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Prostate Cancer

Author: Stephen W. Leslie Author: Taylor L. Soon-Sutton Editor: William P. Skelton Updated: 10/4/2024 10:54:48 PM

Introduction

Prostate cancer is the most commonly diagnosed malignancy in men globally and the fifth leading cause of cancer-related deaths in men.[1][2] In 2020, there were 1,414,249 newly diagnosed cases and 375,000 deaths worldwide annually due to this disease.[1][2][3][4][5] Globally, prostate cancer is the most commonly diagnosed malignancy in more than 50% of countries (112 out 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 (PHI) scoring, the 4K test, exosome testing, genomic analysis, magnetic resonance imaging (MRI), Prostate Imaging–Reporting and Data System (PI-RADS) 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 cancer has spread to the bones or other areas outside the prostate, treatment options include pain medications, bisphosphonates, rank ligand inhibitors, hormonal therapy, chemotherapy, radiopharmaceuticals, immunotherapy, focused radiation, and other targeted therapies. Outcomes depend on age, associated health problems, tumor histology, and the extent of cancer.[12]

Etiology

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Etiology

The major known risk factors for prostate cancer include age, ethnicity, obesity, and family history.[13] The overall incidence increases as people get older; however, the aggressiveness of the cancer tends to decrease as individuals get older.[14]

Additional risk factors for prostate cancer include male gender, older age, positive family history, increased height, obesity, hypertension, lack of exercise, persistently elevated testosterone levels, exposure to Agent Orange, and ethnicity.[15][16][17]

5-Alpha Reductase Inhibitors

Medications, such as finasteride and dutasteride, may reduce the incidence of low-grade cancer, but they do not appear to affect high-grade risk and, thus, do not significantly improve survival. These medications reduce PSA levels by about 50%, which must be accounted for when comparing sequential 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 underwent more PSA tests, prostate examinations, and biopsies, but no association was found regarding the development of lethal disease, overall survival (OS), or cancer-specific survival. However, overall and localized disease rates were reduced in men taking 5-alpha reductase medications.[21][23]

Genetics

Although the exact cause of prostate cancer remains unclear, genetics play a significant role. 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 2 first-degree relatives affected have a 5-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]
  • Patients also have a higher risk of biochemical recurrence after radical prostatectomy surgery.
  • In the United States, Black men are more commonly affected compared to 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 compared to non-Hispanic Whites.[33]
  • No single gene is responsible for prostate cancer, although many genes have now been implicated.[34]
  • Mutations in breast cancer 1 (BRCA1), and particularly BRCA2, are associated with breast and prostate cancer.[34]
  • P53 mutations in localized prostate cancer are relatively rare and are more frequently observed in metastatic disease. As a tumor suppressor gene, p53 produces the p21 protein, which slows 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, including hereditary prostate cancer gene 1, various androgen and Vitamin D receptor genes, HPC1, HPC2, HPCX, CAPB, mutL homolog 1 (MLH1), mutS homologs 2 and 6 (MSH2 and MSH6), 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), and the TMPRSS2-ETS gene family, such as TMPRSS2-ERG and TMPRSS2-ETV1/4, all of which tend to promote cancer cell growth.[26][34][36] (Note: This is only a partial listing. Clinically significant germline mutations are discussed in subsequent sections.)
  • A Genetic Risk Score, including high-risk genetic markers and SNPs, has been proposed to help with the risk stratification of prostate cancer, especially in families. However, this type of testing is not yet ready for individual patient diagnostics.[37]

Diet

Prostate cancer is generally linked to the typical Western diet.[38] However, there is minimal evidence that demonstrates an association between trans fat, saturated fat, or carbohydrate intake and prostate cancer risk.[39] 

  • A diet high in unsaturated fats, such as lard, has been shown in mouse models to significantly enhance the progression of prostate cancer.[40]
  • Alcohol consumption appears to have little or no effect on prostate cancer risk.[41][42] However, some evidence suggests 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 dairy 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] suggesting that vitamin D supplements may be helpful in prostate cancer patients who are deficient in the vitamin.
  • Red 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 that a vegetarian diet may reduce prostate cancer rates, but this is not considered a conclusive or significant influence.[53]
  • Increased consumption of soy products, which contain phytoestrogens, may reduce prostate cancer risk by either having a direct estrogenic effect or by inhibiting 5-alpha reductase.[54][55]
  • Folic acid supplements have 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 and tomatoes, may help reduce prostate cancer risk and has been shown to reduce Gleason Grade progression in patients on Active Surveillance for low-grade prostate cancer.[60][61]

Chemical Exposure and Medications

Prostate cancer is associated with certain medications, surgical procedures, and medical conditions.[62]

  • The use of statins, metformin, and nonsteroidal anti-inflammatory drugs (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 and 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 exposed to Agent Orange tended to present with prostate cancer at a younger age and higher clinical stage compared to veterans without such exposure. However, overall outcomes were similar.[68] Agent Orange exposure may increase the risk of prostate cancer recurrence, particularly after surgery.[69]

Sexual Activity

Having multiple lifetime sexual partners or engaging in sexual activity early in life may increase the risk of prostate cancer. On the other hand, 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]
  • Although human papillomavirus (HPV) has been proposed to have a role in prostate cancer incidence, the evidence remains inconclusive.[74]

Vasectomy and Prostate Cancer

There was once a belief that there was a link between vasectomy and prostate cancer, but larger follow-up studies have failed to confirm this association.[75] However, a recent meta-analysis has suggested a possible link, leaving the question unresolved.[75][76]

Epidemiology

Prostate cancer is the most commonly diagnosed organ cancer in men and the second leading cause of cancer-related death among men in the United States, with lung cancer being first.[77][78][79]

According to the American Cancer Society, although relatively few men with prostate cancer die from the disease, there were an estimated 268,490 new cases and 34,500 deaths in the United States in 2022.

Prostate cancer is more prevalent in developed countries.[80] The overall 5-year survival rate is 99% in the United States.[81] Although the overall incidence has increased, the mortality rate has slowly decreased since 1992, when PSA testing became widely available.[82] Approximately 99% of all prostate cancers occur in men older than 50, but when it develops in younger men, it can be more aggressive.[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] In contrast, it is less common in men of Asian and Hispanic descent compared to Whites.[85]

The World Health Organization (WHO) reports that the countries with the highest incidence of prostate cancer are Guadeloupe, Martinique, Ireland, Barbados, Saint Lucia, Estonia, Puerto Rico, France, Sweden, and the Bahamas. Guadeloupe has the highest incidence at 184 per 100,000, whereas in the Bahamas, it drops to 98 per 100,000 compared to the global average rate of 30.7 per 100,000. The United States ranks 14th in incidence. The lowest incidence is reported in Asian countries.

According to the WHO, countries with the highest mortality rates for prostate cancer are Grenada, Zimbabwe, Barbados, Haiti, Zambia, Jamaica, Trinidad and Tobago, the Bahamas, the Dominican Republic, Saint Lucia, and the Ivory Coast. This group's mortality rate ranges from 80 per 100,000 in Grenada to 30 per 100,000 in the Ivory Coast, compared to the global average mortality rate of 7.7 per 100,000. The mortality rate in the United States is 11.46 per 100,000, which is ranked 126th. The lowest reported mortality rate for 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. However, when Asians migrate to the United States, their risk increases, although it remains lower than the general population of American men.[86]

  • In Europe, prostate cancer is the third most diagnosed cancer after breast and colorectal cancers.[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 WHO 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. In Sweden, prostate cancer is the leading cause of cancer mortality in men, even surpassing lung cancer.

More than 80% of men develop prostate cancer by 80. However, it is often slow-growing, lower-grade, and relatively harmless, having minimal impact on survival in this age group.

In 2015, there were an estimated 3 million prostate cancer survivors in the United States. This rise is expected to increase to 4 million by 2025.[88]

Prostate cancer is rare in men younger than 45, accounting for 0.5% of all newly diagnosed prostate cancer cases, but its 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, chemical exposures, environmental carcinogenic exposures, and changing referral patterns.[89] In younger men, prostate cancer can be fast-growing and lethal.

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

  • The majority of new cases are diagnosed in men aged 65 to 74 (38.2%), with a median age at diagnosis of 66 years.
  • Currently, 3,085,209 men are living in the United States with prostate cancer, and the overall risk of a man dying from prostate cancer is 1 in 39, or approximately 2.6%.
  • The median age of death for men with prostate cancer is 80 years.
  • Overall, the vast majority of men with prostate cancer die from unrelated problems. 
  • About 20% of men diagnosed with prostate cancer 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.

Impact of the 2012 United States Preventive Services Task Force Negative Recommendation on Routine Prostate-Specific Antigen Screening

Since the United States Preventive Services Task Force (USPSTF) recommended against routine PSA screenings in 2012, there have been several 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%.
  • A 24% increase in the number of patients identified with PSA levels more than 10 ng/mL from 8.5% before 2012 to 13.2% after.
  • Patients with PSA levels more than 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 vary by ethnicity, with African Americans having the highest incidence and mortality rates, significantly surpassing the levels of the general population. 

A large study in the Veterans Affairs healthcare system, involving almost 8 million veterans, found that African American men tended to have higher PSA levels, develop cancer at an earlier age, and are almost twice as likely to be diagnosed with 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, accounting 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 versus 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 per 100,000 population from the 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 cm long, about the size of a walnut, and weighs approximately 20 g. The function of the prostate is to produce about one-third of the total seminal fluid.[95]

The prostate gland is located in the male pelvis at the base of the penis, below (inferior) 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. Hormonal therapies, such as testosterone deprivation, are effective in treating prostate cancer, though castration-resistant tumors may produce their own intracellular androgens.[99]

Prostate cancer typically begins with a mutation in normal prostate glandular cells, often starting in the peripheral basal cells.[100] Prostate cancer is most commonly found in the peripheral zone of the prostate, which is the area that can be palpated during a 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 multiply, initially spreading to the surrounding prostate tissue, forming a tumor nodule. Such a tumor may grow outside the prostate (extracapsular extension) or may remain localized within the prostate for decades. Prostate cancer commonly metastasizes to the bones and lymph nodes. Metastases to the bone are believed 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 proven to be the most reliable and predictive histological grading system over time. Developed initially by pathologist Dr. Donald Gleason in the 1960s, it has stood the test of time and has been universally adopted for all descriptions of prostate cancer.[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. Patterns are graded from 1 to 5, with 1 indicating an almost normal microscopic glandular pattern and appearance and 5 representing the absence of glandular architecture and the presence of only abnormal cancer cells in sheets.[104]

The Gleason score always contains 2 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 is any secondary or minor pattern, graded 1 to 5. So the absolute best and lowest risk Gleason score is Gleason 1+1=2, and the worst high-grade pathology is Gleason 5+5=10. In real life, these histological extremes are rarely observed.[105]

If only 1 Gleason grade or pattern is observed, then the Gleason score consists 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 are any Gleason score of 3+3=6 or less.[105]

Intermediate-grade cancers are classified as having a Gleason score of 3+4=7, meaning 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 is considered high-grade cancer.[105]

Although the architecture or pattern described by the Gleason score is a key component in the histological diagnosis of prostate cancer, it is not the sole criterion. For example, prostate-specific membrane antigen (PSMA) is a transmembrane carboxypeptidase that exhibits folate hydrolase activity, which is overexpressed in prostate cancer tissues, indicating the presence of 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 include the following: [111]

  • Infiltrative glandular growth pattern
  • Absence of a basal cell layer
  • Atypically enlarged cell nuclei with prominent 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 involving 960 patients with intermediate-grade (Gleason 3+4=7) prostate cancer followed for at least 4 years, 86% of patients with less than 34% positive biopsies demonstrated a stable PSA compared to only 11% of patients with more than 50% of positive biopsies.

Cancer volume is another important prognostic parameter, but it is difficult to measure accurately with available technology. Currently, prostatic MRI is the best available tool for estimating tumor volume.[112]

Perineural invasion can help predict extracapsular tumor extension and may be associated with slightly higher tumor aggressiveness. However, studies have conflicting results regarding its clinical usefulness.[113]

The New Gleason Scoring System

In 2016, the WHO proposed a new classification system based on clinical experience with the old Gleason scoring system. The update was motivated by findings that clinical outcomes showed minimal differences in lower Gleason scores but varied more significantly in higher grades. The summary of the new Gleason system is as follows: [114]

  • Grade Group 1 (Gleason score ≤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, or cribriform glands; 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 NCI. Some of the institutions involved are Mayo Clinic, Johns Hopkins University, Duke University, Cleveland Clinic, Memorial Sloan Kettering Cancer Center, Roswell Park, MD Anderson, and the Dana-Farber/Brigham Cancer Center, among others. These institutions periodically review and set guidelines for screening, diagnosis, and management of all stages and types of cancers through 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: All criteria must be met to qualify

  • Stage T1c disease
  • The tumor is confined to the prostate with a negative DRE
  • Gleason Grade Group 1 (3+3=6) or lower
  • PSA <10 ng/mL
  • PSA density <0.15 ng/mL/g
  • Less than 3 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 DRE
  • Gleason Grade Group 1 (3+3=6) or lower
  • PSA <10 ng/mL
  • Does not meet very low-risk criteria

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
  • No more than 1 additional intermediate-risk factor, such as:
    • Stage T2b to T2c disease (the tumor involves more than half 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:

  • 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 2 of the following intermediate-risk factors:
    • Stage T2b to T2c disease (tumor involves more than 1/2 of 1 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
  • 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 pelvic wall)
  • Primary Gleason pattern 5
  • More than 4 biopsy cores with Gleason Grade Group 4 or 5 (Gleason Score 4+4=8 or higher)

Premalignant Lesions

High-grade prostatic intraepithelial neoplasia: The Gleason system is an effective method for 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 typically appear. The cells typically show very large nucleoli in high-grade PIN, 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 premalignant and is called high-grade PIN. A low-grade PIN is considered benign and is typically not reported.[115]

The high-grade PIN was first described in 1969, and 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 demonstrate high-grade PIN on careful examination. These findings make rebiopsy 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 believed but still relatively high at 24%. A repeat prostate biopsy at 6 to 12 months has long been recommended. However, additional options are now available, such as saturation prostate biopsies, MRI prostate imaging, genomic testing, and MRI-TRUS fusion-guided biopsies.[116]

Some have recommended following these patients 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 complete discussion with the patient of the risks, benefits, and limitations of each alternative.

Atypical Small Acinar Proliferation

Atypical small acinar proliferation is considered a premalignant lesion, indicating the presence of small foci of atypical prostatic glands suspicious for cancer, though there is insufficient evidence to confirm malignancy. As first described by Montironi et al. in 2006, it is characterized as a focus of small acinar structures formed by atypical epithelial cells.[117]

Studies show a 40% to 50% likelihood of finding overt prostate cancer on repeat biopsy, which has led to the consensus recommendation to perform another prostatic biopsy, with or without MRI guidance, 3 to 6 months after an 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 higher PSA velocity, higher PSA densities, and shorter PSA doubling times.[119]

Recent suggestions indicate that in some cases of high-grade PIN or atypical small acinar proliferation, newer genomic testing, alterations in MRI prostate imaging, and monitoring of PSA level changes may help identify patients who can be closely monitored as an alternative to mandatory repeat biopsies. While this is not yet the standard of care, preliminary data suggest that rerebiopsiesould be avoided in up to two-thirds of these patients in selected cases without compromising safety.[118][120]

The simultaneous presence of high-grade PIN and atypical small acinar proliferation in a patient is generally believed to increase the overall risk of developing malignancy. However, this association 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. Unlike prostate cancer, adenosis is characterized by 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, 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 typically 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 indeed a risk factor. African American ethnicity also increases the risk. A history of positive germline mutations, such as BRCA1 or BRCA2, suggests an increased risk of prostate cancer and possibly some other malignancies. This germline mutation is indicated 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 a DRE. There might also be some asymmetry or general firmness on the exam. A rock-hard prostate is highly 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. The spread into the femur is typically to the proximal part of the bone.[126]

Evaluation

Prostate-Specific Antigen Testing

PSA is a serine protease enzyme produced by the columnar epithelial cells of the prostatic ducts and acini. The enzyme's role is to break down the large proteins of the semen into smaller molecules, reducing semen viscosity over time and improving sperm function and fertility. Elevated PSA levels have long been associated with prostate cancer.[127] 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 PSA, with cancer cells leaking more PSA into the surrounding extracellular fluid, eventually increasing serum levels. 

There are multiple causes for an elevated PSA, which have nothing to do with cancer, including prostate disease, trauma, inflammation, prostatitis, urogenital procedures, biopsies, and prostatic enlargement. Some physicians recommend a 2- to 6-week course of prostate-specific antibiotics, typically a quinolone, doxycycline, or sulfamethoxazole/trimethoprim, to attempt to lower PSA levels caused by prostatitis or low-grade inflammation and avoid further investigations for possible prostate cancer; however, this practice is controversial and not generally recommended, as many studies have failed to show a significant benefit.[128][129][130][131][132] Please see StatPearls' companion resource, "Prostate-Specific Antigen," for more information.

Elevated PSA levels, typically 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 2 abnormal PSA levels or a palpable nodule on a DRE are required to justify further investigation or a biopsy.[85]

In 2012, the USPSTF recommended not performing routine prostate cancer screening using PSA testing, giving it a grade D recommendation. This decision was based on the early results of 2 large trials that suggested significant overdetection and overtreatment of low-risk prostate cancer compared to minimal benefit. The recommendation was highly contested, with critics highlighting procedural and statistical errors, immature data, and multiple studies demonstrating a 50% improvement in long-term cancer-specific survival for screened populations. Critics also warned of dire consequences if the recommendation proved incorrect.[133] When long-term data became available, the USPSTF reversed its position and now recommends PSA testing in men aged 55 to 70 after discussing the pros and cons with the patient. Full implementation of the original USPSTF recommendations was estimated to result in an additional 25,000 to 30,000 preventable prostate cancer deaths annually in the United States.[134][135]

The value of PSA screenings remains somewhat controversial due to concerns about potential 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.[136] Most professional organizations now recommend PSA testing for men aged 45 to 50 and continuing until 70 to 75 after thoroughly discussing the benefits, risks, and controversies. 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 diseases that previously have received definitive therapy.

To improve standard PSA testing, various alternative pre-biopsy screening options are available: [137]

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 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: PSA density is the total PSA divided by the prostatic volume as determined by MRI or ultrasound. The formula for the volume of the prostate is prostate volume = width × height × length × π/6. For most clinical purposes, π/6 can be estimated as 0.52 to simplify calculations. The PSA density is intended to minimize the effect of benign prostatic enlargement. A PSA density greater than 0.15 suggests malignancy.[138]

PSA velocity: 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 is considered suspicious.[139]

Post-Prostate-Specific Antigen Pre-Biopsy Prostate Cancer Bioassay Risk Stratification Tests

Several Food and Drug Administration (FDA)-approved bioassay tests are now available to help risk-stratify patients with persistently elevated levels of PSA up to 10 mg/mL, aiming to reduce unnecessary biopsies in low-risk patients. Both blood and urine sample tests are available. Most tests include different laboratory tests bundled together to provide a single risk score or estimate. Some require a digital prostate massage before 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 generally proceed 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 do not benefit from the results. Patients with apparent suspicious, hard prostatic nodules or suspected metastatic disease, and those with persistent PSA levels over 10 ng/mL do not need this type of testing. Similar to PSA testing, patients aged 75 or older and those with less than a 10-year life expectancy are generally not eligible for bioassay testing, as they are unlikely to benefit. 

As these tests 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 (NPV) score. An NPV is defined as the number of test subjects found to be truly negative if their test scores were negative. Generally, an NPV 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.

When comparing the various tests, it is important to consider some questions and variables when selecting a bioassay risk stratification test.

  • 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 warrants 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 the final test report 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 are being conducted to validate and prove the utility of the test?
  • How was the original NPV score obtained?
  • Are clinical patient data needed to run the risk stratification algorithm?
  • Do clinical patient data need 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 recommended by the NCCN or American Urological Association (AUA) guidelines?
  • Is the test result valid independently without the need to provide any clinical patient data? 
  • Is the test result valid independently without providing 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 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 require the patient to repeat the test?
  • Do the test results affect patient care or treatment? If not, then the test may be unnecessary.

Predictive bioassay testing that includes clinical variables, such as SelectMDx and 4K, has sometimes been considered more reliable than tests that do not, such as PHI, ExoDx Prostate Intelliscore exosome, and PCA3.[140] However, these tests that require significant clinical patient information to achieve their competitive NPV scores are, by definition, less reliable when used alone and are not truly independent as they rely on clinical data and computer algorithms for statistical validation. As 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 clinician uses their clinical judgment based on the same clinical patient information used in formulating the bioassay test result, factors such as age, PSA level, PSA density, and prior biopsies are counted twice, giving them disproportionate weight and bias.

A superior test is 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 clinical judgment. Many clinicians prefer tests that are independent of PSA levels and do not require significant patient clinical data, yet still offer statistically equivalent and valid results, including NPV, leaving them free to interpret the test report using knowledge of the patient's clinical history and PSA results. A preferred test is the one that allows for home administration, 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 provides over 90% NPV for Gleason pattern 4 disease, as lower-grade disease is not generally treated. 

Risk Stratification Bioassay Tests

ExoDx Prostate Intelliscore or Exosome test: This test uses PCA3 and urinary TMPRSS2:ERG to detect clinically significant prostate cancer. The test analyzes exosomal RNA for 3 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 DRE or prostatic massage is required, and a kit for home use kit is available, making testing much more convenient for patients. The NPV is 91.3%, with a sensitivity rating of 91.9%.[141] The ExoDx exosome test performs particularly well for Gleason 4+3=7 patients, with an NPV of 97% in this group.[142]

4K test: This test measures serum total PSA, free PSA, intact PSA, and human kallikrein antigen 2 and includes clinical DRE results and information from any prior biopsies. These results are compared to a huge, age-matched database, and a percentage risk of significant prostate cancer is calculated. Clinically significant prostate cancer is typically defined as Gleason 3+4=7 or higher disease. A 10% or more risk analysis typically suggests proceeding with a biopsy. Interestingly, the 4K test is not any better than PSA testing alone when used for tracking active surveillance patients.[143]

MyProstateScore: This test is a predictive algorithm developed at the University of Michigan and includes PSA, PCA3, and urine TMPRSS2:ERG (a genetic fusion found in about 50% of all prostate cancers). A negative is that it requires a prostate massage before obtaining an initial urinary stream sample. Future upgrades are under development that eliminate the need for a prostate massage. Initial reports were uncertain about the MyProstateScore outperforming PCA3 alone, but later validation studies reported that the sensitivity for Gleason Grade Group 2 or higher disease is 97% with a 98% NPV, which is very competitive.[144][145] MyProstateScore has proven superior to PSA density for evaluating patients with PI-RADS 3 findings on MRI scans.[146]

Prostate Cancer Antigen 3: Prostate Cancer Antigen 3 (PCA3) is an RNA-based genetic test performed from a urine sample, typically obtained immediately after a prostatic massage. PCA3 is a long, noncoding RNA molecule overexpressed exclusively in prostatic malignancies. PCA3 is upregulated 66-fold in prostate cancers. If PCA3 is elevated, it suggests the presence of prostate cancer. PCA3 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. [147]

Prostate Health Index: The 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.[148]

SelectMDx: This urine-based test measures the urinary messenger RNA levels of the HOXC6 and DLX1 biomarkers after a prostatic DRE. The test uses reverse transcriptase quantitative polymerase chain reaction technology. The risk stratification analysis and algorithm include other clinical information such as age, PSA density, family history, prior biopsy results, and DRE findings. Results are reported straightforwardly as either: [149]

  • Low risk: Indicates a very low risk of Gleason 7 or higher disease, where a biopsy may safely be reasonably avoided. The NPV is 99.6% for Gleason 8 or higher disease and 98% for Gleason 7 or higher.
  • 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.[150]

  • During prostate biopsies, TRUS can occasionally detect 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. This technique 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][151]

Prostate Imaging–Reporting and Data System 

Unlike computed tomography (CT) or x-rays, MRI typically shows denser tissue as dark areas. Standard MRI of the prostate typically requires a 3 Tesla MRI machine and optimally uses intravenous (IV) contrast, although noncontrast (bi-parametric) MRI tests are quicker, cheaper, and still quite useful. IV contrast demonstrates early vascular entry (faster inflow) and quicker washout from cancerous lesions or nodules compared to normal prostatic tissue. 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 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 also provides improved imaging but is often 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 PI-RADS score. A PI-RADS score of 1 or 2 is highly unlikely to be cancer. A PI-RADS score of 4 or 5 is highly suspicious for clinically significant disease (Gleason 3+4=7 and higher). PI-RADS 3 is equivocal. Histological confirmation with a biopsy is recommended for all PI-RADS 3, 4, and 5 lesions.[152]

PI-RADS 3 lesions typically 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 PI-RADS 3 patients biopsied show intermediate- or high-grade prostate cancer pathology.[153]

Recent studies of PI-RADS 3 lesions have identified several clinical risk factors clearly associated with significant, higher-grade disease (Gleason score 3+4=7 and higher).[154]

Risk Factors Identified for Prostate Imaging–Reporting and Data System 3 Lesions

  • Age 70 or older
  • Smaller prostate volume (less than 36 cc)
  • Presence of a palpable nodule on a DRE
  • The size of the lesion or nodule is more than 0.5 cm [155][156]

The studies reported that 100% of the PI-RADS 3 patients with all the above risk factors had clinically significant disease, whereas 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 PI-RADS 3 lesions greatly improves the identification of aggressive disease in PI-RADS 3 cases while safely avoiding uncomfortable and unnecessary biopsies in the rest. Equivocal cases may benefit from risk stratification bioassay testing.

Use of Magnetic Resonance Imaging for Men with Elevated Prostate-Specific Antigen Levels

Controversial issues include doing an MRI on all men with elevated PSA levels, avoiding biopsies on PI-RADS 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 PI-RADS 3 lesions show clinically significant (Gleason 4) disease on biopsy, a number considered too high to overlook. 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 NPV has been reported as low as 72% to 76%, meaning that a negative MRI report could miss about 1 in 4 high-grade prostate cancers.[157][158] 

For this reason, it has been suggested that bioassay markers 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 PI-RADS 3 individuals. [159]

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

  • Cognitive recognition: Based on knowledge of the lesion's anatomical location, the urologist can use standard TRUS imaging to target the expected geographic area of the suspicious lesion, even if the lesion is not directly visible.
  • MRI-TRUS fusion guidance: This commercially available technique 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, which has delayed the widespread implementation of this technology despite its proven benefits.[160]
  • Direct MRI image guidance: Although possible, direct MRI guidance for prostate biopsies is less favored due to the high cost, prolonged MRI machine usage, coordination with a urologist, and the need for specialized biopsy equipment compatible with 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—is a PSA density of less than 0.15 ng/mL.[161]

Which Should be Done First: Risk Stratification Bioassays or Prostatic Magnetic Resonance Imaging?

There is no consensus among urologists about this issue, as the decision often depends on the availability of testing and the relative cost. Two primary approaches exist, both requiring patients to have a PSA level below 10 ng/mL. Patients with consistent PSA levels >10 ng/mL should generally go directly to an MRI and a biopsy. The choice comes down to whether the clinician prioritizes minimizing unnecessary biopsies or maximizing cancer detection.

Minimize unnecessary biopsies for low-risk patients: The primary goal of this approach is to minimize the number of unnecessary prostate biopsies. A bioassay test is performed first. If the result is negative, no further testing or imaging is required, and routine surveillance is resumed. If the bioassay is positive, an MRI is performed, followed by a biopsy if indicated. About 25% of patients 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 ng/mL), men who do not want to undergo a biopsy, or situations 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 whether a biopsy can safely be omitted.

Maximize cancer detection for high-risk patients: The main focus is to avoid missing significant cancer, so the MRI is performed first. If the MRI is positive (PI-RADS 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 whether a TRUS-guided biopsy should still be performed. The bioassay test is used here to confirm a negative MRI result. For low-risk patients with equivocal findings on MRI (PI-RADS 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 performed 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 exclusively adopting either methodology, a reasonable approach is to perform the MRI initially in higher-risk individuals. However, the bioassay risk stratification test should be started first in lower-risk patients, where a negative finding results in continued observation only.

High-resolution micro-ultrasonography: High-resolution micro-ultrasonography of the prostate uses new specialized ultrasound technology to improve imaging and help detect cancer. High-frequency (29 MHz) micro-ultrasound transducers provide 3 times the spatial resolution of standard ultrasound.[162] This technique is faster, more affordable, and simpler compared to MRI scans, with the added benefit of detecting a suspicious lesion and immediately performing 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.[163] Early studies indicate rough equivalence to MRI (noninferiority) in cancer detection (sensitivity) and somewhat superior NPV (85% versus 77%).[162][164] Multicenter prospective studies comparing micro-ultrasound and multiparametric MRI biopsies found essential equivalence in prostate cancer detection rates.[165][166] Combining MRI and micro-ultrasonography has demonstrated an improved cancer detection rate of clinically significant disease.[162][163] In a study, about 24% of the suspicious lesions were not observed on MRI but only on micro-ultrasonography.[162] This technique also lends itself to future combined therapy with focal laser ablation or high-intensity focused ultrasound (HIFU).[167]

However, there are a few issues. Performing the prostatic biopsy simultaneously with diagnostic imaging means there is less time for patient discussion and outside review of the findings before the biopsy is performed. There is also no time for interdisciplinary evaluations and analysis, such as between urologists and radiologists, for equivocal, difficult, or complex cases.[168] The effect of extreme tumor location, especially anterior lesions where ultrasonic signals are diminished, has not been adequately addressed.[168] Clinicians must be trained to interpret these new images, and the necessary equipment should be readily available.[168] This new technology is promising and appears to be a reasonable alternative to prostatic MRIs, but further validation is required to determine its ultimate clinical utility. This technology appears especially useful for the growing active surveillance population.[168][169][170] 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.[168] 

Positron Emission Tomography 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. Positron emission tomography (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, representing a metastasis or malignant recurrence. Compared to conventional radiological techniques, such as CT and MRI, PET scans appear to be far more accurate and highly specific. This technique can detect very small amounts of metastatic or recurrent malignant disease, even at relatively low PSA levels, and is rapidly becoming the new diagnostic standard despite its 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 allow for a more definitive comparison.[171] However, a recent review suggests that PET/MRI is 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.[172] However, a PET/MRI costs at least 50% more than a PET/CT.[173]

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.[174]

PSMA is a membrane-bound metallopeptidase 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.[175][176][177] PSMA-based PET correlated with CT is rapidly emerging as the gold standard imaging modality for staging intermediate and advanced prostate cancer, and the early detection of recurrences and metastases. Compared to alternative imaging technologies, such as CT, MRI, and bone scans, PSMA PET/CT offers superior sensitivity and specificity for detecting metastatic lymph nodes 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.[178] When used for initial staging, all PSMA-based scans should be performed before 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. Such accuracy is largely due to the incredible overexpression of PSMA in prostate cancer cells (by 100- to 1000-fold), which results in very high PSMA tracer uptake by prostatic malignancies.[178] 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 to 0.9, 1 to 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 level of at least 0.2 ng/mL or more.

Prostascint, which uses indium-111 (In) capromab pendetide, is a relatively large compound with an antibody targeting an intracellular PSMA glycoprotein. This compound can only penetrate necrotic prostate cancer cells, as it relies on the loss of cellular phospholipid membrane integrity for intracellular transport.[179] Previous use of indium-111 PSMA-based scans (Prostascint) was quite disappointing, so the NCCN no longer recommends them and have been replaced by newer PSMA-based and non–PSMA-based PET scans, as noted below.[180][181][182]

[F-18]-Fluorodeoxyglucose (F-18-FDG) PET scans are designed to target rapidly growing cells, such as cancers, that absorb glucose faster than normal tissues. F-18-FDG scans use a tagged glucose analog radiotracer molecule that 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 widely used for various malignancies. However, its use in urology has been limited due to 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 fast-growing and incorporate more F-18-tagged glucose, show up better on F18-FDG PET scans.[183][184] Nevertheless, F-18-FDG is generally not considered optimal for prostate cancer PET/CT scanning for these reasons, and the relatively high uptake overlaps with normal prostatic tissue, benign prostatic hyperplasia, 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.[185][186][187] F-18-FDG is not a PSMA-based scan, and its half-life is 110 min. The NCCN does not currently recommend it for prostate cancer imaging.[185]

C-11-Acetate is similar to C-11-Choline, as 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.[188] C-11-Acetate has a very short half-life of only 20 minutes, so an on-site cyclotron must be available. C-11-Acetate 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 for detecting recurrent prostate cancer. Choline, an essential dietary and cellular nutrient, supplies methyl groups required for numerous metabolic activities, such as the synthesis of phosphatidylcholine and sphingomyelin (required for cell membranes), and especially acetylcholine. Choline is also involved in cell membrane signaling, lipid metabolism, and gene expression regulation. 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.[189] High uptake levels in the prostate can be misleading as high-grade PIN, prostatitis, benign prostatic hyperplasia, and even normal prostatic tissue can produce false-positive results.[190] C-11-Choline has a 53% to 96% positive predictive value in biochemically recurrent prostate cancer. C-11-Choline is not a PSMA-based scan and has a very short half-life of 20 min; therefore, 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. Although C-11-choline is FDA-approved for detecting recurrent disease or suspected progression, it is not recommended for initial staging by the NCCN.

NCCN-Recommended PET Scans for Prostate Cancer

F-18 Sodium fluoride: 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.[191] Therefore, it has been suggested that it be used in combination with other PET tracers for more comprehensive detection. F-18 NaF is not a PSMA-based scan. F-18 NaF has an 82% to 97% positive predictive value for skeletal metastases and has a half-life of 110 min. F-18 NaF requires a cyclotron for its production and 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: 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.[179] F-18 fluciclovine has been shown to detect prostate cancer recurrences in 79.3% of cases.[192] This analog has a relatively long half-life of 110 min. One of its limitations is that as 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. F-18 fluciclovine is not a PSMA-based scan. F-18 fluciclovine has an 87% to 91% correct localization rate in biochemically recurrent diseases and has a half-life of 110 minutes. F-18 fluciclovine requires a cyclotron for its production and 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: Fluorine-18 piflufolastat (F-18 piflufolastat or F-DCFPyL) is a fluorine-based molecule that targets PSMA. F-18 piflufolastat is a small molecule that helps visualize PSMA-expressing lymph nodes, soft tissue, and bony metastases in PET imaging and can detect 85% to 87% of prostate cancer metastases.[193] Compared to gallium 68 prostate-specific membrane antigen 11 (Ga-68-PSMA-11), detection results are roughly equivalent, but F-18 piflufolastat has a longer half-life of 110 min, which is an advantage.[194] F-DCFPyL may offer other advantages regarding availability and cost, and slightly improved detection rates.[194][193] F-DCFPyL requires a cyclotron for its generation and is FDA-approved for detecting prostate cancer metastases, progression, and biochemical recurrences. The NCCN guidelines recommend it for initial staging and biochemical recurrences or disease progression. 

Gallium 68 prostate-specific membrane antigen 11: Ga-68-PSMA-11 is a larger radiotracer molecule that interacts directly with the extracellular active zone of PSMA, allowing detection without requiring cell death.[179] Ga-68-PSMA-11 has a half-life of 68 min. 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. Whether a Foley catheter or straight catheter is beneficial for eliminating residual urinary tracers in patients unable to void remains unclear. Overall, Ga-68-PSMA-11 outperformed F18 fluciclovine in a head-to-head study (82.8% versus 79.3%) and was superior in detecting metastases and recurrences outside the bladder area.[192] Ga-68-PSMA-11 has 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.[195] Ga-68-PSMA-11 is also superior to C-11-choline and F-18 fluciclovine in detecting malignant tissue at low PSA levels (<2 ng/dL).[196] 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 and is recommended by NCCN for both initial staging and biochemical recurrences or disease progression. 

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. These imaging modalities offer nearly identical sensitivity, specificity, and positive predictive values for detecting metastases for initial staging, biochemical recurrences, and suspected disease progression. Studies have indicated that F-18 piflufolastat (F-DICFPyL) and Ga-68 PSMA have higher detection sensitivity for metastases compared to 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), which is described later.[197][198][199][200] 

All of the above PET scans can be used in cases of equivocal bone scans. Ga-68 and F-18 piflufolastat are generally 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 and pelvis and the traditional technetium 99 bone scan for future prostate cancer assessments.[199] Conventional imaging is generally unnecessary if a PSMA-based PET scan is performed.

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

  • Experimentally, F-18 PSMA-1007 has demonstrated superior sensitivity and specificity in detecting early biochemical recurrence compared to Ga-68-PSMA-11.[201]
  • Zirconium-89-PSMA-617 (Zr-89-PSMA-617), which is still investigational, has shown superiority in early testing compared to Ga-68-PSMA-11. The main advantage of Zr-89-PSMA-617 lies in its longer half-life, which takes several days to decay, allowing for improved imaging, particularly in patients with prostate cancer, 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.[202] In a small preliminary study involving 20 patients in Hamburg, Germany, individuals 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 offers 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.[202]
  • 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 has a much longer half-life of 12.7 hours.[203] This agent also has a lower positron range than Ga-68, giving it better spatial resolution. Further, Cu-68 provides beta decay and positron emission and, therefore, can provide both diagnostic and therapeutic benefits from a single dose.[204]

Biopsy

When prostate cancer is suspected, a biopsy is typically performed. This procedure is almost always performed using TRUS to ensure adequate sampling from all regions of the prostate. A common approach is the 12-core sextant biopsy, where 2 tissue samples are taken from 3 zones, such as base, mid-gland, and apex, on both sides of the prostate. The purpose is to identify the extent and exact location of the tumor.[150] 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.[205]

  • A prostate biopsy gun uses a unique 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, typically starting the day before the biopsy and continuing for 3 days (ciprofloxacin) or 1 to 2 hours before the biopsy. Although 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.[206]
  • Pre-biopsy rectal cultures are suggested to help optimize prophylactic antibiotic selection.[207][208]
  • A Fleets enema is recommended shortly before the biopsy to help clean the rectum.
  • The transperineal approach should be considered in immunocompromised or high-risk patients to further reduce infection risks.[205]

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 superimposed it over the ultrasound image. The 2 images are matched, allowing the MRI target to be visible on the TRUS to 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. Please see StatPearls' companion resource, "Gleason Score," for more information.

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 patients who might be candidates for active surveillance or radical prostate surgery. The goal is to ensure that patients eligible for active surveillance have low-risk genomic profiles. If their genomic analysis indicates higher risk, they should be counseled accordingly.[209][210] In general, genomic testing 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. Genomic markers are not recommended for patients with very low or very high-risk disease.

ConfirmMDx: 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 atypical small acinar proliferation. ConfirmMDx estimates the likelihood of finding prostate cancer when the initial biopsy is negative and is most useful when the initial prostate biopsies are negative in patients at high risk for occult prostate cancer. ConfirmMDx has been shown to have an NPV of 96% for detecting Gleason Grade 4 or 5 disease (Gleason sum 7 or higher).[211][212]

Decipher test: This test evaluates tissue for the expression of 22 RNA biomarkers to calculate the probability of clinical metastasis within 5 years of definitive therapy, the prostate cancer-specific mortality at 10 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 men originally identified as high-risk who are unlikely to develop metastatic disease and might safely avoid salvage radiation therapy after radical prostatectomy surgery. This test is most useful for higher-risk patients with localized disease who have already undergone radical prostatectomy and are potential candidates for salvage radiation and androgen deprivation therapy. Studies have demonstrated that 60% of 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 patients identified as low-risk by genomic testing did not develop metastases within 5 years of their radical prostatectomy procedures.[140][212] Although the Decipher test 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.[212] Similar to the Prolaris test, it can also be used in high-risk diseases.

Oncotype Dx Prostate Score Test: This test measures 17 gene expressions and is an automated immunofluorescence-based assay. The Oncotype Dx Prostate Score Test calculates the patient's chances of having organ-confined disease after radical prostatectomy surgery using genomic information from the biopsy specimen. The test focuses on 4 specific areas of gene expression—the stromal response, androgen signaling, cellular proliferation, and organization. This test 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.[212] A similar increase in the selection of active surveillance using Oncotype Dx was also found in a complementary study in the Veterans Affairs healthcare system.[213] Oncotype Dx is best suited for patients with localized, low, or favorable intermediate-risk disease (Gleason 3+3=6 or Gleason 3+4=7), where either active surveillance or definitive primary therapy is a reasonable treatment option.[212][214][215][216]

ProMark test: This protein-based assay measures the expression of 8 specific proteins involved in cell signaling, cellular proliferation, and stress response. The ProMark test identifies the most aggressive cells in the tumor. This test 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. Similar to Oncotype Dx, ProMark is most useful and optimized for patients with localized disease that is low-risk or favorable intermediate-risk histologically.[212] Please see StatPearls' companion resource, "Gleason Score," for more information.

Prolaris test: This test was the first commercially available genomic tumor marker to evaluate prostate cancer aggressiveness.[217] The Prolaris test analyzes 46 genes and specifically measures the RNA expression of 31 genes involved in cell cycle progression. The test is designed to indicate the risk of biochemical recurrence and prostate cancer-specific mortality over the next 10 years when combined with the PSA level, clinical stage, percentage of positive biopsy cores, biopsy grade group, and AUA risk group.[212] In a large prospective registry, the Prolaris test changed the initial treatment selection in 47.8% of 1600 participants, with 75% opting for a less aggressive therapy and 25% choosing a more definitive treatment option.[218] 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 versus 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.[144][212] Similar to the Decipher test, the Prolaris test is also useful in patients after radical prostatectomy surgery and in high-risk cases for prognostic purposes.[212]

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

  • High-risk factors for prostate cancer, but the initial biopsy is negative: ConfirmMDx
  • Localized disease with low-risk histology considering active surveillance versus 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 [219][212]

Research into improved genomic analyses and clinically useful biomarkers is ongoing. For example, one of the more promising biomarkers analyzes 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.[220]

Other interesting markers include Post-Operative Therapy Outcomes Score (PORTOS), 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.[208][221]

Treatment / Management

The first step in managing prostate cancer is determining whether treatment is necessary. In many cases, especially with low-grade tumors, prostate cancer grows so slowly that treatment may not be required, particularly for elderly patients or those with other health conditions that limit their life expectancy to 10 years or less.

Active Surveillance

Many low-risk prostate cancer cases can be monitored through active surveillance, which involves regular, periodic PSA testing and at least 1 additional biopsy 12 to 18 months after the initial diagnosis. Active surveillance is appropriate for men with low-grade prostate cancer (Gleason 3+3=6 or less with a PSA level less than 20) and small-sized tumors. 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. Tissue-based biomarkers and genomic testing can provide valuable insights by accurately assessing the true risk of cancer progression and aggressiveness in these borderline situations. Genomic testing may be most helpful when PSA levels are between 10 and 20 ng/mL or with increased tumor volume.[144][214][222](A1)

In addition to regular PSA testing, an MRI of the prostate can also be used to monitor patients, reducing the need for repeated biopsies. The purpose of close observation is to identify patients, typically about 25% of the total, who experience significant PSA increases, clinical progression, or an upgrade to a higher Gleason score, which may indicate a shift toward more aggressive cancer. In such cases, definitive treatment can be initiated, while most patients avoid the costs, adverse effects, and complications of curative therapy.

Although no specific biomarker or bioassay has been prospectively tested and validated for active surveillance protocols, their theoretical use seems 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.[223]

Certain characteristics have shown prognostic significance in a large multi-institutional database for patients on active surveillance. 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.[224] The length of Gleason pattern 4 on the original biopsy has also been identified as a factor that increases the risk of future progression for patients on active surveillance.[225]

The best management option depends on the cancer stage, Gleason score, PSA levels, individual patient preferences, overall health, comorbidities, quality of life, and age. Although heritable factors from germline testing may influence decisions for patients on active surveillance, family history alone has not been found to significantly impact the risk of progression.[226][227]

Currently, only an estimated 32% to 49% of eligible low-risk prostate cancer patients in the United States are enrolled in active surveillance protocols.

Imaging may help reduce the number of biopsies required for patients on active surveillance. The need for a confirmatory biopsy at 12 to 18 months discourages patients from accepting active surveillance. The impact of MRI scans on active surveillance protocols is currently uncertain. Studies have demonstrated that even when patients have negative serial MRI scans and stable PSA levels, there is still a 14% chance of disease progression.[228] Therefore, to identify such hidden cancers, a follow-up biopsy is recommended at 3 years, regardless of other findings, such as a stable PSA and negative serial MRIs.[228]

The addition of PSMA-PET scans has not significantly increased the detection rate of clinically significant cancers in patients on active surveillance. However, with a reported NPV of about 86%, it has the potential to reduce scheduled routine or confirmatory biopsies by up to 80%.[229] 

Localized Disease

In cases of localized prostate cancer, treatment selection generally has minimal impact on OS for at least the next 10 years. Therefore, definitive therapy should only be offered to patients who are reasonably expected to live another 10 years or longer based on age and comorbidities.[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 adverse effects (about 50% less) compared to radical prostatectomy surgery, with very similar OS.

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 adverse 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 cancer) with the risks of lifestyle alterations (treatment adverse 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

The use of MRI localization has opened the door for local ablative therapy in selected patients with localized disease by allowing precise identification of suspicious or significant tumors. In many cases, the risks, complications, and adverse effects of definitive whole-gland therapy outweigh many of the benefits of oncological control. Therefore, there is a need to find a treatment modality between active surveillance and definitive whole-gland therapy with lower costs and fewer adverse effects. Focal ablative therapy could potentially meet this need.[230]

Focal ablative therapy employs various ablative energies, such as microwave, cryotherapy, laser, and HIFU, to target and treat localized malignant prostatic lesions. Ablative therapies typically have lower costs and substantially fewer adverse effects compared to traditional definitive whole-gland therapy.[231] Optimal patients have 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.[232]

However, the effectiveness of focal ablative therapy in controlling or curing localized prostate cancer remains uncertain. The choice of technology and its efficacy in providing optimal cancer control with minimal adverse effects is still under investigation. Currently, focal ablative therapies for localized prostate cancer are considered investigational in the United States.

  • HIFU is a local treatment modality that uses focused ultrasound to heat and ablate prostatic tissue, including isolated malignant lesions. Although 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. This method is inexpensive, avoids radiation, can be repeated if necessary, and has minimal adverse effects. However, its long-term efficacy and role in prostate cancer treatment are still being evaluated.[231][233][234][235]
  • Focal laser ablation uses laser fibers to heat and destroy prostatic cancer nodules based on MRI imaging using MRI fusion-guided targeting. Although still investigational, focal laser ablation appears to be a particularly promising minimally invasive treatment modality for well-selected patients with highly localized prostate cancer.[231][234][235][236]
    • (B3)

Hormone Therapy

In 1941, Dr. Charles Huggins, a urologist from the University of Chicago, discovered that androgen deprivation (castration) could cause prostate glands to atrophy and lead to the regression of prostate cancer.[237][238][239][240] He was awarded the Nobel Prize for Medicine in 1966 for his discovery, which is the basis for all hormonal (testosterone deprivation-based) treatments used in prostate cancer. The discovery was the first effective systemic therapy for prostate cancer, and it is still useful in inducing remission. This beneficial hormonal effect typically lasts an average of about 2 years, but virtually all prostate cancers eventually escape and regrow.(B3)

Although bilateral orchiectomy was originally used to produce castration levels of testosterone, current hormonal therapy is typically administered with injectable medications.

Initial therapy with leuprolide, goserelin, and similar luteinizing hormone–releasing hormone (LHRH) agonists should be preceded with 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. Similar to injectable degarelix, relugolix is a direct LHRH antagonist and causes a very rapid decrease in serum testosterone. Relugolix is quite effective as it has been shown to sustain castrate levels of testosterone in 97% of men tested (compared to 89% of men treated with leuprolide) and appears to have fewer major cardiovascular events.[241] Similar to degarelix, relugolix is approved for prostate cancer that is locally advanced, castrate-resistant, or metastatic, and for patients with biochemical recurrences.[241]

Choosing the appropriate anti-androgen hormonal therapy depends on the clinical situation, ease of administration, availability, cost, insurance coverage, physician experience, and individual patient preference.[242] Patients with very high PSA levels or where there is a need for an acute and immediate reduction in testosterone levels benefit from anti-androgen options, such as degarelix or relugolix, but for the majority of prostate cancer patients starting hormonal therapy, the choice of initial hormonal therapy depends on the clinical situation, ease of administration, availability, cost, insurance coverage, physician experience, and individual patient preference.[241][242](B3)

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. A 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 brachytherapy seed implants) can be started. The hormonal therapy is typically continued for at least 1 year and optimally for at least 2 years after radiation. Intermittent hormone therapy is another option in selected cases to minimize the adverse 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 benefit from initiating docetaxel at the same time. However, this advantage does not appear to extend to low-volume metastatic prostate cancer.

Adverse 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 increases clotting risk, low-density lipoprotein cholesterol, body fat, triglycerides, and insulin resistance while decreasing lean body mass and glucose tolerance. One of the most concerning cardiac effects is the potential to prolong the QTc interval. These effects can be minimized by aggressively treating comorbidities, reducing cardiac risk factors, and eliminating all other drugs that also tend to prolong QTc interval. Urologic medications that typically increase the QTc interval include levofloxacin, amitriptyline, and imipramine. Patients with significant cardiovascular risk factors or pre-existing heart disease are at increased risk and should be monitored closely by cardiology or primary care. Medical check-ups every 3 months 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 the highest.[243][244]

The most common adverse 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 treatment for preventing hot flashes is oral medroxyprogesterone 20 mg/d or cyproterone 100 mg/d.[245] Medroxyprogesterone is also available as an injection and 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 United States but is used elsewhere in the world for advanced prostate cancer. Cyproterone 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 that it could cause a rapid progression of prostate cancer.[246][247] Gabapentin appears to be reasonably effective in managing hot flashes at a dosage of 300 mg 3 times a day.[248] Selective serotonin reuptake inhibitors (SSRIs) such as venlafaxine, fluoxetine, paroxetine, and sertraline have demonstrated moderate efficacy in suppressing hot flashes and are quite safe, but they are not as effective as progesterone.[245] Finally, oxybutynin has shown some activity in suppressing male hot flashes anecdotally but has not yet been studied adequately to be routinely recommended.[249][250] 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. (A1)

A baseline dual-energy x-ray absorptiometry (DEXA) scan for bone density is recommended for all patients starting hormonal therapy and are expected to remain on it for 1 year or longer. The National Osteoporosis Foundation (NOF) and NCCN Clinical Practice Guidelines recommend repeating the scan every 2 years during therapy. In a Danish study, two-thirds of prostate cancer patients were found to have osteoporosis even before any hormonal therapy had been initiated.[251] Bone density deterioration is estimated at a rapid 13% per year for patients on hormonal treatment for prostate cancer.[252] The increase in skeletal fractures is almost 4-fold over baseline after 2 years.[253] Prostate cancer patients with such fractures face a markedly increased mortality risk 7 times higher than similar patients without fractures.[254] Despite clear recommendations for a baseline and follow-up DEXA scan every 2 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.[255][256][257] In a recent review of the AUA Quality Registry, only about 5% of eligible patients received a DEXA scan within an acceptable timeframe. Even in patients older than 80, 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.[258][259](A1)

After the DEXA scan, full osteoporosis treatment—including calcium citrate and vitamin D supplements and a bisphosphonate or rank ligand inhibitor—is suggested for all patients with a T-score below −2.5. Preventive therapy should also be considered for patients with a T-score between −1.5 and −2.5 based on age older than 75, body mass index <19 kg/m2, glucocorticoid therapy, a history of falls, or other significant risk factors, such as cardiovascular disease, dementia, depression or Parkinson disease.[260] 

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 patients with prostate cancer on long-term hormonal therapy develop osteoporosis, osteoporotic fractures, or osteopenia after 2 years of therapy.[259] Calcium citrate is the preferred calcium supplement, and a daily intake of 5000 units of vitamin D is suggested. The American Society of Clinical Oncology recommends a daily calcium intake of at least 1000 to 1200 mg (dietary and supplements) for patients on hormonal therapy.[261] Other helpful measures include decreased alcohol intake, stopping smoking, and increased exercise (especially weight-bearing activities).(A1)

Differential Diagnosis

The differential diagnosis for prostate cancer includes:

  • 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 most significant potential for a definitive cure for localized prostate cancer and a significant improvement in OS, cancer-specific survival, and the development of distant metastases. These benefits are not typically apparent until ten years after treatment and are most pronounced in men diagnosed before 65. Radical prostatectomy is not an appropriate therapy if the tumor is fixed to surrounding structures or there are distant metastases.[262]

The majority of such surgeries are now being performed robotically or laparoscopically. Overall, there appears to be little difference in adverse effects or survival between minimally invasive (robotic) or open surgical approaches. The surgeon's experience is the most critical factor associated with a successful outcome, regardless of the technique used.[263][264]

Individual patient issues include activity level, age, continence, comorbidities, performance status, presurgical erectile function, the necessity of lymphadenectomy, and whether a nerve-sparing technique is utilized. A bilateral nerve-sparing approach is recommended whenever it does not compromise the complete removal of the malignancy. MRI imaging is beneficial in making these determinations.[265]

Lymph Node Dissections

Lymph node dissection is performed based on the anticipated incidence of 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).[266]

The optimal extent of the lymph node dissection is uncertain. A greater and more extensive lymph node dissection is likely to find a more significant number of positive lymph nodes. In the past, a pelvic lymph node dissection was sufficient, but it is now known that metastases often go directly to the common iliac, paraaortic, perirectal, or presacral nodes, so a more extended dissection is recommended, particularly in higher-risk disease.[267]

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.[266]

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.[268]

Salvage radiation therapy is recommended to target any residual cancer that may remain near the site of the resected prostate. Typically, this therapy delivers 60 to 70 Gy of radiation, substantially lower than the dose used in primary definitive radiation therapy.[269] Without treatment, metastatic disease can develop from microscopic cancer remnants after radical prostate surgery in about 8 years, and OS averages about 10 to 13 years.[270]

Salvage radiation therapy may also be recommended if PSA levels become detectable at a later date, indicating the possible presence of residual disease that was previously undetectable but is now growing in the immediate area of the prostatic bed. However, it is important to note that there is no guarantee that all remaining cancers are within the radiation field. Salvage radiation therapy should not be considered if there is clear evidence of distant metastatic tumor spread.[271]

Early data suggest that everolimus at 10 mg/d can be safe, helpful, and effective when combined with salvage radiation therapy for post-prostatectomy biochemical failures or recurrences.[272]

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.[273]

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.[274]

A meta-analysis of 7 randomized clinical trials comparing the efficacy of definitive radiation therapy between Black and White men found that Black men had a higher overall success rate with radiation therapy.[275] 

Identifying the location of recurrent disease can be challenging in cases of biochemical recurrence. Salvage radiation therapy to the prostatic bed is not effective if there are distant metastases or if the disease has spread beyond the potential radiation field. PSMA gallium PET/CT scans can help identify local recurrences, but PSA levels need to be over 1 to 1.5 ng/mL for the recurrence site to be visible on the scan.[276][277]

Complications of Radical Prostatectomy

Complications of radical prostatectomy include erectile dysfunction, especially if no nerve-sparing surgery was performed; urinary incontinence, especially stress incontinence that is reported in 52% of patients initially; urethral strictures, affecting 8% to 11% of patients; and an increased risk of inguinal hernias, occurring in 6% to 8% of cases. Overall mortality rates are less than 1% in most series. Rates for erectile dysfunction vary greatly depending on preoperative potency and age, the type of surgery performed (nerve-sparing or not), and the use of penile rehabilitation techniques.[278][279]

If radiation therapy is performed first and fails, salvage radical prostatectomy surgery becomes challenging and often impossible due to scarring, fibrosis, and loss of anatomical landmarks. However, cryotherapy is still possible as a salvage treatment.[280]

Cryotherapy

Cryotherapy, which uses freezing technology to destroy cancer cells, has a long history. This technique 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.[281]

While cryotherapy offers effective tissue ablation and destruction, it has some complications and is highly dependent on technology. 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 balls in real-time. Advances in technology have addressed these issues. Improvements include the use of TRUS 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, simultaneous use of multiple smaller probes based on argon gas for freezing instead of the harder-to-use liquid nitrogen, incorporation of a thaw cycle into the protocol, and the standard placement of urethral warming catheters to protect the urethra from injury.[282]

Using 2 freeze-thaw cycles instead of 1, 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 prostate size but does not otherwise improve survival outcomes with cryotherapy.[282]

The incidence of erectile dysfunction is relatively high with cryotherapy, which is an issue that should be discussed with patients before treatment.[283]

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.[280][284]

Cryotherapy has demonstrated the ability to control tumors that are resistant to all other therapies but still susceptible to ablation by alternating freeze-thaw cycles. These cycles 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. As cryotherapy cannot treat nodal involvement, lymph node dissections may be needed.[285]

Focal or limited cryotherapy is a possible experimental option in selected patients.[286][287]

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, PSA levels are expected to decrease for about 18 months. Treatment failure is usually noted by a rise in PSA levels of 2 ng/mL or more above the baseline level before initiation of radiation therapy.[288]

External Beam Radiation Therapy

Treatment fields are calculated and individualized from MRIs or CT scans, as some patients require treatment for the seminal vesicles and 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.[289][290]

The current standard of care is to use conformal techniques, such as intensity-modulated radiation therapy (IMRT) and image-guided radiation therapy. 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 adverse effects.[291][292]

Treatment typically consists of daily exposures (5 days a week) for up to 8 weeks, resulting in 38 to 45 fractions of 1.8 to 2 Gy. The American College of Radiology recommends a total dose of 75 to 78 Gy. The radiation oncologists use a total dose of 77.4 Gy at the institution. Doses higher than 81 Gy are not recommended due to increased risks of radiation cystitis and proctitis.[293][294]

The use of hormonal therapy in combination with radiation has demonstrated improved OS in intermediate- and high-risk diseases. Hormonal therapy increases tumor radiosensitivity by interfering with DNA double-stranded break repair, which 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 suggest that adding enzalutamide to standard hormonal therapy enhances this radiosensitizing effect.[295][296]

Several drugs are under investigation as potential radiosensitizers for prostate cancer. In addition to hormonal therapy and enzalutamide described above, agents being explored include statins, IL-37, parthenolide, and even green tea. So far, none of these are currently recommended for clinical use.[297][298][299]

Complications from External Beam Radiation Therapy

Significant areas of concern include prostate size and potential radiation-related adverse effects on the bowel and bladder, such as radiation proctitis and cystitis.[300]

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 unsuccessful, 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).[301]

Erectile dysfunction is another relatively common complication reported in 30% to 45% of men who were potent before starting radiation therapy.[302] Patients may also experience fatigue and an increased risk of fractures.[303] There is a slightly higher incidence of secondary malignancies after definitive radiation therapy.[304]

Stereotactic Ablative Radiotherapy

The role of stereotactic radiotherapy in prostate cancer is less well-defined compared to 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, typically only about 1 week. Higher fractionated dosages beyond 8 Gy are not recommended as they have been associated with increased toxicity and adverse effects. Stereotactic radiotherapy is less suitable for patients with large prostate volumes (greater than 75 to 100 mL) or prior TURP surgery. Most experts prefer real-time tracking, and early reports suggest that using urethral catheterization during treatment planning and simulation improves urethral identification. Newer stereotactic ablative radiotherapy (SABR) delivery systems include gantry devices currently undergoing clinical trials. Using SABR for metastatic cancer may be reasonable to reduce the seeding of additional tumors, which may ultimately increase overall and progression-free survival (PFS). 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.[294][305][306]

SABR may increase the patient's immune response by releasing additional tumor antigens due to the larger fractional radiation dosage, prompting the increased immunological response.[294]

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. However, early reports suggest improved biochemical (PSA) control compared to standard external beam radiation therapy.[294]

Brachytherapy (Radioactive Seed Implants)

Brachytherapy is another form of radiation therapy that involves surgically implanting tiny radioactive seeds into the prostate. Conceptually, this technique allows a higher total dose to be delivered to the prostate without increasing exposure to surrounding structures. Brachytherapy also allows for optimal treatment in patients where transportation and other issues make standard external beam therapy more difficult. Most prostates accept from 75 to 125 seeds.[307]

Hormonal therapy can shrink the prostate if it is too large for treatment (greater than 60 gm). Three months of hormonal therapy decrease the size of the prostate by about 30%.[308]

When combined with brachytherapy, hormonal therapy has been shown to improve survival outcomes, so it is usually recommended.[309] Seeds are placed transperineally using TRUS and a template plan previously worked out by a radiation therapist or physicist.[310] Radioactive materials used include iodine 125, palladium 103, and cesium 131. Cesium has the shortest half-life.[311][312]

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. These trials found no significant clinical benefit to adding a brachytherapy boost, even in higher-risk patients.[313][314]

High-dose-rate brachytherapy: High-dose-rate brachytherapy can also be performed using hollow needles placed through the perineum, which are then loaded with iridium 192. These needles typically are left in place for 24 to 40 hours when the patient is admitted to a hospital. The newer trend is to treat with only 2 fractions/d, allowing the patient to go home at night.[312]

External beam radiation can then be used to treat regional lymph nodes and other areas outside the prostate that are not adequately controlled by the seeds alone.[311][315]

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 more effective than the external beam in some patients.

The most common complications reported from brachytherapy include worsening of the 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. Using stranded seeds, such as Rapidstrands, significantly reduces the seed migration rate. The clinical impact of seed migration is still unclear.[316]

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 pathological findings indicating an increased cancer recurrence risk (clinical principle).
  • If adverse pathological signs, such as seminal vesicle invasion, positive surgical margins, and extraprostatic extension, are found, inform the patient that the risk for biochemical (PSA) recurrence, local recurrence, or clinical progression of cancer is lower following a combination of radical prostatectomy and adjuvant radiation therapy compared to radical prostatectomy alone (clinical principle).
  • If adverse pathological 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).
  • In patients with a PSA recurrence, a restaging evaluation should be considered (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 adverse urinary, bowel, and sexual effects, but also discuss the treatment's potential benefits to control disease recurrence (clinical principle).

Proton beam therapy can theoretically deliver a higher radiation dose more precisely compared to standard techniques. Although 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 suggest that outcomes are similar between proton beam therapy and standard IMRT.[317][318] Carbon ion therapy is another type of particle beam irradiation under investigation in Japan. Preliminary data appear promising.[319]

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.[320]

Technology is continually changing to optimize radiation delivery to cancer while minimizing adverse effects, peripheral exposure, spillage, and long-term complications. Comparing outcomes between radiation therapy and radical surgery results is challenging, as current data reflect results from radiation treatments administered 10 to 15 years ago when the technology was less advanced than today.

The best available data suggest no significant difference in OS 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 typically defined as either locally advanced, a higher Gleason score (Gleason 4+4=8 or higher), or a rapid PSA doubling time of 10 months or less. Treatment for aggressive prostate cancers may involve radical prostatectomy, radiation therapy, HIFU, cryosurgery, hormonal therapy, chemotherapy, targeted therapy, immunotherapy, radiopharmaceuticals, or some combination of these. Early use of combinatorial therapies is helpful in many patients presenting with aggressive or advanced, localized disease.[26][296][321]

If cancer has spread beyond the prostate, treatment options significantly change. Hormonal therapy with androgen deprivation therapy (ADT) is the standard of care backbone, with additional therapy such as antiandrogens, targeted therapy, limited radiation therapy, radiopharmaceuticals, immunotherapy, and chemotherapy 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.[296]

Castrate-Sensitive and Castrate-Resistant Disease

Most hormone-sensitive cancers eventually become resistant to hormonal therapy and resume growth, despite castrate levels of testosterone (<50 ng/dL). At this point, the disease is considered castrate-resistant prostate cancer and requires additional treatment, such as chemotherapy. In the United States, it has been estimated that 106,505 men have localized (nonmetastatic) castrate-resistant prostate cancer, with 90% of these cases ultimately progressing to the bone and other metastases, potentially causing severe pain, pathological fractures, and spinal cord compression with paralysis.[322] Although standard therapy for castrate-sensitive disease in the past was ADT monotherapy, with the addition of secondary agents upon the development of castration resistance, upfront intensification in the castrate-sensitive space has improved patient outcomes, as discussed in detail below.

Systemic Therapy 

Systemic therapy in the modern era typically consists of docetaxel chemotherapy and modified hormonal therapy.

  • Docetaxel is the standard initial chemotherapy agent used to treat castrate-resistant prostate cancer, with a median survival benefit of 2 months to 3 months.[323]
  • The early use of docetaxel in hormone-naive patients with high-volume disease (defined as either visceral metastases or four or more bone metastases with one outside the spine or pelvis) appears to be beneficial based on significantly increased survival noted in several studies (STAMPEDE, CHAARTED, and RTOG 0521).[324][325][326][327]
  • The second-line chemotherapy treatment is cabazitaxel.[328][329]
  • Enzalutamide, abiraterone, darolutamide, and apalutamide are newer, second-generation antiandrogens that often work even when initial hormonal therapy has failed.[330]
  • Abiraterone is a CYP17A inhibitor that can block testosterone production inside tumor cells. In the castrate-sensitive setting, when compared to standard ADT, the addition of abiraterone and prednisone increased median PFS from 14.8 months to 33.0 months (hazard ratio (HR) 0.47), with median OS improvement from 34.7 months to not reached (HR 0.62).[331] In the castrate-resistant setting, abiraterone and prednisone improved median OS from 30.3 months to 34.7 months (HR 0.81).[332]
  • The combination of docetaxel and abiraterone for metastatic or locally advanced hormone-sensitive prostate cancer appears justified by recent studies.[333][334]
  • The PEACE-1 trial demonstrated that in men with newly discovered, castrate-sensitive metastatic disease, adding abiraterone to docetaxel and hormonal therapy extended median PFS to 4.5 years compared to 2 years with standard therapy. The benefit was most pronounced in men with the most significant metastatic burden.[335] The overall median lifetime survival benefit in men with high-volume prostate cancer metastases was 1.5 years.[335]
  • Enzalutamide, apalutamide, and darolutamide are androgen receptor signaling inhibitors that prevent the androgen receptor translocation into the cell nucleus.
  • Enzalutamide is approved in multiple settings for the treatment of metastatic prostate cancer. In the castrate-sensitive setting, the ARCHES trial showed that enzalutamide reduced disease progression or death from 19.0 months to not reached (HR 0.39).[336] In the metastatic castrate-resistant setting, the PREVAIL trial showed an 81% risk reduction in PFS and a 29% reduction in the risk of death.[337] The PROSPER trial demonstrated enzalutamide extended metastasis-free survival in nonmetastatic castrate-resistant prostate cancer from 14.7 months to 36.6 months.[338]
  • Enzalutamide has also been recently improved in the biochemical-recurrent nonmetastatic setting. In patients with a biochemical recurrence post-definitive therapy for their prostate cancer (either surgery or radiation) with a PSA doubling time of 9 months, it was found that limited treatment with 9 months of enzalutamide improved metastasis-free survival [339]. Due to the heterogeneity in the clinical management of biochemical-recurrent prostate cancer, only time reveals the extent to which this approach is being adopted into standard practice.
  • Apalutamide is approved in the metastatic castrate-sensitive and metastatic castrate-resistant settings. The TITAN trial showed that in castrate-sensitive prostate cancer, its addition to ADT, compared to standard ADT monotherapy, resulted in improvement in PFS (2-year PFS 68.2% in the ADT + apalutamide group compared to 47.5% in the ADT monotherapy group, HR 0.48) and improvement in OS (2-year OS 82.4% with apalutamide compared to 73.5%, HR 0.67).[340] In the castrate-resistant setting, based on the SPARTAN trial, apalutamide improved median metastasis-free survival from 16.2 months to 40.5 months (HR 0.28).[341]
  • Darolutamide has a similar mechanism of action to the 2 other androgen receptor signaling inhibitors but is currently approved in only two settings—in the metastatic castrate-sensitive setting in combination with docetaxel (triplet therapy) and the nonmetastatic castrate-resistant setting. The ARASENS trial compared the addition of darolutamide to ADT + docetaxel in metastatic castrate-sensitive prostate cancer and found that the addition of darolutamide resulted in an improvement of survival, with a 32.5% decreased risk of death.[342] The ARAMIS trial examined docetaxel in the nonmetastatic castrate-resistant setting, with darolutamide improving median metastasis-free survival from 18.4 months to 40.4 months.[343]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.[173]
  • Although no head-to-head studies exist, all of the second-generation antiandrogens substantially improve PFS and OS over placebo. Determining the optimal treatment approach—whether to use antiandrogens or chemotherapy—requires further randomized trials.[344][345][346] Treatment decisions should be individualized based on disease volume and patient comorbidities, with the potential use of triplet therapy (ADT, docetaxel, and either darolutamide or abiraterone plus prednisone) for high-volume disease.
  • The presence of Androgen Receptor Splice Variant 7 (AR-V7) messenger RNA 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.[347][348]
  • Patients who progress after treatment with second-generation hormonal agents, such as enzalutamide or abiraterone, should be considered for polyadenosine diphosphate-ribose polymerase (PARP) inhibitor therapy, such as olaparib and rucaparib, if they have BRCA1, BRCA2, or ATM germline or somatic mutations.[349][350][351][352][353]
  • Although similar, it appears that enzalutamide and apalutamide may provide slightly better overall and metastasis-free survival. In contrast, darolutamide appears to have better tolerability with fewer adverse effects.[342][354][355][356]
  • Circulating tumor cells can be detected in the blood of castrate-resistant prostate cancer patients. The critical number that significantly shortens survival appears to be 5 or more tumor cells per 7.5 mL of blood.[357][358]
  • Immunotherapy treatment with sipuleucel-T in castrate-resistant prostate cancer has been shown to increase survival but only by 5 months in patients with advanced disease (PSA >50).[359] Although it is indicated for men with metastatic, castration-resistant prostate cancer, it is often administered too late to achieve maximal effectiveness.
  • The PI3K-AKT-mTOR pathway may play a crucial role in the development of castrate resistance.[360]

About 90% of patients with castrate-resistant prostate cancer develop bony prostate cancer metastases, which can be extremely painful. Therefore, much of the therapy at this stage focuses on managing bone involvement.[361]

Bisphosphonates, such as zoledronic acid, and RANK-ligand inhibitors, such as denosumab, have improved quality of life and reduced pathological fractures in castrate-resistant prostate cancer patients. Unfortunately, these agents have not been shown to improve survival. Before using either of these agents, a dental evaluation 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 5000 units of daily supplemental vitamin D is also suggested for these patients.[258][259][362][363]

Radium-223 dichloride is a radiopharmaceutical that works particularly well on bone metastases from prostate cancer. Radium-223 dichloride has been shown to improve OS in castrate-resistant prostate cancer patients by 30%, which sounds good but is only about 3 to 4 months for most recipients. Radium 223 specifically targets the bone as it is calcium-mimetic and is ineffective in visceral, soft tissue, and nodal disease. Therefore, it should be used for castrate-resistant prostate cancer patients with bone metastases but without organ, soft tissue, or significant 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 (improvement of median OS from 11.2 months to 14.0 months, HR 0.70). [364] 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.[365][366]

Lutetium 177 vipivotide tetraxetan is now FDA-approved for use in metastatic castrate-resistant prostate cancer in patients with positive PSMA PET/CT scans whose disease has progressed following treatment with a second-generation antiandrogen and at least one course of taxane-based chemotherapy. The technology combines a beta particle radiation source with a PSMA-specific binder, creating a radioligand that targets PSMA-expressing cells and delivers beta radiation directly to them and their surrounding microenvironment. The treatment has a good safety profile and is relatively well-tolerated, extending PFS and OS by about 4 to 5 months in this difficult-to-treat patient population.[197][198]

Sipuleucel-T, a prostate cancer vaccine, has been found to result in a survival benefit for men with metastatic, castrate-resistant prostate cancer, but it provides only a relatively limited improvement in life expectancy. It is an autologous, dendritic cell-based vaccine that targets prostatic acid phosphatase. This vaccine is the only vaccine-based therapy currently available for prostate cancer in the United States, but a number of others are in various stages of development. Identifying reliable prostate cancer biomarkers is crucial for optimizing future immunotherapy and tailoring treatments to individual patients.[367][368]

PARP inhibitors are a type of enzyme that helps repair DNA damage in cells. PARP inhibitors, such as olaparib, rucaparib, talazaparib, and niraparib, 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 DNA damage repair gene (DDRG) germline or somatic mutations. Olaparib showed a median survival benefit of about 5 months (more than double the median PFS) compared to enzalutamide or abiraterone treatment alone and was most effective in patients with BRCA2 mutations on germline testing.[350] Rucaparib demonstrated a 63% PSA response rate.[369] Patients with PALB2, BRIP1, and RAD51B mutations responded quite well to rucaparib therapy, whereas those with ATM, cyclin-dependent kinase 12 (CDK12), and CHEK1 germline mutations were generally refractory to the drug.[349][370] PARP inhibitors have demonstrated the ability to extend OS and make prostate cancer more radiosensitive in early clinical trials.[349][350][351][352][353][369][371][372] This radiosensitizing effect could further increase their efficacy as more research is conducted in this area.[371] 

Currently, there are 4 FDA-approved PARP inhibitors for the treatment of metastatic castrate-resistant prostate cancer. Olaparib is approved both as monotherapy for any homologous recombination repair (HRR) gene alteration [350] and in combination with abiraterone + prednisone for BRCA-mutated disease. [351] Rucaparib is approved as monotherapy for BRCA-mutated disease.[373] Talazoparib is approved in combination with enzalutamide for HRR gene alterations,[374] and niraparib is approved in combination with abiraterone + prednisone for BRCA-mutated disease.[375] 

Summary of Prostate Cancer Systemic Therapy

  • All protocols begin with hormonal therapy using an LHRH agonist or antagonist. Due to improved outcomes and survival, a second-generation antiandrogen should be added to ADT in the upfront setting for the majority of patients. In advanced or aggressive cases, triplet therapy with docetaxel and a second-generation antiandrogen should be used.
  • Docetaxel is the recommended first-line chemotherapy.
  • Cabazitaxel is a second-line chemotherapy drug. Although similar in efficacy to docetaxel, cabazitaxel  is better tolerated and preferred in patients at risk for neutropenia, extremely frail patients, or older patients. However, it is more expensive compared to docetaxel.
  • Patients with ATM, BRCA1, BRCA2, CHEK2, Fanconi anemia complementation group A (FANCA), and PALB2 germline mutations that involve DDRGs 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 treatment with second-generation antiandrogens and chemotherapy may be candidates for PARP inhibitors. Germline and somatic testing, especially BRCA1/2, should be performed to assess for DDRGs. Also, consider obtaining an AR-V7 blood test.
  • Patients with BRCA1 and BRCA 2 mutations respond better to PARP inhibitors compared to those with ATM or other mutations.[376]
  • Patients with MLH1, MSH2, MSH6, and PMS2 that involve DNA mismatch repair (MMR) genes may respond to an immunotherapy drug such as pembrolizumab, although this is a small group of patients.[377]
  • Patients with castrate-resistant prostate cancer and bone metastases benefit from either zoledronic acid or denosumab to minimize bone pain and fractures.
  • Sipuleucel-T, Radium 223, Lutetium 177, and PARP inhibitors should be used appropriately in castrate-resistant prostate cancer patients for both palliative and therapeutic benefits. Therapy incorporating these inhibitors has demonstrated improved quality of life, clinical symptom reduction, cancer-specific survival, and overall survival.
  • The role of mitoxantrone is minimal, offering more benefit for symptom relief than survival, and palliative care options should be thoroughly discussed with patients.
  • Platinum-based chemotherapy has a role in refractory or aggressive variant disease.
  • Docetaxel or cabazitaxel, administerd 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 disease progression on standard therapeutic options should consider participation in a clinical trial whenever possible. 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 prostatic cancer growth, proliferation, aggressiveness, and metastases. 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.[378] Excellent research opportunities exist in the area of protein kinase inhibitors, which reduce specific kinase activity or interrupt kinase-mediated signal pathways.[379][380]

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.[381] 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 one of the first treatments based on this therapeutic modality.[197]

Actinium 225 is another radiopharmaceutical against PSMA currently being investigated in clinical trials [382]

Another promising area of research involves prostate cancer stem cells. These small prostate cancer cell populations induce tumor onset, growth, and development. They contribute to the development of resistance to chemotherapy and promote metastasis. The 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.[383]

The development of hormonal-resistant prostate cancer involves several families of chromatin modifiers. Targeting the bromodomain and extra-terminal protein family represents a promising, new, and novel approach to treating castrate-resistant prostate cancer. However, the limited understanding of the mechanisms underlying androgen resistance and the associated genetic factors suggests that these therapies may not be widely available in the near future.[384]

Second-generation antiandrogens 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.[385] Researchers at the University of California, Davis, have developed a molecule called LX-1, targeting both AR and the AKR1C3 enzyme, intending to circumvent the development of castration resistance. Androgen receptor proteolysis targeting chimeras are also a promising avenue, with the ability to induce degradation of the AR target rather than just inhibition, and is currently being investigated in clinical trials.[386]

Ipilimumab is a type of monoclonal antibody that activates cytotoxic T lymphocytes by directly blocking CTLA-4 (cytotoxic T-lymphocyte antigen) T-cell receptor sites, which otherwise downregulate the immune system. Although ipilimumab is primarily used as immunotherapy for melanoma and other solid tumors, such as renal cell carcinoma, non–small cell lung cancer, and colorectal cancer, it has been found to show some activity in prostate cancer. Two large ipilimumab prostate cancer trials showed an improvement in PFS, but OS was not statistically improved.[387][388] However, a few patients have experienced long-term prolonged survival of up to 64 months.[389] Further research, including germline testing, is needed to better identify patients who may benefit from this extended survival.

Nivolumab is another monoclonal antibody cancer therapy that inhibits the activity of PD-1 receptors on T cells, enhancing T-cell activity and anti-tumor immune response. Nivolumab plus ipilimumab showed no additional efficacy in incidentally found localized prostate cancer in patients undergoing cystoprostatectomy for bladder cancer.[390], but nivolumab did show a signal when combined with docetaxel in an early-phase clinical trial.[391]

Targeted, individually customized anticancer therapies offer great potential for controlling malignancy and reducing adverse effects by selectively delivering cytotoxic material to malignant cells. One promising approach involves designed ankyrin repeat proteins (DARPs), non–immunoglobulin-based scaffold proteins engineered to deliver cytotoxic material exclusively to prostate cancer cells. Epithelial cell adhesion molecule (EpCAM) is overexpressed 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.[392] Such 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 demonstrate germline, inheritable abnormalities and that about 10% of patients with metastatic castration-resistant disease carry inherited gene mutations.[393][394][395] 

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.[396] 

Hereditary prostate cancer due to germline mutations has an autosomal dominant pattern or transmission and is typically characterized by early onset.[397] Multiple trials are underway, including patients with both metastatic prostate cancer and localized disease, to determine how germline testing can best be used to select optimal, personalized therapies.[398] Identifying a hereditary predisposition to cancer among both male and female family members can lead to optimized screening of individuals with earlier detection and treatment of any newly discovered malignancies.[398]

  • Overall, the most commonly found germline mutation in familial prostate cancer is BRCA2, followed by ATM, CHEK2, and BRCA1.[399]
  • Patients with germline mutations of BRCA1, BRCA2, or ATM were found to have a higher likelihood of cancer upgrading during active surveillance.[400][401]
  • 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.[397][398]
  • BRCA1 and BRCA2 mutation status is an independent prognostic indicator of metastasis-free survival in patients with localized disease undergoing definitive therapy (either radiation or radical prostatectomy).[402][403]
  • Men with BRCA1 or BRCA2 mutations are also at higher risk for male breast cancer, melanoma, and pancreatic cancer.[397][398]
  • Men with BRCA1 or BRCA2 mutations face an overall increased risk of prostate cancer (3.8-fold 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 noncarriers.[403][404]
  • These men also have worse outcomes after radical prostatectomy or radiation therapy.[403]
  • 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.[405]
  • Higher Gleason scores have been associated with BRCA2, ATM, and NBN mutations.[406]
  • 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.[398][407]
  • Patients with metastatic castration-resistant cancer and a BRCA1, BRCA2, or ATM mutation that has progressed despite hormonal therapy, including either enzalutamide or abiraterone, benefit from a Poly(ADP-ribose) polymerase (PARP) inhibitor, such as olaparib or rucaparib.[398][351][398] If patients were initially solely treated with ADT, combinatorial therapies with a combinatorial PARP inhibitor with second-generation antiandrogens, such as olaprib/abiraterone, niraparib/abiraterone, and talazoparib/enzalutamide, have shown benefit.[351][375][374]
  • Mutations in the HOXB13 gene, usually found in people of West African descent, are associated with an 8- to 10-fold increase in the lifetime risk of prostate cancer and an earlier presentation than noncarriers.[398][408][409]
  • Patients with Lynch syndrome are at an increased risk for several malignancies, including colorectal, melanoma, pancreatic, urothelial, prostate, skin cancers, and ovarian and uterine cancers in women.[398]
  • Patients with pancreatic cancer harboring BRCA mutations have increased sensitivity to platinum-based chemotherapies.[410] For metastatic castrate-resistant prostate cancer, there is evidence that patients harboring HRR gene mutations, specifically BRCA, have increased sensitivity to platinum-based chemotherapies.[411][412] Currently, the presence of an HRR gene mutation qualifies for treatment with PARP inhibitors, either alone or in combination with second-generation antiandrogens, depending on prior therapies before developing castration resistance. However, this may be an interesting biomarker to predict response to platinum-based chemotherapy. 

Who Should Undergo Germline Testing and When

Germline testing should be offered to any prostate cancer patient when the results could impact their therapeutic or clinical management or have implications for their family members.[398] Generally, germline testing is recommended for men with metastatic or locally advanced prostate cancer, as they have a higher likelihood of carrying heritable mutations. Germline testing 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.[398] 

Germline testing is strongly recommended for patients with advanced or metastatic castration-resistant prostate cancer to identify DDRGs such as ATM, BRCA1, and BRCA2, which typically respond well to PARP inhibitor medications, such as olaparib and rucaparib, and platinum-based chemotherapy.

The optimal time to discuss germline testing with patients is not well established, but it is advisable to bring it up early, particularly when metastatic disease develops. Delays in testing and appointments with genetic counselors can be challenging, and discussing genetic testing simultaneously with new diagnoses of metastatic disease may overwhelm patients and their families. Germline testing can be performed anytime if the patient meets the eligibility criteria.

Germline testing is not the same as somatic or tissue-based biomarkers and genetic alterations. While both are often complementary, germline mutations are inheritable and occur in the germ cells (eggs and sperm). In contrast, somatic mutations arise in nonreproductive cells, such as prostate cells, and cannot be passed on to offspring.

Internationally, about 75% of clinicians have access to germline testing, but only about 18% of patients with metastatic castration-resistant prostate cancer are currently being tested.[413][414] The most commonly tested mutations were ATM, BRCA1, and BRCA2.[413] The most common reasons for failing to perform germline testing include cost, lack of physician awareness, insurance and reimbursement issues, the need to send samples to external laboratories, limited access to genetic counselors, physician uncertainty on interpreting results, and patient refusals.[414]

As the indications for germline testing have expanded, the number of genetic counselors has not kept pace, resulting in significant delays in patients being able to see a genetic counselor. Consequently, this situation places a greater burden on primary care practitioners, urologists, and oncologists to discuss germline testing with patients, creating difficulties or hesitations in ordering the tests. Establishing a collaborative relationship with genetic counseling services or a dedicated counselor can improve patient management by coordinating optimal testing, defining screening criteria, selecting appropriate mutation panels, and identifying suitable laboratories.

Registry and Research Opportunities in Germline Testing for Patients

  • 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 a free newsletter is provided 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.[398][400]

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

Germline testing should also be considered if any of the following conditions are met:

  • 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 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 or 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), and 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 and opportunities for research into targeted therapies for this high-risk group.[415][416]

Understanding germline status helps 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.[398]

Specific Germline Mutations

There are about 170 germline mutations that have been identified and linked to prostate cancer.[399] Of these, 14 appear with sufficient frequency and are associated with enough potential clinical significance to warrant testing.[398] 

The NCCN recommends at least 11 mutations for germline testing in prostate cancer—ATM, BRCA1, BRCA2, CDK12, CHEK2, PALB2, RAD51D, 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 2 general types—DDRGs and DNA MMR genes.

  • DDRGs include ATM, BRCA1, BRCA2, CHEK2, CDK12, FANCA, RAD51D, and PALB2. This group often responds to PARP inhibitor therapy, although the benefit is largely driven by BRCA1 and BRCA2 mutations. Patients with DDRG mutations also appear to respond to cisplatin, which is currently being investigated and has promising efficacy, but with a significant toxicity profile.[417][418] The combination of PARP inhibition and radiation therapy may also prove useful in patients with this type of mutation.[419] 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.[416]
  • MMR mutations include MLH1, MSH2, MSH6, and PMS2. Patients with these genetic defects tend to respond to immunotherapy such as pembrolizumab, although it is of low prevalence in prostate cancer compared to other malignancies.[420][421]

Ataxia telangiectasia mutated gene: ATM is a key DNA damage control response gene that is also associated with an increased risk of breast, colorectal, pancreatic, and stomach cancers in addition to prostate cancer. ATM carriers have a high relative risk of metastatic prostate cancer of 6.3%.[405][422] Prostate cancer patients with ATM mutations typically have a worse prognosis compared to 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 PARP inhibition therapy.[423]

Breast cancer susceptibility genes: BRCA1 and BRCA2 mutations have been associated with several cancers, particularly breast and ovarian cancer. These tumor suppressor genes 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 have a penetration of about 2% to 2.5%. Of Ashkenazi Jewish men who develop prostate cancer, 3.2% to 4% are carriers.[424] Men whose families have many female breast cancer patients have a 2 to 3-fold increased risk of prostate cancer.[425] 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 noncarriers.[426] Like carriers with ATM mutations, BRCA patients are more likely to progress if placed on an active surveillance protocol. Patients with metastatic castration-resistant prostate cancer and a BRCA2 mutation that progresses rapidly despite initial chemotherapy might benefit from PARP inhibitor therapy such as olaparib or rucaparib.[398] Other PARP inhibitor medications are being studied, along with their use with cisplatin in advanced prostate cancer patients with BRCA2 and ATM mutations.[417][418][420] Prostate cancer screening for BRCA1 and BRCA2 carriers is recommended starting at age 40 with a 3 ng/mL cutoff threshold.

Cyclin-dependent kinase 12: CDK12 is an important enzyme that regulates genetic transcription, translation, cell growth, RNA splicing, and DNA damage response (DDR).[427] CDK12 mutations are found in 3% to 7% of metastatic castration-resistant prostate cancer patients.[428] These mutations are associated with a high rate of metastatic spread and decreased OS.[429] Patients with CDK12 mutations tend not to respond well to taxane-based chemotherapy, hormonal treatment, or PARP inhibitors but might respond to PD-1 inhibitors.[430] 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.[431] Experimentally, the use of bipolar androgen therapy or Radium-223, both of which cause double-strand DNA breaks), significantly increased the beneficial effect of immunotherapies, such as sipuleucel-T and nivolumab, in patients with CDK12 mutations.[428] these initial treatments are believed to sensitize the immune system, enhancing the effectiveness of subsequent immunotherapy.[428]

Checkpoint kinase 2: CHEK2 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 cell carcinoma, and prostate cancers.[405][432] 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%.[433]

Epithelial cell adhesion molecule: EpCAM, also known as CD326, is overexpressed in many rapidly growing cancers, including prostate cancer. EpCAM is involved in cell signaling, migration, cellular adhesion, proliferation rate, invasion capacity, metastatic potential, and differentiation.[434] 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.[435] EpCAM also offers some potential research opportunities for new targeted therapies currently under investigation.[392]

Fanconi anemia complementation group A: FANCA is associated with prostate cancer and Fanconi anemia. Increased sensitivity to DNA-damaging agents is caused when the FANC complex is disrupted by the FANCA mutated protein.[436] 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.[436] About 6% of prostate cancers exhibit a FANCA mutation.[437][438] Such mutations may have clinical significance as it has been shown that patients with the FANCA mutation may exhibit significantly increased sensitivity to cisplatin therapy.[438] They may also respond to PARP inhibitor therapy.[439]

Homeobox B13: HOXB13 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.[409][440][441][442] HOXB13 is involved in protein synthesis regulation and androgen receptor activity as a homeobox gene. Evidence indicates that HOXB13 mutations may block an important tumor suppressor gene and increase mitotic kinases, potentially contributing to prostate cancer metastasis.[443] Although it currently has no known therapeutic role or implications, it may be useful in family counseling.

KLK3|179T: 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.[444]

MLH1, MSH2, MSH6, and PMS2: These DNA MMR genes are most often associated with Lynch syndrome.[445] Of these, MSH2 has shown the closest correlation with an increased prostate cancer risk.[446] The estimated hereditary prostate cancer risk in individuals with these mutations is 2% to 3.7%.[447] However, an earlier study suggested a 5-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.[448]

P53: P53 mutations in localized prostate cancer are relatively rare and are more frequently observed in metastatic disease. P53 is a tumor suppressor gene that produces p21 protein, which slows 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 indicators of prostate cancer.[35]

Partner and localizer of BRCA2: PALB2 is closely associated with BRCA1 and BRCA2, as it is an essential component involved in creating the BRCA complex that launches homologous recombination processes.[449] Although relatively rare, PALB2 appears to have a significant role in heritable prostate cancer when present.[350][450] PARP inhibitors can be effective in PALB2 carriers with prostate cancer.[439]

Nibrin: NBN 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 3-fold negative prognostic impact on prostate cancer survival.[406][451][452]

The validity of the NCCN guidelines on screening criteria and which mutations to include in germline testing has been called into question.[450] In a 2019 Tulane study involving 3607 men with prostate cancer, 17.2% were found to have germline mutations, but 37% of these cases (229) are missed under the current NCCN screening criteria and germline testing guidelines.[450] Either their personal or family history did not meet the screening criteria, or the recommended germline testing omitted their particular mutation.[450] The NCCN guidelines on germline testing and screening criteria should, therefore, be viewed as a baseline starting point and not necessarily the optimal protocol for every individual. 

Some experts have suggested testing for all the HRR mutations, including ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, and RAD54L; the MMR mutations, including PMS2, MLH1, MSH2, and MSH6; EpCAM; HOXB13, especially in African Americans; FANCA; NBN; KLK3|179T; and p53. This decision to pursue such testing depends 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. Specific genetic testing platforms test for the aforementioned genes and additional genes as part of their panels.[453] If genetic counseling services are limited in your area, contact the National Society of Genetic Counselors for assistance and a directory of their members. Genetic counseling services are also available online.

Three germline mutation sets have been associated with rapid biochemical recurrence following definitive cancer therapy—PI3K/AKT/mTOR, KRAS signaling (upregulation), and inflammatory response.[454]

Kisspeptin 1 (KISS1) has been shown to promote tumor angiogenesis, significantly enhancing malignant tumor growth while facilitating tissue invasion and malignant cell migration.[455]

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.[226][370][416][444] Clinicians should obtain as much germline mutation data as reasonably feasible, considering factors such as cost and insurance coverage.

Clinicians who order germline tests are ultimately responsible for discussing the results with their patients and arranging for genetic counseling if appropriate. Challenges such as insufficient knowledge of germline testing and result interpretation, a lack of familiarity with patient counseling, reliance on outside labs for testing, insurance uncertainties, and a shortage of genetic counselors pose significant barriers to the broader and more effective use of germline testing.

Staging

An important part of evaluating prostate cancer is determining its stage. The 3-stage TNM (tumor/nodes/metastases) classification is the most commonly used staging system. This system includes 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.[456][457]

Key Distinction in Prostate Cancer Staging

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, as 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 ≤5% of tissue resected (TURP specimen)
    • T1b: Tumor is an incidental histologic finding in >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 invades adjacent structures (other than seminal vesicles)

Pathologic Tumor Staging 

  • pT1: No pathologic T1 classification exists
  • 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.[458]
  • MRI is excellent for evaluating the prostatic capsule for an extracapsular extension and the regional lymph nodes and seminal vesicles for possible tumor involvement.[459][460]
  • 68-Gallium PSMA PET/CT and PET/MRI scans and similar PET scans are FDA-approved tests for reliably detecting even early metastatic prostate cancer. These scans offer significantly improved sensitivity and specificity over standard imaging by combining molecular activity testing with conventional morphologically based radiographic studies. Although 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.[461][462][463] 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 Prostate-Specific Antigen Level in Younger Men (Ages 40 to 45)

The European Association of Urology Guidelines states that for men in their early 40s, a PSA level exceeding 1 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. These studies demonstrate that a single PSA test of less than 1 ng/mL in men in their 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 also helps find the small percentage of men who develop very aggressive and highly lethal prostate cancer before age 50.

For example, Vince Flynn, the best-selling author of American Assassin, died of metastatic prostate cancer at 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 outcome data from multiple sources. These tools generally include some combination of age, Gleason score, biopsy information, and PSA levels and may also require other clinical information, such as the number of positive biopsies with the percentage of tumor involvement and clinical and pathological staging.[464] Multiple nomograms exist, including the Briganti, Rotterdam, and Stanford models. Three of the most popular nomograms available online for free include the following:

  • Partin tables from Johns Hopkins University [465][466][467]
  • Memorial Sloan Kettering Cancer Center prostate cancer nomograms [212][468]
  • Cancer of the Prostate Risk Assessment score from the University of California, San Francisco [469]

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. Choosing not to pursue surgical intervention can lead to renal failure, which typically progresses slowly and painlessly.[470][471]

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 process may be preferable to forcing them to endure increasingly severe and debilitating pain from advancing disease and bone metastases. Although treating the ureteral obstruction might provide temporary relief, it usually extends survival by only a few months. This decision is deeply personal and should be made after reviewing and discussing all available options well in advance. Palliative care and hospice services should certainly be involved at this point if not engaged previously.

The 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.[472]

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

Although 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. Medical conditions such as a recent cardiac stent placement or a history of pulmonary embolisms requiring prolonged anticoagulant therapy may also preclude performing a biopsy.

With the use of MRI imaging, genomic analysis, validated prostatic nomograms, and all of the other pre-biopsy predictive tests, it is feasible 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 must be thoroughly informed about the standard of care and the potential risks and benefits of treatment without absolute confirmation of an aggressive prostatic malignancy.[473]

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%. In contrast, patients presenting with distant metastases have a 5-year overall survival rate of only 29%.

The most important prognostic indicators for patients undergoing treatment are their age and general health at diagnosis, 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.[474]

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.[475]

  • 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 compared to any other identifiable disease or disorder.
  • Older men with low-grade disease have approximately a 20% OS 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 WHO (Life Tables by Country). 

Possible Urinary Marker for Aggressive Prostate Cancer in African American Men

A study at the NCI investigated the potential role of urinary thromboxane B2 (TXB2) as a possible marker for aggressive prostate cancer. TXB2 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.[476] The reason for this remains unclear. Investigators also found that aspirin reduced TXA2 synthesis and all-cause mortality in the high urinary TXB2 group, suggesting a possible therapeutic benefit.[476]

Palliative Care and Hospice

Palliative care focuses on treating cancer symptoms and improving the 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 involve palliative care and hospice services early enough in the disease course to initiate patient assistance immediately without undue delays.[477]

Pearls and Other Issues

Prostate-Specific Antigen Testing: The Controversy

PSA is a protein produced by the prostate and is abundant in semen. The function of PSA is to break down seminogelin in the semen, which helps in liquefaction. The expression of PSA is androgen-regulated.[478]

PSA was initially 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 started to increase significantly about 7 to 9 years before the clinical diagnosis of malignancy. Although 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. In addition, PSA testing cannot reliably distinguish between low-risk/low-grade diseases and high-risk/high-grade cancers.

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

Although it unquestionably increases prostate cancer detection rates, the value of PSA testing is less clear in avoiding overtreatment, improving the quality of life, and lengthening OS, 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%, whereas 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 male population in the United States increasing by 28.6% (from 126 million to 162 million).

More impressively, according to the NCI, since 1992, the death rate from prostate cancer in the United States has dropped by a remarkable 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 adverse effects of unnecessary biopsies and curative therapies, as most men with prostate cancer have slow-growing, low-grade cancers for whom definitive, curative therapy often causes considerable harm with little or no survival benefit.

  • In 2012, the USPSTF recommended against all routine screening PSA tests due to the risks of overtreatment without proof of any substantial survival benefit. This recommendation initially seemed reasonable as most prostate cancers are low-grade and remain asymptomatic. The USPSTF concluded that the potential benefits of PSA testing and earlier definitive cancer therapy did not outweigh the increased risks of adverse 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, and the 4K test, MRI prostate imaging, and MRI-TRUS fusion-guided biopsies, and 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.[479]
  • The original 2012 USPSTF recommendation was also inconsistent with numerous studies showing a 50% or more cancer-specific survival benefit in PSA-screened populations compared to their unscreened cohorts if followed for more than 10 years.[480]

The Current United States Preventive Services Task Force Recommendation

For men aged 55 to 69, the decision to undergo PSA screening for prostate cancer should be individualized, following a thorough discussion of the benefits, risks, and limitations of such screening.[481][6]

Routine PSA screenings are not recommended for men older than 75, based on the conclusion that definitive treatment of localized cancers in most older men has minimal effect on OS while introducing significant treatment-related adverse effects and morbidities to many. Screening is also not recommended in men with a life expectancy of less than 10 years. 

Many professional organizations now have guidelines and recommendations regarding PSA screening for prostate cancer. Most recommend 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. Nonetheless, patients and family members should make this decision after thoroughly discussing the pros and cons of continuing screening.

Prostate Cancer Screening: The Pros and Cons

Screening options include a DRE and a PSA blood test. Such screenings may lead to a biopsy with some associated risks. TRUS has no role in prostate cancer screenings.[482]

Routine screening with a DRE, and particularly PSA testing, has become very controversial. Some of the arguments for and against screening include:

Against Prostate-Specific Antigen Screenings

  • Most patients had no real change in OS for at least the first 10 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 miss the rapidly growing, aggressive tumors that are the most lethal.
  • Increased patient anxiety from low-risk, low-grade prostate cancer ultimately does not affect survival.
  • Unnecessary biopsies contribute to patient anxiety, are uncomfortable, add cost, and may have complications such as infections and bleeding.
  • Several recent large studies show little or no survival benefit to large-scale screenings.
  • As suggested by some recent studies (PIVOT), prostate cancer screenings may not be beneficial if treatment offers little or no survival benefit.
  • Countries with robust healthcare systems that do not perform widespread PSA testing have noted similar reductions in prostate cancer-specific survival compared to countries such as the United States with extensive PSA screenings.

In Favor of Prostate-Specific Antigen 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 does not reduce its mortality.
  • Modern tools, including active surveillance, MRI imaging, MRI-TRUS fusion biopsies, and genomic testing, help avoid overtreatment.
  • Eliminating routine PSA screenings, as recommended by the earlier 2012 USPSTF report, has already caused a significant reduction of about 30% in prostate cancer diagnoses. At least some of these cancers are high-grade and 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.[483]
  • Many of the larger studies suggesting a lack of survival benefit to large-scale PSA screenings are poorly conducted, significantly biased, severely contaminated, and full of significant statistical errors.
  • Well-conducted studies comparing PSA-screened and unscreened populations show a cancer-specific survival advantage at or above 50% for the screened groups if followed for more than 10 years.
  • According to the NIH, prostate cancer mortality has dropped over 44% since 1992, when PSA testing became widely available in the United States. This improvement is almost double the benefit in 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.
  • NIH estimates that ceasing PSA screenings could result in an additional 25,000 to 30,000 annual deaths from preventable prostate cancer within a decade.
  • Only 9% of all new prostate cancer cases present with advanced disease, compared to 32% before the PSA era, representing a 72% reduction.
  • Less than 4% of all new cases initially present with metastatic disease compared to 21% before widespread PSA screenings. This 80% reduction in the incidence of metastatic prostate cancer at the time of initial diagnosis can only be explained by the benefits of PSA screenings.
  • Diagnostic testing and treatment options are constantly being improved to lower costs and minimize side effects while increasing survival and enhancing quality of life. However, these new minimally invasive technologies cannot be utilized without early PSA screening.

Recommended General Guide to Prostate-Specific Antigen Testing

  • An initial PSA test at 40 to 45 years 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.
  • Routine PSA screenings are recommended only in reasonably healthy men between the ages of 45 and 75 who wish to undergo testing after thoroughly discussing the benefits, limitations, and potential risks.
  • Screening is not recommended for patients unlikely to accept treatment if cancer is detected.
  • Screening is not recommended for healthy men older than 75 with normal PSA levels, as they are not likely to benefit from treatment.
  • Screening is recommended only in men who are reasonably expected to have at least a 10-year life expectancy from the time of diagnosis. For most newly discovered localized prostate cancers, the survival benefit from treatment does not begin until at least 10 years after therapy.
  • Screening is recommended in men at high risk due to ethnicity, family history, or proven germline mutations.
  • Screening is recommended in men with an abnormal DRE suggestive of cancer regardless of age.
  • PSA testing should be offered to all men who request it, provided they are fully informed of the risks, benefits, and limitations of screening, even if they fall outside standard guidelines.

Summary of Genomic Prostate Cancer Tests (Beyond Prostate-Specific Antigen)

Pre-biopsy: Initial basic screening includes total PSA, free and total PSA, and PSA density levels. At least 2 separate PSA levels should be conducted 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 2 tests.

Improved pre-biopsy liquid biopsy screening tests include PCA3, the PHI, MyProstateScore, the 4K blood test, ExoDx or Exosome test, and SelectMDx. These tests have over 90% NPV and can safely exclude about 25% of patients with persistently elevated PSA levels from further testing and unnecessary biopsies. These tests are best used before MRI imaging or a biopsy in men with persistently elevated PSA levels or as a confirmation after a negative MRI examination in borderline cases.[137][484]

Post-biopsy: For patients with a negative initial tissue biopsy who are being considered for a repeat prostatic biopsy, tissue-based genomic bioassays such as ConfirmMDx provide valuable risk stratification and analysis.

  • Men on active surveillance can be tracked and followed with genomic testing or serial PCA3 testing in addition to standard PSA levels.
  • The Prolaris test is most beneficial for patients with low- or intermediate-grade disease who are considered for active surveillance or definitive therapy.
  • Patients with low- 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 such as Decipher or Prolaris, which serves as a prognostic marker of cancer control outcomes.

Clinical Trials

Patients should be encouraged to consider participation in prostate cancer clinical trials whenever possible. These trials can be found through several sources:

  • The American Cancer Society provides information on prostate cancer clinical trials sponsored by the NCI and the National Institutes of Health.
  • The Prostate Cancer Clinical Trials Consortium 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 at the Memorial Sloan Kettering Cancer Center in New York City. There are 43 participating or affiliated clinical research sites.
  • For a comprehensive list of all open prostate cancer clinical trials in the United States, visit 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 consisting of specialty-trained nurses, nurse practitioners, clinician assistants, primary care providers, oncologists, radiation therapists, genetic counselors, and urologists must collaborate to manage the following challenges:

  • Addressing 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 such as the American Medical Association, American Cancer Society, and AUA
  • Adapting to frequently changing guidelines
  • Decreased PSA screenings following the USPSTF report of 2012, a drop of 30%
  • Dealing with the ongoing PSA testing controversy
  • Understanding the proper use of newly available genomic tests and determining which are optimal at different stages 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 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 compared to 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 2 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 identifying 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 issues and many more 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]

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