Continuing Education Activity

Worldwide, prostate cancer is the most commonly diagnosed malignancy and the sixth leading cause of cancer death in men. Diagnosis is primarily based on prostate-specific antigen (PSA) testing, MRI scans, and prostate tissue biopsies, although PSA testing for screening remains controversial. New diagnostic technologies including risk stratification bioassay tests, germline testing, and various PET scans are now available. When the cancer is limited to the prostate, it is considered localized and potentially curable. If the disease has spread outside the prostate, bisphosphonates, rank ligand inhibitors, hormonal treatment, chemotherapy, radiopharmaceuticals, immunotherapy, focused radiation, and other targeted therapies can be used. This activity is a current, comprehensive review of the evaluation and management of patients with prostate cancer and highlights the role of the interprofessional team in improving care for affected patients.

Objectives:

• Describe the etiology of prostate cancer.
• Review the pathophysiologic basis of prostate cancer.
• Outline how to properly manage a patient affected by prostate cancer.
• Summarize how an optimally functioning interprofessional team would coordinate care to enhance outcomes for patients with prostate cancer.

Introduction

Worldwide, prostate cancer is the most commonly diagnosed male malignancy and the fifth leading cause of cancer death in men.[1][2] This amounted to 1,414,249 newly diagnosed cases and 375,000 deaths worldwide yearly from this disease in 2020.[1][2][3][4][5] Globally, prostate cancer is the most commonly diagnosed malignancy in more than fifty percent of countries (112 of 185).[6]

Fortunately, most prostate cancers tend to grow slowly and are low-grade with relatively low risk and limited aggressiveness.[7]

There are no initial or early symptoms in most cases, but late symptoms may include fatigue due to anemia, bone pain, 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.[8][9]

Newer diagnostic modalities include free and total PSA levels, PCA3 urine testing, Prostate Health Index scoring (PHI), the"4K" test, exosome testing, genomic analysis, MRI imaging, PIRADS scoring, and MRI-TRUS fusion guided biopsies.[10] 

When the cancer is limited to the prostate, it is considered localized and potentially curable.[11]

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.[12]

Etiology

The known major risk factors are age, ethnicity, obesity, and family history.[13] 

The overall incidence increases as people get older, but fortunately, cancer aggressiveness decreases with age.[14]

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.[15][16][17]

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 prostate-specific antigen (PSA) readings.[18][19][20][21] Taking 5-alpha reductase inhibitors does not appear to affect prostate cancer risk.[22] The Health Professionals Follow-up Study examined the use of 5 alpha-reductase and prostate cancer in 38,000 men followed for over 20 years. Men taking the medication received more PSA tests, prostate examinations, and biopsies, but no association was found regarding the development of lethal disease, overall survival, or cancer-specific survival. However, rates of overall and localized disease were reduced in men taking 5-alpha-reductase medications.[21][23]

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.[24] In general, patients with genetic or hereditary prostate cancer tend to develop their malignancies at an earlier age, have more rapid progression, are more likely to be locally advanced, and have a higher risk of recurrence after surgery.[25] Hereditary prostate cancer has the highest heritability of any major cancer in men.[26] A family history of hereditary breast and ovarian cancer or Lynch syndrome increases the risk of prostate cancer, indicating a genetic connection.[27][28] 

• Men in the top 1% high-risk profile category have an almost 6-fold increase in developing prostate cancer compared to controls.
• Men with a first-degree relative (father or brother) with prostate cancer have twice the risk of the general population.[29]
• Risk increases with an affected brother more than with an affected father.[30]
• The risk increases further if the first-degree relative had early-onset (<55 years) disease.
• 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.[31] 
• 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.[32]
• The incidence and mortality for Hispanic men with prostate cancer are one-third lower than non-Hispanic whites.[33]
• No single gene is responsible for prostate cancer, although many genes have now been implicated.[34]
• Mutations in BRCA1 and particularly BRCA2 have been associated with breast cancer and prostate cancer.[34]
• P53 mutations in localized prostate cancer are relatively rare and are more frequently seen in metastatic disease. P53 is generally considered a tumor suppressor gene. Its activity produces p21 protein, which acts to slow cell division. Loss of p53 activity reduces tumor androgen sensitivity, increases prostate cancer cell proliferation, and promotes tumor growth. Therefore, p53 mutations are generally considered a late and ominous finding in prostate cancer.[35]
• 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.[26][34][36] (Note: This is only a partial listing. Clinically significant germline mutations will be reviewed later.)
• A Genetic Risk Score (GRS), including high-risk genetic markers and SNPs, has been proposed to help with the risk stratification of prostate cancer, especially in families; but this type of testing is not yet ready for individual patient diagnostics.[37]

Diet

Prostate cancer is generally linked to the consumption of the typical Western diet.[38]

• There is little, if any, evidence that demonstrates an association between trans fat, saturated fat, or carbohydrate intake and prostate cancer.[39]
• However, a lard diet (high in unsaturated fats) has been shown in a mouse model to significantly enhance the progression of prostate cancer.[40]
• Alcohol consumption appears to have little or no effect on prostate cancer risk.[41][42] But there is some evidence to suggest that a moderate intake of red wine may be beneficial.[43]
• Vitamin supplements do not lower the risk, and in fact, some vitamins may increase it.[38]
• High calcium intake is associated with advanced prostate cancer.[38]
• Diets high in saturated fat and milk products seem to increase the cancer risk.[44]
• Whole milk consumption after a diagnosis of prostate cancer has been linked to an increased risk of recurrence, especially in overweight men.[45]
• Lower vitamin D blood levels may increase the risk of developing prostate cancer.[46]
• Prostate cancer patients with vitamin D deficiencies have a higher overall and cancer-specific mortality.[47][48]
• This suggests that vitamin D supplements may be helpful in prostate cancer patients who are deficient in the vitamin.
• 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.[49]
• Fish consumption may lower prostate cancer deaths but does not affect the occurrence rate.[50]
• However, high dietary omega-3 fatty acids from fish oil have been linked to an increased risk of clinically significant, high-grade prostate cancer.[51][52]
• Some evidence supports the belief that a vegetarian diet lowers rates of prostate cancer, but this is not considered a conclusive or significant influence.[53]
• Increased soy products in the diet seem to reduce prostate cancer risk. These products contain phytoestrogens that may have a direct estrogenic effect or by inhibition of 5 alpha-reductase.[54][55]
• Folic acid supplements have also not been shown to significantly affect the risk of developing prostate cancer.[56][57]
• Lycopene from tomatoes appears to have a protective effect against prostate cancer.[58][59]
• Overall, a Mediterranean diet (rich in anti-oxidants from olive oil, tomatoes, etc.) appears to be somewhat helpful in reducing prostate cancer risk.[60] 
• It has also been shown to reduce Gleason Grade progression in patients on Active Surveillance for low-grade prostate cancer.[61]

Chemical Exposure and Medications

Prostate cancer is linked to some medications, surgical procedures, and medical conditions.[62]

• The use of statins, metformin, and NSAIDs, especially those with anti-COX-2 activity, may decrease prostate cancer risk.[63]
• Metformin inhibits the COX2/PGE2 axis, which blocks prostate cancer progression by suppressing tumor-associated macrophages. This effect is increased in patients on androgen deprivation therapy.[64]
• Regular aspirin, now used by an estimated 23.7 million men, appears to reduce prostate cancer risk.[65]
• This effect may be from both anti-inflammatory activities as well as reduced angiogenesis.[66]
• The beneficial effect of aspirin and NSAIDs appears to be more significant in aggressive prostate cancer and those with prostatitis.[67] 
• Veterans who have had Agent Orange exposure tended to present with prostate cancer at a younger age and higher clinical stage than veterans without such contact. However, overall outcomes were similar.[68]
• Agent Orange exposure may increase the risk of prostate cancer recurrence, particularly following surgery.[69]

Sexual Activity

Multiple lifetime sexual partners or starting sexual activity early in life increases the risk of prostate cancer. Frequent ejaculation may decrease overall prostate cancer risk, but reducing ejaculatory frequency is not associated with a corresponding increase in the incidence of advanced disease.[70][71]

Infections

Infections may be associated with the incidence and development of prostate cancer.[72]

• Infections with chlamydia, gonorrhea, or syphilis seem to increase the risk of developing prostate cancer.[73]
• Human Papilloma Virus (HPV) has been proposed to have a role in prostate cancer incidence, but the evidence is inconclusive.[74]

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.[75] However, the latest meta-analysis has again suggested an association, so the question remains unresolved.[75][76]

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.[77] Lung cancer is first.[78][79]

According to the American Cancer Society, relatively few patients with prostate cancer die of the disease, although this still amounts to 268,490 new cases diagnosed and an estimated 34,500 deaths in the United States in 2022.

• Prostate cancer occurs more commonly in the developed world.[80]
• The overall 5-year survival rate is 99% in the United States.[81]
• The overall incidence has increased, although the death rate has slowly decreased since 1992 when PSA testing became widely available.[82]
• Ninety-nine percent of all prostate cancers occur in those over the age of 50, but it can be quite aggressive when it occurs in younger men.[83]
• In the United States, prostate cancer is much more common in African Americans at more than double the rate of the general population.[84]
• It is less common in men of Asian and Hispanic descent than in Whites.[85]

The World Health Organization (WHO) reports that the countries with the highest incidence of prostate cancer are Guadaloupe, Martinique, Ireland, Barbados, St. Lucia, Estonia, Puerto Rico, France, Sweden, and the Bahamas. The incidence is highest in Guadaloupe at 184/100,000 which drops down to 98/100,000 in the Bahamas compared to the worldwide average rate of 30.7 per 100,000. The US is rated 14th. The lowest incidence is reported in Asian countries.

The highest mortality rates for prostate cancer are reported by the WHO in Grenada, Zimbabwe, Barbados, Haiti, Zambia, Jamaica, Trinidad/Tobago, Bahamas, the Dominican Republic, St. Lucia, and the Ivory Coast. Within this group, the mortality rate ranges from 80/100,000 in Grenada to 30/100,000 in the Ivory Coast. This is compared to the worldwide average mortality rate of 7.7 per 100,000. The mortality rate in the US is 11.46 per 100,000 which is ranked 126th. The lowest reported mortality rate from prostate cancer is in Nepal and Yeman at <1 per 100,000.

Prostate cancer incidence is generally 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.[86]

• In Europe, prostate cancer is the third most diagnosed cancer after breast and colorectal.[87]
• 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.[87]
• The World Health Organization reports that Sweden, where they do very few PSA tests and tend to be less aggressive in treating prostate cancer, has a mortality rate that is about 2.5 times the rate in the United States. This makes prostate cancer the number one cause of cancer mortality in Swedish men, even exceeding deaths from lung cancer.

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

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.[88]

Prostate cancer is uncommon in men younger than 45 years (0.5% of all newly diagnosed prostate cancer cases), but the incidence is increasing in most countries worldwide. The reasons for this include prior underdiagnosis, the increase in PSA screenings, and overdiagnosis. Other risk factors that may be contributing include recent trends of increased obesity, metabolic syndrome, physical inactivity, HPV infections, substance and chemical exposures, environmental carcinogenic exposures, and changing referral patterns.[89] Prostate cancer can be very fast-growing and lethal in this younger age group. 

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 2020, they reported 174,650 new cases of prostate cancer and 31,620 deaths in the United States.[77] The American Cancer Society estimates 268,490 new cases and 34,500 deaths from prostate cancer in the US in 2022.

• 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. 
• About 20% of men diagnosed with prostate cancer will ultimately die from cardiovascular disease.[90][91] 
• The cardiovascular risk appears to be increased by androgen deprivation therapy.[92]
• In the United States, Kentucky has the highest incidence and mortality rate from prostate cancer.

Effect of the 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:[93]

• A drop in the diagnosed incidence of low-grade prostate cancer. Low-grade disease (Gleason 3+3=6 or lower) dropped from 30.1% before 2012 to 17.1%.
• An increase in intermediate and high-grade disease; High-grade disease (Gleason 4+4=8 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 African Americans having the highest incidence and mortality rates, far exceeding the levels for the general population. 

In the largest available study in the VA system involving almost 8 million veterans, it was found that African American men tended to have higher PSA levels, develop cancer earlier, and were almost twice as likely to have a diagnosis of prostate cancer as Whites.[94]

According to 2022 estimates from the American Cancer Society, prostate cancer is the most common organ cancer in African American men. It accounts for about 37% of all cancers in male African Americans (41,600 individuals) and 17% of all cancer-related deaths. This rate is 72% higher in African Americans than in Whites. The overall lifetime risk of developing or dying from prostate cancer is 1:6 in African Americans compared to 1:8 in Whites. The overall prostate cancer-specific death rate is more than double in the African American male population (37.9 vs. 17.8 per 100,000). The good news is that the prostate cancer death rate is dropping even faster for African Americans than for Whites or the general population.[32]

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.[95]  

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.[95]

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.[96]

The prostate is primarily glandular tissue, which produces fluid that constitutes about 25% to 30% 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.)[95][97][98]

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.[99]

Cancer begins with a mutation in normal prostate glandular cells, usually beginning with the peripheral basal cells.[100]

Prostate cancer is most commonly found in the peripheral zone, primarily that portion of the prostate that can be palpated via digital rectal examination (DRE).[101]

• 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 and 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 partially due to 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 influence prostatic health or the development of prostate cancer.[102]

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. Developed initially 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.[103]

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.[104]

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 rarely seen.[105]

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.[106]

Low-grade tumors would be any Gleason score of 3+3=6 or less.[105]  

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 a smaller portion was the more aggressive Gleason grade 4.[107] 

A Gleason score of 4+3=7 or higher would be considered high-grade cancer.[105]

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 criterion. For example, prostate-specific membrane antigen (PSMA) is a transmembrane carboxypeptidase that exhibits folate hydrolase activity which is overexpressed in prostate cancer tissues. Its presence would suggest prostate cancer.[108] The presence of neuroendocrine cells and a cribriform pattern are negative prognostic indicators.[109][110]

Other significant microscopic histological features and prognostic indicators of prostate cancer would include:[111]

• 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
• Cribriform pattern
• Perineural invasion
• Neuroendocrine cells

The number of positive biopsies also has a 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% of their biopsies found to be positive.

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.[112]

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.[113]

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:[114]

• 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, Grade Group 1 is histologically considered "low grade," Grade Group 2 is "intermediate grade," and Grade Group 3 or higher is "high grade" disease.

The National Comprehensive Cancer Network

The National Comprehensive Cancer Network (NCCN) is a consortium of 31 major academic cancer centers in the United States, most designated as Comprehensive Cancer Centers by the National Cancer Institute. Some of the institutions involved include the Mayo Clinic, Johns Hopkins University, Duke University, the Cleveland Clinic, Memorial Sloan Kettering Cancer Center, Roswell Park, MD Anderson, and the Dana-Farber/Brigham Cancer Center, among others. They periodically review and set guidelines for screening, diagnosis, and management of all stages and types of cancers via a consensus process. Their recommendations are considered the definitive, authoritative standard guidelines for cancer screening, diagnosis, and treatment in the United States.

The National Comprehensive Cancer Network Clinical Prostate Cancer Risk Stratification:

Very Low Risk: (Must meet all criteria to qualify)

• Stage T1c disease
• The tumor is confined to the prostate with a negative digital rectal examination
• Gleason Grade Group 1 (3+3=6) or lower
• PSA <10 ng/mL
• PSA density <0.15 ng/mL/g
• Less than three biopsy tissue samples were positive with <50% cancer involvement in any single core sample

Low Risk: 

• Stage T1 to T2a disease
• The tumor is confined to the prostate with a negative digital rectal examination
• Gleason Grade Group 1 (3+3=6) or lower
• PSA <10 ng/mL
• It does not qualify as "Very Low Risk" for any reason

Favorable Intermediate Risk:

• The tumor is confined to the prostate
• No high or very high-risk factors
• Gleason Grade Group 1 or 2 (3+3=6) or (3+4=7)
• Less than 50% of biopsy cores are positive

         AND no more than one additional intermediate risk factor such as any of the following:

• Stage T2b to T2c disease (the tumor involves more than 1/2 of one side but is still confined to the prostate)
• Gleason Grade Group 2 or 3 (3+4=7) or (4+3=7)
• PSA 10 to 20 ng/mL

Unfavorable Intermediate Risk: Tumor confined to the prostate, no high or very high-risk factors, and either: the percentage of biopsy cores positive is 50% or more OR Gleason Grade Group 3 (4+3=7) OR two or three of the following intermediate-risk factors:

• The tumor is confined to the prostate
• No high or very high-risk factors

         AND Either:

• Gleason Grade Group 3 (4+3=7) 

         OR:

• More than 50% of the biopsy cores are positive

         OR at least two of the following intermediate-risk factors:

• Stage T2b to T2c disease (tumor involves more than 1/2 of one side but is still confined to the prostate)
• Gleason Grade Group 2 or 3 (3+4=7) or (4+3=7)
• PSA 10 to 20 ng/mL

High Risk: No very high-risk factors AND any of the following:

• The tumor extends outside the prostate (Stage T3a)
• PSA is >20 ng/mL
• Gleason Grade Group 4 or 5 (Gleason 4+4=8 or higher)

Very High Risk: Any of the following:

• Two or three high-risk factors
• Stage T3b (tumor invading the seminal vesicles)
• Stage T4 (tumor invading adjacent organs other than the seminal vesicles, such as the external sphincter, rectum, bladder, levator muscles, and/or pelvic wall)
• Primary Gleason pattern 5
• More than four biopsy cores with Gleason Grade Group 4 or 5 (Gleason Score 4+4=8 or higher) 

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.[115]

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 the 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 additional options are now available. These include saturation prostate biopsies, MRI prostate imaging, genomic testing, and MRI-transrectal ultrasound fusion-guided biopsies.[116]

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 of atypical prostatic glands that are suspicious for cancer, but there is insufficient overall evidence of malignancy to formally diagnose cancer. As first described by Montironi et al. in 2006, it is described as "a focus of small acinar structures formed by atypical epithelial cells."[117]

There is a reported 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.[118] In some studies, the majority of the cancers found were significant (Gleason sum >6), especially in patients with a greater PSA velocity, higher PSA densities, and shorter PSA doubling times.[119]

Recently, it's been suggested that in some cases of high-grade PIN or atypical small acinar proliferation, it may be possible to use newer genomic testing, alterations in MRI prostate imaging, and PSA level changes to identify patients who can be closely monitored as an alternative to mandatory repeat biopsies. While not yet the standard of care, the opportunity to avoid re-biopsies in up to 2/3 of these patients is very attractive and appears to be safe, at least on a preliminary basis, in selected patients at this time.[118][120]

It is generally thought that the presence of both high-grade PIN and atypical small acinar proliferation in the same patient increases the overall risk of developing a malignancy, but this has not been definitively proven.

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.[121][122]

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.[123]

Prostate cancer may also be associated with problems involving sexual function and performance, such as difficulty achieving an erection or painful ejaculation.[124]

A family history of prostate cancer is certainly a risk factor. African American ethnicity also increases the risk. A history of positive germline mutations, such as BRCA1 or BRCA2, would suggest an increased risk of prostate cancer and possibly some other malignancies. This germline mutation is suggested if there is a family history of early breast cancer in female family members or close relatives.

A family history of colon cancer might suggest Lynch syndrome, which is associated with both prostate cancer and urothelial malignancies.

The most common positive physical finding of prostate cancer is a firm or hard nodule on digital rectal examination. There might also be some asymmetry or general firmness on the exam. A rock-hard prostate would be very suggestive of at least locally advanced disease.

Prostate cancer can result in spinal cord compression, causing tingling, leg weakness, pain, paralysis, and urinary and fecal incontinence.[125]

Metastatic prostate cancer can cause severe bone pain, often in the back (vertebrae), pelvis, hips, or ribs. Spread into the femur is usually to the proximal part of the bone.[126]

Evaluation

PSA Testing

PSA is a serine protease enzyme produced by the columnar epithelial cells of the prostatic ducts and acini.[127] Its function is to break down the large proteins of the semen into smaller molecules. This causes the semen to become less viscous over time and improves sperm function and fertility. Elevated PSA levels have long been associated with prostate cancer.[128] The highest levels are found in the semen, with some PSA leaking from the prostate into the lymphatic and vascular systems. Both benign and malignant cells produce prostate-specific antigen, with cancer cells leaking more PSA into the surrounding extracellular fluid, which eventually increases levels in the serum. 

There are multiple causes for an elevated PSA which have nothing to do with cancer, including prostate disease, trauma, inflammation, prostatitis, urogenital procedures, biopsies, prostatic enlargement, etc. Some physicians will recommend a two to six-week course of prostate-specific antibiotics (usually a quinolone, doxycycline, or sulfamethoxazole/trimethoprim) to attempt to lower the PSA if due to prostatitis or low-grade inflammation and avoid further investigations for possible prostate cancer; however, this practice is controversial and not generally recommended as a number of studies have failed to show a significant benefit to this approach.[127][129][130][131][132][133]

Elevated Prostate-Specific Antigen (PSA) levels (usually greater than 4 ng/ml) in the blood are 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. At least two abnormal PSA levels or the presence of a palpable nodule on a digital rectal examination (DRE) are required to justify further investigation or a biopsy.[85]

In 2012, the United States Preventive Services Task Force (USPSTF) recommended not performing routine prostate cancer screening using PSA testing, giving it a grade D recommendation. This was based on the early results of two large trials that suggested too much overdetection and overtreatment of low-risk prostate cancer compared with too little benefit. This was bitterly contested by many groups and individuals who pointed out the many significant procedural and statistical errors in the studies, the immaturity of the data, the numerous studies that consistently showed a 50% cancer-specific long-term survival advantage in screened populations, and the terrible consequences if their conclusions turned out to be incorrect.[134] When long-term data became available, the USPSTF reversed its position and now recommends PSA testing in men 55 to 70 years after discussing the pros and cons with the patient. It has been estimated that if the original USPSTF recommendations had been fully implemented, an additional 25,000 to 30,000 preventable deaths from prostate cancer would occur yearly in the United States.[135][136]

The value of PSA screenings remains somewhat controversial due to concerns about possible continuing 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.[137] Most professional organizations now recommend PSA testing for appropriately aged men starting at age 45 to 50 and continuing until age 70 to 75 after a full discussion about the benefits, risks, and controversies. In response, several pre-biopsy screening modalities have been developed, including bioassay risk stratification tests, prostatic MRI imaging, and active surveillance strategies to treat low-risk, low-grade disease that previously would have received definitive therapy.

In an attempt to improve on standard PSA testing alone, many alternative pre-biopsy screening tests are now available:[138]

Free and Total PSA: The percentage of free PSA in the blood can be a useful indicator of malignancy. A free PSA percentage is considered valid if the total PSA is between 4 and 10 ng/ml. The free PSA percentage is calculated by multiplying the free PSA level by 100 and dividing it 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 clinical 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.[139]

PSA Velocity compares serial and 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, an annual increase of 0.35 ng/ml would be considered suspicious.[140]

Post-PSA Pre-Biopsy Prostate Cancer Bioassay Risk Stratification Tests

A number of newer tests have been FDA-approved and introduced to help risk-stratify patients with persistently elevated PSA levels up to 10 mg/ml. The original intention was to eliminate unnecessary biopsies in patients at low risk for prostate cancer. Both blood and urine sample tests are available. Most include several different laboratory tests bundled together to provide a single risk score or estimate. Some require a digital prostate massage prior to specimen collection, and several need significant clinical patient information, which is used in a proprietary algorithm to arrive at their conclusion. Risk stratification bioassay testing is valid, approved, and certified only for PSA levels at or below 10 ng/ml. Patients with a PSA level greater than 10 ng/ml will generally go directly to a biopsy with or without a preliminary MRI. Bioassay risk stratification testing may be justified in selected patients with PSA levels greater than 10 ng/ml who are otherwise reluctant to undergo a biopsy and require further confirmation of their relative risk. 

Some tests may have included patients in their testing cohorts that should have been excluded due to PSA levels outside the optimal range, prior biopsies, previous or continuing prostate treatments, or other forms of possible selection bias.

These tests should not be used in patients who would not benefit from the results. Patients with obvious suspicious, hard prostatic nodules or suspected metastatic disease and those with persistent PSA levels over 10 ng/ml would not need this type of testing. Like PSA testing, patients 75 years and older and those with less than a 10-year life expectancy are generally not eligible for bioassay testing as they are unlikely to benefit. 

Since they were designed and intended to exclude patients at low risk from further testing and biopsies, the most significant statistic for their use is the "negative predictive value" score. A negative predictive value is defined as the number of test subjects found to be truly negative if their test scores were negative. Generally, a negative predictive value of 90% or more is considered valid and useful for cancer detection, and all FDA-approved, commercially available tests in this category meet that standard. The list of available tests is rapidly expanding, with several more expected to be released commercially soon. 

In comparing the various tests, some of the questions to ask and variables to consider in selecting a bioassay risk stratification test include the following:

• Can the test be used for patients on active surveillance? If not, is the testing company doing or considering a study to evaluate its use in these patients?
• Can the test be repeated later if the PSA changes? If so, what degree of change in the PSA would warrant a repeat test?
• Does the test need a blood or a urine sample?
• Does the test include or require a PSA level to be valid and reportable?
• How clear is the final test report? How easy is it to understand?
• How much staff time is needed to obtain and process the test sample, including paperwork?
• How much variability is there in the test results?
• How reliable is the test?
• How many ongoing studies and research is being done for further validation and utility of the test?
• How was the original negative predictive value score obtained?
• Is clinical patient data needed to run the risk stratification algorithm?
• Is clinical patient data needed to obtain a result?
• Is home testing available?
• Is the test available in your area?
• Is the test designed to assess the risk of any prostate cancer or just Gleason pattern 4 and higher?
• Is the test listed as recommended in the NCCN or AUA guidelines?
• Is the test result valid independently without the need to provide any clinical patient data? 
• Is the test result valid independently without the need to provide any PSA information?
• Is there a patient version of the test report? 
• What about insurance coverage and patient cost? Does the company offer an indigent patient program?
• What is actually being measured? Genetic material (RNA), PSA, PCA3, or other biomarkers?
• What is the average turnaround time?
• What is the expected percentage of "unreportable" test results that will require the patient to repeat the test?
• Will the test results affect patient care or treatment? (If not, then the test may be unnecessary.)

In general, predictive bioassay testing that includes clinical variables (SelectMDx and "4K") has sometimes been considered more reliable than those tests which do not (PHI, "EPI" exosome, and PCA3).[141] However, those tests which require significant clinical patient information to achieve their competitive negative predictive value scores are, by definition, less reliable when used alone and are not truly independent as they rely on the clinical data and computer algorithms for statistical validation. Since they depend on the clinical information to provide a substantial part of their final conclusion, the test is incomplete and invalid by itself without the addition of the patient data and the computer algorithms. When the physician uses his individual clinical judgment based on the same clinical patient information used in formulating the bioassay test result, then those factors (age, PSA level, PSA density, prior biopsies, etc.) are essentially counted twice, giving them disproportionate weight and bias.

It's been suggested that a superior test would be totally independent of any bias from the medical history, family history, or even the PSA level, allowing such information to be considered by each clinician using their own clinical judgment. Many clinicians prefer those tests which are totally independent of the PSA level and do not require significant patient clinical data yet still offer statistically equivalent and valid results (negative predictive value, etc.), leaving them free to interpret the test report using knowledge of the patient's clinical history and PSA results. A preferred test would be one that the patient could perform at home, is based on genetics, requires minimal staff time to arrange and administer, does not require a prostatic massage, produces few "unreportable" errors that force patients to repeat the process, and still provide over 90% negative predictive value for Gleason pattern 4 disease since lower grade disease is not generally treated. 

Risk Stratification Bioassay Tests

"ExoDx Prostate Intelliscore (EPI)" or "Exosome Test" 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 or higher, or any Gleason Grade Pattern 4 or 5) prostate cancer. Unlike other urine-based tests for prostate cancer, no digital rectal examination or prostatic massage is required, and a kit for home use kit is available, making testing much more convenient for patients. The overall negative predictive value is 91.3%, with a sensitivity rating of 91.9%.[142] The ExoDx exosome test performs particularly well for Gleason 4+3=7 patients, with a negative predictive value of 97% in this group.[143]

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.[144]

MyProstate Score(MPS) 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). One negative is that it requires a prostate massage prior to obtaining an initial urinary stream sample. Future upgrades are under development that would eliminate the need for a prostate massage. Initial reports were uncertain about the MyProstateScore outperforming PCA3 alone, but later validation studies reported sensitivity for Gleason Grade Group 2 or higher disease is 97% with a 98% negative predictive value which is very competitive.[145][146] It has also been shown to be superior to PSA density in the evaluation of patients with PIRADS 3 findings on MRI scans.[147]

Prostate Cancer Antigen 3 (PCA3) is an RNA-based genetic test performed from a urine sample, usually 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 help monitor patients with low-grade prostate cancers on active surveillance. [148]

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 combines 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.[149]

"SelectMDx" is a urine-based test that 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 analysis and algorithm. Results are reported very straight-forwardly as either:[150]

1. Low risk: Very low risk of Gleason 7 or higher disease, where a biopsy may safely be reasonably avoided. The 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.

Prostate Imaging

Ultrasound and MRI are the primary imaging modalities used for initial prostate cancer detection and diagnosis.[151]

• During prostate biopsies, transrectal ultrasound (TRUS) 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 genuinely "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 diagnose prostate cancer without necessarily requiring histological confirmation.
• Prostate MRI is also used for surgical planning in men considering radical prostatectomy and 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 diagnosing 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.[112][152]

Prostate Imaging, Reporting, and Data System (PIRADS)

Unlike CT or x-rays, MRI imaging 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. The use of a flexible, phased array coil that is shaped and worn like a pair of shorts has been designed to further improve prostate MRI imaging by moving the antenna as close as physically possible to the prostate. This modified MRI antenna ("Procure" prostate MRI coil) significantly improves prostate imaging, especially from 1.5 Tesla MRI units, is compatible with most MRI machine manufacturers, and is commercially available. An endorectal coil will also provide improved imaging but is often quite uncomfortable for patients, especially during a lengthy MRI session. 

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.[153]

PIRADS 3 lesions usually demonstrate benign histology on biopsy, but low-grade prostate cancer is possible and 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.[154]

Recent studies of PIRADS 3 lesions have identified several clinical risk factors clearly associated with significant, higher-grade disease (Gleason score 3+4=7 and higher).[155]

Risk Factors Identified for PIRADS 3 Lesions [156][157]

1. Age 70 or older
2. Smaller prostate volume (less than 36 cc)
3. Presence of a palpable nodule on digital rectal examination
4. The size of the lesion or nodule is 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, and 0% if they had no risk factors.  Incorporating these and other risk factors and 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. Equivocal cases may benefit from risk stratification bioassay testing.

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 at 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.[158][159] 

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 biomarker test can help identify individuals at higher risk before any clinical disease progression. The addition of a bioassay risk stratification prostate cancer biomarker to a prostatic MRI can help more reliably eliminate unnecessary biopsies, particularly in equivocal situations such as selected PIRADS 3 individuals. [160]

When an MRI identifies a suspicious area, there are several ways to target or highlight the lesion for improved biopsies:[112] 

• 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 superimposed and merged with the TRUS image, providing a clear visual target for ultrasound-guided biopsies. The equipment currently costs about $150,000, but there is no added reimbursement beyond standard TRUS-guided biopsies at present, which has delayed the widespread implementation of this technology despite its proven benefits.[161]
• 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 requires special biopsy equipment that can be used during MRI imaging.

A recent meta-analysis concluded that the single most useful predictive factor of not finding significant prostate cancer in men with negative MRI studies (other than a specific biomarker or bioassay test) was a PSA density of less than 0.15 ng/ml.[162]

Which Should be Done First: Risk Stratification Bioassays or Prostatic MRI?

There is no general consensus among urologists about this issue. To some degree, this depends on the availability of testing and the relative cost. There are two basic approaches, and both require that patients have a PSA level of less than 10 ng/ml. (Patients with consistent PSA levels >10 should generally go directly to an MRI and a biopsy.) It comes down to a question of what use the clinician wishes to make of the testing: minimize unnecessary biopsies as much as possible or maximize cancer detection. 

The "Minimize Unnecessary Biopsies" Approach for Low-Risk Patients: The intention and primary goal of this approach is to minimize as many "unnecessary" prostate biopsies as possible. The bioassay test is done first. If it's negative, no further testing or imaging is necessary, and routine surveillance is resumed. If the bioassay is positive, perform an MRI and proceed with the appropriate prostate biopsy. About 25% of patients will have low or negative values on their bioassay risk analysis, so a biopsy can safely be avoided in these individuals. This approach is best suited for lower-risk patients, PSA <7, men who do not want a biopsy, or where the primary focus is to safely avoid as many prostate biopsies as possible. Overall, this approach can safely avoid about 25% to 33% of biopsies. Some reports have indicated that the maximal implementation of this approach can avoid up to 55% of all prostate biopsies. The bioassay test becomes the primary screening tool in low-risk patients with PSA elevations to determine if a biopsy can safely be omitted. 

The "Maximize Cancer Detection" Approach for High-Risk Patients: The main focus is to avoid missing significant cancer, so the MRI is done first. If the MRI is positive (PIRADS 3, 4, or 5), the patient proceeds immediately to a Fusion guided biopsy. A bioassay test can be performed subsequently if the MRI is negative to determine if a TRUS-guided biopsy should still be done. The bioassay test is used here as confirmation of a negative MRI result. For low-risk patients with equivocal findings on MRI (PiRADS 3), performing a bioassay risk stratification test is not unreasonable to help determine the need for a prostate biopsy. For high-risk patients where a biopsy is likely to be done regardless of the MRI or bioassay results, only the MRI should be performed to identify suspicious intraprostatic targets for a fusion-directed biopsy.

Rather than adopt either methodology exclusively, a reasonable approach would be to perform the MRI initially in higher-risk individuals but start with the bioassay risk stratification test first in lower-risk patients where a negative finding would result in continued observation only.

High-resolution micro-ultrasonography of the prostate utilizes new specialized ultrasound technology to improve imaging and help detect cancer. High-frequency (29 MHz) micro-ultrasound transducers provide three times the spatial resolution of standard ultrasound.[163] It is quicker, cheaper, and simpler than MRI scans. It also has the advantage of being able to detect a suspicious lesion and immediately perform the biopsy at the same visit. Micro-ultrasonography of the prostate is an office procedure that can be used in patients who are unable or unwilling to undergo MRI scanning.[164] Early studies indicate rough equivalence to MRI (non-inferiority) in cancer detection (sensitivity) and somewhat superior negative predictive value (85% vs 77%).[163][165] Multicenter prospective studies comparing micro-ultrasound and multiparametric MRI biopsies found essential equivalence in prostate cancer detection rates.[166][167] Combining MRI and micro-ultrasonography has demonstrated an improved cancer detection rate of clinically significant disease.[163][164] In one study, about 24% of the "suspicious" lesions were not seen on MRI but only on micro-ultrasonography.[163] It also lends itself to future combined therapy with focal laser ablation or high-intensity focused ultrasound (HIFU).[168]

However, there are a few issues. Performing the prostatic biopsy at the same time as the diagnostic imaging means there is less time for patient discussion and outside review of the findings before the biopsy is done. There is also no time for interdisciplinary evaluations and analysis, such as between urologists and radiologists, for equivocal, difficult, or complex cases.[169] The effect of extreme tumor location, especially anterior lesions where ultrasonic signals are diminished, has not been adequately addressed.[169] Clinicians will need to be trained to interpret these new images, and the necessary equipment will need to be readily available.[169] This new technology is certainly promising and appears to be a reasonable potential alternative to prostatic MRIs, but further validation is needed to determine its ultimate clinical utility. It seems particularly useful potentially in the growing active surveillance population.[169][170][171] However, the issues regarding training, reimbursement, equipment cost, availability, and the ability to clearly identify suspicious lesions in all areas of the prostate need to be resolved before prostatic high-resolution micro-ultrasonography becomes part of the standard diagnostic armamentarium for prostate cancer.[169] 

Positron Emission Tomography (PET) Scanning in Prostate Cancer

CT scans have many limitations in examining patients for recurrence. They are notoriously poor at detecting prostate cancer metastases or recurrences in patients with low PSA levels. PET scans combine a tissue marker with a radioactive, positron-emitting isotope. The radioligand is administered to the patient, and the tissue marker binds to the target malignancy. The radio-isotope releases positrons that can be identified by nuclear scan imaging. This image can be superimposed on a CT or MRI scan to clearly demonstrate the precise anatomic location of any positron-emitting target tissue, which would represent a metastasis or malignant recurrence. Compared to conventional radiological techniques (CT and MRI), positron emission tomography (PET) scans appear to be far more accurate, highly specific, and can be used to detect very small amounts of metastatic or recurrent malignant disease even at relatively low PSA levels. They are rapidly becoming the new diagnostic standard despite their higher cost.

PSMA PET/MRI scans appear to be diagnostically at least equivalent to PSMA PET/CT imaging, but there have been no head-to-head studies that would allow for a more definitive comparison.[172] However, a recent review suggests that PET/MRIs are better than PET/CT scans in local tumor staging, especially in detecting malignancies in pelvic soft tissue, lymph nodes, and particularly extracapsular extension but are equivalent in finding extrapelvic metastases in visceral organs or bones.[173] However, a PET/MRI costs at least 50% more than a PET/CT.[174]

The International Society of Urological Pathology has suggested that PSMA PET/CT could be used in all newly diagnosed prostate cancer patients with significant Gleason grade 4 or any Gleason grade 5 histology PSA >20 or clinical T3 or higher disease.[175]

Prostate-Specific Membrane Antigen (PSMA) is a membrane-bound metallopeptidase. It is overexpressed in 90% to 100% of all prostate cancer cells, making it a reliable tissue marker that can be used for tumor-specific imaging and targeted therapy.[176][177][178] Prostate-specific membrane antigen (PSMA) based positron emission tomography (PET) correlated with computed tomography (CT) is rapidly emerging as the gold standard imaging modality for staging intermediate and advanced prostate cancer as well as the early detection of recurrences and metastases. Compared to alternative imaging technologies (CT scan, MRI, Bone Scan), PSMA PET/CT scanning offers superior sensitivity and specificity for metastatic lymph node detection and bone metastases. Evidence supporting its use is growing, although many studies are retrospective or fail to provide histopathological confirmation of the PSMA PET findings.[179] When used for initial staging, all PSMA-based scans should be performed prior to initiating androgen deprivation therapy which can affect the imaging results. 

There are literally thousands of articles and studies on PubMed covering PSMA. The overall sensitivity and specificity of PSMA-based scanning far exceed any other imaging modality available for prostate cancer detection, staging, or identification of recurrent disease, even with low PSA levels. This is largely due to the incredible overexpression of PSMA in prostate cancer cells (by 100 to 1,000 fold), which results in very high PSMA tracer uptake by prostatic malignancies.[179] Several new radioactive tracers have made it possible to reliably detect prostate cancer recurrences, even in patients with very low PSA levels. A pooled analysis of 43 studies using PSMA-based PET/CT scans in men with prostate cancer recurrences after definitive treatment found that for PSA levels <0.5, 0.5-0.9, 1-1.9, and 2 ng/mL or more, the detection rates were 45%, 61%, 78%, and 94% respectively. Generally, a PSMA-based PET scan is reasonable at a PSA of at least 0.2 ng/mL or more.

Prostascint, which uses Indium 111 (In) capromab pendetide, is a relatively large compound that includes an antibody targeting an intracellular PSMA glycoprotein. It can only penetrate necrotic prostate cancer cells, as it relies on the loss of cellular phospholipid membrane integrity for intracellular transport.[180] Previous use of Indium 111 PSMA-based scans (Prostascint) was quite disappointing, so they are no longer recommended by the NCCN and have been replaced by newer PSMA-based and non-PSMA-based PET scans, as noted below.[181][182][183]

[F-18]-fluorodeoxyglucose (F-18-FDG) PET scans are designed to target rapidly growing cells like cancers that absorb glucose faster than normal tissues. F-18-FDG scans use a tagged glucose analog radiotracer molecule which becomes incorporated into malignant cells. The Fluorine-18 tracer ligand then makes the tissue visible on PET scans. F-18-FDG has been available since the late 1990s and has been widely used for various malignancies. However, its use in urology has been limited by its relatively high renal excretion, which hides many malignancies of the urinary tract and the relatively slow metabolic activity of prostate cancer. Higher grade, castration-resistant, and neuroendocrine prostate cancers, which are faster growing and incorporate more F-18 tagged glucose, will tend to show up better on F18-FDG PET scans.[184][185] Nevertheless, F-18-FDG is generally not considered optimal for prostate cancer PET/CT scanning for these reasons, as well as the relatively high uptake overlap with normal prostatic tissue, BPH, and prostatitis. However, it can be useful in detecting recurrences and staging other fast-growing urological malignancies such as testicular and renal cancer and bladder carcinomas.[186][187][188] F-18-FDG is not a PSMA-based scan, and its half-life is 110 minutes. The NCCN does not currently recommend it for prostate cancer imaging.[186]

C-11-Acetate is very similar to C-11-Choline, reviewed below. Acetate is quickly absorbed by cells and converted to acetyl-CoA, which is then used primarily for energy or fatty acid production. Malignant prostate cells tend to overproduce fatty acids, and increased fatty acid synthase activity has been associated with the aggressiveness of prostatic malignancies.[189] C-11-Acetate has a very short half-life of only 20 minutes, so an on-site cyclotron needs to be available. It has generally been outperformed by other radiotracer elements for PET scanning in prostate cancer, so the NCCN does not currently recommend it for prostate cancer PET scanning. 

C-11-Choline was one of the first FDA-approved PET scans available to detect recurrent prostate cancer. Choline is an essential dietary and cellular nutrient. It supplies methyl groups required for numerous metabolic activities, such as the synthesis of phosphatidylcholine and sphingomyelin (required for cell membranes), and especially acetylcholine. It also is involved in cell membrane signaling, lipid metabolism, and modulating gene expression. Prostate cancer cells demonstrate a substantially increased uptake and concentration of choline compared to normal prostatic cells. Therefore, radioactive carbon-11 tagged choline molecules can detect high choline absorbing tissues such as metastatic prostate cancer when scanned for areas of focal radioactivity with a PET scan.[190] High uptake levels in the prostate can be misleading as high-grade prostatic intraepithelial neoplasia (HGPIN), prostatitis, BPH, and even normal prostatic tissue can produce false-positive results.[191] C-11-Choline has a 53% to 96% positive predictive value in biochemically recurrent prostate cancer. It is not a PSMA-based scan. Its half-life is a very short 20 minutes, so an on-site cyclotron is necessary, limiting its usefulness. Ga-68-PSA-11 and other radiotracers for PET scanning in prostate cancer have largely replaced c-11-Choline scanning. It is FDA-approved for detecting recurrent disease or for suspected progression. It is not recommended for initial staging by the NCCN.

The NCCN has Recommended the Following PET Scans for Prostate Cancer:

F-18 Sodium Fluoride (F-18 NaF) is a radioactive tracer primarily used to detect skeletal metastases. Higher regional blood flow and bone turnover in malignant prostatic bony metastases cause increased focal radiotracer uptake. F-18 NaF is more sensitive than standard bone scans for identifying bony metastases but does not provide much additional information outside the skeleton.[192] For that reason, it has been proposed that it be used together with other PET scanning tracers to provide additional detection capabilities. It is not a PSMA-based scan. F-18 NaF has an 82% to 97% positive predictive value for skeletal metastases and has a 110-minute half-life. F-18 NaF requires a cyclotron for its production. It is FDA-approved only for the detection of skeletal metastases. The NCCN guidelines recommend it as an alternative to standard bone scans. 

Fluorine-18-fluciclovine (F-18 fluciclovine) is a radiolabeled amino acid analog of leucine that takes advantage of the upregulated amino acid transport in prostate cancer cells.[180] It has been shown to detect prostate cancer recurrences in 79.3% of cases.[193] It has a relatively long half-life of 110 minutes. One of its limitations is that since it uses an amino acid analog, there is some background uptake in surrounding tissue such as bone and muscle, but there is relatively little urinary excretion making it most useful in detecting prostate cancers near and around the bladder. It is not a PSMA-based scan. It has an 87% to 91% correct localization rate (CLR) in biochemically recurrent disease and enjoys a half-life of 110 minutes. F-18 fluciclovine requires a cyclotron for its production. It is FDA-approved for use in men with a suspected recurrence or progression of prostate cancer based on increasing PSA levels following prior therapy but not for initial staging. The NCCN guidelines do not currently recommend it for initial staging, although it may be used for biochemical recurrences or suspected disease progressions.

Fluorine-18 piflufolastat injection (F-18 piflufolastat, F-DCFPyL) is a fluorine-based molecule that targets PSMA. It is a small molecule that helps visualize PSMA-expressing lymph nodes, soft tissue, and bony metastases in PET imaging. It is able to detect 85% to 87% of prostate cancer metastases.[194] Compared to Ga-68-PSMA-11, detection results are roughly equivalent, but F-18 piflufolastat has a longer half-life of 110 minutes which is an advantage.[195] F-DCFPyL may offer other advantages regarding availability, cost, and slightly improved detection rates.[195][194] It requires a cyclotron for its generation. F-18 piflufolastat is FDA-approved for detecting prostate cancer metastases, progression, and for biochemical recurrences. The NCCN guidelines recommend it for both initial staging and biochemical recurrences or disease progression. 

Gallium 68 (Ga) prostate-specific membrane antigen (PSMA) 11 (Ga-68-PSMA-11) is a larger radiotracer molecule. It interacts directly with the extracellular active zone of PSMA and does not require cell death to be useful.[180] It has a half-life of 68 minutes. With Ga-68-PSMA-11, there is more urinary excretion of the agent, but it is more sensitive and specific in binding only to prostate cancer cells. To minimize interference from accumulated tracer in the urinary bladder, the patient is asked to void immediately before entering the scanner. It is unclear if a foley catheter or straight cath to eliminate residual urinary tracer is helpful in patients unable to void.  Overall, Ga-68-PSMA-11 outperformed F18 fluciclovine in a head-to-head study (82.8% vs. 79.3%) and was superior in detecting metastases and recurrences outside the bladder area.[193] It enjoys a 92% positive predictive value for identifying biochemical disease recurrence and can potentially be extremely valuable in assessing treatment response, but this aspect requires further investigation.[196] It is also superior to C-11-choline and F-18 fluciclovine in detecting malignant tissue at low PSA levels (<2 ng/dL).[197] Gallium-68 can be produced by cyclotron or by a specially dedicated generator. Ga-68-PSMA-11 is FDA-approved for the detection of prostate cancer metastases and recurrences. It is recommended for both initial staging and biochemical recurrences or disease progression per NCCN guidelines. 

Both F-18 piflufolastat (F-DCFPyL) and Ga-68-PSMA are currently recommended by the NCCN for both initial prostate cancer staging and the evaluation of biochemical recurrences or disease progression. They have nearly identical sensitivity, specificity, and positive predictive values for the detection of metastases for initial staging, biochemical recurrences, and suspected disease progression. Studies have indicated that F-18 piflufolastat (F-DICFPyL) and Ga-68 PSMA enjoy a high detection sensitivity for metastases than C-11 choline or F-18 fluciclovine PET imaging, particularly at very low PSA levels, which is why they are currently preferred by the NCCN.

Ga-68-PSMA-11 PET/CT scanning is currently the preferred imaging modality for identifying metastatic sites for targeted prostate cancer therapy and is the basis for an FDA-approved target-seeking selective radiotherapy (Lutetium 177 vipivotide tetraxetan) that is described later.[198][199][200][201] 

All of the above PET scans can be used in cases of equivocal bone scans. Ga-68 and F-18 piflufolastat would generally be preferred over the rest for this purpose, except for F-18 NaF, which is particularly well suited as a better alternative to traditional bone scans.

Ga-68-PSMA-11 PET/CT, F-DCFPyl, and similar PSMA and non-PSMA-based PET scans, along with whole-body MRIs, are the new state-of-the-art imaging modalities that can replace the classic CT scan of the abdomen & pelvis as well as the traditional technetium 99 bone scan for the detection and staging of all future prostate cancers.[200] There is no need for conventional imaging if a PSMA-based PET scan is performed.

Other agents currently being investigated as radiotracers for prostate cancer PET scanning include:

• Experimentally, F-18 PSMA-1007 had superior sensitivity and specificity in detecting early biochemical recurrence than Ga-68-PSMA-11.[202] 
• Zirconium-89-PSMA-617 (Zr-89-PSMA-617), which is still investigational, has shown superiority in early testing compared to Ga-68-PSMA-11. This is primarily due to the much longer half-life of zirconium-89, which takes several days to decay. This allows for improved imaging, particularly in those prostate cancer patients, about 5% to 10%, who demonstrate relatively low PSMA expression. Animal studies and early human reports indicate superior detection in this group of patients and no inferiority compared to GA-68-PSMA-11 in the remainder.[203] In a small, preliminary sample of 20 patients in Hamburg, Germany, those who tested negative with Ga-68-PSMA-11 scans all demonstrated a positive result with the new Zr-89-PSMA-617 agent. Theoretically, this new agent could offer a great potential benefit, particularly in patients with borderline or mildly positive PSMA PET scans and higher-risk patients with an unexpectedly negative Ga-68-PSMA-11 scan.[203]
• F-18 Rhodium PSMA-7.3 PET/MRI is currently undergoing trials at MD Anderson Cancer Center for early biochemical prostate cancer recurrence.
• Cu-64-PSMA performs similarly to F-18-PSMA scans in detecting prostate cancer, but it has a much longer half-life of 12.7 hours.[204] It also has a lower positron range than Ga-68, giving it better spatial resolution. Further, Cu-68 provides beta decay as well as positron emission and, therefore, can provide both diagnostic and therapeutic benefits from a single dose.[205]

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.[151] The transperineal biopsy approach reduces the risk of infection from about 1% to almost zero. This approach is gaining popularity, especially in Europe, where it is the preferred and recommended method of prostatic biopsy.[206]

• 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 continuing for three days (ciprofloxacin) or 1 to 2 hours before the biopsy. While fluoroquinolones have been the most commonly used antibiotics for prostate biopsy prophylaxis, rising resistance rates have suggested using alternative agents such as cefpodoxime, ceftriaxone, or gentamycin (5 mg/kg). Of these, oral cefpodoxime (200 mg to 400 mg) is commonly recommended as an oral cephalosporin-based antibiotic that avoids the need for parenteral administration, does not contribute to quinolone resistance, and has shown equivalent efficacy for prostate biopsy prophylaxis.[207] 
• Pre-biopsy rectal cultures are suggested to help optimize prophylactic antibiotic selection.[208][209]
• A Fleets enema is recommended shortly before the biopsy to help clean the rectum.
• Consider using a transperineal approach in immunocompromised patients or those at high-risk for infection.[206]

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. Fusion-guided biopsies use the MRI image with the "suspicious" area highlighted as a target and superimpose it over the ultrasound image. The two images are matched, which allows the MRI target to be visible on the transrectal ultrasound so it can be biopsied. The rest of the biopsy procedure is the same. 

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.

Histologically, prostate cancer is classified by its Gleason Score, which is based on its microscopic architecture and cellular arrangement rather than any specific characteristics of its individual cells. This is best described in the companion article on the Gleason Score for Prostate Cancer.[210]

Genomic (Somatic) Tumor Biomarkers (Post-Biopsy)

Tissue samples can be analyzed for various genomic tumor markers. Several commercial genomic tests can now 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 or radical prostate surgery. The intention is to confirm that the patients who are eligible and select active surveillance also have low-risk genomic markers. They should be counseled accordingly if their genomic analysis shows a higher risk.[211][212] In general, they should only be considered in patients with localized disease and at least a 10-year life expectancy, a Gleason Score that is no worse than 3+4=7 or intermediate-risk histologically, and where the results of the genomic testing are likely to make a significant difference in treatment selection. None are recommended for very low-risk or very high-risk disease.

ConfirmMDx is a genomic marker test that 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. ConfirmMDx estimates the likelihood of finding prostate cancer when the initial biopsy is negative. It is most useful when the initial 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).[213][214]

The Decipher test evaluates tissue for the expression of 22 RNA biomarkers to calculate the probability of clinical metastasis within five years of definitive therapy. It also calculates the prostate cancer-specific mortality at ten years, the 5-year risk of developing metastases, and the chances of finding high-grade disease after radical prostatectomy. The test aims 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 and/or androgen deprivation 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 their 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 five years of their radical prostatectomy procedures.[141][214] While Decipher can be used for any patient with localized disease, low to intermediate-risk cancers, and a 10-year life expectancy, it is most helpful in higher-risk individuals, those with positive surgical margins, and patients with extraprostatic extension (T3), where it can help decide on the use of adjuvant radiation and hormonal therapy.[214] Like the Prolaris test, it can also be used in high-risk disease.

Oncotype Dx Prostate measures 17 gene expressions and is an automated immunofluorescence-based assay. It calculates the patient's chances of having organ-confined disease after radical prostatectomy surgery using genomic information from the biopsy specimen. Oncotype Dx looks at four specific areas of gene expression: the stromal response, androgen signaling, cellular proliferation, and organization. It has been shown to change treatment recommendations by 18%, primarily through a reduction in radiation therapy of 33% and a 10% increase in active surveillance.[214] A similar increase in the selection of active surveillance by using Oncotype Dx was also found in a complementary VA study.[215] It is best suited for patients with localized disease and low or favorable intermediate-risk disease (Gleason 3+3=6 or Gleason 3+4=7), where either active surveillance or definitive primary therapy are reasonable treatment options.[214][216][217][218]

The ProMark test is a protein-based assay looking at eight specific proteins involved in cell signaling, cellular proliferation, and stress response. This type of test will tend to identify the most aggressive cells in the tumor. It is intended to indicate the probability of non-organ confined disease after radical prostatectomy surgery and the likelihood of finding a Gleason Score equal to or greater than 4+3=7 in the post-operative specimen. The ProMark test estimates the probability of finding higher-risk or non-organ-confined disease after radical surgery. Like Oncotype Dx, it is most useful and optimized for patients with localized disease that is low-risk or favorable intermediate-risk histologically.[210][214]

The Prolaris test was the first commercially available genomic tumor marker to evaluate prostate cancer aggressiveness.[219] It looks at 46 genes and specifically measures the RNA expression of 31 genes involved in cell cycle progression. It is designed to indicate the risk of biochemical recurrence and prostate cancer-specific mortality over the next ten years when combined with the PSA level, clinical stage, percentage of positive biopsy cores, biopsy grade group, and AUA risk group.[214] In a large prospective registry, the Prolaris test changed the initial treatment selection in 47.8% of the 1,600 participants. 75% selected a less aggressive therapy, and 25% opted for a more definitive treatment option.[220] The test is most useful in facilitating decision-making for individuals with localized disease and low or intermediate-risk cancers (both favorable and unfavorable) who are considering active surveillance vs. definitive treatment. Prolaris can identify cancer-specific mortality for men on active surveillance and with biochemical recurrence for those who have had radiation therapy or undergone TURP surgery.[145][214] Like Decipher, the Prolaris test is also useful in patients after radical prostatectomy surgery and in high-risk cases for prognostic purposes.[214]

Clinical Summary of Commercially Available Tissue-based Prostate Cancer Biomarkers Useful for Risk Stratification in Men with Localized Disease:[210][214]

• High-risk factors for prostate cancer, but the initial biopsy is negative: ConfirmMDx
• Localized disease with low-risk histology considering active surveillance vs. definitive therapy: Prolaris
• Localized disease with low-risk histology considering radical prostatectomy: Oncotype Dx Prostate, ProMark, Decipher, or Prolaris
• Localized disease with higher risk factors or histology: Decipher or Prolaris
• Post-TURP with incidentally discovered prostate cancer: Prolaris
• Post-radical prostatectomy surgery: Decipher or Prolaris
• Post-radical prostatectomy surgery with positive margins or other high-risk factors: Decipher
• Post-radiation therapy: Prolaris

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 be a reliable indicator of high-grade prostate cancer and distinguish between intermediate and high-grade malignancies.[221]

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.[209][222]

Treatment / Management

The first decision in managing prostate cancer is determining whether any treatment is needed. Prostate cancer, especially low-grade tumors, often grows 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

Many low-risk cases can now be followed with active surveillance. Patients in active surveillance 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. Some intermediate-grade tumors (Gleason 3+4=7) may also qualify. The 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 tissue-based biomarkers and 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. Genomic testing may be most helpful when the PSA is in the 10 to 20 ng/ml range or with increased tumor volume.[145][216][223]

Along with serial PSA levels, an 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 be offered appropriately while the vast majority are safely spared the costs, inconvenience, side effects, and complications of definitive curative therapy.

No specific biomarker or bioassay has been prospectively tested and validated in active surveillance protocols for prostate cancer, although theoretically, their use would seem appropriate. Serial PSA and PSA density measurements appear useful but are not definitive or as reliable as a biopsy. As a replacement for repeated biopsies every 18 to 24 months, serial prostatic MRIs (for PSA density) and an appropriate bioassay may eventually prove a suitable alternative. Risk calculators for active surveillance have been validated, are generally underutilized, and are very cost-effective.[224]

For patients on active surveillance, certain characteristics tended to have prognostic significance in a large multi-institutional database. High-risk clinicopathological features were associated with an earlier time to cancer progression/upgrading. High tumor volume was also found to have a significant negative prognostic effect as these patients tended to behave more like higher-risk malignancies.[225] The length of Gleason pattern 4 on the original biopsy has also been shown to have an impact on increasing the risk of future progression for patients on active surveillance.[226]

The best option depends on the cancer stage, Gleason score, and PSA level, as well as individual patient preferences, overall health, comorbidities, quality of life, and age. Heritable factors from germline testing may play an important role in patients on active surveillance, but family history alone has not been shown to be a significant prognostic risk factor for progression.[227][228]

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.

The use of imaging in active surveillance patients may significantly eliminate the requirement for many biopsies in this group. The need for a confirmatory biopsy at 12 to 18 months tends to discourage patients from accepting active surveillance. It is unclear at this time how MRI scans may affect active surveillance protocols, but it has been shown that even negative serial MRI scans and stable PSA levels could not guarantee a lack of progression which occurs in 14% of such patients.[229] A follow-up biopsy is therefore recommended at 3 years regardless of other findings (such as a stable PSA and negative serial MRIs)  to identify such "hidden" cancers.[229]

The addition of PSMA-PET scans has not significantly increased the detection rate of clinically significant cancers in patients on active surveillance, but with a reported negative predictive value of about 86%, it has the potential to reduce scheduled routine or confirmatory biopsies by up to 80%.[230] 

Localized Disease

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 ten 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.[123]

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[231]

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.[231]

Focal ablative therapy can use any one of a number of ablative energies, including microwave, cryotherapy, laser, high-intensity focused ultrasound (HIFU), 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.[232] 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.[233]

The unsettled issue 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 its long-term efficacy. Its role in treating prostate cancer has yet to be determined.[232][234][235][236]
• 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.[232][235][236][237]

Hormone Therapy[238][239]

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.[240][241] He was awarded the Nobel Prize for Medicine in 1966 for this discovery which is the basis for all hormonal (testosterone deprivation-based) treatments 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 the initiation of hormonal therapy with these agents. This prophylactic anti-androgen therapy is not necessary with degarelix or relugolix because they are direct LHRH antagonists, and there is no testosterone surge with this class of drug.

Relugolix is an oral LHRH antagonist that is now FDA approved and available. Like injectable degarelix, it is a direct LHRH antagonist and causes a very rapid decrease in serum testosterone. It is quite effective as it caused sustained castrate levels of testosterone in 97% of men tested (compared with 89% of men treated with leuprolide) and appears to have fewer major cardiovascular events as well.[242] Like degarelix, it is approved for prostate cancer that is locally advanced, castrate-resistant, or metastatic, as well as for patients with biochemical recurrences.[242]

Choosing which anti-androgen hormonal therapy to use depends on the clinical situation, ease of administration, availability, cost, insurance coverage, physician experience, and individual patient preference.[243] Patients with very high PSA levels or where there is a need for an acute and immediate reduction in testosterone levels would benefit from an anti-androgen such as degarelix or relugolix, but for the majority of prostate cancer patients starting hormonal therapy, the choice of which initial hormonal therapy depends on the clinical situation, ease of administration, availability, cost, insurance coverage, physician experience, and individual patient preference.[242][243]

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 does not appear to be a 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.  There are conflicting reports regarding a possible connection between long-term androgen deprivation therapy and cardiovascular risk and metabolic syndrome. 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 three months have 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.[244][245]

The most common side effect of hormonal therapy is hot flashes in up to 80% of men on hormonal therapy. These hot flashes can sometimes be quite uncomfortable and occur up to 10 times a day in some individuals. Other symptoms are occasionally reported, along with hot flashes, including irritability, anxiety, or heart palpitations. Men who develop hot flashes after starting hormonal therapy usually report that they tend to decrease in frequency and intensity over time, and they typically disappear within three to four months of stopping the anti-androgen therapy. 

The most effective preventive therapy for hot flashes is oral medroxyprogesterone 20 mg/day or cyproterone 100 mg/day.[246] Medroxyprogesterone is also available as an injection. It contains the synthetic hormone progestin, a progesterone-receptor agonist that is well absorbed when taken in pill form and is generally considered the best therapy for severe hot flashes in men. Cyproterone is a synthetic progesterone derivative that is not approved by the FDA in the US but is used elsewhere in the world for advanced prostate cancer. It is also quite effective in controlling hot flashes. Megestrol (Megace) is a synthetic progesterone that is also very effective in minimizing hot flashes. However, some studies suggest it could cause a rapid progression of prostate cancer.[247][248] Gabapentin appears to be reasonably effective in managing hot flashes at a dose of 300 mg three times a day.[249] SSRIs such as venlafaxine, fluoxetine, paroxetine, and sertraline have demonstrated moderate activity in suppressing hot flashes and are quite safe, but they are not as effective as progesterone.[246] Finally, oxybutynin has shown some activity in suppressing male hot flashes anecdotally but has not yet been studied adequately to be routinely recommended.[250][251] Many clinicians typically start with an SSRI and then consider adding either gabapentin or megestrol, reserving medroxyprogesterone for the most severe and intractable cases. Estrogen therapy is effective for eliminating male hot flashes but can cause gynecomastia, potentially dangerous thromboembolism, and blood clots, so it is not recommended. 

A baseline DEXA scan for bone density is recommended for all patients starting hormonal therapy and are expected to remain on it for one year or longer. It should be repeated every two years while on therapy, according to the National Osteoporosis Foundation (nof.org.faq.590) and NCCN Clinical Practice Guidelines. In a Danish study, two-thirds of prostate cancer patients were found to have osteoporosis even before any hormonal therapy had been initiated![252] Bone density deterioration is estimated at a rapid 13% per year for patients on hormonal treatment for prostate cancer.[253] The increase in skeletal fractures is almost fourfold over baseline after two years.[254] Prostate cancer patients with such fractures face a markedly increased mortality risk seven times higher than similar patients without fractures.[255] Despite clear recommendations for a baseline and follow-up DEXA scan every two years in prostate cancer patients receiving long-term hormonal therapy, multiple studies have confirmed that this important test and osteoporosis preventive therapy is often omitted.[256][257][258] In a recent review of the AUA Quality Registry (AQUA), only about 5% of eligible patients received a DEXA scan within an acceptable timeframe! Even in patients over 80 years of age, who have the highest osteoporosis and fracture risk, only 3.6% had the scan. A baseline and follow-up DEXA scan is highly recommended, particularly in patients expected to be on long-term hormonal therapy and in high-risk groups such as the elderly.[259][260]

After the DEXA scan, full osteoporosis treatment (calcium citrate and vitamin D supplements and a bisphosphonate or rank ligand inhibitor) is suggested for all patients with a T score <-2.5. Preventive therapy should also be considered for patients with a T score between -1.5 and -2.5 based on age >75, BMI <19 kg/meter squared, glucocorticoid therapy, a history of falls, or other significant risk factors such as cardiovascular disease, dementia, depression or Parkinson disease.[261] 

Castrate-resistant prostate cancer patients with bone metastases should receive high dose IV zoledronic acid (bisphosphonate) or denosumab (rank ligand inhibitor) specifically to minimize skeletal-related events such as fractures. 

Osteoporosis preventive therapy, including calcium and vitamin D supplements together with a bisphosphonate or rank ligand inhibitor, should be considered in all men on long-term hormonal treatment to prevent or at least minimize bone loss as the vast majority of prostate cancer patients on long-term hormonal therapy will demonstrate osteoporosis, osteoporotic fractures or osteopenia after two years of therapy.[260] Calcium citrate is the preferred calcium supplement, and 5,000 units of vitamin D a day is suggested. The American Society of Clinical Oncology (ASCO) recommends a daily calcium intake of at least 1,000 to 1,200 mg (dietary and supplements) for patients on hormonal therapy.[262] Other helpful measures include decreased alcohol intake, stopping smoking, and increased exercise (especially weight-bearing activities).

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 ten 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.[263]

The majority of such surgeries are now being done robotically or laparoscopically. There does not appear to be much difference overall in side effects or survival between minimally invasive (robotic) or open surgical approaches. The surgeon's experience appears to be the most critical factor associated with a successful outcome, regardless of which technique is used.[264][265]

Individual patient issues would include activity level, age, continence, comorbidities, performance status, presurgical erectile function, 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.[266]

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).[267]

The optimal extent of the lymph node dissection is uncertain. A greater and more extensive lymph node dissection is 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.[268]

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, suggesting the possibility of a benefit from the procedure.[267]

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.[269]

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 primary definitive radiation therapy.[270]

Without treatment, metastatic disease can develop from microscopic cancer remnants after radical prostate surgery in about eight years, and overall survival averages about 10 to 13 years.[271]  

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 all remaining cancer will be within the radiation field, and it should not be considered with clear evidence of distant metastatic tumor spread.[272]

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.[273]

Alternatively, 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 help assess and reliably estimate an individual patient's relative risk in these situations.[274]

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.[275]

A meta-analysis compared the results of definitive radiation therapy for Blacks compared to Whites using seven different randomized clinical trials. It found that Black men actually had a higher overall success rate with radiation therapy.[276] 

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 help identify local recurrences, but the PSA level needs to be over 1 to 1.5 for the recurrence site to be visible on the scan.[277][278]

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.[279][280]

If radiation therapy is done first and fails, then salvage radical prostatectomy surgery becomes challenging and often impossible due to scarring, fibrosis, and loss of anatomical landmarks. However, cryotherapy would still be possible as a salvage treatment.[281]

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.[282]

Cryotherapy provides very good tissue ablation and destruction but has some complications and is very technology-dependent. Early use of this technology was delayed due to the size of the original Nitrogen probes, the development of 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, the use of multiple strategically placed interstitial temperature sensors to prevent over-freezing, simultaneously utilizing multiple smaller probes 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.[283]

Using 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 appear to improve the cancer-free results.  Hormonal therapy can help reduce the prostate size but does not otherwise improve survival outcomes with cryotherapy.[283]

The incidence of erectile dysfunction is relatively high with cryotherapy, which is an issue that should be discussed with patients before treatment.[284]

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.[281][285]

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.[286]

Focal or limited cryotherapy is a possible experimental option in selected patients.[287][288]

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.[289]

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.[290][291]

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 higher dosages to be given to the prostate and tumor while not significantly increasing exposure to the surrounding tissues to minimize late side effects.[292][293]  

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.[294][295]

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 radiosensitivity 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.[296][297]

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.[298][299][300]

Complications from External Beam Radiation Therapy

Significant areas of concern include prostate size and potential radiation side effects on the bowel and bladder (radiation proctitis and cystitis).[301]

There is an increased risk of hematuria in up to 15% of patients, especially if anticoagulated. Managing hemorrhagic complications of radiation cystitis includes oral pentosan polysulfate 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).[302]

Erectile dysfunction is another relatively common complication reported in 30% to 45% of men who were potent before starting radiation therapy.[303]

There are also possible issues with fatigue and increased fracture risk.[304]

There is a slightly higher incidence of secondary malignancies after definitive radiation therapy.[305]

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 that are currently undergoing clinical trials. It is hypothesized that using SABR for metastatic cancer may be reasonable to reduce the 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.[295][306][307]

Stereotactic ablative radiation therapy (SABR) may increase the patient's immune response.  The proposed mechanism is by releasing additional tumor antigens due to the larger fractional radiation dosage, which then prompts the increased immunological response.[295]  

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.[295]

Brachytherapy (Radioactive Seed Implants)

Brachytherapy is another form of radiation therapy that involves surgically implanting tiny radioactive seeds into the prostate. Conceptually, this allows 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 make standard external beam therapy more difficult. Most prostates will accept from 75 to 125 seeds.[308]

Hormonal therapy can 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%.[309]

When combined with brachytherapy, hormonal therapy has been shown to improve survival outcomes, so it is usually recommended.[310]

Seeds are placed transperineally using TRUS and a template plan that has been previously worked out by a radiation therapist or physicist.[311]

Radioactive materials used include iodine 125, palladium 103, and cesium 131. Cesium has the shortest half-life.[312][313]

Several trials have examined outcomes between standard radiation therapy (hormonal deprivation plus external beam radiotherapy) with or without a brachytherapy booster in locally advanced or aggressive prostate cancers. No clinically significant improvement was noted between these groups suggesting no benefit to the addition of a brachytherapy boost even in higher-risk patients.[314][315]

High-Dose Rate Brachytherapy can also be done using hollow needles placed through the perineum, 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.[313]

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.[312][316]

Outcomes are similar to external beam radiation and radical prostatectomy surgery, but there are no head-to-head trials. However, some evidence suggests 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.[317]

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 of metastatic prostate cancer and 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 radiation dose 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 intensity-modulated radiation therapy (IMRT).[318][319]

Carbon Ion Therapy is another type of particle beam irradiation under investigation in Japan. Preliminary data appears promising.[320]

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.[321]

Technology is continually changing to optimize radiation delivery to cancer while minimizing side effects, peripheral exposure, spillage, and long-term complications. 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.[26][297][322]  

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.[297]

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.[323]

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.[324]
• The early use of docetaxel in hormone naive patients with high volume or high-grade localized disease appears to be beneficial based on significantly increased survival noted in several studies (STAMPEDE, CHAARTED, RTOG 0521, and GETUG 12).[325][326][327][328][329]
• The second-line chemotherapy treatment is cabazitaxel.[330][331]
• Enzalutamide, abiraterone, darolutamide, and apalutamide are newer, second-generation hormonally based anti-androgens that often work even when initial hormonal therapy has failed.[332]
• 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.[333][334]
• The combination of docetaxel and abiraterone for metastatic or locally advanced hormone-sensitive prostate cancer appears justified by recent studies.[333][335]
• The PEACE-1 trial looked at men with newly discovered, hormone-sensitive metastatic disease. All were given full hormonal therapy. Those men given abiraterone plus docetaxel in addition to standard hormonal therapy had a median progression-free survival of 4.5 years compared to 2 years for those treated with standard therapy. The benefit was greatest in those men with the most significant metastatic burden.[336] The overall median lifetime survival benefit in men with high-volume prostate cancer metastases was 1.5 years.[336]
• Enzalutamide works by interfering with androgen receptor binding and intracellular communication functions. It provides a 5-month overall survival advantage.[337]
• 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 agonist therapy compared to only 14.7 months with LHRH therapy alone. This is very similar to the benefit of apalutamide (see below). However, an increase in ischemic cardiac events was noted in the enzalutamide-treated group (2.7% vs. 1.2%), so caution is necessary for patients with significant heart disease.[337][338]
• Apalutamide is a newer anti-androgen that is also FDA approved for use in non-metastatic, castration-resistant prostate cancer (enzalutamide is the other.)[339] Its mechanism of action is similar to enzalutamide. Studies report that the time to symptomatic cancer progression as well as metastasis-free survival was significantly longer with apalutamide than with placebo. The median metastasis-free survival was more than two 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.[340]
• 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 plus androgen deprivation therapy reduced the risk of radiographic progression or death by 52% (vs. placebo plus androgen deprivation therapy) and extended survival with a 33% reduction in the mortality risk.[339]
• The newest FDA-approved second-generation anti-androgen is darolutamide. While no head-to-head studies exist, all of the second-generation anti-androgens substantially improve overall survival over placebo. Like the other second-generation anti-androgens, improved survival was found when they were added to LHRH-agonist therapy and docetaxel compared to placebo.[341]
• Starting a second-generation hormonal agent such as enzalutamide or apalutamide may cause a temporary increase in PSMA uptake on PET/CTs called a "flare" in about half the patients treated.[174]
• 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.[340][342][343] 
• 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.[344][345]
• Patients who progress after treatment with second-generation hormonal agents (enzalutamide or abiraterone) should be considered for PARP inhibitor therapy (olaparib and rucaparib) if they have BRCA1, BRCA2, or ATM germline or somatic mutations.[346][347][348][349][350]
• While similar, it appears that enzalutamide and apalutamide may provide slightly better overall and metastasis-free survival, while darolutamide appears to have better tolerability with fewer side effects.[341][351][352][353]
• 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.[354][355]
• Immunotherapy treatment with sipuleucel-T in CRPC has been shown to increase survival but only by five months in patients with advanced disease (PSA >50).[356] It is indicated for men with metastatic, castration-resistant prostate cancer but is usually used too late for maximal effectiveness. In patients with a PSA less than 22.1, median survival increased by over a year. (See more details below.)
• Only a small subset of people respond to androgen signaling blocking drugs.[357]

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 the bone.[358]

Bisphosphonates like zoledronic acid and rank ligand inhibitors like denosumab have improved quality of life and reduced pathological fractures in CRPC patients. Unfortunately, these agents have not been shown to improve survival. Before using either of these agents, a dental checkup is recommended due to their association with osteonecrosis of the jaw. Calcium and vitamin D supplements are recommended when either medication is used. Calcium citrate is the preferred calcium supplement due to its increased solubility and absorption while 5,000 units of daily supplemental vitamin D is also suggested for these patients.[259][260][339][359]

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. Radium 223 specifically targets the bone and is ineffective in visceral, soft tissue, and nodal disease. Therefore it should be used in castrate-resistant prostate cancer with bone metastases but without significant organ, soft tissue, or lymph node involvement. Radium 223 therapy improves the 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 suggest that there may be an increased risk of fractures and deaths associated with Radium 223 when used together with abiraterone and prednisone.[360][361]

Lutetium 177 vipivotide tetraxetan is now FDA approved for use in metastatic castrate-resistant prostate cancer in patients with positive gallium 68 PSMA-11 PET/CT scans who have failed hormonal therapy and at least one course of docetaxel or cabazitaxel. The technology binds a beta particle source with a PSMA-specific binder into a unique radioligand which seeks out PSMA-expressing cells and exposes them and their immediate microenvironment to beta radiation. The treatment has a good safety profile and is relatively well tolerated. It has been found to extend progression-free and overall survival in this extremely difficult group of patients by about 4 or 5 months.[198][199]

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 except in patients with PSA levels <22 where it has improved median survival by over one year. (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 patient.[362][363] 

Polyadenosine diphosphate-ribose polymerases (PARP) are a type of enzyme that helps repair DNA damage in cells. PARP inhibitors, such as olaparib and rucaparib, prevent cancer cells from repairing DNA damage which facilitates apoptosis. They are considered a type of targeted therapy as they work best in patients with DDRG germline or somatic mutations. Olaparib showed a median survival benefit of about five months (more than double the median progression-free survival) compared to enzalutamide or abiraterone treatment alone and was most effective in patients with BRCA2 mutations on germline testing.[347] Rucaparib demonstrated a 63% PSA response rate.[364] Patients with PALB2, BRIP1, and RAD51B mutations responded quite well to rucaparib therapy, while those with ATM, CDK12, and CHEK1 germline mutations were generally refractory to the drug.[346][365] Both PARP inhibitors have demonstrated the ability to extend overall survival and make prostate cancer more radiosensitive in early clinical trials.[346][347][348][349][350][364][366][367] This may greatly increase their usefulness and efficacy in the future once this aspect of their clinical effect has been adequately studied.[366] Olaparib and rucaparib are FDA-approved for use in men with metastatic castrate-resistant prostate cancer who have BRCA1, BRCA2, or ATM mutations that have progressed after enzalutamide or abiraterone therapy.

Summary of Prostate Cancer Chemotherapy

• All protocols start with hormonal therapy (LHRH agonist or antagonist therapy with an anti-androgen). In advanced or aggressive cases, a second-generation anti-androgen should be used and possibly docetaxel.
• Docetaxel is the recommended first-line chemotherapy.
• Second-line chemotherapy is cabazitaxel. While similar in efficacy to docetaxel, cabazitaxel is preferred in patients at risk for neutropenia, extremely frail, or older patients as it is better tolerated. However, cabazitaxel is more costly than docetaxel.
• Platinum-based chemotherapy can be used next, such as carboplatin, oxaliplatin, or cisplatin which are usually used together with paclitaxel, capecitabine, or estramustine.
• Mitoxantrone only has a minor role in prostate cancer chemotherapy, although a few patients who've failed docetaxel have responded to it. It may have a greater effect on symptom relief than survival. 
• Docetaxel or cabazitaxel together with carboplatin is often recommended in more aggressive cancers. 
• Etoposide, together with carboplatin or cisplatin, is suggested for neuroendocrine tumors, which are often very aggressive.
• Patients with ATM, BRCA1, BRCA2, CHEK2, FANCA, and PALB2 germline mutations that involve DNA damage repair genes (DDRG) tend to have an unusual sensitivity to platinum-based chemotherapy and are likely to respond to PARP inhibitors such as olaparib and rucaparib.
• Patients who fail enzalutamide or abiraterone may be candidates for PARP inhibitors. Check for BRCA1, BRCA2, and ATM germline status. Also, consider obtaining an AR-V7 blood test.
• Patients with BRCA1 and BRCA 2 mutations respond better to PARP inhibitors than those with ATM or other mutations.[368] 
• Patients with MLH1, MSH2, MSH6, and PMS2 that involve DNA mismatch repair genes may respond to an immunotherapy drug such as pembrolizumab.[369]
• Patients with castrate-resistant prostate cancer and bone metastases will benefit from either zoledronic acid or denosumab to minimize bone pain and fractures.
• Sipuleucel-T, Radium 223, Lutetium 177, and PARP inhibitors (olaparib, rucaparib) should be used appropriately in castrate-resistant prostate cancer patients for both palliative and therapeutic benefits as they have all shown improvements in the quality of life, clinical symptom reduction, and cancer-specific as well as overall survival. They are often used too late in the course of the disease for optimal patient benefit.
• Whenever possible, patients who are failing initial chemotherapy should consider participation in a clinical trial. The most complete listing of all open clinical trials in prostate cancer in the United States can be found at clinicaltrials.gov. 

Areas of Future Research

The activity of various protein kinases is associated with the development of androgen-independent (castrate-resistant) prostate cancer. Protein kinases are involved in the growth, proliferation, aggressiveness, and metastases of prostatic cancers. Some are also involved in the androgen receptor signaling pathway and offer the possibility of changing the cellular response to androgen deprivation through specific protein kinase inhibitor therapy.[370] Excellent research opportunities exist in the area of protein kinase inhibitors which would reduce specific kinase activity or interrupt kinase-mediated signal pathways.[371][372]

Another PARP inhibitor (niraparib) shows good efficacy and safety in metastatic castration-resistant prostate cancer clinical trials.[373] Talazoparib and ipatasertib are similar PARP inhibitor drugs also currently undergoing clinical testing.

Research is ongoing in the challenging area of identifying molecular biomarkers that could potentially predict the response to immunotherapy to allow for individual customization of such treatment for patients with advanced, aggressive, or metastatic prostate cancer. New immunotherapy treatments, such as immune checkpoint inhibitor combinations, bispecific T-cell engager immunological therapies, and chimeric antigen receptors, are under development and early test results appear promising.[374] Radiopharmaceuticals similar to lutetium 177 show great promise in targeting individualized markers on prostate cancer cells and then delivering specific, customized treatment there. Lutetium 177 is just one of the first treatments based on this therapeutic modality.[198]

Another promising area of research involves prostate cancer stem cells. These are small populations of prostate cancer cells that induce tumor onset, growth, and development. They contribute to the development of resistance to chemotherapy and promote metastasis. Upregulation of cell surface markers found on these prostatic cancer stem cells is closely associated with more rapid cancer growth, metastases, and an overall poor prognosis.[375]

The development of hormonal-resistant prostate cancer involves several families of chromatin modifiers. Targeting the bromodomain and extra-terminal protein family would be a promising, new, and novel approach to treating castrate-resistant prostate cancer. Our relative lack of knowledge of androgen resistance mechanisms and genetics means that such therapies are not likely in the near future.[376]

Second-generation anti-androgens fail at least in part due to androgen-receptor mutations or splicing adjustments. These actions result in cell reactivation. Various mechanisms of reducing androgen receptor protein levels and activity are being investigated, including androgen receptor nuclear localization inhibition, N-terminal suppression, heat-shock protein blockage, and proteasome-mediated accelerated degradation.[377]

Ipilimumab is a type of monoclonal antibody that activates cytotoxic T lymphocytes by direct blockage of CTLA-4 (cytotoxic T-lymphocyte antigen) T-cell receptor sites, which would otherwise downregulate the immune system. Ipilimumab is primarily used as immunotherapy for melanoma but has been found to have some activity in prostate cancer. Two large ipilimumab prostate cancer trials showed an improvement in progression-free survival, but overall survival was not statistically improved.[378][379] However, a few patients have enjoyed long-term prolonged survival of up to 64 months.[380] Further testing, possibly involving specific germline testing, is needed to better identify patients likely to see such a prolonged survival benefit.

Nivolumab is another monoclonal antibody cancer therapy that inhibits the activity of PD-1 receptors on T-cells. This results in a net increase in T-cell activity and an enhanced anti-tumor immune response. Nivolumab plus ipilimumab showed minimal additional efficacy in treating prostate cancer, but when combined with docetaxel, there was an improved response in castrate-resistant prostate cancer patients.[381][382]

Targeted, individually customized anticancer therapies offer great potential for controlling the malignancy and reducing side effects by delivering cytotoxic material selectively only to malignant cells. One way of doing this is by using designed ankyrin repeat proteins (DARP). These are non-immunoglobulin-based scaffold proteins designed to deliver a cytotoxic payload exclusively to prostate cancer cells. Epithelial cell adhesion molecule (EpCAM) is over-expressed in 40% to 60% of prostate cancers and is associated with more rapid tumor growth, higher risk of metastasis, resistance to chemotherapy, and decreased cancer-specific survival. Experimentally in vitro, it was possible to use a specially designed DARP molecule to deliver a Pseudomonas exotoxin A variant into EpCAM-expressing prostate cancer cells. The toxin was rapidly internalized, and normal prostatic cells were left unharmed.[383] This and similar therapies offer great hope for individualized, effective, and safe targeted treatments in the near future.

Germline Testing in Prostate Cancer

We know that up to 17% of men with prostate cancer will demonstrate germline, inheritable abnormalities and that about 10% of patients with metastatic castration-resistant disease carry inherited gene mutations.[384][385][386] 

Germline testing intends to identify heritable, genetic cancer predispositions, inform individual patients and family members of any increased cancer risks, suggest customized screenings for selected, affected individuals, help guide prognostic predictions, and assist in treatment decisions.[387] 

Hereditary prostate cancer due to germline mutations has an autosomal dominant pattern or transmission and is typically characterized by early onset.[388] Multiple trials are underway, including patients with both metastatic prostate cancer and localized disease, to determine how best to use germline testing information to help select the optimal customized therapy for that individual.[389] Identifying a hereditary predisposition to cancer among both male and female family members can lead to optimized screening of those individuals with earlier detection and treatment of any newly discovered malignancies.[389]

• Overall, the most commonly found germline mutation in prostate cancer is BRCA2. This is followed by ATM, CHEK2, and BRCA1.[390]
• Patients with germline mutations of BRCA1, BRCA2, or ATM were found to have a higher likelihood of cancer upgrading during active surveillance.[391][392] 
• BRCA1 and BRCA2 mutations have been found in up to 11.8% of men with metastatic prostate cancer and 5% to 7% of patients with localized disease.[388][389]
• BRCA1 and BRCA2 mutation status has been found to be an independent prognostic indicator of metastasis-free survival in patients with localized disease undergoing definitive therapy (either radiation or radical prostatectomy).[393][394] 
• Men with BRCA1 or BRCA2 mutations are also at higher risk for male breast cancer, melanoma, and pancreatic cancer.[388][389]
• Men with these mutations face an overall increased risk of prostate cancer (3.8 times higher risk for BRCA1 and 8.6 fold higher risk for BRCA2) and are more likely to present with advanced disease. a higher Gleason Score, and tend to have shorter cancer-specific survival than non-carriers.[394][395]
• They also have worse outcomes after radical prostatectomy or radiation therapy.[394]
• Germline mutations were found in 43% of younger prostate cancer patients (<55 years) compared to only 9% in men over 85 years with similar clinical disease.[396]
• Higher Gleason scores have been associated with BRCA2, ATM, and NBN mutations.[397] 
• The NCCN recommends that men with a BRCA2 mutation should start annual prostate cancer screenings at age 40. A cutoff of 3 ng/ml has been suggested for this group. The same is suggested for men with BRCA1 mutations.[389][398]
• Patients with metastatic castration-resistant cancer and a BRCA1, BRCA2, or ATM mutation that has progressed despite hormonal therapy including either enzalutamide or abiraterone will benefit from a Poly(ADP-ribose) polymerase (PARP) inhibitor, such as olaparib or rucaparib.[389][348][389]
• Mutations in the HOXB13 gene, usually found in people of West African descent, are associated with an eight to tenfold increase in the lifetime risk of prostate cancer as well as an earlier presentation than non-carriers.[389][399][400]
• Patients with Lynch syndrome enjoy an increased risk for several malignancies, including colorectal, melanoma, pancreatic, urothelial, prostate, skin cancers, and ovarian and uterine cancers in women.[389]

Who Should Undergo Germline Testing and When

Germline testing should be offered to any prostate cancer patient when the results could have a therapeutic or clinical impact on that individual or any of his family.[389] In general, this means we should consider germline testing in all men with metastatic or locally advanced disease because they are more likely to carry heritable mutations. It should also be considered in patients with intraductal or cribriform histology, as these findings are closely associated with BRCA mutations. Other patients at higher risk for germline mutations include those with Gleason pattern 5 histology, early age of cancer diagnosis, or a positive family history of cancer (particularly breast, colorectal, ovary, pancreas, prostate, or uterus), especially if they appeared at a younger age or died from the malignancy.[389] 

Germline testing is strongly recommended for patients with advanced or metastatic castration-resistant prostate cancer to see if they have DNA damage repair genes (DDRGs) such as ATM, BRCA1, and BRCA2, which typically respond well to PARP inhibitor medications (olaparib and rucaparib) as well as platinum-based chemotherapy.

The optimal timing for discussing germline testing with patients is unclear. We prefer to discuss it as early as possible once the patient becomes eligible. There are often delays in getting the tests and obtaining appointments with genetic counselors. Trying to deal with these issues at the same time as receiving bad news about newly metastatic disease or increased cancer spread may be too much for many patients and families to handle. As long as patients meet the criteria, germline testing can be done at any time.

Germline testing is not the same as somatic or tissue-based biomarkers and genetic alterations. While they are often complementary, the two tests are different, although they can be done simultaneously.[389] Germline mutations occur in eggs and spermatozoa that are involved in human reproduction. Therefore, these mutations are inheritable by their offspring and may also be found in family relatives. Somatic mutations are found in other cell types, such as prostate cells that are not directly involved in human reproduction and therefore cannot be inherited by any offspring.

Internationally, about 75% of physicians have access to germline testing, but only about 18% of patients with metastatic castration-resistant prostate cancer are currently being tested.[401][402] The most commonly tested mutations were ATM, BRCA1, and BRCA2.[401] The most common reasons for failing to perform germline testing were cost, limited physician awareness of germline testing for prostate cancer, cost and reimbursement (insurance) issues, the need to send samples to an outside laboratory, lack of genetic counselors to refer patients to, lack of physician knowledge of how to use the germline test results, and patient refusals.[402]

As the indications for germline testing have expanded, the number of genetic counselors has not caused significant delays. This puts a greater burden on primary care practitioners, urologists, and oncologists to discuss germline testing with patients and causes difficulties ordering the tests themselves. It is helpful to develop a working relationship with a genetic counseling service or a specific counselor to better coordinate patient management and identify optimal testing parameters, screening criteria, mutation panels, and laboratories.  

Registry and Research Opportunities in Germline Testing for Patients:[389][391]

• Patients who undergo germline testing are encouraged to consider joining the PROGRESS Registry at Thomas Jefferson University. The registry is being used for research purposes and provides a free newsletter to participating patients.
• A multi-institutional registry of genetic information together with clinical data collected from prostate cancer patients treated with PARP inhibitors called the PRECISION Registry is being initiated as an international collaboration between Duke University, Thomas Jefferson University, and the University of British Columbia. 

Current NCCN Prostate Cancer Guidelines recommend germline Testing for all men with metastatic prostate cancer, regional (node-positive) disease, or high-risk/very high-risk localized disease, regardless of age.

OR With Any of the Following:

Any first, second, or third-degree relative who developed:

• Breast, endometrial, or colorectal cancer by the age of 50
• Pancreatic, ovarian, or male breast cancer at any age
• Metastatic prostate cancer, regional (node-positive) disease, and high-risk or very high-risk localized disease at any age

Father or brother with prostate cancer by age 60.

Two or more relatives with breast or prostate cancer at any age.

Three or more first or second-degree relatives with Lynch-syndrome-related cancers (especially if diagnosed by age 50), including biliary, colorectal, endometrial, gastric, glioblastoma, ovarian, pancreas, small intestine, or urothelial cancer of the upper urinary tracts.

Known family history of pathogenic germline variants such as ATM, BRCA1, BRCA2, CHEK2, EpCAM, PALB2, PMS2, MLH1, MSH2, and MSH6.

Ashkenazi Jewish ancestry.

Personal history of male breast cancer.

The NCCN also suggests that germline testing should be considered in intermediate-risk patients with intraductal/cribriform histology or a personal history of cancer of the biliary tract, colorectal area, endometrium, stomach, glioblastoma, melanoma, ovary, pancreas, small intestine, or urothelial malignancy of the upper urinary tracts regardless of age.

Curiously, African American men have shown a relatively low incidence of germline mutations despite their well-known genetic predisposition to aggressive prostate cancer compared to the general population. However, a higher incidence of RAD family mutations (RAD51, RAD54L, RAD54B), as well as PMS2 and BRCA1 in African Americans (but not White race individuals in the US), might explain this difference and offer an opportunity for better risk-stratification as well as opportunities for research into targeted therapies for this high-risk group.[403][404]

Knowing and understanding germline status will help clinicians adjust their monitoring and cancer screening protocol appropriately for specified groups and individuals, offer more aggressive adjunctive treatment earlier to affected patients identified with certain high-risk germline mutations, ensure their ability to offer new treatment approaches (such as targeted genetic therapies) at some point in the future to advanced cancer patients, and be able to counsel individual family members who have a higher inherited, genetic risk of malignancy.[389]

Specific Germline Mutations

There are about 170 germline mutations that have been identified and linked to prostate cancer.[390] Of these, fourteen appear with sufficient frequency and/or are associated with enough potential clinical significance to warrant testing.[389] 

The NCCN recommends at least the following nine mutations for germline testing in prostate cancer: ATM, BRCA1, BRCA2, CHEK2, PALB2, PMS2, MLH1, MSH2, and MSH6. Some experts have recommended adding EpCAM, HOXB13 (especially in African Americans), FANCA, P53, and NBN. 

Germline mutations are mostly of two general types. DNA Damage Repair Genes (DDRGs) and DNA Mismatch Repair (MMR) genes.

• DDRGs would include ATM, BRCA1, BRCA2, CHEK2, FANCA, and PALB2. This group often responds to PARP inhibitor therapy (except possibly ATM). These patients also appear to respond to cisplatinum which is currently being investigated and looks promising but is somewhat toxic.[405][406] The combination of PARP inhibition and radiation therapy may also prove useful in patients with this type of mutation.[407] There are 276 known DDRG germline mutations. African Americans with prostate cancer appear to have relatively high numbers of RAD51, RAD54B, RAD54L, PMS2, and BRCA1 mutations compared to non-African American prostate cancer patients.[404] 
• MMR mutations would include MLH1, MSH2, MSH6, and PMS2. Patients with these genetic defects tend to respond to immunotherapy such as pembrolizumab.[408][409]

ATM (ataxia telangiectasia mutated) is a key DNA damage control response gene that is also associated with an increased risk of breast, colorectal, pancreatic, and stomach cancers and prostate. ATM carriers have a high relative risk of metastatic prostate cancer of 6.3%.[396][410] Prostate cancer patients with ATM typically have a worse prognosis than controls. They are also more likely to progress if placed on active surveillance. While they will respond to standard prostate cancer therapies, ATM carriers may be relatively unresponsive to Poly ADP-ribose polymerase (PARP) inhibition therapy.[411]

BRCA1 and BRCA2 (breast cancer susceptibility gene) mutations have been associated with a number of cancers, particularly breast and ovarian cancer. These are tumor suppressor genes that are involved in the repair of damaged DNA strands. Men of Ashkenazi Jewish heritage are more likely than the general population to be carriers of these genetic mutations, which will have a penetration of about 2% to 2.5%. Of Ashkenazi Jewish men who develop prostate cancer, 3.2% to 4% will be carriers.[412] Men whose families have many female breast cancer patients have a two to three-fold increased risk of prostate cancer.[413] Overall median survival for prostate cancer patients who are BRCA2 carriers has been estimated at 4.8 years compared to 8.5 years for a matched patient cohort who are non-carriers.[414] Like carriers with ATM mutations, BRCA patients are more likely to progress if placed on an active surveillance protocol. Patients with metastatic castration-resistant cancer and a BRCA2 mutation that progresses rapidly despite initial chemotherapy might benefit from PARP inhibitor therapy such as olaparib or rucaparib.[389] Other PARP inhibitor medications are being studied and their use with cisplatinum in advanced prostate cancer patients with BRCA2 and ATM mutations.[405][406][408] Prostate cancer screening for BRCA1 and BRCA2 carriers is recommended starting at age 40 with a 3 ng/mL cutoff threshold.

CDK12 (cyclin-dependent kinase 12) is an important enzyme involved in regulating genetic transcription, translation, cell growth, RNA splicing, and DNA damage response (DDR).[415] CDK12 mutations are found in 3% to 7% of metastatic castration-resistant prostate cancer patients.[416] These mutations are associated with a high rate of metastatic spread and decreased overall survival.[417] Patients with CDK12 mutations tend not to respond well to taxane-based chemotherapy, hormonal treatment, or PARP inhibitors but might respond to PD-1.[418] These patients show increased chemokines (immune signaling proteins) which increase immune cell penetration into malignant tumors suggesting that an immune-based checkpoint therapy might work.[419] Experimentally, the use of bipolar androgen therapy or radium-223 (both of which cause double-strand DNA breaks) greatly increased the beneficial effect of immunotherapy (sipuleucel-T and nivolumab) in patients with CDK12 mutations.[416] It is thought the initial treatment sensitized or primed an immune response which enhanced the subsequent immunotherapy.[416]

CHEK2 (checkpoint kinase 2) is a tumor suppressor gene involved in the DNA-signaling pathway. Mutations in this gene have been associated with an increased risk for breast, ovarian, colon, thyroid, renal malignancies, and prostate cancer.[396][420] CHEK2 mutations are relatively rare in men of African, Asian, or Hispanic ethnicity. In Sweden, the CHEK2 gene was found to be the most frequent genetic mutation in their prostate cancer population at 3.8%.[421]

EpCAM (epithelial cell adhesion molecule, also known as CD326) is over-expressed in many rapidly growing cancers, including prostate cancer. It is involved in cell signaling, migration, cellular adhesion, proliferation rate, invasion capacity, metastatic potential, and differentiation.[422] Overexpression of EpCAM is found in 40% to 60% of all prostate cancers and is associated with increased resistance to chemotherapy and radiation, more rapid tumor growth, higher likelihood of metastases, cancer recurrences, and decreased survival.[423] It also offers some potential research opportunities for new targeted therapies currently being evaluated.[383]

FANCA (Fanconi anemia) is associated with prostate cancer as well as Fanconi anemia. Increased sensitivity to DNA damaging agents is caused when the FANC complex is disrupted by the FANCA mutated protein.[424] The FANC proteins provide resistance to abnormal DNA interstrand cross-linkages and provide overall chromosomal stability by creating the FANC protein complex. When this process is disrupted by the FANCA mutation, increased DNA damage is likely, and the risk for prostate cancer increases.[424] About 6% of prostate cancers will exhibit a FANCA mutation.[425][426] This may have clinical significance as it has been shown that patients with the FANCA mutation may exhibit significantly increased sensitivity to cisplatinum therapy.[426] They may also respond to PARP inhibitor therapy.[427]

HOXB13 (homeobox B13) is a chromosome 17 transcription factor that has been found in 6% of all early prostate cancers and is generally considered a highly specific gene for prostate cancer risk, especially in the African American population.[400][428][429][430] It is a homeobox transcription gene which means it is involved in the coding for protein synthesis. It also helps regulate androgen receptor activity. There is also evidence that HOXB13 mutations may block an important tumor suppressor gene and increase mitotic kinases, which would promote prostate cancer metastases.[431] While it currently has no known role in therapy, it may be useful in family counseling.

KLK3|179T appears to have only a relatively modest negative effect on prognosis by itself unless it is also associated with DDRG mutations where much more rapid progression of cancer is noted.[432]

MLH1, MSH2, MSH6, and PMS2 are all DNA mismatch repair genes. They are most often associated with Lynch syndrome.[433] Of these, MSH2 has shown the closest correlation with an increased prostate cancer risk.[434] The estimated hereditary prostate cancer risk in individuals with these mutations is 2% to 3.7%.[435] However, an earlier study suggested a five-fold increase in prostate cancer risk in men with Lynch syndrome, albeit without the earlier presentation or aggressiveness demonstrated by other forms of heritable prostate cancer.[436]

P53 mutations in localized prostate cancer are relatively rare and are more frequently seen in metastatic disease. P53 is generally considered a tumor suppressor gene. Its activity produces p21 protein, which acts to slow cell division. Loss of P53 activity reduces tumor androgen sensitivity, increases prostate cancer cell proliferation, and promotes tumor growth. Therefore, P53 mutations are generally considered late and ominous findings in prostate cancer.[35]

PALB2 (partner and localizer of BRCA2) is closely associated with BRCA1 and BRCA2 as it is an essential component involved in creating the BRCA complex that launches homologous recombination processes.[437] While relatively rare, it appears to have a significant role in heritable prostate cancer when present.[347][438] PARP inhibitors can be effective in PALB2 carriers with prostate cancer.[427]

NBN (nibrin) is the gene responsible for producing nibrin, a protein involved in critical DNA repair. NBN mutations are found in 2.21% of all malignancies but are most prevalent in breast cancer, followed by lung, colorectal, and prostate cancer. NBN is a relatively uncommon germline mutation but, when present, has a significant three-fold negative prognostic impact on prostate cancer survival.[397][439][440]

The validity of the NCCN guidelines on screening criteria and which mutations to include in germline testing has been called into question.[438] In a 2019 study from Tulane of 3607 men with prostate cancer, 17.2% were found to have germline mutations, but 37% (229) of these would have been missed under the current NCCN screening criteria and germline testing guidelines.[438] Either their personal or family history did not meet the screening criteria, or the recommended germline testing would have omitted their particular mutation.[438] The NCCN guidelines on germline testing and screening criteria should therefore be viewed as a minimal baseline starting point and not necessarily the optimal protocol for every individual. 

Some experts have suggested testing for all the above-listed germline mutations as recommended by the NCCN (ATM, BRCA1, BRCA2, CHEK2, PALB2, PMS2, MLH1, MSH2, and MSH6) as well as EpCAM, HOXB13 (especially in African Americans), FANCA, NBN, KLK3|179T, CDK12, and p53. This will depend on commercial availability, cost, insurance coverage, potential usability of the resulting information, availability of quality genetic counseling, and the overall reliability of the testing provided. If genetic counseling services are limited in your area, contact the National Society of Genetic Counselors at NSGC.org for assistance and a directory of their members. Genetic counseling services are also available online.

Three sets of germline mutations have been associated with rapid biochemical recurrence following definitive cancer therapy. These are PI3K/AKT/mTOR, KRAS signaling (up), and Inflammatory response.[441]

KISS1 (Kisspeptin 1) has been shown to promote tumor angiogenesis. It also significantly increases malignant tumor growth while facilitating tissue invasion and malignant cell migration.[442]

Other germline mutations that appear potentially beneficial to patients with prostate cancer but require more study to determine their significance include APC, BRIP1, BARD1, CHEK1, FOXA1, KMT2D, PMS2, POLG, PPP2R2A, RAD51, RAD51B, RAD51C, RAD51D, RAD54B, RAD54L, and ZFHX3.[227][365][404][432] It has been recommended that physicians obtain as many of these germline mutations as reasonably possible for future reference.

Caution: Physicians who order germline tests are ultimately responsible for discussing the results with their patients and arranging for genetic counseling if appropriate. This extra burden on physicians, as well as a general lack of knowledge about germline testing, result interpretation, how to counsel patients, the need for outside laboratory resources for the actual testing, questions about insurance coverage, and the lack of genetic counselors, are all impediments to the more widespread and effective use of germline testing.

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.[443][444]

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), which 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.[445]
• Magnetic resonance imaging is excellent when used to evaluate the prostatic capsule for an extracapsular extension and the regional lymph nodes and seminal vesicles for possible tumor involvement.[446][447]
• 68-Gallium prostate-specific membrane antigen (PSMA) PET/CT and PET/MRI scans and similar PET scans are FDA-approved tests for reliably detecting even early metastatic prostate cancer. They appear to offer significantly improved sensitivity and specificity over standard imaging by combining molecular activity testing with conventional morphologically based radiographic studies. While indicated to detect metastatic and recurrent disease, they can also be used in the initial 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.[448][449][450] Lutetium 177 vipivotide tetraxetan has recently been FDA-approved for therapeutic use with Gallium-68 PSMA-11 PET/CT scans. 

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, and survival after radical prostatectomy, based on outcomes data from various sources. They generally 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 and clinical and pathological staging.[451] Multiple nomograms exist, including the Briganti, Rotterdam, and Stanford models. Three of the most popular nomograms available online for free include the following, which can be found at their respective academic institutional websites are:

• Partin tables from Johns Hopkins University [452][453][454]
• Memorial Sloan Kettering Cancer Center (MSKCC) prostate cancer nomograms [214][455]
• Cancer of the Prostate Risk Assessment (CAPRA) score from the University of California, San Francisco [456]

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. Forgoing surgical procedures at this point leads to renal failure, which is usually painless, as it occurs slowly and incrementally.[457][458]

Gradually increasing renal failure is usually a painless and natural way to expire peacefully. Patients slowly become more lethargic and eventually 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 a very difficult and personal decision. There is no right or wrong answer, but there certainly is a choice. It is suggested that patients and families approaching this decision point review and discuss the options available, and make a decision long before it becomes necessary. 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 potential 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 challenging 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 no survival advantage to treating both kidneys in these situations.[459]

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

While a positive tissue biopsy is always preferred before 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 experiences 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.[460]

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."[461]

Life Expectancy

There is no clear evidence that either radical prostate surgery or radiation therapy has a significant survival advantage over the other, so treatment selection has relatively little effect on life expectancy.[462]

• 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.

Life expectancy tables can be found online at the respective websites of the Social Security Administration, Memorial Sloan Kettering Cancer Center (Male Life Expectancy Tool), and the World Health Organization (Life Tables by Country). 

Possible Urinary Marker for Aggressive Prostate Cancer in African American Men

A study at the National Cancer Institute investigated the potential role of urinary thromboxane B2 (TXB2) as a possible marker for aggressive prostate cancer.  (Thromboxane B2 is a metabolite of TXA2, a cyclooxygenase-derived eicosanoid associated with metastatic disease.) In this study, 977 men with prostate cancer were followed for a median of 8.4 years. Investigators found a statistically significant and distinct association between high urinary TXB2 levels and mortality in African American men with prostate cancer but not in similar Caucasian American patients of European ancestry.[463] The reason for this remains unclear. They also found that aspirin appeared to reduce TXA2 synthesis and all-cause mortality in the high urinary TXB2 group suggesting a possible therapeutic benefit.[463]

Palliative Care and Hospice

Palliative Care focuses on treating cancer symptoms 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.[464]

Pearls and Other Issues

PSA Testing: The Controversy[465]

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 sex or 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. Since then, according to the American Cancer Society, prostate cancer detection rates have increased substantially, by 58%, while the prostate cancer-specific death rate has declined by about 15% and the total number of yearly deaths from prostate cancer has remained about the same despite the US male population increasing by 28.6% (from 126 million to 162 million).

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% which 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 biomarker analogs such as PCA3, SelectMDx, ExosomeDx, MyProstateScore (MPS), 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.[466]
• 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 ten years.[467]

The Current USPSTF Recommendation[468]

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.[6]

Routine PSA screenings are not recommended in men 75 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. It is also not recommended in men who realistically have <10 years of life expectancy. 

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. Some guidelines lower the age to stop routine screening at age 70 depending on health status and family history. Regardless, this is an individual decision best made by patients and family members after a thorough discussion of the pros and cons of continuing screening.

Prostate Cancer Screening: The Pros and Cons [469]

Screening options include a 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 PSA testing, has become very controversial. Here are some of the arguments for and against:

Against PSA Screenings

• There was 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 negative biopsies 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, low-grade prostate cancer will ultimately 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.
• As suggested by some recent studies (PIVOT), there is little point in doing prostate cancer screenings if treatment offers little or no survival benefit. 
• 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 will not 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 diagnoses. At least some of these cancers will ultimately be high-grade and will undoubtedly increase prostate cancer mortality.
• A review of the SEER data indicated that the incidence of metastatic prostate cancer increased significantly immediately after the USPSTF recommendations against PSA testing were released. This increase was noted in all age groups and ethnicities.[470]
• 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 consistently at or above 50% for the screened groups if followed for more than ten 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 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, it provides a baseline, and it can help identify the rare but aggressive malignancies that appear prior to age 50.
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 ten years after therapy.)
6. We encourage screening in men at high risk due to ethnicity, family history, or proven germline mutations.
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)

Pre-biopsy

Initial basic screening would include total PSA, free and total PSA, and PSA density levels. At least two separate PSA levels should be done before proceeding with more advanced testing. Some experts suggest using 4 to 6 weeks of a prostate-specific antibiotic (such as doxycycline, a fluoroquinolone, or sulfamethoxazole/trimethoprim) between the two tests.

Improved pre-biopsy "liquid biopsy" screening tests would include PCA3, the Prostate Health Index (PHI), MyProstateScore (MPS), the "4K" blood test, ExoDx or Exosome test, and SelectMDx. Overall, these tests have over 90% negative predictive value and can safely exclude about 25% of patients with persistently elevated PSA levels from further testing and unnecessary biopsies. They are best utilized prior to MRI imaging or a biopsy in men with persistently elevated PSA levels or as a confirmation after a negative MRI examination in borderline cases.[138][471]

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 genomic bioassay such as ConfirmMDx.
• Men on active surveillance can be tracked and followed with genomic testing or serial PCA3 testing in addition to standard PSA levels.
• Patients with low-grade or intermediate-grade disease being considered for either active surveillance or definitive therapy would benefit most from the Prolaris test.
• Patients with low-grade or intermediate-grade disease considering radical prostatectomy can be evaluated with either the Decipher, Oncotype Dx Prostate, Prolaris, or ProMark test.
• Patients who are post-radiation therapy or diagnosed with prostate cancer after TURP surgery can best be tracked with the Prolaris genomic biomarker 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 such as either Decipher or Prolaris.

Clinical Trials

Patients should be encouraged to consider participation in prostate cancer clinical trials whenever possible. These can be found at several locations.

• Cancer.org will present clinical trials in prostate cancer sponsored by the National Cancer Institute and the National Institute of Health.
• The Prostate Cancer Clinical Trials Consortium (PCCTC) is a clinical research group jointly sponsored by the Department of Defense Prostate Cancer Research Program and the Prostate Cancer Foundation. The coordinating center is located at Memorial Sloan Kettering Cancer Center in New York City. There are 43 participating or affiliated clinical research sites. Information on the clinical trials available there can be found at pcf.org or pcctc.org.

For the most complete and comprehensive list of all open prostate cancer clinical trials in the United States, go to clinicaltrials.gov, a free service provided by the National Institutes of Health and the National Library of Medicine.

Enhancing Healthcare Team Outcomes

Prostate cancer diagnosis and treatment can be complex and is often controversial. an interprofessional team of specialty-trained nurses, nurse practitioners, physician assistants, primary care providers, oncologists, radiation therapists, genetic counselors, and urologists must work together 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 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
• Adopting advances in radiation therapy, including stereotactic ablative therapy (SABR)
• Clarifying the proper use of active surveillance; finding and using acceptable alternatives to mandatory repeat prostatic biopsies such as 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, docetaxel, and sipuleucel-T treatments
• Fully implementing baseline and follow-up DEXA scans every two years for patients expected to be on long-term hormone suppression
• Starting all long-term hormonal therapy patients on prophylactic therapy for osteoporosis to minimize skeletal fractures
• Ordering germline testing appropriately and learning how best to use the information learned from it to optimally benefit and counsel patients and their families
• Incorporating PET scans for initial staging and to identify early recurrences
• The need for better implementation of the various specialties involved in prostate cancer patient care, including primary care, urology, radiation therapy, palliative care, genetic counseling, 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 to coordinate care and be involved in patient education and monitoring compliance. The interprofessional team can thus improve outcomes for patients with prostate cancer. [Level 5]