • Mutations in BRCA1 and BRCA2 have been associated with prostate cancer as well as breast cancer.[22]
  • P53 mutations in primary prostate cancer are relatively rare and are more frequently seen in metastatic disease. Therefore, p53 mutations are generally considered a late and ominous finding in prostate cancer.
  • Over 100 Single Nucleotide Polymorphisms (SNPs) and other genes have been linked to an increased risk of prostate cancer.  These include: hereditary prostate cancer gene 1, various androgen and Vitamin D receptors, HPC1, HPC2, HPCX, CAPB, mutL homolog 1 (MLH1), mutS homologs 2 and 6 (MSH2 and MSH6, respectively), postmeiotic segregation increased 2 (PMS2), homeobox B13 (HOXB13), checkpoint kinase 2 (CHEK2), nibrin (NBN), BRCA1-interacting protein C-terminal helicase 1 (BRIP1), ataxia telangiectasia mutated (ATM), the TMPRSS2-ETS gene family; TMPRSS2-ERG and TMPRSS2-ETV1/4 which all tend to promote cancer cell growth. (Note: This is only a partial listing.)[23][24][22][24][23]
  • A Genetic Risk Score (GRS), including high risk genetic markers and SNPs, has been proposed to help with risk stratification of prostate cancer especially in families; but this type of testing is not yet ready for individual patient diagnostics.[25]

Diet

Prostate cancer is generally linked to the consumption of the typical Western diet.[26]

  • There is little, if any, evidence that demonstrates an association between trans fat, saturated fat, or carbohydrate intake and prostate cancer.[27]
  • Vitamin supplements do not lower the risk, and in fact, some vitamins may increase it.[26]
  • High calcium intake is associated with advanced prostate cancer.[26]
  • Diets high in saturated fat and milk products seem to increase the risk.[28]
  • Whole milk consumption after a diagnosis of prostate cancer has been linked to an increased risk of recurrence, especially in overweight men.[29]
  • Lower vitamin D blood levels may increase the risk of developing prostate cancer.[30][30]
  • Red meat and processed meats also appear to have little effect overall, but some studies suggest increased meat consumption is associated with a higher risk.[31]
  • Fish consumption may lower prostate cancer deaths, but does not affect the occurrence rate.[32]
  • Some evidence supports the belief that a vegetarian diet lowers rates of prostate cancer, but this is not considered conclusive or significant influence.[33]
  • Folic acid supplements have also not been shown to affect the risk of developing prostate cancer.[34]

Chemical Exposure

Prostate cancer is linked to some medications, medical procedures, and medical conditions.[35]

  • Use of statins and metformin may decrease prostate cancer risk as well as NSAIDs, especially those with anti-COX 2 activity.[36]
  • Regular aspirin, now used by an estimated 23.7 million men, also appears to reduce prostate cancer risk.[37]
  • This beneficial effect of NSAIDs appears to be more significant in aggressive prostate cancer and those with prostatitis.[38] 
  • Agent Orange exposure may increase the risk of prostate cancer recurrence, particularly following surgery.[39]

Gender

Multiple lifetime sexual partners or starting sexual activity early increases the risk of prostate cancer. Frequent ejaculation may decrease prostate cancer risk, but reduced ejaculatory frequency is not associated with an increased risk of advanced prostate cancer.[40][41]

Infections

Infections may be associated with the incidence and development of prostate cancer.[42]

  • Infections with chlamydia, gonorrhea, or syphilis seem to increase the risk of developing prostate cancer.[43]
  • Human Papilloma Virus (HPV) has been proposed to have a role in prostate cancer incidence, but the evidence for this is inconclusive.[44]

Vasectomy and Prostate Cancer

There was once thought to be an association between vasectomy and prostate cancer; but larger, follow-up studies have failed to confirm any such relationship.[45]

Epidemiology

Prostate cancer is the most commonly diagnosed organ cancer in men and the second leading cause of male cancer death in the United States. Lung cancer is first.[46][47]

Relatively few patients with prostate cancer die of the disease although this still amounts to over 26,000 deaths per year in the United States.[48] 

  • Prostate cancer occurs more commonly in the developed world.[49]
  • The overall 5-year survival rate is 99% in the United States.[50]
  • Incidence rates have been increasing although the death rate has been decreasing since 1992 when PSA testing became widely available.[51]
  • Ninety-nine percent of all prostate cancers occur in those over the age of 50, but when it occurs in younger men, it can be quite aggressive.[52]
  • In the United States, prostate cancer is more common in African Americans by more than double the rate in the general population.[53]
  • It is less common in men of Asian and Hispanic descent than in Whites.[54]

In Sweden, where they do very few PSA tests and tend to be less aggressive in treating prostate cancer, the death rate for men with this malignancy is about 2.5 times the mortality rate in the United States; making it the number one cause of cancer mortality in Swedish men, even exceeding lung cancer.

Prostate cancer incidence is higher in developed countries and is least common in Asian men living in Asia. When Asians come to live in the United States, their incidence of prostate cancer increases but it remains lower than the overall risk for the general population of American men.[55]

  • In Europe, prostate cancer is the third most diagnosed cancer after breast and colorectal.[56]
  • In the United Kingdom, it is the second most common cause of male cancer death after lung cancer, similar to the situation in the United States.[56]

More than 80% of men will develop prostate cancer by age 80. However, in this age group, it will probably be slow growing, lower grade, relatively harmless and have little impact on their survival.

In 2015, there were an estimated 3 million prostate cancer survivors in the United States. This is expected to increase to 4 million by 2025.[57]

According to the National Cancer Institute (NCI), every American man has a lifetime risk of 11.6% of developing clinically significant prostate cancer (Gleason 3 + 4 = 7 or higher).

For 2018, The NCI is expecting 164,690 new cases of prostate cancer and 29,430 deaths in the United States which is an increase from 2017.

  • The majority of new cases are diagnosed in men from 65 to 74 years of age (38.2%) with a median age at diagnosis of 66 years.
  • There are currently 3,085,209 men living in the United States with prostate cancer, and the overall risk of an individual male dying from prostate cancer is 1 in 39 or about 2.6%.
  • The median age of death for those men dying of prostate cancer is 80 years.
  • Overall, the vast majority of men with prostate cancer will die from unrelated problems. 
  • Prostate cancer is uncommon in men younger than 45 years (0.5% of all newly diagnosed prostate cancer cases), but it can be very fast growing and lethal when it occurs in this age group.

Effect of 2012 United States Preventive Services Task Force (USPSTF) Negative Recommendation on Routine PSA Screening

Since the USPSTF recommendation against routine PSA screenings in 2012, there have been a number of consistent changes in the clinical and pathological characteristics of prostate cancer as reported in August 2018.  These findings include the following:[58]

  • Drop in the diagnosed incidence of low-grade prostate cancer. Low-grade disease (Gleason 3 + 3 or better) dropped from 30.1% before 2012 to 17.1%.]=
  • An increase in intermediate and high-grade disease. High-grade disease (Gleason 4 + 4 or higher) increased from 6.2% before 2012 to 17.5%.
  • 24% increase in the number of patients identified with PSA levels over 10 ng/ml from 8.5% before 2012 to 13.2% after.
  • Patients identified with PSA levels over 20 ng/ml increased 44% overall; from 2.4% before 2012 to 4.2% after.
  • The incidence of seminal vesicle invasion, lymph node involvement, and positive surgical margins also increased after 2012.
  • In particular, the incidence of lymph node involvement more than doubled after 2012 to 7.5%. 

These findings are not unexpected given the reduced number of PSA screenings and the adoption of active surveillance regimens for lower risk cancers. 

Ethnicity

Mortality statistics for prostate cancer are very ethnic dependent with blacks in America having the highest incidence and mortality rates, far exceeding the levels for the general population.

Prostate cancer mortality rates calculated as deaths/100,000 population from the National Cancer Institute (NCI) and the Surveillance, Epidemiology, and End Results (SEER) databases are as follows:

  • 42.0: Blacks
  • 20.1: General Population
  • 19.4: American Indians
  • 18.7: Whites (Caucasians)
  • 16.5: Hispanics
  •   8.8: Asians

Pathophysiology

The prostate is roughly 3 centimeters long, about the size of a walnut, and weighs approximately 20 grams. Its function is to produce about a third of the total seminal fluid.[59]  

The prostate gland is located in the male pelvis at the base of the penis.  It is below (inferior) to the urinary bladder and immediately anterior to the rectum.[59]

The prostate surrounds the posterior part of the urethra, but this can be misleading. The posterior urethra, prostatic urethra, and proximal urethra all describe the same anatomy as there is no difference between the internal lining of the prostate and the urethra; they are the same entity.[60]

The prostate is primarily made up of glandular tissue which produces fluid that constitutes about 30% to 35% of the semen. This prostatic portion of the semen nourishes the sperm and provides alkalinity which helps maintain a high pH.  (The seminal vesicles produce the rest of the seminal fluid.)[59][61][62][61]

The prostate gland requires androgen (testosterone) to function optimally. This is why hormonal therapy (testosterone deprivation) is so effective. Castrate resistant tumors are thought to generate intracellular androgens.[63]

Cancer begins with a mutation in normal prostate glandular cells, usually beginning with the peripheral basal cells.[64]

Prostate cancer is most common in the peripheral zone which is primarily that portion of the prostate that can be palpated via digital rectal examination (DRE).[65]

  • Prostate cancer is an adenocarcinoma as it develops primarily from the glandular part of the organ and shows typical glandular patterns on microscopic examination.
  • The cancer cells grow and begin to multiply, initially spreading to the immediately surrounding prostate tissue forming a tumor nodule.
  • Such a tumor may grow outside the prostate (extracapsular extension) or may remain localized within the prostate for decades.
  • Prostate cancer commonly metastasizes to the bones and lymph nodes.
  • Metastases to the bone are thought to be at least partially a result of the prostatic venous plexus draining into the vertebral veins.

The prostate accumulates zinc and produces citrate. However, increased dietary or supplemental zinc and citrate do not appear to have any influence on prostatic health or the development of prostate cancer.[66]

Histopathology

The Gleason Scoring System

The Gleason prostate cancer score has been shown, over time, to be the most reliable and predictive histological grading system available. Originally developed by pathologist Dr. Donald Gleason in the 1960s, it has stood the test of time and has been universally adopted for all prostate cancer pathological descriptions.[67]

The Gleason scoring system is based on the microscopic arrangement, architecture or pattern of the glands in the prostate rather than on the individual cellular characteristics that define most other cancers. The pattern is given a grade from 1 to 5 with 1 representing an almost normal microscopic glandular pattern and appearance, to 5 where no glandular architecture remains, and there are only sheets of abnormal cancer cells.[68]

The Gleason score always contains two grades in the form of numbers and then a total score. The predominant Gleason grade pattern is always the first number, 1 to 5, and the second number would be any secondary or minor pattern, also graded 1 to 5. So the absolute best and lowest risk Gleason score would be Gleason 1 + 1 = 2, and the worst high-grade pathology would be Gleason 5 + 5 = 10. In real life, these histological extremes are almost never seen.[69]

If only one Gleason grade or pattern is seen, then the Gleason score would consist of the same Gleason grade repeated and added together as in Gleason 3 + 3 = 6; which happens to be the most commonly found Gleason score.[70]

Low-grade tumors would be any Gleason score of 3 + 3 = 6 or less.[69]  

Intermediate-grade cancers would be a Gleason score of 3 + 4 = 7. This would mean that most of the tumor was Gleason grade 3, but there was a smaller portion that was the more aggressive Gleason grade 4.[71] 

A Gleason score of 4 + 3 = 7 or higher would be considered high-grade cancer.[69]

While architecture or pattern, as described by the Gleason score, is certainly a major component of the histological diagnosis of prostate cancer, it is not the only criteria. For example, prostate specific membrane antigen is a transmembrane carboxypeptidase that exhibits folate hydrolase activity which is overexpressed in prostate cancer tissues. Its presence would suggest prostate cancer.[72]

Other significant microscopic histological features and indicators of prostate cancer would include:[73]

  • Infiltrative glandular growth pattern
  • Absence of a basal cell layer
  • Atypically enlarged cell nuclei with large nucleoli
  • Increased mitotic figures
  • Intraluminal wispy blue mucin
  • Pink amorphous secretions
  • Intraluminal crystalloids
  • Adjacent High-Grade Prostatic Intraepithelial Neoplasia (High-Grade PIN)
  • Amphophilic cytoplasm

The number of positive biopsies also has prognostic value. In a study of 960 intermediate grade (Gleason 3 + 4 = 7) prostate cancers followed for at least four years, 86% of patients with less than 34% positive biopsies demonstrated a stable PSA compared with only 11% of patients who had more than 50% positive biopsies.

Cancer volume is another important prognostic parameter, but it is difficult to measure accurately with available technology.  Prostatic MRI is currently our best instrumentation for estimating tumor volume.[74]

Perineural invasion is somewhat helpful in predicting extracapsular tumor extension and may be associated with slightly higher tumor aggressiveness, but studies are conflicting on its clinical usefulness.[75]

The "New" Gleason Scoring System

In 2016, the World Health Organization (WHO) proposed a new classification system based on clinical experience with the old Gleason scoring system that suggested very little difference in clinical outcomes in lower Gleason score patients, but somewhat different ones in the higher grades.  The following is a summary of the "New" Gleason system:[76]

  • Grade group 1 (Gleason score less than or equal to 6): Only individual discrete well-formed glands
  • Grade group 2 (Gleason score 3 + 4 = 7): Predominantly well-formed glands with a lesser component of poorly-formed, fused or cribriform glands
  • Grade group 3 (Gleason score 4 + 3 = 7): Predominantly poorly-formed, fused, or cribriform glands with a lesser component of well-formed glands
  • Grade group 4 (Gleason score 8): Only poorly-formed/fused/cribriform glands; or predominantly well-formed glands with a lesser component lacking glands; or predominantly lacking glands with a lesser component of well-formed glands
  • Grade group 5 (Gleason scores 9 or 10): Lacks gland formation (or with necrosis) with or without poorly-formed, fused or cribriform glands

In clinical practice, group 1 is considered "low grade," Group 2 is "intermediate grade," and group 3 or higher is "high grade" disease.

Pre-Malignant Lesions

High-Grade Prostatic Intraepithelial Neoplasia (High-Grade PIN)

The Gleason system is a very good way of grading prostate cancers, but there are situations where the microscopic appearance of prostatic tissue is not malignant even though the individual cells appear very abnormal and dysplastic; similar to how most cancer cells in other tissues would typically appear.  In high-grade PIN, cells will usually show very large nucleoli, but marked pleomorphism is not present.  The prostatic ducts and glandular patterns appear normal with a normal peripheral basal cell layer. This condition is considered pre-malignant and is called high grade prostatic intraepithelial neoplasia (high-grade PIN). A low-grade PIN is considered benign and is usually not reported.[77]

First described in 1969, only the high-grade PIN lesions are clinically significant as they are closely associated with prostate cancer. For example, 80% to 90% of all radical prostatectomy specimens will demonstrate high-grade PIN on careful examination. These findings make rebiopsy or at least close observation reasonable and necessary in cases where only high-grade PIN is initially found.

Recent studies suggest that the actual risk of finding invasive or high-grade prostate cancer in men with high-grade PIN is lower than previously thought but still relatively high at 24%. A repeat prostate biopsy at 6 to 12 months has long been recommended, but there are additional options now available. These include saturation prostate biopsies, MRI prostate imaging, genomic testing, and MRI-transrectal ultrasound fusion guided biopsies.[78]

Some have suggested that these patients be followed with an active surveillance program, similar to what is used in patients with proven, low-grade prostate cancer. With a lack of consensus on the recommended follow-up, each case needs to be evaluated and treated individually after a full discussion with the patient of the risks, benefits, and limitations of each alternative.

Atypical Small Acinar Proliferation (ASAP)

Also considered a premalignant lesion, atypical small acinar proliferation indicates that there are small foci or atypical prostatic glands that are suspicious for cancer but there is insufficient overall evidence of malignancy to diagnose cancer. There is a 40% to 50% chance of finding overt prostate cancer on repeat biopsy, so the consensus recommendation is to repeat the prostatic biopsy with or without MRI image guidance 3 to 6 months after the initial diagnosis of atypical small acinar proliferation.[79]

Atypical Adenomatous Hyperplasia (Adenosis)

First described in 1941, atypical adenomatous hyperplasia is defined as a well-circumscribed nodule or lobule of small prostatic glands that are closely packed. What sets it apart from a diagnosis of prostate cancer is the presence of basal cells and the absence of significant cytologic atypia. There is some controversy regarding whether atypical adenomatous hyperplasia is a premalignant lesion or not, but the consensus suggests that it has relatively low malignant potential by itself and does not routinely warrant a repeat biopsy.[80][81]

History and Physical

Early prostate cancer is usually asymptomatic. However, it may sometimes cause symptoms similar to benign prostatic hyperplasia including frequent urination, nocturia, difficulty starting and maintaining a steady stream, hematuria, and dysuria.[82]

Prostate cancer may also be associated with problems involving sexual function and performance, such as difficulty achieving an erection or painful ejaculation.[83]

Metastatic prostate cancer can cause severe bone pain, often in the vertebrae, pelvis, hips or ribs. Spread into the femur is usually to the proximal part of the bone.[84]

Prostate cancer can result in spinal cord compression; causing tingling, leg weakness, pain, paralysis, and urinary as well as fecal incontinence.[85]

Digital rectal examination (DRE) may detect prostate abnormalities, asymmetry, and suspiciously hard nodules but is not considered a definitive test for prostate cancer by itself. An abnormal DRE initially uncovers about 20% of all prostate cancers.[86]

Evaluation

PSA and Other Pre-Biopsy Prostate Cancer Predictive Tests

Elevated Prostate Specific Antigen (PSA) levels (usually greater than 4 ng/ml) in the blood is how 80% of prostate cancers initially present even though elevated PSA levels alone correctly identify prostate cancer only about 25% to 30% of the time. We recommend at least 2 abnormal PSA levels or the presence of a palpable nodule on DRE to justify a biopsy and further investigation.[54]

The value of PSA screenings remains controversial due to concerns about possible overtreatment of low-risk cancers, overdiagnosis, complications from "unnecessary biopsies," the presumed "limited" actual survival benefit from early diagnosis and treatment, and the true value of definitive therapy intended to cure.[87]

In an attempt to improve on PSA testing alone, many alternative pre-biopsy screening tests are now available:[88]

Free and Total PSA: The percentage of free PSA in the blood can be a useful indicator of malignancy.  If the total PSA is between 4 and 10 ng/ml, a free PSA percentage is considered valid.  The free PSA percentage is calculated by multiplying the free PSA level by 100 and dividing by the total PSA value.

The actual risk estimates will vary by age group, but as a general guide:

  • If the free PSA percentage is more than 25%, the cancer risk is less than 10%.
  • If the free PSA percentage is less than 10%, the cancer risk is about 50%.

PSA Density is the total PSA divided by the prostatic volume as determined by MRI or ultrasound (US). The formula for the volume of the prostate is prostate volume = width x height x length x pi/6. For most purposes, Pi/6 can be estimated as 0.52 to make the calculations easier. The PSA density is intended to minimize the effect of benign prostatic enlargement. In general, if the PSA density is greater than 0.15, it is considered suggestive of malignancy.[89]

PSA Velocity compares serial, annual PSA serum levels. An annual PSA increase of greater than 0.75 ng/ml or greater than 25% suggests a potential cancer of the prostate (total PSA 4 to 10 ng/ml). If the total PSA is 2.6 to 4 ng/ml, then an annual increase of 0.35 ng/ml would be considered suspicious.[90]

Prostate Cancer Antigen 3 (PCA3) is an RNA based genetic test performed from a urine sample obtained immediately after a prostatic massage. PCA3 is a long, non-coding RNA molecule that is overexpressed exclusively in prostatic malignancies. It is upregulated 66 fold in prostate cancers. If PCA3 is elevated, it suggests the presence of prostate cancer.  It is more reliable than PSA as it is independent of prostate volume. PCA3 is best used to determine the need for a repeat biopsy after initial negative histology. Serial PCA3 testing may also be helpful in monitoring patients with low-grade prostate cancers on active surveillance. [91]

The Prostate Health Index (PHI) is a blood test that includes free PSA, total PSA, and the [-2] proPSA isoform of free PSA. A formula is used to combine these test results mathematically to give the PHI score. This PHI score appears to be superior to PSA, free and total PSA, and PCA3 in predicting the presence of prostate cancer.[92]

Mi-Prostate Score is a predictive algorithm developed at the University of Michigan.  It includes PSA, PCA3 and urine TMPRSS2:ERG (a genetic fusion found in about 50% of all prostate cancers).  While better than PSA alone, it is currently uncertain if this algorithm significantly outperforms PCA3 alone.[93]

The "4K" Test measures serum total PSA, free PSA, intact PSA and human kallikrein antigen 2. It includes clinical DRE results as well as information from any prior biopsies. These results are compared to a very large, age-matched database and a percentage risk of "significant" prostate cancer is calculated. Clinically significant prostate cancer is usually defined as Gleason 3 + 4 = 7 or higher disease. A risk analysis of 10% or more would typically suggest proceeding with a biopsy.  Interestingly, the "4K" test has not been shown to be any better than PSA testing alone when used for tracking active surveillance patients. [94]

"ExoDx Prostate Intelliscore (EPI)" uses PCA3 and urinary TMPRSS2:ERG to detect clinically significant prostate cancer.  The test analyzes exosomal RNA for three biomarkers known to be expressed in the urine of men with high-grade prostate cancer. A proprietary algorithm is then used to assign a risk score that predicts the presence of high-grade (Gleason Score = 7) prostate cancer. Unlike other urine based tests for prostate cancer, no digital rectal examination or prostatic massage is required.  Negative predictive value is  91.3% with a sensitivity rating of 91.9%. [95][91]

A urine based test measures the urinary mRNA levels of the HOXC6 and DLX1 biomarkers following a prostatic digital rectal exam. Measurements are done utilizing reverse transcriptase quantitative polymerase chain reaction technology. Other clinical information such as age, PSA density, family history, prior biopsy results, and digital rectal examination findings are included in the risk stratification. Results are reported very straight-forwardly as either:[96]

  1. Low risk: Very low risk of Gleason 7 or higher disease, where a biopsy may safely be reasonably avoided. Negative predictive value is 99.6% for Gleason 8 or higher disease and 98% for Gleason 7 or higher.
  2. Increased risk: A biopsy should be considered due to the increased likelihood of finding clinically significant disease.

In general, predictive testing that includes clinical variables (Select MDx and "4K") is considered somewhat more reliable than those tests which do not (PHI, ExoDx, and PCA3).[97]

Prostate Imaging

Ultrasound and MRI are the main imaging modalities used for initial prostate cancer detection and diagnosis.[98]

  • Transrectal ultrasound (TRUS) during prostate biopsies can sometimes see a potentially "suspicious hypoechoic area," but ultrasound alone is not a reliable diagnostic test for prostatic malignancy. TRUS is best used for directing the needle for prostate biopsies.
  • Prostate MRI has much better soft tissue resolution than ultrasound and can identify areas in the gland that are truly "suspicious" with a high degree of accuracy and reliability (positive predictive value greater than 90%).
  • In Europe, a positive MRI finding is sometimes sufficient to make a diagnosis of prostate cancer without necessarily requiring histological confirmation.
  • Prostate MRI is also used for surgical planning in men considering radical prostatectomy and for improved biopsies, instead of saturation biopsies, when cancer is strongly suspected despite a negative initial TRUS-guided biopsy.
  • MRI of the prostate may also have a role in active surveillance as an alternative to periodic or repeated biopsies.

Prostatic MRI is becoming a standard imaging modality for the diagnosis of prostate cancer. It can identify and grade suspicious prostate nodules to help with staging and localization, check for extracapsular extension, evaluate the seminal vesicles for possible tumor involvement and determine enlargement of regional lymph nodes that might indicate early metastatic disease.[74][99]

Prostate Imaging, Reporting and Data System (PIRADS)

MRI imaging, unlike CT or x-rays, typically shows denser tissue as dark areas.  Standard MRI imaging of the prostate usually requires a 3 Tesla (3T) MRI machine and optimally uses intravenous (IV) contrast, although non-contrast (bi-parametric) MRI tests are quicker, cheaper and still quite useful. IV contrast will demonstrate early vascular entry (faster inflow) and quicker washout from cancerous lesions or nodules compared to normal prostatic tissue.

Various MRI tissue characteristics ultimately determine the relative cancer risk which is documented in the final report as a PIRADS score. A PIRADS score of 1 or 2 is highly unlikely to be cancer. A PIRADS score of 4 or 5 is highly suspicious for clinically significant disease (Gleason 3 + 4 = 7 and higher). PIRADS 3 is equivocal. Histological confirmation with a biopsy is recommended for all PIRADS 3, 4 and 5 lesions.[100]

PIRADS 3 lesions usually demonstrate benign histology on biopsy, but low-grade prostate cancer is possible and it cannot reliably exclude intermediate or high-grade pathology. About 20% (17% to 25%) of all PIRADS 3 patients biopsied will show intermediate or high-grade prostate cancer pathology.[101]

Recent studies of PIRADS 3 lesions have identified several clinical risk factors that were clearly associated with significant, higher grade disease (Gleason score 3 + 4 = 7 and higher).[102]

Risk Factors Identified for PIRADS 3 Lesions Include:[103][104]

  1. Age 70 or older
  2. Smaller prostate volume (less than 36 mL)
  3. Presence of a palpable nodule on DRE
  4. Size of lesion or nodule greater than 0.5 cm. 

The studies reported that 100% of the PIRADS 3 patients with all the above risk factors positive showed clinically significant disease, 0% if they had no risk factors.  Incorporating these and other risk factors as well as genomic analysis testing into a workable clinical algorithm for patients with PIRADS 3 lesions would greatly improve our ability to identify those with aggressive, clinically significant disease while safely avoiding uncomfortable and unnecessary biopsies in the rest.

Controversies in MRI use for men with elevated PSA levels.  

Controversial issues include doing an MRI on all men with elevated PSA levels, avoiding biopsies on PIRADS 3 lesions and possibly avoiding biopsies on all men with negative MRI readings.  None of these suggested policies are currently recommended. For example, 20% of PIRADS 3 lesions will show clinically significant (Gleason 4) disease on biopsy which is considered too high a number to miss.  The degree of variability in image interpretation makes it difficult to be confident in MRI reports alone.  Even in experienced centers of excellence for MRI, the negative predictive value (NPV) has been reported as low as 72% to 76% meaning that a negative MRI report will miss about one in four high grade prostate cancers. [105][106]

For this reason, it has been suggested that a bioassay marker be used for additional confirmatory testing in patients with elevated PSA levels who are not proceeding to a prostatic biopsy based on negative MRI findings.  Similarly, before starting patients with low risk disease on long term active surveillance, a confirmatory genomic test can be useful to help identify those individuals who are at higher risk prior to any clinical disease progression.

When an MRI identifies a suspicious area, there are several ways to target or highlight the lesion for improved biopsies:[74] 

  • Cognitive Recognition means that with an understanding of the anatomical location of the suspicious lesion, the urologist can use standard TRUS imaging and target the expected geographic area of the suspicious lesion even without being able to see it directly.
  • MRI-TRUS Fusion guidance is now commercially available. This allows the suspicious lesion highlighted on the MRI to be electronically merged with the TRUS image, providing a visual target for ultrasound-guided biopsies. The equipment for this currently costs about $150,000, but there is no added reimbursement beyond standard TRUS guided biopsies at present, which has delayed widespread implementation of this technology despite its proven benefits.[107]
  • Direct MRI Image Guidance for prostate biopsies can be done but generally is not preferred. It is costly, ties up the MRI machine for a lengthy period, needs to be coordinated with the urologist who performs the procedure, and it requires special biopsy equipment that can be used during MRI imaging.

Biopsy

If cancer is suspected, a prostate biopsy is usually performed. This is almost always done with transrectal ultrasound guidance to make sure that all areas of the prostate are adequately sampled. The most commonly used pattern is to take two specimens from each of three areas (base, mid-gland, and apex) on both sides. This is called a 12 core sextant biopsy. The purpose is to better identify the extent and exact location of the tumor.[98]

  • A prostate biopsy gun uses a special hollow core needle that can be inserted into the prostate, then quickly advanced, opened and closed in a fraction of a second to capture a short, thin prostatic tissue sample.
  • Antibiotics should be used to prevent infectious complications, usually starting the day before the biopsy and continued for 3 days. Fluoroquinolones have been the most commonly used antibiotics for this purpose, but pre-biopsy rectal cultures are suggested to help optimize prophylactic antibiotic selection.[108]
  • A Fleets enema is also recommended shortly before the biopsy to help clean out the rectum.

Prostatic imaging with MRI is becoming increasingly important, particularly in highly suspicious cases where the initial non-MRI guided biopsy was negative, instead of "saturation" biopsies.

The Only Test that can Dependably and Conclusively Confirm a Cancer Diagnosis is Still a Histologically Positive Prostate Biopsy, Which Remains the Recommended Standard of Care.

Genomic Tumor Markers (Post-Biopsy)

Tissue samples can be analyzed for various genomic tumor markers.  Several commercial genomic tests are now able to reliably estimate a patient's prognosis, tumor aggressiveness and relative genetic risk from a single prostate cancer tissue sample.  These genomic markers are probably best used for patients with low and intermediate risk cancers (Gleason 3 + 3 = 6 and Gleason 3 + 4 = 7) to help with treatment selection, particularly for those patients who might be candidates for active surveillance. The intention is to confirm that the patients who are eligible and select active surveillance also have low-risk genomic markers. If their genomic analysis shows higher risk, they should be counseled accordingly.[109][110][109]

Another genomic marker test uses DNA methylation analysis of cytosines to determine the relative risk of significant occult disease from a tissue sample in high-risk men with histologically negative biopsies, High-grade PIN, or ASAP. It is most useful when the prostate biopsies are negative in patients at high risk for occult prostate cancer.  It has been shown to have a negative predictive value of 96% for detecting Gleason Grade 4 or 5 disease (Gleason sum 7 or higher). [111]

Another test measures 17 gene expressions and is an automated immunofluorescence based assay.  Both are most useful in men with low grade (Gleason 3+3=6) or intermediate grade (Gleason 3=4=7) disease where either active surveillance or definitive primary therapy are reasonable treatment options.[112][113]

Gene expressions from 46 different genetic sites is measured by another proprietary test.  It is most useful for men on active surveillance, who have undergone radiation therapy or where patients had a positive finding of prostate cancer after transurethral resection (TURP).  It has been associated with cancer specific mortality for men on active surveillance and with biochemical recurrence for those who have had radiation therapy or undergone TURP surgery.[93]

One test uses the expression of 22 RNA biomarkers to calculate the probability of clinical metastasis within 5 years of definitive therapy and prostate cancer specific mortality at 10 years. The purpose is to help avoid overtreatment by reclassifying those men originally identified as high risk who are unlikely to develop metastatic disease and might safely avoid salvage radiation therapy after radical prostatectomy surgery. It is most useful for higher risk patients with localized disease who have already undergone radical prostatectomy and are potential candidates for salvage radiation therapy. Studies have demonstrated that 60% of the men considered high risk after surgery were reclassified to a lower risk category following a genomic classifier designed to predict the development of distant metastases after surgical treatment of prostate cancer. Salvage radiation therapy was safely avoided in 50% of the high-risk patients tested, and 98.5% of those identified as low risk by genomic testing did not develop metastases within 5 years of their radical prostatectomy procedures.[97]

Research is ongoing into improved genomic analyses and clinically useful biomarkers. For example, one of the more promising biomarkers looks at the overexpression of regenerating liver-3 phosphatase (PRL-3) which has been associated with high-grade, aggressive prostate cancer.  The difference in nuclear/cytoplasmic ratio of PRL-3 seems to be able to reliably distinguish intermediate-grade disease (Gleason 3 + 4 = 7) from the more aggressive, high-grade disease (Gleason 4 + 3 = 7 and higher). Digital analysis of PRL-3 immunostained tumor samples could potentially not only be a reliable indicator of high-grade prostate cancer but could also distinguish between intermediate and high-grade malignancies.[114]

Other interesting markers include Post-Operative Therapy Outcomes Score (PORTOS), which is a panel specifically designed to predict response to external beam radiotherapy, and PAM50 subtyping which seems to predict response to hormonal therapy PRL-3, PORTOS, PAM50, and many other similar experimental biomarkers are currently being investigated for their potential role in clinical decision-making in prostate cancer.[115]

Treatment / Management

The first decision in managing prostate cancer is determining whether any treatment at all is needed. Prostate cancer, especially low-grade tumors, often grow so slowly that frequently no treatment is required; particularly in elderly patients and those with comorbidities that would reasonably limit life expectancy to 10 additional years or less.

Active Surveillance[116]

Many low-risk cases can now be followed with active surveillance. In active surveillance, patients are usually required to have regular, periodic PSA testing and at least one additional biopsy 12 to 18 months after the original diagnosis. Active surveillance is appropriate for men with low-grade prostate cancer (Gleason 3+3=6 or less with a PSA less than 20) and limited sized cancers. Genomic testing can be considered in these cases but may be most helpful when the PSA is in the 10 to 20 ng/ml range, or there is increased tumor volume.[93][112][93]

It is estimated that only 32% to 49% of eligible low-risk prostate cancer patients are currently on an active surveillance protocol in the United States. 

Use of active surveillance for selected, lower risk, intermediate-grade prostate cancers (Gleason 3 + 4 = 7 with a PSA less than 10) is controversial but seems reasonable in selected cases. This is where genomic testing can offer some real benefits; by reliably estimating and clarifying the true relative risk of tumor progression and aggressiveness in these borderline situations.

MRI of the prostate can also be used to follow these patients and avoids the discomfort of repeated biopsies. The purpose of close observation is to identify those patients, usually about 25% of the total, who will significantly increase PSA levels, clinically progress or upgrade to a higher Gleason score. This indicates possible conversion to a more aggressive cancer and definitive treatment can then be offered appropriately while the vast majority are safely spared the costs, inconvenience, side effects, and complications of curative therapy.

The best option depends on the cancer stage, Gleason score, and the PSA level as well as individual patient preferences, health, comorbidities, quality of life, and age.

Localized Disease[82]

In localized disease, it should be understood that for the majority of patients, treatment selection makes very little difference in overall survival for at least the next 10 years. Therefore, definitive therapy should only be offered to those patients who are reasonably expected to live another ten years or longer based on age and co-morbidities.

Definitive treatment of localized disease now includes radiation therapy (external beam and/or brachytherapy radioactive seed placement), radical prostatectomy and cryotherapy (usually reserved for radiation therapy failures). Radiation therapy tends to have much fewer side effects (about 50% less) than radical prostatectomy surgery with very similar overall survival.

Therefore, for most patients with potentially curable, localized disease, good performance status, reasonably good quality of life and greater than 10-year life expectancy, the choice of treatment should be an informed patient decision made after discussions including both urology (surgery) and radiation therapy.

Because definitive therapy can have significant side effects such as erectile dysfunction and urinary incontinence, discussions often focus on balancing the goals of therapy (possible cancer cure, the potential for increased survival, psychologically "getting rid" of the cancer) with the risks of lifestyle alterations (treatment side effects, complications, cost, possible lack of ultimate survival benefit and questionable quality of life improvement over doing nothing).

Focal Ablation Therapy for Localized Prostate Cancer[117]

The use of MRI localization has opened the door for local ablative therapy for selected patients with localized disease since we can now clearly identify the precise location of suspicious or significant tumors.  In many cases, the risks, complications and side effects of definitive whole-gland therapy outweigh many of the benefits of oncological control. There is a need to find a treatment modality between active surveillance and definitive whole-gland therapy with lower cost and fewer side effects. Focal ablative therapy is potentially the answer.

Focal ablative therapy can use any one of a number of ablative energies including microwave, cryotherapy, laser, high intensity focused ultrasound, etc., to precisely treat a localized malignant prostatic lesion. Ablative therapies typically have lower costs and substantially fewer side effects than traditional definitive whole-gland therapy. Optimal patients would be those with a single, isolated Gleason 7 (3 + 4 or 4 + 3) lesion and no evidence of extraprostatic or more widespread disease on MRI or prostatic biopsies.[118]

The issue that is unsettled is how effectively focal ablative therapy will control or cure localized prostate cancer and which technologies will ultimately provide the best combination of cancer control and minimal side effects. Focal ablative therapies for localized prostate cancer are currently considered investigational in the United States.

  • High-Intensity Focused Ultrasound is a local treatment modality that uses focused ultrasound to heat and ablate prostatic tissue including isolated malignant lesions. While not specifically approved for prostate cancer use in the United States, it has been used for this purpose in other parts of the world with reasonably good results in selected patients. It is relatively inexpensive, avoids radiation, can be repeated if necessary and has minimal side effects, but there are questions about its efficacy, particularly long-term. Its role in the treatment of prostate cancer has yet to be clearly determined.
  • Focal Laser Ablation uses laser fibers to heat and destroys prostatic cancer nodules based on MRI imaging using MRI-Fusion guided targeting. While still investigational, focal laser ablation appears to be a particularly promising minimally invasive treatment modality for well-selected patients with highly localized prostate cancer.

Hormone Therapy[119][120]

In 1941, Urologist Charles Huggins MD from the University of Chicago discovered that androgen deprivation (castration) would cause prostate glands to atrophy and prostate cancer to regress. He was awarded the Nobel Prize for Medicine in 1966 for this discovery which is the basis for all hormonal (testosterone deprivation based) treatment used in prostate cancer. This was the first effective systemic therapy for prostate cancer, and it still is extremely useful in putting cancer into remission. This beneficial hormonal effect typically lasts an average of about two years, but virtually all prostate cancers will eventually escape and regrow.

While bilateral orchiectomy was originally used to produce castration levels of testosterone, current hormonal therapy is usually done with injectable medications.

Initial therapy with leuprolide, goserelin and similar luteinizing hormone-releasing hormone (LHRH) agonists should be preceded by anti-androgen therapy, such as bicalutamide when the PSA level is greater than 10 ng/ml to prevent any clinical response to the temporary testosterone surge that typically accompanies initiation of hormonal therapy with these agents. This prophylactic anti-androgen therapy is not necessary with degarelix because it is a direct LHRH antagonist and there is no testosterone surge with this drug.

Hormonal therapy has been found to improve survival when combined with radiation therapy but not with radical prostatectomy for intermediate (Gleason 3 + 4 = 7) and higher grade disease. One common plan is to start with leuprolide or similar agents and monitor the PSA level monthly until it becomes undetectable or nadirs at which time definitive radiation therapy (cyberknife, external beam and/or brachytherapy seed implants) can be started. The hormonal therapy is usually continued for at least one year and optimally for at least two years after radiation. Intermittent hormone therapy is another option in selected cases to minimize the side effects of sustained, very low testosterone levels. Castration levels of testosterone have historically been considered <50 ng/dL, but newer data suggest that optimal results are obtained when testosterone levels are maintained at less than 20 ng/dL.

Patients with high volume prostate cancer and metastases who are being started on hormonal therapy will benefit from initiating docetaxel at the same time.  There appears to be no similar survival advantage in low volume prostate cancers with metastases.

Side effects of hormonal therapy include hot flashes, reduced libido, and loss of bone density resulting in osteopenia or osteoporosis. Hot flashes can be minimized with venlafaxine and similar SSRIs, gabapentin, megestrol acetate, or Depo-Provera injections. There are conflicting reports regarding a possible connection between long-term androgen deprivation therapy and cardiovascular risk. Long-term hormonal therapy for prostate cancer will tend to increase clotting risk, LDL cholesterol, body fat, triglycerides, and insulin resistance while decreasing lean body mass and glucose tolerance. Its most profound and potentially dangerous cardiac effect may be to prolong the QTc interval. These effects can be minimized by aggressively treating comorbidities, reducing cardiac risk factors and eliminating all other drugs that also tend to prolong QTc interval. Urologic medications that typically increase the QTc interval include levofloxacin, amitriptyline, and imipramine. Patients with significant cardiovascular risk factors or pre-existing heart disease are at increased risk and should be monitored closely by cardiology or primary care. Medical check-ups every 3 months has been recommended for this particular high-risk group of patients, especially during the first year of hormonal therapy when the risk of an acute cardiovascular event is highest.[121]

Use of calcium with Vitamin D supplements, along with a bisphosphonate or rank ligand inhibitor, is recommended in long-term hormonal treatment (typically defined as 1 year or longer) to prevent bone loss. A baseline DEXA scan is suggested.[122][123]

Differential Diagnosis

  • Acute bacterial prostatitis
  • Prostatic abscess
  • Chronic bacterial prostatitis
  • Benign prostatic hyperplasia
  • Nonbacterial prostatitis
  • Tuberculosis of the genitourinary system

Surgical Oncology

Radical Prostatectomy

Radical prostatectomy offers the greatest potential for a definitive cure for localized prostate cancer and a significant improvement in overall survival, cancer-specific survival and the development of distant metastases. These benefits over other definitive, curative therapies are not evident before 10 years after treatment for localized disease and are most pronounced in men younger than 65 years at the time of diagnosis. Radical prostatectomy is not an appropriate therapy if the tumor is fixed to surrounding structures or there are distant metastases.[124]

The majority of such surgeries are now being done robotically or laparoscopically. There does not appear to be much of a difference overall in side effects or survival between minimally invasive (robotic) or open surgical approaches. The experience of the surgeon appears to be the most critical factor associated with a successful outcome regardless of which technique is used.[125][126][125]

Individual patient issues would include activity level, age, continence, comorbidities, performance status, and presurgical erectile function as well as whether or not lymphadenectomy will be performed and if a nerve-sparing technique will be used. It is recommended that a bilateral nerve-sparing approach is used whenever it will not compromise the complete removal of the malignancy. MRI imaging is very helpful in making these determinations.[127]

Lymph Node Dissections

Performing a lymph node dissection is based on the expected incidence of finding malignant involvement. In general, it can be safely omitted in selected patients with low-risk disease (smaller tumors with lower PSA levels and favorable Gleason scores).[128]

The optimal extent of the lymph node dissection is uncertain. A greater and more extensive lymph node dissection is obviously likely to find a larger number of positive lymph nodes. In the past, a pelvic lymph node dissection was sufficient, but it is now known that metastases will often go directly to the common iliac, paraaortic, perirectal or presacral nodes, so a more extended dissection is recommended; particularly in higher risk disease.[129]

No improvement in overall longevity from lymph node dissections has been clearly demonstrated, although some men with the microscopic lymphatic disease have had prolonged survival which suggests the possibility of a benefit from the procedure.[128]

Salvage Radiation Therapy After Radical Prostatectomy

The serum PSA should become and remain undetectable after successful radical prostatectomy surgery. If this cannot be achieved or if there are positive margins after surgery, salvage radiation therapy should be considered.[130]

This is recommended based on the likelihood that the supplemental radiation may control the relatively small amount of cancer that might remain in the vicinity of the resected prostate. Typically, salvage radiation therapy is 60 to 70 Gy, which is substantially less than for primary definitive radiation therapy.[131]

Without treatment, metastatic disease can develop from microscopic cancer remnants after radical prostate surgery in about 8 years and overall survival averages about 10 to 13 years.[132]  

Salvage radiation therapy may also be recommended if the PSA becomes detectable at a later date, indicating possible residual disease that was present but previously undetectable could now be growing in the immediate area of the prostatic bed. Of course, there is no guarantee that any and all remaining cancer will be within the radiation field and it should not be considered with clear evidence of distant metastatic tumor spread.[133]

Early data suggest that everolimus at 10 mg/day can be safe, helpful and effective when combined with salvage radiation therapy for post-prostatectomy biochemical failures or recurrences.[134]

As an alternative, some patients with only limited positive margins or extracapsular extension may choose close monitoring and delay the salvage radiation therapy until there is a PSA spike, rise or other evidence of disease progression. However, this risks developing distant metastases that could have been prevented with earlier radiation treatment. A genomic classifier designed to predict the development of distant metastases after surgical treatment of prostate cancer can be helpful in assessing and reliably estimating an individual patient's relative risk in these situations.[135]

PSA doubling time is another prognostic indicator. A slow doubling time might reasonably suggest observation instead of therapy for lower risk patients. Patients with a rapid PSA doubling time generally have poorer outcomes.[136]

Identifying the location of recurrent disease can be difficult when there is a biochemical recurrence. There is little point in salvage radiation therapy to the prostatic bed if there are distant metastases or spread outside the possible radiation field. Prostate Specific Membrane Antigen (PSMA) Gallium PET/CT scans can be helpful in identifying local recurrences, but the PSA level needs to be over 1 to 1.5 for the recurrence site to be visible on the scan.[137][138]

Complications of Radical Prostatectomy include erectile dysfunction (especially if no nerve-sparing surgery was performed), urinary incontinence (especially stress type reported in 52% initially), urethral strictures (8% to 11%) and an increased risk of inguinal hernias (by 6% to 8%). Overall mortality rates are less than 1% in most series. Rates for erectile dysfunction vary greatly depending on pre-operative potency and age as well as the type of surgery performed (nerve-sparing or not) and the use of penile rehabilitation techniques.[139][140]

If radiation therapy is done first and fails, then salvage radical prostatectomy surgery becomes very challenging and is often impossible due to scarring, fibrosis, and loss of anatomical landmarks. However, cryotherapy would still be possible as a salvage treatment.[141]

Cryotherapy

The use of freezing technology to kill cancer cells is not new; it was first used in London in the 19th century for breast and cervical cancers.  Modern cryotherapy required the development of closed circulation liquid Nitrogen probes and one of the first uses of this new technology was for benign prostatic hyperplasia in 1966.[142]

Cryotherapy provides good tissue ablation and destruction, but has some complications and is very technology dependent. Early use was delayed due to the size of the original Nitrogen probes, urethral injuries and the inability to monitor the exact location of the probes and ice-ball in real time. These problems were solved by technological advances including the use of transrectal ultrasound to visualize the size and shape of the ice-ball, more precise freezing probe placement, use of multiple strategically placed interstitial temperature sensors to prevent over-freezing, utilizing multiple smaller probes simultaneously based on Argon gas for freezing instead of the harder to use liquid nitrogen, adding a thaw cycle to the protocol, and the standard placement of urethral warming catheters to protect the urethra from injury.[143]

The use of two freeze/thaw cycles instead of just one, rapid freezing to -40 C with slow thawing, and appropriate use of hormonal therapy to shrink larger prostates (greater than 60 gm) before treatment appears to improve the cancer-free results.  Hormonal therapy can help reduce prostate size but does not otherwise improve survival outcomes with cryotherapy.[143]

The incidence of erectile dysfunction is relatively high with cryotherapy which is an issue that should be discussed with patients before treatment.[144]

Cryotherapy can be the primary surgical therapy for prostate cancer, but it is probably most useful as a salvage surgical treatment after radiation therapy has failed.  In these cases, evidenced by persistent or rising PSA after radiation treatment, additional radiation or radical surgery is often extremely difficult, hazardous or no longer even possible. Hormonal therapy is often used in such cases but is not a curative option.[141][145]

Cryotherapy has shown it can control tumors resistant to all other therapies which will still be susceptible to ablation by alternating freeze-thaw cycles that disrupt cell membranes resulting in tissue destruction. In such cases, it is important to be sure that the malignancy is still confined to the prostate. Since cryotherapy cannot treat nodal involvement, lymph node dissections may be needed.[146]

Focal or limited cryotherapy is a possible experimental option in selected patients.[147]

Radiation Oncology

The goal of radiation therapy is to provide a lethal dose of radiation to the tumor without harming the surrounding normal tissue of the bladder and rectum.

No post-radiation prostate biopsies are recommended unless additional local therapy is being considered.

After radiation therapy, the PSA is expected to decrease for about 18 months.

Treatment failure is usually noted by a rise in PSA level of 2 ng/ml or more above the baseline level before initiation of radiation therapy.[148]

External Beam Radiation Therapy

Treatment fields are calculated and individualized from MRIs or CT scans, as some patients will need treatment for the seminal vesicles and/or regional lymph nodes. These other areas are included in the radiation field when there is direct evidence of tumor involvement, or the calculated likelihood of malignancy is 15% or more.[149][150]

The current standard of care is to use conformal techniques, such as intensity modulated radiation therapy (IMRT), and image-guided radiation therapy (IGRT). Such conformal techniques allow for higher dosages to be given to the prostate and tumor while not significantly increasing exposure to the surrounding tissues to minimize late side effects.[151][152]  

Treatment usually consists of daily exposures (5 days a week) for up to 8 weeks. This typically amounts to a minimum of 38 to 45 fractions of 1.8 to 2 Gy.  The American College of Radiology recommends a total dose of 75 to 78 Gy. (At our institution, our radiation oncologists use a total dose of 77.4 Gy.)  Doses higher than 81 Gy are not recommended due to increased risks of radiation cystitis and proctitis.[153][154][153]

The use of hormonal therapy in combination with radiation has demonstrated improved overall survival in intermediate and high-risk disease.  It appears that hormonal therapy increases tumor radio-sensitivity by interfering with DNA double-stranded break repair.  That is why the addition of hormonal treatment with LHRH agonists or similar medications before starting radiation therapy is now generally considered the standard of care. Preliminary data suggests adding enzalutamide to standard hormonal therapy will enhance this radio-sensitizing effect.[155][156]

Various drugs are being investigated as possible prostate cancer radio-sensitizers. Besides hormonal therapy and enzalutamide described above, these include statins, IL-37, parthenolide, and even green tea. So far, none are currently recommended for clinical practice.[157][158][159]

Complications from External Beam Radiation Therapy

Major areas of concern include prostate size and potential radiation side effects to the bowel and bladder (radiation proctitis and cystitis).[160]

There is an increased risk of hematuria in up to 15% of patients, especially if anticoagulated. Management of hemorrhagic complications of radiation cystitis includes oral pentosan polysulfate (Elmiron) and hyperbaric oxygen therapy. Severe hematuria may require cystoscopy and continuous bladder irrigation. If not successful, bladder instillations with 1% alum, aminocaproic acid (Amicar) and formalin may be required (up to a 10% formalin solution can be used but 4% is the preferred concentration).[161]

Erectile dysfunction is another relatively common complication that has been reported in 30% to 45% of men who were potent before starting radiation therapy.[162]

There are also possible issues with fatigue and increased fracture risk.[163]

There is a very slightly higher incidence of secondary malignancies after definitive radiation therapy.[164]

Stereotactic Ablative Radiotherapy (SABR)

The role of stereotactic radiotherapy in prostate cancer is less well defined than standard external beam radiation. With stereotactic therapy, the individual fractionated dosages are higher, typically 7 to 8 Gy each, which allows for a much reduced total treatment time, usually only about a week. Higher fractionated dosages beyond 8 Gy are not recommended as they have been associated with increased toxicity and side effects. Stereotactic radiotherapy is less suitable for patients with very large prostate volumes (greater than 75 to 100 mL) or prior TURP surgery. Most experts prefer real-time tracking, and early reports suggest using urethral catheterization during treatment planning and simulation improves urethral identification.  Newer SABR delivery systems include gantry devices which are currently undergoing clinical trials. It is hypothesized that using SABR for metastatic cancer may be reasonable to reduce seeding of additional tumors which may ultimately increase overall and progression-free survival. This strategy has already been shown to improve survival in metastatic non-small cell lung cancer but is still theoretical for use in prostate cancer.[165][166][154][165]

Stereotactic ablative radiation therapy (SABR) may increase the patient's immune response.  The proposed mechanism is through the release of additional tumor antigens, due to the larger fractional radiation dosage, which then prompts the increased immunological response.[154]  

Overall, stereotactic radiotherapy appears to be similar in efficacy to other definitive treatments for low and intermediate risk prostate cancers. This treatment is a reasonable alternative for appropriate low and intermediate risk patients who desire the markedly reduced treatment schedule and have access to the technology. There have not been sufficient numbers of higher risk patients reported to date to comfortably recommend stereotactic radiation to the high-risk prostate cancer group, although early reports suggest improved biochemical (PSA) control compared to standard external beam radiation therapy.[154]

Brachytherapy (Radioactive Seed Implants)

Brachytherapy is another form of radiation therapy that involves surgically implanting tiny radioactive seeds into the prostate. Conceptually, this allows for a higher total dose to be delivered to the prostate without increasing exposure to surrounding structures. It also allows for optimal treatment in patients where transportation and other issues would make standard external beam therapy more difficult. Most prostates will accept from 75 to 125 seeds.[167]

Hormonal therapy can be used to shrink the prostate if it is too large for therapy (greater than 60 gm). Three months of hormonal therapy will decrease the size of the prostate by about 30%.[168]

When combined with brachytherapy, hormonal therapy has been shown to improve survival outcomes so it is usually recommended.[169]

Seeds are placed transperineally using TRUS and a template plan that has been previously worked out by a radiation therapist or physicist.[170]

Radioactive materials used include iodine 125, palladium 103, and cesium 131. Cesium has the shortest half-life.[171][172]

High-Dose Rate Brachytherapy can also be done, using hollow needles placed through the perineum which are then loaded with iridium 192 or similar. These typically are left in place for 24 to 40 hours during which time the patient is admitted to a hospital. The newer trend is to treat with only 2 fractions per day, allowing the patient to go home at night.[172]

External beam radiation can then be used to treat regional lymph nodes and other areas outside the prostate not adequately controlled by the seeds alone.[173][171][173]

Outcomes are similar to external beam radiation and radical prostatectomy surgery, but there is no head to head trials. However, there is some evidence suggesting that brachytherapy might be somewhat more effective than external beam at least in some patients.

The most common complications reported from brachytherapy include exacerbation of urinary tract and rectal problems along with erectile dysfunction and seed migration. In other words, the complications are very similar to external beam therapy with the additional risk of radioactive seed embolization which may occur in up to 55% of brachytherapy patients. The use of stranded seeds, such as "Rapidstrands," significantly reduces the seed migration rate. The clinical impact of seed migration is still unclear.[174]

American Urological Association and American Society for Radiation Oncology Joint Guidelines Statement on Radiation Therapy:

  • If a patient is undergoing radical prostatectomy for localized prostate cancer, discuss the possibility of adverse pathologic findings indicating an increased cancer recurrence risk (clinical principle).
  • If adverse pathologic signs, such as seminal vesicle invasion, positive surgical margins, and extraprostatic extension, are found, inform the patient that the risk for biochemical (prostate-specific antigen [PSA]) recurrence, local recurrence, or clinical progression of cancer is lower following a combination of radical prostatectomy and adjuvant radiation therapy than it is after radical prostatectomy alone (clinical principle).
  • If adverse pathologic signs are found at prostatectomy, offer adjuvant radiation therapy to the patient (standard; evidence strength, Grade A).
  • Inform patients that PSA recurrence after surgery is associated with a higher risk for metastatic prostate cancer and with increased mortality risk (clinical principle).
  • Biochemical recurrence should be defined as a detectable or rising post-surgery PSA value of at least 0.2 ng/mL, with a second confirmatory level of at least 0.2 ng/mL (recommendation; evidence strength, Grade C).
  • A restaging evaluation should be considered in patients with a PSA recurrence (option; evidence strength, Grade C).
  • Offer salvage radiation therapy to patients who, after radical prostatectomy, demonstrate PSA or local recurrence but have no distant metastatic disease (recommendation; evidence strength, Grade C).
  • Inform patients that radiation therapy is most effective against PSA recurrence when PSA levels are relatively low (clinical principle).
  • Inform patients that radiation therapy may cause short or long-term urinary, bowel, and sexual adverse effects, but also discuss the treatment’s potential benefits as a means of controlling disease recurrence (clinical principle).

Proton Beam Therapy can theoretically deliver a higher dose of radiation more precisely than standard techniques. While theoretically an improvement, there are no randomized trials comparing proton beam therapy directly with standard radiation treatment. The current recommendation from the American Society for Radiation Oncology states that the best available data suggests that outcomes are similar between proton beam therapy and standard IMRT.[175][176]

Carbon Ion Therapy is another type of particle beam irradiation that is under investigation in Japan. Preliminary data appears promising.[177]

Treatment Selection: Radiation Therapy versus Radical Prostatectomy

Radiation therapy and radical prostatectomy surgery are both highly effective for controlling most cases of localized prostate cancer.  Treatment selection is then based on other factors such as patient preference, co-morbidities, age, availability of high-quality therapy, and transportation issues.[178]

Technology is continually changing to optimize radiation delivery to cancer while minimizing side effects, peripheral exposure, spillage, and long-term complications.  That is why it is difficult to compare radiation therapy and radical surgery results as we are looking now at the outcomes data from radiation therapy delivered 10 to 15 years ago when the technology was less advanced than what is typically given today.

The best available data suggest no significant difference in overall survival in most cases of potentially curable, localized, prostate cancer treated with either external beam radiation therapy, stereotactic radiotherapy, brachytherapy (radioactive seed implants), or radical prostatectomy surgery.

Medical Oncology

Aggressive Prostate Cancer 

Aggressive disease in prostate cancer is usually defined as either locally advanced, higher Gleason score (Gleason 4 + 5 = 9 or higher) or rapid PSA doubling time of two years or less. Treatment of aggressive prostate cancers may involve radical prostatectomy, radiation therapy, high-intensity focused ultrasound, chemotherapy, oral chemotherapeutic drugs, cryosurgery, hormonal therapy, immunotherapy, or some combination of these. Early use of chemotherapy has been shown to be helpful in many patients presenting with aggressive or advanced, localized disease.[156][179][24][156]  

If cancer has spread beyond the prostate, treatment options significantly change. Hormonal therapy, limited radiation therapy, radiopharmaceuticals, immunotherapy, and chemotherapy are the standard treatments reserved for a disease that has spread beyond the prostate and is no longer considered curable. For example, limited radiation therapy can dramatically help control prostatic bleeding or alleviate the excruciating bone pain from a metastatic cancer deposit.[156]

Castrate-Resistant Disease

Most hormone-sensitive cancers eventually become resistant to hormonal therapy and resume growth. At this point, the disease is considered castrate-resistant prostate cancer (CRPC) and requires additional treatment, usually chemotherapy. It has been estimated that 106,505 men in the US have localized (non-metastatic) CRPC.  Of these, 90% will ultimately progress to the bone and other metastases potentially causing severe pain, pathological fractures and spinal cord compression with paralysis.[180]

PSMA and Choline PET Scans

Prostate Specific Membrane Antigen (PSMA) is a membrane-bound metallopeptidase.  It is overexpressed in 90% to 100% of all prostate cancer cells which makes it a reliable tissue marker that can be used for tumor specific imaging as well as therapy.  Compared to conventional radiological techniques (CT and MRI), PET scans appear to be far more accurate.  Choline PET/CT scans are also proving to be useful imaging modalities to locate prostate cancer.  All of these PET based technologies are best used for biochemical recurrences (rising PSA) after definitive therapy.  Some can use either a diagnostic imaging agent, such as Gallium 68, or a therapeutic nuclide (PSMA-617).  These are emerging technologies and their use in clinical practice is still being determined.[181][182][183] 

Chemotherapy in the modern era typically consists of docetaxel in addition to modified hormonal therapy. 

  • Docetaxel is the standard initial chemotherapy agent used to treat CRPC with a median survival benefit of 2 to 3 months.[184]
  • The early use of docetaxel in hormone naive patients with high volume or high grade localized disease appears to be beneficial based on increased survival noted in several studies (STAMPEDE, CHAARTED, RTOG 0521 and GETUG 12).[185][186][187][187][188][189]
  • Second-Line chemotherapy treatment is cabazitaxel.[190][191]
  • Enzalutamide, abiraterone, and apalutamide are newer, hormonally based drug treatments that often work even when initial hormonal therapy has failed.[192]
  • Abiraterone is a CYP17 inhibitor that can block testosterone production inside tumor cells. It increases overall survival by an average of 4.6 months. This survival advantage is increased if given to hormonally sensitive patients.[193][194][193]
  • The combination of docetaxel and abiraterone for metastatic or locally advanced hormone-sensitive prostate cancer appears justified by recent studies.[193][195][193]
  • Enzalutamide works by interfering with androgen receptor binding and intracellular communication functions. It provides a 5-month overall survival advantage.[196]
  • Enzalutamide has been approved for non-metastatic CRPC, identified by at least two PSA rises. Studies show median metastasis-free survival of 36.6 months with enzalutamide and LHRH therapy compared to only 14.7 months with LHRH therapy alone.  This is very similar to the benefit from apalutamide (see below).  However, an increase in ischemic cardiac events was noted in the enzalutamide treated group (2.7% vs 1.2%) so caution should be used in patients with significant heart disease.[196][197]
  • Apalutamide (Erleada) is the newest anti-androgen that is also FDA approved fo[198]r use in non-metastatic, castration-resistant prostate cancer (enzalutamide is the other.)  Studies report that the time to symptomatic cancer progression as well as metastasis-free survival were significantly longer with apalutamide than with placebo. The median metastasis-free survival was more than 2 years longer (40.5 months vs. 16.2 months) in the group treated with apalutamide compared to the control (placebo) group. The most common, significant adverse effects noted from apalutamide were falls, fractures, rashes, and seizures.[199]
  • Apalutamide has also shown major activity in metastatic castrate sensitive patients when given along with androgen deprivation therapy (ADT) compared to standard ADT alone.  In a phase 3 clinical trial (TITAN, NCT02489318) involving over 1,000 patients, apalutamide significantly delayed disease progression and extended survival.
  • There are no head to head studies comparing these anti-androgens, and it is still unclear which anti-androgen is "best" or if giving standard chemotherapy would be the better approach.  This determination will require additional randomized trials. [199][200][201]
  • The presence of Androgen Receptor Splice Variant 7 (AR-V7) mRNA in circulating tumor cells predicts a relatively poor response from abiraterone, enzalutamide or apalutamide. A blood test for AR-V7 is now commercially available and is currently recommended for patients who fail initial treatment with any of these oral hormonal agents. Interestingly, a positive AR-V7 blood test also suggests an enhanced response to chemotherapy.[202][203][202] 
  • Circulating tumor cells can be detected in the blood of CRPC patients. The critical number that significantly shortens survival appears to be 5 or more tumor cells per 7.5 ml of blood.[204][205]
  • Immunotherapy treatment with sipuleucel-T in CRPC has been shown to increase survival but only by four months.[206]
  • Only a small subset of people respond to androgen signaling blocking drugs.[207]

About 90% of patients with CRPC will develop bony prostate cancer metastases which can be extremely painful; therefore, much of the therapy at this stage is directed at bone.[208]

Bisphosphonates like zoledronic acid and rank ligand inhibitors like denosumab (Xgeva), have been shown to improve quality of life and reduce pathological fractures in CRPC patients. Unfortunately, these agents have not been shown to improve survival.  Before use of either of these agents, a dental checkup is recommended due to their association with osteonecrosis of the jaw.  They should always be used with supplemental oral calcium and Vitamin D.[198][209][198]

Radium Ra 223 dichloride is a radiopharmaceutical that works particularly well on bone metastases from prostate cancer. It has been shown to improve overall survival in CRPC patients by 30% which sounds good but is only about 3 to 4 months for most recipients. Xofigo specifically targets bone and is ineffective in visceral, soft tissue and nodal disease.  Therefore it should be used in CRPC with bone metastases but without significant organ, soft tissue or lymph node involvement. Xofigo improves quality of life, reduces bone fracture rates and extends survival even if only for a relatively short time. It can be used with all other prostate cancer therapies. However, some data suggested that there may be an increased risk of fractures and deaths associated with the use of Ra-223 together with abiraterone and prednisone. [210][211]

Sipuleucel-T, a prostate cancer vaccine, has been found to result in a tangible survival benefit for men with metastatic, castrate-resistant prostate cancer but it is quite expensive and provides only a relatively limited improvement in life expectancy. (Note: The drug remains available even though its manufacturer, Dendreon, has declared bankruptcy.)  It is an autologous, dendritic cell-based vaccine that targets prostatic acid phosphatase.  It is the only vaccine-based therapy currently available for prostate cancer in the U.S. but a number of others are in various stages of development. We need to develop reliable prostate cancer biomarkers to help determine which future immunotherapy will offer the most benefit for each individual patient.[212][213] 

Staging

An important part of evaluating prostate cancer is determining the stage. The most commonly used staging system is the three-stage TNM (tumor/nodes/metastases) classification. Its components include the size and extent of the tumor, the presence of involved lymph nodes, the PSA level, the Gleason score (from a biopsy or surgical specimen) and the presence of metastases. When cancer cells spread from the prostate to other parts of the body, they most commonly go to the bones and lymph nodes.[214][215]

The Key Distinction in Prostate Cancer Staging is Whether or Not the Cancer is Confined to the Prostate and is Therefore Potentially Curable.

  • T1 and T2 cancers are limited to just the prostate and are considered "localized."
  • T3 cancer has spread outside the prostatic capsule but has not reached the rectum or bladder. Cancer may also have spread to the seminal vesicles (stage T3c), and this tends to be an ominous sign.
  • T4 cancers have spread outside the prostate to adjacent regional structures such as the bladder. They may also metastasize to the lungs, lymph nodes or liver which would be identified by their N (nodes) or M (metastasis) scores. Stage T4 prostate cancers with distant metastases have an overall 5-year survival rate of only 29%.

Clinical Tumor Staging

  • TX Primary tumor cannot be assessed
  • T0 No evidence of primary tumor
  • T1 Clinically invisible tumor; not palpable or visible by imaging
  • T1a Tumor incidental histologic finding in less than or equal to 5% of tissue resected (TURP specimen)
  • T1b Tumor is an incidental histologic finding in greater than 5% of tissue resected (TURP specimen)
  • T1c Tumor identified by needle biopsy (because of elevated PSA level); tumors found in one or both lobes by needle biopsy but not palpable or visible by imaging
  • T2 Tumor confined within the prostate
  • T2a Tumor involves up to half of one prostatic lobe
  • T2b Tumor involves more than half of one lobe but not both lobes
  • T2c Tumor involves both lobes of the prostate
  • T3 Tumor extending through the prostatic capsule; but no invasion into the prostatic apex or beyond the capsule
  • T3a Extracapsular extension (unilateral or bilateral)
  • T3b Tumor invading seminal vesicle(s)
  • T4 Tumor is fixed or invading adjacent structures (other than seminal vesicles)

Pathologic Tumor Staging 

  • pT1 There is no pathologic T1 classification
  • pT2 Organ confined tumor
  • pT2a Unilateral, involving half of one side or less
  • pT2b Unilateral, involving more than half of one side but not fully involving the other side
  • pT2c Bilateral disease
  • pT3 Extraprostatic extension
  • pT3a Extraprostatic extension or microscopic invasion of the bladder neck
  • pT3b Seminal vesicle invasion
  • pT4 Direct invasion of the bladder, rectum or pelvis

Testing For Evidence of Tumor Spread

CT scans, MRIs, bone scans and PET Scans can evaluate for any cancer spread within the abdomen and pelvis, particularly to the regional and para-aortic lymph nodes.

  • Bone scans can detect early metastases to the bones, but the PSA usually needs to be at least 20 before this is likely to be positive.[216]
  • Magnetic resonance imaging is excellent when used to evaluate the prostatic capsule for an extracapsular extension as well as the regional lymph nodes and seminal vesicles for possible tumor involvement.[217][218]
  • 68-gallium prostate-specific, membrane antigen (PSMA), PET/CT scan is a new FDA-approved test for detecting metastatic prostate cancer. It appears to offer improved sensitivity and specificity over standard imaging by combining molecular activity testing with conventional morphologically based radiographic studies. While indicated for the detection of metastatic and recurrent disease, it may also prove to be useful in the staging of high risk localized disease, such as from high Gleason score cancers. 68-gallium PSMA PET/CT scanning can also be used for targeted therapy by switching the imaging radiotracer for a therapeutic moiety.[219][220][221]

Prognosis

Predictive Value of a Single, Early PSA Level in Younger Men (Ages 40 to 45)

The European Association of Urology Guidelines states that for men in their early 40s, any PSA level beyond one ng/ml indicates a higher long-term prostate cancer risk and warrants closer monitoring. This statement is supported by evidence from several long-term studies and databases such as the Baltimore Longitudinal Study of Aging, the Department of Defense Serum Repository Study, the Duke Prostate Database Report, and the Malmo Preventive Project, among others. These studies all demonstrate that a single PSA test of less than 1 ng/ml in a man in his early 40s is an excellent predictor of good prostate health and not getting prostate cancer for the next 25 years or so.  Performing a PSA test in this young age group would also help find the small percentage of men who develop very aggressive and highly lethal prostate cancer before age 50.

For example, the best-selling author of "American Assassin," Vince Flynn, died of metastatic prostate cancer at age 47.  Getting his initial PSA test at age 50 would not have helped him.

Predictive Tables and Nomograms

Various predictive tables and nomograms are now available to help predict outcomes, positive lymph nodes, survival after radical prostatectomy, based on outcomes data from various sources. They include some combination of age, Gleason score, biopsy information, and PSA level. They may also require other clinical information such as the number of positive biopsies with the percentage of tumor involvement, as well as clinical and pathological staging.[222]

When Advanced Prostate Cancer Causes Bilateral Hydronephrosis

Prostate cancer may directly extend into the bladder sub-trigonally, causing hydronephrosis and eventually renal failure if both ureters become obstructed. When this happens, a decision needs to be made whether or not to proceed with treatment. This is typically late in the course of the disease and is usually painless, as it occurs slowly and incrementally.[223][224][223]

Gradually increasing renal failure is usually a painless and natural way to peacefully expire. Patients slowly become more lethargic and eventually just go to sleep. This may be preferable to forcing them to endure increasingly severe and debilitating pain from advancing disease and bone metastases. Treating the ureteral blockage may improve survival temporarily, but typically for just a few months.

This is an important decision point for the patient and family. Palliative care and/or hospice services should certainly be involved at this point if not engaged previously.

Treatment of hydronephrosis for obstructive prostate cancer may include surgical transurethral resection of the tumor inside the bladder over the expected location of the ureterovesical junction and intramural ureters. The resection only needs to be sufficient to unroof or expose the ureteral lumen, but this is not always technically possible due to the loss of landmarks, anatomical distortion and possible lack of mobility of the scope due to cancer. Once the ureteral lumen is exposed, a double J stent can be used to maintain urinary drainage. Double J stents can be difficult to place in these cases unless the ureteral lumen is surgically exposed or opened first.

Nephrostomy tubes are another possible solution when one or both ureters cannot be identified or opened transurethrally.  In such cases, antegrade placement of a double J stent from above is far easier than the standard transurethral retrograde method.

Ultimately, only one kidney needs to be drained and made functional.  Studies have shown there is no survival advantage to treating both kidneys in these situations.[225]

Do We Absolutely, Positively Need to Have a Positive Prostate Tissue Biopsy to Treat Prostate Cancer?

While a positive tissue biopsy is always preferred prior to treatment, situations arise where it may not be practical or obtainable.  Patients may present requiring treatment who have a history of prostate cancer treated elsewhere with no confirmatory records immediately available. Other patients may have had prior bad experience with an earlier biopsy and are now refusing all new diagnostic procedures.  Perhaps there are medical issues, such as a new cardiac stent or a history of pulmonary embolisms, which require an extended period of significant anticoagulants that preclude doing the biopsy.

With the use of MRI imaging, genomic-analysis testing, validated prostatic nomograms, and all of the other pre-biopsy predictive tests, it is not unreasonable to consider initiating some degree of prostate cancer treatment in selected cases even without absolute histological confirmation of malignancy if the likelihood of cancer is sufficiently high.  Such cases are likely to be infrequent, and patients need to be fully informed regarding the standard of care as well as the possibility of treatment complications and side effects without the absolute assurance that they have a prostatic malignancy that is sufficiently aggressive and dangerous to justify the therapy.[226]

Prognosis and Survival

In the United States, patients with localized or regional disease at the time of diagnosis have a 5-year survival rate of nearly 100% while patients presenting with distant metastases have a 5-year overall survival rate of only 29%.

In patients who undergo treatment, the most important prognostic indicators are patient age and general health at the time of diagnosis, as well as the cancer stage, pre-therapy PSA level, and Gleason score.

A poorer prognosis is associated with higher grade disease, more advanced stage, younger age, increased PSA levels and a shorter "PSA doubling time."[227]

Life Expectancy

There is no clear evidence that either radical prostate surgery or radiation therapy have a significant survival advantage over the other, so treatment selection has relatively little effect on life expectancy.[228]

  • Patients with localized, low-grade disease (Gleason 2 + 2 = 4 or less) are unlikely to die of prostate cancer within 15 years.
  • After 15 years, untreated patients are more likely to die from prostate cancer than any other identifiable disease or disorder.
  • Older men with low-grade disease have approximately a 20% overall survival at 15 years, due primarily to death from other unrelated causes.
  • Men with high-grade disease (Gleason 4 + 4 = 8 or higher) typically experience higher prostate cancer mortality rates within 15 years of diagnosis.

Palliative Care and Hospice

Palliative Care focuses on treating the symptoms of cancer and improving quality of life. The goal of palliative care is symptom control and pain relief rather than curing cancer.

Cancer pain related to bone metastases may be treated with bisphosphonates, rank ligand inhibitors, opioids, radiopharmaceuticals, and palliative radiation therapy.

Spinal cord compression can be treated with steroids, surgery, or radiation therapy.

A common mistake is failing to get palliative care and Hospice services involved early enough in the course of the disease so they can start patient assistance immediately when needed, without undue delays.[229]

Pearls and Other Issues

PSA Testing: The Pros and the Cons[230]

Prostate Specific Antigen (PSA) is a protein produced by the prostate and is abundant in semen. Its natural function is to divide seminogelin in the semen, which helps in liquefaction. The expression of PSA is androgen-regulated. 

It was originally used as a prostatic tissue stain to help determine the etiology of tumors of unknown origin. Later, serum levels of PSA were used as a prostate cancer screening tool because serum PSA levels start to increase significantly about seven to nine years before the clinical diagnosis of malignancy.  While a good indicator of prostatic disorders, PSA elevation is not specific for cancer as it is also elevated in benign prostatic hyperplasia, infection, infarction, inflammation (prostatitis) and after prostatic manipulation.  It also cannot reliably distinguish between low risk/low grade disease and high risk/high grade cancers.

About 80% of the patients currently diagnosed with prostate cancer are initially investigated due to an elevated serum PSA. 

While it unquestionably increases prostate cancer detection rates, the value of PSA testing is less clear in avoiding overtreatment, improving quality of life and lengthening overall survival; which is why routine PSA screening for prostate cancer remains quite controversial.

PSA testing became widely available in the United States in 1992, and since then, prostate cancer detection rates have increased substantially.

More impressively, according to the National Cancer Institute, since 1992 the death rate from prostate cancer in the United States has dropped by an amazing 44% that is substantially due to PSA screenings resulting in earlier prostate cancer diagnosis and treatment.

The current controversy is whether PSA screening provides sufficient benefits to offset the complications and side effects of "unnecessary" biopsies and curative therapies since most men with prostate cancer will have slow-growing, low-grade cancers for whom definitive, curative therapy often causes considerable harm with little or no survival benefit.

  • In 2012, the United States Preventive Services Task Force (USPSTF) recommended against all routine screening PSA tests due primarily to the risks of overtreatment without proof of any substantial survival benefit. This initially seemed reasonable as most prostate cancers are low-grade and remain asymptomatic. They concluded the potential benefits of PSA testing and earlier definitive cancer therapy did not outweigh the increased risks of side effects and complications from overtreatment.
  • This conclusion was made before the current, widespread use of active surveillance for low-grade, localized disease, advanced PSA test analogues such as PCA3 and the "4K" test, MRI prostate imaging and MRI-TRUS fusion guided biopsies, genomic marker analysis of low and intermediate risk cancers, all of which mitigate in favor of PSA cancer screening as long as reasonable steps are taken to avoid overtreatment. [231]
  • The original 2012 USPSTF recommendation was also inconsistent with numerous studies showing a 50% or more cancer-specific survival benefit in PSA screened populations compared to their unscreened cohorts if followed for more than 10 years. [232]

The Current USPSTF Recommendation[233]

For men 55 to 69 years of age, the decision regarding whether to be screened for prostate cancer by PSA should be an individual one after a full discussion about the benefits, harms, and limitations of such screening.[234]

Routine PSA screenings are not recommended in men 70 years or over, based on the conclusion that definitive treatment of localized cancers for most older men has minimal effect on overall survival while adding significant treatment side effects and morbidities to many.

Many professional organizations now have guidelines and recommendations regarding PSA screening for prostate cancer. Most include a recommendation for an informed discussion with patients about the benefits and potential risks of screenings, biopsies, definitive therapy, and possible overtreatment.

Prostate Cancer Screening: The Pros and Cons[235]

Screening options include the digital rectal exam and a prostate-specific antigen (PSA) blood test. Such screenings may lead to a biopsy with some associated risks. Transrectal ultrasound has no role in prostate cancer screenings.

Routine screening with a DRE and particularly a PSA test has become very controversial. Here are some of the arguments for and against:

Against PSA Screenings

  • No real change in overall survival for most patients for at least the first ten years after the initial diagnosis.
  • Many patients (about three quarters) are getting biopsies which are negative or show only low-risk disease which is often overtreated.
  • Screenings are only likely to catch relatively slow-growing tumors and will miss the rapidly growing, aggressive tumors that are the most lethal.
  • Increased patient anxiety from low-risk, a low-grade prostate cancer that ultimately will not affect survival.
  • "Unnecessary" biopsies contribute to patient anxiety, are uncomfortable, add cost and may have complications like infections and bleeding.
  • Several recent large studies show little or no survival benefit to large-scale screenings.
  • There is little point in doing prostate cancer screenings if treatment offers little or no survival benefit, as suggested by some recent studies (PIVOT). 
  • Foreign countries with good healthcare systems which do not perform widespread PSA testing have noted similar reductions in prostate cancer-specific survival compared to countries like the United States with extensive PSA screenings.

In Favor of PSA Screenings

  • Prostate cancer is still the second leading cause of cancer death in men, and the incidence is increasing.
  • Ignoring our best diagnostic screening test for prostate cancer is not going to reduce its mortality.
  • We now have active surveillance, MRI imaging, and MRI-TRUS fusion biopsies as well as genomic testing so that we can avoid overtreating patients.
  • Eliminating routine PSA screenings, as recommended by the earlier USPSTF report of 2012, has already caused a significant reduction of about 30% in prostate cancer diagnosis. At least some of these cancers will ultimately be high-grade and will undoubtedly increase prostate cancer mortality.
  • Many of the larger studies suggesting a lack of survival benefit to large scale PSA screenings have been shown to be poorly done, significantly biased, severely contaminated, and full of major statistical errors.
  • Well done studies comparing PSA screened and unscreened populations, clearly show a cancer-specific survival advantage that is consistently at or above 50% for the screened groups if followed for more than 10 years.
  • According to the NIH, prostate cancer mortality has dropped over 44% since 1992 when PSA testing became widely available in the United States. This is almost double the benefit in foreign countries that do not perform extensive PSA testing.
  • The prostate cancer death rate in Sweden, where PSA testing is minimal, is higher than for lung cancer and more than double the mortality rate for prostate cancer in the United States.
  • Long-term studies from Scandinavia and elsewhere prove that definitive treatment works, but it may take more than 10 to 15 years to become evident.
  • It has been estimated by the NIH that in 10 years, an additional 25,000 to 30,000 men could die each year from preventable, potentially curable prostate cancer if we completely stopped all PSA screenings.
  • Only 9% of all new prostate cancer cases present with advanced disease, compared with 32% before the PSA era.  This represents a 72% reduction!
  • Less than 4% of all new cases initially present with metastatic disease compared to 21% before widespread PSA screenings.  This is an 80% reduction in the incidence of metastatic prostate cancer at the time of initial diagnosis that can only be explained by the benefits of PSA screenings.
  • We are constantly improving diagnostic testing and treatment options to lower costs and minimize side effects while increasing survival and improving quality of life; but without early PSA screening, these new minimally invasive technologies cannot be used.

Recommended General Guide to PSA Testing

  1. An initial PSA test at 40 to 45 years of age is recommended because it is highly predictive of future prostate cancer risk.
  2. We recommend routine PSA screenings only in reasonably healthy men from 45 to 75 years of age who wish it after a frank discussion of the benefits, limitations and potential risks of screening.
  3. We do not recommend screening in patients who would not accept treatment even if cancer were found.
  4. We do not recommend routine screening in healthy men over age 75 with normal PSA levels up to that point, as they are not likely to benefit from treatment.
  5. We encourage screening only in men who are reasonably expected to have at least a 10-year life expectancy from the time of diagnosis. For most newly discovered localized prostate cancers, the survival benefit from treatment does not begin until at least 10 years after therapy.
  6. We encourage screening in men at high risk due to ethnicity or family history.
  7. We recommend PSA testing in men with an abnormal digital rectal examination suggestive of cancer regardless of age.
  8. Finally, regardless of the above, we recommend doing PSA testing in all men who request it as long as they are fully aware of the risks, benefits, and limitations of screening, even if they fall outside the usual guidelines.

Summary of Genomic Prostate Cancer Tests (Beyond PSA):[88][236]

Pre-biopsy

Initial basic screening would include total PSA, free and total PSA, and PSA Density levels.

Improved pre-biopsy screening tests would include PHI, the amount of serum PSA, with the amounts of two genes in the urine, urinary 3-gene expression validated test, the "4K test" and testing the expression of two mRNA cancer-related biomarkers (HOXC6 and DLX1). 

Post-biopsy

A patient with a negative initial tissue biopsy being considered for a repeat prostatic biopsy can best be further analyzed and risk-stratified by tissue-based gene assay, the "4K" test or PCA3.

Patients with low grade or intermediate grade disease being considered for either active surveillance or definitive therapy would benefit most from either genomic test.

Men on active surveillance can be tracked and followed with genomic testing or serial PCA3 testing in addition to standard PSA levels.

Patients who are post radiation therapy or who were diagnosed with prostate cancer after TURP surgery can be tracked with genomic test.

Overall prognosis, cancer-specific survival, and risk of metastases are best assessed in post-radical prostatectomy patients with a genomic test that serves as a prognostic marker of cancer control outcomes.

 

 

Enhancing Healthcare Team Outcomes

Prostate cancer diagnosis and treatment can be complex and is often controversial. An interdisciplinary team of specialty-trained nurses, nurse practitioners, physician assistants, primary care providers, and urologists must work to manage:

  • Unrealistic patient expectations
  • New diagnostic aids and treatments are becoming available at a rapid rate.
  • Conflicting recommendations and guidelines from the USPSTF and other professional organizations like the American Medical Association, the American Cancer Society, and the American Urological Association.
  • Recommendations and guidelines that seem to be changing almost daily.
  • Decreased PSA screenings following the USPSTF report of 2012, a drop of 30%.
  • The entire PSA testing controversy.
  • Confusion about how best to use the newly available genomic tests and which ones are optimal at each stage of evaluation.
  • The need to better define the role and improve the diagnostic accuracy and reliability of prostatic MRI.
  • Fully implementing MRI image directed biopsy technology such as MRI-TRUS fusion guidance.
  • Advances in radiation therapy which include stereotactic ablative therapy (SABR). 
  • Clarifying the proper use of active surveillance; finding and using acceptable alternatives to mandatory repeat prostatic biopsies such as with MRIs or PET scans.
  • The lack of good, minimally invasive curative therapies for a localized disease that are less expensive and better tolerated than definitive radiation therapy or radical surgery.
  • No clear protocol for the best timing or sequence for Radium Ra 223 dichloride, taxotere, and Sipuleucel-T (Provenge) treatments.
  • The need for better implementation of the various specialties involved in prostate cancer patient care including primary care, urology, radiation therapy, and medical oncology through improved communications and cooperation.

These and many more issues continue to challenge clinicians who deal with prostate cancer patients and men at risk for this common, potentially lethal male malignancy.

The interprofessional team can optimize the treatment of these patients through communication and coordination of care. Primary care providers, urologists, oncologists, radiation oncologists, and nurse practitioners provide diagnoses and care plans. Specialty care urologic nurses should work with the team for coordination of care and are involved in patient education and monitor compliance. The interdisciplinary team can thus improve outcomes for patients with alopecia. [Level V]


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A 55-year-old male is found to have a hard nodular prostate on routine rectal examination. The radiologist reports vertebral densities which are thought to be osteoblastic lesions. There is also an elevation of prostate-specific antigen in the blood. What other marker may also be elevated?



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What is the most common internal cancer in males living in United States?



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Which of the following cancers can induce osteoblastic changes in the spine?



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In the United States, what is the most common clinical sign associated with the detection of prostate cancer?



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Carcinoma of the prostate usually starts in which portion?



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A 65-year-old male presents with elevation of both acid and alkaline phosphatase. Which of the following is a probable diagnosis?



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A 75-year-old male is being treated with leuprolide and flutamide. What malignancy is being treated?



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What is the best initial screening test for prostate cancer?



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What is the 5-year survival rate for bone metastasis from prostate cancer?



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How does prostate cancer most commonly present itself during the performance of a digital rectal exam?



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What is meant by stage T2B prostate cancer?



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What is the approximate five-year survival rate after early detection of prostate cancer?



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Where does prostate cancer begin?



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A 75-year-old male presents with low back pain. Plain radiographs show sclerotic changes in the lumbar vertebrae and the pelvis. The radiologist states that this could be degenerative spondyloarthropathy but that metastatic prostate carcinoma cannot be excluded. What would be the most cost-effective next step?



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Select the true statement about prostate cancer.



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Which of the following is a risk factor for prostate cancer?



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Which of the following is an accurate diagnostic tool for prostate cancer?



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A 70 year old male has biopsy of prostatic nodule that shows small glands with a single layer of epithelial cells and prominent, enlarged nucleoli. Which portion of the prostate has the highest incidence of these findings?



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A 73-year-old male presents with low back pain without radiation or injury. He has had no medical care in 5 years and has no significant past medical history. His back is nontender and neurologic exam is normal. Rectal exam shows an enlarged, rock hard prostate that is nodular. The alkaline phosphatase and the prostate specific antigen are both twice normal. What is the most likely diagnosis?



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What are the T2 weighted imaging findings in prostate cancers of the peripheral zone?



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What are the T2 weighted imaging findings in prostate cancer of the transitional zone?



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Where would a prostate MRI show a low T2 signal?



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From a management position, it is most important to distinguish between which two stages of prostate cancer?



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What is the key imaging finding in stage III prostate cancer?



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Which of the following is evidence of extracapsular spread of cancer on MRI of the prostate?



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According to the SEER (Surveillance, Epidemiology and End Results) Database, what is the increased risk of high-grade prostate cancer associated with long-term exposure to testosterone therapy?



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What does the presence of AR-V7 (androgen receptor splice variant-7 messenger RNA) detected in circulating tumor cells in patients with castrate-resistant prostate cancer indicate?



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What physical finding on a digital rectal exam is the most striking characteristic of early prostatic carcinoma?



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What percent of prostatic carcinoma is found in the gland's posterior lobe?



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Which lab test should probably be avoided in a forty-year-old male?



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At present, which is true of the majority of prostate cancers that are identified in the United States?



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A 77-year-old male presents with a weakened urinary stream, weight loss, and fatigue. A rectal exam is done which reveals a 2 cm hard nodule. Biopsy shows a transitional cell malignancy. What feature in the patient's medical history may be a clue to this particular malignancy?



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A 63-year old is in the clinic for a routine health check up. He states that his father had prostate cancer and he would like to take dietary precautions to prevent it. What are the recommendations from the recent prostate cancer prevention trials regarding diet?



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A 55-year-old male with prostate cancer is treated with goserelin. Which of the following agents is the best choice for adjunctive therapy in this patient's treatment regimen?



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Which of the following parameters are most consistent with an MRI diagnosis suggestive of prostate cancer?



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A 67-year-old man undergoes a prostate biopsy showing bilateral Gleason 4+5=9 prostate cancer. His PSA is 35. MRI of prostate shows extracapsular extension and seminal vesicle invasion. Bone scan is negative. CT scan shows enlarged obturator nodes and periaortic lymph nodes. According to AJCC 8th edition staging, what is his clinical stage?



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What is the advantage of Gleason group compared to Gleason score?



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Prostate Cancer - References

References

Brown LC,Ahmed HU,Faria R,El-Shater Bosaily A,Gabe R,Kaplan RS,Parmar M,Collaco-Moraes Y,Ward K,Hindley RG,Freeman A,Kirkham A,Oldroyd R,Parker C,Bott S,Burns-Cox N,Dudderidge T,Ghei M,Henderson A,Persad R,Rosario DJ,Shergill I,Winkler M,Soares M,Spackman E,Sculpher M,Emberton M, Multiparametric MRI to improve detection of prostate cancer compared with transrectal ultrasound-guided prostate biopsy alone: the PROMIS study. Health technology assessment (Winchester, England). 2018 Jul     [PubMed]
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Kyriakopoulos CE,Liu G, Chemohormonal Therapy for Hormone-Sensitive Prostate Cancer: A Review. Cancer journal (Sudbury, Mass.). 2016 Sep/Oct     [PubMed]
Parker C, Report from the ESMO 2018 presidential symposium-Radiotherapy to the primary tumour for men with newly diagnosed metastatic prostate cancer: survival results from STAMPEDE. ESMO open. 2018     [PubMed]
Vale CL,Burdett S,Rydzewska LHM,Albiges L,Clarke NW,Fisher D,Fizazi K,Gravis G,James ND,Mason MD,Parmar MKB,Sweeney CJ,Sydes MR,Tombal B,Tierney JF, Addition of docetaxel or bisphosphonates to standard of care in men with localised or metastatic, hormone-sensitive prostate cancer: a systematic review and meta-analyses of aggregate data. The Lancet. Oncology. 2016 Feb     [PubMed]
Teo MY,Scher HI, CHAARTED/GETUG 12--docetaxel in non-castrate prostate cancers. Nature reviews. Clinical oncology. 2015 Dec     [PubMed]
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Rathbun JT,Franklin GE, Radium-223 (Xofigo) with concurrent abiraterone or enzalutamide: predictive biomarkers of improved overall survival in a clinically advanced cohort. Current problems in cancer. 2018 May 31     [PubMed]
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Wilt TJ,Brawer MK,Jones KM,Barry MJ,Aronson WJ,Fox S,Gingrich JR,Wei JT,Gilhooly P,Grob BM,Nsouli I,Iyer P,Cartagena R,Snider G,Roehrborn C,Sharifi R,Blank W,Pandya P,Andriole GL,Culkin D,Wheeler T, Radical prostatectomy versus observation for localized prostate cancer. The New England journal of medicine. 2012 Jul 19;     [PubMed]
Loriot Y,Massard C,Fizazi K, Recent developments in treatments targeting castration-resistant prostate cancer bone metastases. Annals of oncology : official journal of the European Society for Medical Oncology. 2012 May;     [PubMed]
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Jha GG,Anand V,Soubra A,Konety BR, Challenges of managing elderly men with prostate cancer. Nature reviews. Clinical oncology. 2014 Jun     [PubMed]
Mullins JK,Loeb S, Environmental exposures and prostate cancer. Urologic oncology. 2012 Mar-Apr     [PubMed]
Rhoden EL,Averbeck MA, [Prostate carcinoma and testosterone: risks and controversies]. Arquivos brasileiros de endocrinologia e metabologia. 2009 Nov     [PubMed]
Kaiser A,Haskins C,Siddiqui MM,Hussain A,D'Adamo C, The evolving role of diet in prostate cancer risk and progression. Current opinion in oncology. 2019 May     [PubMed]
Wallner LP,DiBello JR,Li BH,Van Den Eeden SK,Weinmann S,Ritzwoller DP,Abell JE,D'Agostino R Jr,Loo RK,Aaronson DS,Richert-Boe K,Horwitz RI,Jacobsen SJ, 5-Alpha Reductase Inhibitors and the Risk of Prostate Cancer Mortality in Men Treated for Benign Prostatic Hyperplasia. Mayo Clinic proceedings. 2016 Dec     [PubMed]
Chau CH,Figg WD, Revisiting 5α-reductase inhibitors and the risk of prostate cancer. Nature reviews. Urology. 2018 Jul     [PubMed]
Özkan TA,Cebeci OÖ,Çevik İ,Dillioğlugil Ö, Prognostic influence of 5 alpha reductase inhibitors in patients with localized prostate cancer under active surveillance. Turkish journal of urology. 2018 Mar     [PubMed]
Locke JA,Bruchovsky N, Prostate cancer: finasteride extends PSA doubling time during intermittent hormone therapy. The Canadian journal of urology. 2010 Jun     [PubMed]
Benafif S,Eeles R, Genetic predisposition to prostate cancer. British medical bulletin. 2016 Dec     [PubMed]
Kiciński M,Vangronsveld J,Nawrot TS, An epidemiological reappraisal of the familial aggregation of prostate cancer: a meta-analysis. PloS one. 2011     [PubMed]
Bruner DW,Moore D,Parlanti A,Dorgan J,Engstrom P, Relative risk of prostate cancer for men with affected relatives: systematic review and meta-analysis. International journal of cancer. 2003 Dec 10     [PubMed]
Barfeld SJ,East P,Zuber V,Mills IG, Meta-analysis of prostate cancer gene expression data identifies a novel discriminatory signature enriched for glycosylating enzymes. BMC medical genomics. 2014 Dec 31     [PubMed]
Tan SH,Petrovics G,Srivastava S, Prostate Cancer Genomics: Recent Advances and the Prevailing Underrepresentation from Racial and Ethnic Minorities. International journal of molecular sciences. 2018 Apr 22     [PubMed]
Stephan C,Jung K, Advances in Biomarkers for PCa Diagnostics and Prognostics-A Way towards Personalized Medicine. International journal of molecular sciences. 2017 Oct 20     [PubMed]
Rebbeck TR, Prostate Cancer Genetics: Variation by Race, Ethnicity, and Geography. Seminars in radiation oncology. 2017 Jan     [PubMed]
Chen H,Liu X,Brendler CB,Ankerst DP,Leach RJ,Goodman PJ,Lucia MS,Tangen CM,Wang L,Hsu FC,Sun J,Kader AK,Isaacs WB,Helfand BT,Zheng SL,Thompson IM,Platz EA,Xu J, Adding genetic risk score to family history identifies twice as many high-risk men for prostate cancer: Results from the prostate cancer prevention trial. The Prostate. 2016 Sep     [PubMed]
Lin PH,Aronson W,Freedland SJ, Nutrition, dietary interventions and prostate cancer: the latest evidence. BMC medicine. 2015 Jan 8     [PubMed]
Freedland SJ,Mavropoulos J,Wang A,Darshan M,Demark-Wahnefried W,Aronson WJ,Cohen P,Hwang D,Peterson B,Fields T,Pizzo SV,Isaacs WB, Carbohydrate restriction, prostate cancer growth, and the insulin-like growth factor axis. The Prostate. 2008 Jan 1     [PubMed]
Pettersson A,Kasperzyk JL,Kenfield SA,Richman EL,Chan JM,Willett WC,Stampfer MJ,Mucci LA,Giovannucci EL, Milk and dairy consumption among men with prostate cancer and risk of metastases and prostate cancer death. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2012 Mar     [PubMed]
Song Y,Chavarro JE,Cao Y,Qiu W,Mucci L,Sesso HD,Stampfer MJ,Giovannucci E,Pollak M,Liu S,Ma J, Whole milk intake is associated with prostate cancer-specific mortality among U.S. male physicians. The Journal of nutrition. 2013 Feb     [PubMed]
Schenk JM,Till CA,Tangen CM,Goodman PJ,Song X,Torkko KC,Kristal AR,Peters U,Neuhouser ML, Serum 25-hydroxyvitamin D concentrations and risk of prostate cancer: results from the Prostate Cancer Prevention Trial. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2014 Aug     [PubMed]
Wilson KM,Mucci LA,Drake BF,Preston MA,Stampfer MJ,Giovannucci E,Kibel AS, Meat, Fish, Poultry, and Egg Intake at Diagnosis and Risk of Prostate Cancer Progression. Cancer prevention research (Philadelphia, Pa.). 2016 Dec     [PubMed]
Catsburg C,Joshi AD,Corral R,Lewinger JP,Koo J,John EM,Ingles SA,Stern MC, Polymorphisms in carcinogen metabolism enzymes, fish intake, and risk of prostate cancer. Carcinogenesis. 2012 Jul     [PubMed]
Tantamango-Bartley Y,Knutsen SF,Knutsen R,Jacobsen BK,Fan J,Beeson WL,Sabate J,Hadley D,Jaceldo-Siegl K,Penniecook J,Herring P,Butler T,Bennett H,Fraser G, Are strict vegetarians protected against prostate cancer? The American journal of clinical nutrition. 2016 Jan     [PubMed]
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