Prostate cancer

Cancer of the prostate[6][7] is the second most common cancerous tumor worldwide and is the fifth leading cause of cancer-related mortality among men.[8] The prostate is a gland in the male reproductive system that surrounds the urethra just below the bladder. Most prostate cancers are slow growing. Cancerous cells may spread to other areas of the body, particularly the bones and lymph nodes. It may initially cause no symptoms. In later stages, symptoms include pain or difficulty urinating, blood in the urine, or pain in the pelvis or back. Benign prostatic hyperplasia may produce similar symptoms. Other late symptoms include fatigue, due to low levels of red blood cells.

Prostate cancer
Other namesCarcinoma of the prostate
Position of the prostate
SpecialtyOncology, urology
SymptomsNone, difficulty urinating, blood in the urine, pain in the pelvis, back, or when urinating[1][2]
Usual onsetAge > 50[3]
Risk factorsOlder age, family history, race[3]
Diagnostic methodTissue biopsy, medical imaging[2]
Differential diagnosisBenign prostatic hyperplasia[1]
TreatmentActive surveillance, surgery, radiation therapy, hormone therapy, chemotherapy[2]
Prognosisfive-year survival rate 97.1% (US)[4]
Frequency1.2 million new cases (2018)[5]
Deaths359,000 (2018)[5]

Factors that increase the risk of prostate cancer include older age, family history, and race.[3][9] About 99% of cases occur after age 50.[3] A first-degree relative with the disease increases the risk two- to three-fold.[3] Other factors include a diet high in processed meat and red meat.[3] An increased risk is associated with the BRCA mutations.[10] Diagnosis is by biopsy.[2] Medical imaging may be done to assess whether metastasis is present.[2]

Prostate cancer screening, including prostate-specific antigen (PSA) testing, increases cancer detection but whether it improves outcomes is controversial.[3][11][12][13] Informed decision making is recommended for those 55 to 69 years old.[14][15] Testing, if carried out, is more appropriate for those with a longer life expectancy.[16] Although 5α-reductase inhibitors appear to decrease low-grade cancer risk, they do not affect high-grade cancer risk, and are not recommended for prevention.[3] Vitamin or mineral supplementation does not appear to affect risk.[3][17]

Many cases are managed with active surveillance or watchful waiting.[2] Other treatments may include a combination of surgery, radiation therapy, hormone therapy, or chemotherapy.[2] Tumors limited to the prostate may be curable.[1] Pain medications, bisphosphonates, and targeted therapy,[18] among others, may be useful.[2] Outcomes depend on age, health status and how aggressive and extensive the cancer is.[2] Most men with prostate cancer do not die from it.[2] The United States five-year survival rate is 97.1%.[4]

Globally, it is the second-most common cancer. It is the fifth-leading cause of cancer-related death in men.[19] In 2018, it was diagnosed in 1.2 million and caused 359,000 deaths.[5] It was the most common cancer in males in 84 countries,[3] occurring more commonly in the developed world.[20] Rates have been increasing in the developing world.[20] Detection increased significantly in the 1980s and 1990s in many areas due to increased PSA testing.[3] One study reported prostate cancer in 30% to 70% of Russian and Japanese men over age 60 who had died of unrelated causes.[1]

Signs and symptoms
A diagram of prostate cancer pressing on the urethra, which can cause symptoms
Prostate cancer

Early prostate cancer usually has no clear symptoms.[21] When they do appear, they are often similar to those of benign prostatic hyperplasia. These include frequent urination, nocturia (increased urination at night), difficulty starting and maintaining a steady stream of urine, hematuria (blood in the urine), dysuria (painful urination) as well as fatigue due to anemia, and bone pain.[22] One study found that about a third of diagnosed patients had one or more such symptoms.[23][24]

Prostate cancer is associated with urinary dysfunction as the prostate gland surrounds the prostatic urethra.[25][26] Changes within the gland directly affect urinary function. Because the vas deferens deposits seminal fluid into the prostatic urethra, and secretions from the prostate are included in semen content, prostate cancer may also cause problems with sexual function and performance, such as difficulty achieving erection or painful ejaculation.[23]

Metastatic prostate cancer can cause additional symptoms.[24] The most common symptom is bone pain, often in the vertebrae (bones of the spine), pelvis, or ribs.[27] Spread of cancer into other bones such as the femur is usually to the part of the bone nearer to the prostate. Prostate cancer in the spine can compress the spinal cord, causing tingling, leg weakness, and urinary and fecal incontinence.[28]

Cause

Prostate cancer is caused by the accumulation of genetic mutations to the DNA of cells in the prostate. These mutations affect genes involved in cell growth, DNA damage repair, and cell death. Changes to these genes can cause cells in the prostate to grow uncontrollably, resulting in a tumor.[29] Over time, the tumor may grow large enough to invade nearby organs such as the seminal vesicles or the rectum. Eventually, tumor cells may develop the ability to travel through the lymphatic system to nearby lymph nodes, and/or through the bloodstream to the bone marrow and (more rarely) other body sites.[30] At these new sites, the cancer cells disrupt normal body function and continue to grow. Metastases cause most of the discomfort associated with prostate cancer, and eventually can kill the affected person.[30]

The primary risk factors are obesity,[31] age, and family history. Obese men have been found to have a 34% greater death rate from prostate cancer than those with normal weight.[31] Prostate cancer is uncommon in men younger than 45, but becomes more common with advancing age.[32][33] The average age at the time of diagnosis is 70.[34]

Men with high blood pressure are more likely to develop prostate cancer.[35] A small increase in risk is associated with lack of exercise.[36] Elevated blood testosterone levels[37] may increase risk.

Genetics

Genetics affects risk, as suggested by associations with race, family, and specific gene variants.[38] Up to 10% of prostate cancer is caused by inherited genes; including 40% of early-onset prostate cancers.[39] Men with an affected first-degree relative (father or brother) have more than twice the risk of developing prostate cancer, and those with two first-degree relatives have a five-fold greater risk compared with men with no family history.[39] This risk appears to be greater for men with an affected brother than for those with an affected father. Increased risk also runs in some ethnic groups, with African-American men at particularly high risk – having prostate cancer at higher rates, and having more-aggressive prostate cancers.[39] In contrast, the incidence and mortality rates for Hispanic men are one-third lower than for non-Hispanic whites. Twin studies in Scandinavia suggest that 58% of prostate cancer risk can be explained by inherited factors.[40][41]

Many genes are involved in inherited risk for prostate cancer. The first gene linked to inherited prostate cancer in families was hereditary prostate cancer gene 1 (HPC1).[42][43]

Large genome-wide association studies have identified over 100 gene variants associated with increased prostate cancer risk.[44] The greatest risk increase is associated with variations in BRCA2 (up to an eight-fold increased risk) and HOXB13 (three-fold increased risk), both of which are involved in repairing DNA damage.[44] Variants in other genes involved in DNA damage repair have also been associated with an increased risk of developing prostate cancer – particularly early-onset prostate cancer – including BRCA1, ATM, NBS1, MSH2, MSH6, PMS2, CHEK2, RAD51D, and PALB2.[44] Additionally, variants in the genome near the oncogene MYC are associated with increased risk.[44] As are single-nucleotide polymorphisms in the vitamin D receptor common in African-Americans, and in the androgen receptor, CYP3A4, and CYP17 involved in testosterone synthesis and signaling.[39] Together known gene variants are estimated to cause around 25% of prostate cancer cases.[39]

Lifestyle

Plant-based diets are associated with a lower risk for prostate cancer. Switching to a plant-based diet shows favorable results for cancer outcomes in men with prostate cancer. Especially vegan diets consistently show favorable associations with prostate cancer risk and outcomes.[45]

People who consume high levels of dietary fats are at an increased risk of developing symptomatic prostate cancer, as are those who consume high levels of polycyclic aromatic hydrocarbons (from cooking red meats).[39] Those with a diet rich in cruciferous vegetables, genistein, and lycopene (found in tomatoes) are at a reduced risk of symptomatic prostate cancer.[39]

Several dietary supplements have been studied and found not to impact prostate cancer risk, including selenium, vitamin C, and vitamin E.[46]

The consumption of milk may be related to prostate cancer.[47][48] A 2020 systematic review found the results on milk consumption and prostate cancer inconclusive but stated that individuals with higher risk may reduce or eliminate milk.[49] A 2019 overview stated that the evidence that linked milk to higher rates of prostate cancer was inconsistent and inconclusive.[50]

Lower blood levels of vitamin D may increase risks.[51]

The data on the relationship between diet and prostate cancer are poor.[52] However, the rate of prostate cancer is linked to the consumption of the Western diet.[52] Little if any evidence associates trans fat, saturated fat, and carbohydrate intake and prostate cancer.[52][53] Evidence does not support a role for omega-3 fatty acids in preventing prostate cancer.[52][54] Vitamin supplements appear to have no effect and some may increase the risk.[17][52] High supplemental calcium intake has been linked to advanced prostate cancer.[55]

Fish may lower prostate-cancer deaths, but does not appear to affect occurrence.[56] Some evidence supports lower rates of prostate cancer with a vegetarian diet,[57] lycopene, selenium[58][59] cruciferous vegetables, soy, beans and/or other legumes.[60]

Regular exercise may slightly lower risk, especially vigorous activity.[60][61]

Medication exposure

Some links have been established between prostate cancer and medications, medical procedures, and medical conditions.[62] Statins may also decrease risk.[63]

Infection

Prostatitis (infection or inflammation) may increase risk. In particular, infection with the sexually transmitted infections Chlamydia, gonorrhea, or syphilis seems to increase risk.[64][65]

Papilloma virus has been proposed to have a potential role, but as of 2015, the evidence was inconclusive;[66] as of 2018, the increased risk was debated.[67]

Environment

US war veterans who had been exposed to Agent Orange had a 48% increased risk of prostate cancer recurrence following surgery.[68]

Sex

Although some evidence from prospective cohort studies indicates that frequent ejaculation may reduce prostate cancer risk,[69] no randomized controlled trials reported this benefit.[70] An association between vasectomy and prostate cancer was found, but causality has not been established.[71]

Pathophysiology

The prostate can be divided into central, peripheral, and transitional zones.[72] Most of the glandular tissue is found in the peripheral and central zones (peripheral zone: 70-80% of glandular tissue; central zone: 20% of glandular tissue).[73] Thus, most cancers that develop from glandular tissue are found in the peripheral and central spaces.[74]

Prostate cancer that has metastasized to the lymph nodes
Prostate cancer that has metastasized to the bone

Various gene mutations are associated with the progression of prostate cancer. Most commonly, a gene fusion between TMPRSS2 and the oncogene ERG, a fusion found in more than a quarter of prostate cancer biopsies.[75] Loss of cancer suppressor genes, early in prostatic carcinogenesis, have been localized to chromosomes 8p, 10q, 13q, and 16q. Other tumor suppressor genes that are thought to play a role include KAI1. Relative frequency of loss of E-cadherin and CD44 has also been observed.[76]

The factors that drive disease progression and clinical prognosis remain only partly understood but a variety of molecular determinants has been identified that appear to be involved. The most important of these might be the tyrosine phosphatase ACP1 of which the expression might outperform the Gleason grading system for predicting disease course.[77] Other molecules identified include the transcription factor RUNX2 which may prevent cancer cells from undergoing apoptosis,[78] the PI3k/Akt signaling cascade in conjunction with the transforming growth factor beta/SMAD signaling cascade that also protect against apoptosis.[79] Pim-1 is upregulated in prostate cancer.[18] X-linked inhibitor of apoptosis (XIAP) is hypothesized to promote cancer cell survival and growth,[80] the Macrophage inhibitory cytokine-1 (MIC-1) that stimulates the focal adhesion kinase (FAK) signaling pathway.[81] Nevertheless, it is fair to say that the molecular factors that determine why some patients have quiescent disease while others display prognosis, remain largely obscure.

The androgen receptor helps cancer cells to survive.[82] Prostate-specific membrane antigen (PSMA) stimulates cancer development by increasing folate levels, helping the cancer cells to survive and grow; it increases available folates for use by hydrolyzing glutamated folates.[83]

Metastatic prostate cancer tends to have more genetic mutations than localized disease.[84] Many of these mutations are in genes that protect from DNA damage, such as p53 (mutated in 8% of localized tumors, more than 27% of metastatic ones) and RB1 (1% of localized tumors, more than 5% of metastatic ones).[84] Similarly mutations in the DNA repair-related genes BRCA2 and ATM are rare in localized disease but found in at least 7% and 5% of metastatic disease cases respectively.[84]

The transition from castrate-sensitive to castrate-resistant prostate cancer is also accompanied by the acquisition of various gene mutations. In castrate-resistant disease, more than 70% of tumors have mutations in the androgen receptor signaling pathway – amplifications and gain-of-function mutations in the receptor gene itself, amplification of its activators (e.g. FOXA1), and/or inactivating mutations in its negative regulators (e.g. ZBTB16 and NCOR1).[84] These androgen receptor disruptions are only found in up to 6% of biopsies of castrate-sensitive metastatic disease.[84] Similarly, deletions of the tumor suppressor PTEN are harbored by 12–17% of castrate-sensitive tumors, but over 40% of castrate-resistant tumors.[84] Less commonly, tumors have aberrant activation of the Wnt signaling pathway via disruption of members APC (9% of tumors) or CTNNB1 (4% of tumors); dysregulation of the PI3K pathway via PI3KCA/PI3KCB mutations (6% of tumors) or AKT1 (2% of tumors).[84]

Screening
Main article: Prostate cancer screening

Prostate cancer screening searches for cancers in those without symptoms. This is typically done through blood tests for levels of the protein Prostate-specific antigen (PSA), which are elevated in those who have prostate cancer or other conditions affecting the prostate.[85][86] Such screening is controversial, with attempts to balance early detection of curable prostate cancer against the overdetection and overtreatment of cancers that will not impact an affected person's lifespan.[85] Major national health body guidelines offer differing recommendations, though no major health body currently recommends population-wide prostate cancer screening.[85]

Many national health bodies recommend prostate cancer screening in a subset of the population, typically adult men aged at least 40 who anticipate substantial remaining healthy lifespan, and who are well-informed of the risks of screening by their healthcare provider. The United States Preventive Services Task Force and the American Urological Association recommend men 55–69 years of age be offered screening after counseling to inform them of its risk and benefits.[87] Both recommend against PSA screening after age 70.[88] The Canadian Urological Association (CUA) recommends screening be offered to men at age 50, provided they have at least ten more years of expected lifespan. In men with a family history of prostate cancer, the CUA recommends screening be offered at age 45.[87] Similarly, the European Association of Urology, European Society for Radiotherapy and Oncology, and International Society of Geriatric Oncology recommend PSA testing for men over 50 years, men with family history of prostate cancer or African ancestry over 45 years, and men with cancer-associated BRCA2 variants at 40 years; all provided they have a life expectancy of at least 10 more years.[87] The Japanese Urological Association recommends PSA testing in men at least 50 years old, and men with a family history of prostate cancer starting at 40 years.[87] The Canadian Task Force on Preventive Health Care recommends against prostate cancer screening.[87] Despite roughly similar screening guidelines, uptake of screening also varies by geography – more than 80% of men are screened in the US and Western Europe, 20% of men in Japan, and screening is rare in regions with low human development index.[87]

The nature of prostate cancer screening can also very, but typically involves a blood test to assess PSA levels. The average person's blood has around 1 nanogram (ng) of PSA per milliliter (mL) of blood tested.[89] Those with PSA levels below average are very unlikely to develop dangerous prostate cancer over the next 8 to 10 years.[89] Those with higher than average PSA levels are often recommended to repeat the blood test 4–6 weeks later – PSA levels often fluctuate unrelated to prostate cancer.[90] Even for men with PSA above 3 ng/mL, just 30% will have prostate cancer, and just 10% a high-grade cancer that requires treatment.[91] Those with elevated PSA may undergo secondary screening blood tests that measure subtypes of PSA and other blood proteins to better-predict the likelihood that a person will develop aggressive prostate cancer; 4Kscore, Prostate Health Index, ExoDx Prostate Test, and SelectMDx are all availabe for this purpose.[92]

Diagnosis
Prostate needle biopsy
If already having grown large, a prostate cancer may first be detected on CT scan.

Men suspected of having prostate cancer may undergo several tests to help assess the prostate. One common procedure is the digital rectal examination, in which a doctor inserts a lubricated finger into the rectum to feel the nearby prostate.[93][94] Tumors feel like stiff, irregularly shaped lumps against the rest of the prostate. Hardening of the prostate can also be due to benign prostatic hyperplasia; around 20–25% of those with abnormal findings on their rectal exams have prostate cancer.[95]

A diagnosis of prostate cancer requires a biopsy of the prostate be taken and examined under a microscope by a pathologist. Prostate biopsies are typically taken by a needle guided by imaging – either transrectal ultrasound, magnetic resonance imaging (MRI), or a combination of the two.[96] During a biopsy, a urologist or radiologist obtains tissue samples from the prostate via either the rectum or the perineum. A biopsy gun inserts and removes special hollow-core needles (usually three to six on each side of the prostate) in less than a second.[97] Prostate biopsies are routinely done on an outpatient basis and rarely require hospitalization.[98]

Ultrasound imaging can be obtained transrectally and is used during prostate biopsies.[99] Prostate cancer can be seen as a hypoechoic lesion in 60% of cases. The other 40% of cancerous lesions are either hyperechoic or isoechoic. On Color Doppler, the lesions appear hypervascular.[100]

Antibiotics should be used to prevent complications such as fever, urinary tract infections, and sepsis[101] even if the most appropriate course or dose is undefined.[102] About 55% of men report discomfort during prostate biopsy.[103]

Biopsies are examined under a microscope by a pathologist, who determines the type and extent of cancerous cells present. Cancers are first classified based on their appearance under a microscope. Over 95% of prostate cancers are classified as adenocarcinomas (resembling gland tissue), with the rest largely squamous-cell carcinoma (resembling squamous cells, a type of epithelial cell) and transitional cell carcinoma (resembling transitional cells).[104] Tumor samples can be stained for the presence of PSA and other tumor markers to determine the origin of malignant cells that have metastasized.[105]

Next tumor samples are graded based on how much the tumor tissue differs from normal prostate tissue; the more different the tumor appears, the faster the tumor is likely to grow. The Gleason grading system is commonly used, where the pathologist assigns a number from 1 (similar to prostate tissue) to 5 (least similar) for the most common pattern observed under the microscope, then does the same for the second-most common pattern. The sum of these two numbers is the Gleason score.[104] The total scores of 2 through 5 are no longer commonly used in practice, making the lowest score 6, and the highest score 10. Scores are commonly grouped into Gleason grade groups: a score of 6 or lower is Gleason grade group 1; a score of 7 with the first number (from the most common pattern) 3 and the second number 4 is grade group 2; the reverse – first number 4, second number 3 – is grade group 3; a score of 8 is grade group 4; a score of 9 or 10 is grade group 5.[104] Higher Gleason scores and higher grade groups represent cancer cases likely to be more aggressive with worse prognosis.[104]

Micrograph showing a prostate cancer (conventional adenocarcinoma) with perineural invasion. H&E stain.
Pie chart of histopathologic subdiagnoses of prostate cancer.[106]

Staging
Main article: Prostate cancer staging
Diagram showing T1-3 stages of prostate cancer.

After diagnosis of prostate cancer, the tumor is staged to determine the extent of tumor growth and spread. Prostate cancer is typically staged using the American Joint Committee on Cancer's (AJCC) three-component TNM system, with scores assigned for the extent of the tumor (T), spread to any lymph nodes (N), and the presence of metastases (M).[107] Scores of T1 and T2 represent tumors that remain within the prostate: T1 is for tumors not detectable by imaging or digital rectal exam; T2 is for tumors detectable by imaging or rectal exam, but still confined within the prostate.[108] T3 is for tumors that grow beyond the prostate – T3a is for tumors with any extension outside the prostate; T3b is for tumors that invade the adjacent seminal vesicles. T4 is for tumors that have grown into organs beyond the seminal vesicles.[108] The N and M scores are binary. N1 represents any spread to the nearby lymph nodes. M1 represents any metastases to other body sites.[108]

The AJCC then combines the TNM scores, Gleason grade group, and results of the PSA blood test to categorize cancer cases into one of four stages, and their subdivisions. Cancer cases with localized tumors (T1 or T2), no spread (N0 and M0), Gleason grade group 1, and PSA less than 10 ng/mL are designated stage I. Those with localized tumors, no spread, and PSA between 10 and 20 ng/mL are desigated stage II – subdivided into IIA for Gleason grade group 1, IIB for grade group 2, and IIC for grade group 3 or 4. Stage III is the designation for any of three higher risk factors: IIIA is for a PSA level about 20 ng/mL; IIIB is for T3 or T4 tumors; IIIC is for a Gleason grade group of 5. Stage IV is for cancers that have spread to lymph nodes (N1, stage IVA) or other organs (M1, stage IVB).[107]

In the United Kingdom the Cambridge Prognostic Group (CPG) is used for categorising prostate cancer into 5 risk groups (CPG1 to CPG5).[109]

Several tests can be used to look for evidence of spread. Medical specialty professional organizations, including the American Urological Association and European Association of Urology, recommend against the use of PET scans, CT scans, or bone scans when a physician stages early prostate cancer with low risk for metastasis.[110][111][112][113][114] Those tests would be appropriate in cases such as when a CT scan evaluates spread within the pelvis, a bone scan looks for spread to the bones, and endorectal coil magnetic resonance imaging evaluates the prostatic capsule and the seminal vesicles. Bone scans should reveal osteoblastic appearance due to increased bone density in the areas of bone metastasis—the reverse of what is found in many other metastatic cancers.[115]

Extent of cancer spread for purposes of staging is best assessed by MRI. CT scans may also be used, but are less able to detect spread outside the prostate than MRI. Bone scintigraphy is used to test for spread of cancer to bones, though bone areas that take up the radiopharmaceutical can instead be due to other conditions that affect bone health.[116]

A PSMA scan is a positron emission tomography (PET) imaging technique which targets the overexpression of PSMA in prostate cancer tissue. A range of radiopharmaceuticals have been developed, with more under active research. Gallium-68 (68Ga) PSMA-11 and fluorine-18 (18F) PSMA-DCFPyL received FDA approval for PET-CT imaging in prostate cancer in 2021.[117][118] It has a role in evaluation of prostate cancer patients, especially patients who may go on to receive lutetium-177 (177Lu) PSMA radioligand therapy.[119][120]

In men with high-risk localised prostate cancer, staging with PSMA PET/CT may be appropriate to detect nodal or distant metastatic spread. In 2020, a randomised phase 3 trial compared Gallium-68 PSMA PET/CT to standard imaging (CT and bone scan). It reported superior accuracy of Gallium-68 PSMA-11 PET/CT (92% vs 65%), higher significant change in management (28% vs 15%), less equivocal/uncertain imaging findings (7% vs 23%) and lower radiation exposure (10 msV vs 19 mSv). The study concluded that PSMA PET/CT is a suitable replacement for conventional imaging.[121]

  • Sclerosis of the bones of the thoracic spine due to prostate cancer metastases (CT image)
    Sclerosis of the bones of the thoracic spine due to prostate cancer metastases (CT image)
  • Sclerosis of the bones of the thoracic spine due to prostate cancer metastases (CT image)
    Sclerosis of the bones of the thoracic spine due to prostate cancer metastases (CT image)
  • Sclerosis of the bones of the pelvis due to prostate cancer metastases
    Sclerosis of the bones of the pelvis due to prostate cancer metastases

Prevention

No drug or vaccine is approved by regulatory agencies for the prevention of prostate cancer. Several studies have shown 5α-reductase inhibitors to reduce the incidence of prostate cancer; however, whether they reduce disease is not clear.[46]

Management
Main article: Management of prostate cancer

The first decision is whether treatment is needed. Low-grade forms found in elderly men often grow so slowly that treatment is not required.[122] Treatment may be inappropriate if a person has other serious health problems or is not expected to live long enough for symptoms to appear. Approaches in which treatment is postponed are termed "expectant management".[122] Expectant management is divided into two approaches: Watchful waiting, which has palliative intent (aims to treat symptoms only), and active surveillance, which has curative intent (aims to prevent the cancer from advancing).[122]

Which option is best depends on disease stage, the Gleason score, and the PSA level. Other important factors are age, general health and a person's views about potential treatments and their possible side effects. Because most treatments can have significant side effects, such as erectile dysfunction and urinary incontinence, treatment discussions often focus on balancing the goals of therapy with the risks of lifestyle alterations. A 2017 review found that more research focused on person-centered outcomes is needed to guide patients.[123] A combination of treatment options is often recommended.[124][125][126]

Guidelines for specific clinical situations require estimation of life expectancy.[127] As average life expectancy increases due to advances in the treatment of other diseases, more patients will live long enough for their prostate cancer to express symptoms.[128] An 18-item questionnaire was proposed to learn whether patients have adequate knowledge and understanding of their treatment options. In one 2015 study, most of those who were newly diagnosed correctly answered fewer than half of the questions.[127]

The widespread use of PSA screening in the US has resulted in diagnosis at earlier age and cancer stage, but almost all cases are still diagnosed after age 65, while about 25% are diagnosed after age 75.[129] Though US National Comprehensive Cancer Network guidelines recommend using life expectancy to help make treatment decisions, in practice, many elderly patients are not offered curative treatment options such as radical prostatectomy or radiation therapy and are instead treated with hormonal therapy or watchful waiting.[130]

Localized disease

Many men whose prostate cancer is staged as lower risk are monitored by active surveillance. The tumor is carefully observed over time, with the intention of initiating treatment if signs of progression appear.[131] Active surveillance involves monitoring the tumor for growth or symptoms, which trigger treatment. The monitoring process may involve PSA tests, digital rectal examination, or repeated biopsies every few months.[132] The goal of active surveillance is to postpone treatment, and avoid overtreatment and its side effects, given a slow-growing or self-limited tumor that in most people is unlikely to cause problems.[133] This approach is not used for aggressive cancers, and may cause anxiety for people who wrongly believe that all cancers are deadly or that their condition is life-threatening.[134]

Both surgical and nonsurgical treatments are available, but treatment can be difficult, and combinations can be used.[135] Treatment by external beam radiation therapy, brachytherapy, cryosurgery, high-intensity focused ultrasound, and prostatectomy are, in general, offered to men whose cancer remains within the prostate.[136]

If radiation therapy fails, radical prostatectomy may be an option,[137] though it is a technically challenging surgery.[138] However, radiation therapy after surgical failure may have many complications.[139] It is associated with a small increase in bladder and colon cancer.[140] Radiotherapy and surgery appear to result in similar outcomes with respect to bowel, erectile and urinary function after five years.[141]

Radical prostatectomy is considered the mainstay of surgical treatment of prostate cancer, where the surgeon removes the prostate, seminal vesicles, and surrounding lymph nodes.[142] It can be done by an open technique (a skin incision at the lower abdomen), or laparoscopically. Radical retropubic prostatectomy is the most commonly used open surgical technique.[143] Robotic-assisted prostatectomy has become common.[144] Men with localized prostate cancer, having laparoscopic radical prostatectomy or robotic-assisted radical prostatectomy, might have shorter stays in the hospital and get fewer blood transfusions than men undergoing open radical prostatectomy.[145] How these treatments compare with regard to overall survival or recurrence-free survival is unknown.[145]

Transurethral resection of the prostate is the standard surgical treatment for benign enlargement of the prostate.[144] In prostate cancer, this procedure can be used to relieve symptoms of urinary retention caused by a large prostate tumor, but it is not used to treat the cancer itself. The procedure is done under spinal anesthesia, a resectoscope is inserted inside the penis and the extra prostatic tissue is cut to clear the way for the urine to pass.[146] In localized disease, based on long-term follow-up, radical prostatectomy results in significantly improved oncological outcomes when compared with watchful waiting.[147] Prostatectomy is associated with increased rates of urinary incontinence and erectile dysfunction, but these findings are based primarily on men diagnosed before widespread PSA screening and cannot be highly generalized.[147] When compared to active monitoring/surveillance, on follow-up at ten years, radical prostatectomy probably has similar outcomes for disease-specific survival and probably reduces risk of disease progression and spreading.[147] Urinary and sexual function are probably decreased in patients treated with radical prostatectomy.[147]

Prostate MRI is also used for surgical planning for robotic prostatectomy.[148] It helps surgeons decide whether to resect or spare the neurovascular bundle, determine return to urinary continence, and help assess surgical difficulty.[148] MRI is used in other types of treatment planning, for both focal therapy[149] and radiotherapy.[150]

Metastatic disease

Hormonal therapy and chemotherapy are often reserved for metastatic disease. Exceptions include local or metastasis-directed therapy with radiation may be used for advanced tumors with limited metastasis.[151] Hormonal therapy is used for some early-stage tumors. Cryotherapy (the process of freezing the tumor), hormonal therapy, and chemotherapy may be offered if initial treatment fails and the cancer progresses.[152]

Androgen deprivation therapy takes advantage of the fact that prostate cancer cells typically require androgens (male sex hormones) in order to grow.[153] Various drugs are used to lower androgen levels by blocking the synthesis or action of testosterone, the primary androgen. The first line of treatment is typically GnRH agonists like leuprolide, goserelin, triptorelin, or leuprolide mesylate by injection monthly or less frequently if needed.[154][155] GnRH agonists cause a brief rise in testosterone levels at treatment initiation, which can worsen disease in people with significant symptoms of metastases.[156] In these people, GnRH antagonists like degarelix or relugolix are given instead, and can also rapidly reduce testosterone levels.[156] Androgen ablation therapy causes remission in 80–90% of patients undergoing therapy, resulting in a median progression-free survival of 12 to 33 months. After remission, an androgen-independent phenotype typically emerges, wherein the median overall survival is 23–37 months from the time of initiation of androgen ablation therapy.[157] How androgen-independence is established and how it re-establishes progression is unclear.[158]

The second line hormonal therapy abiraterone increases survival by about 4.6 months.[159] Enzalutamide is another second line hormonal agent with a five-month survival advantage. Both abiraterone and enzalutamide are currently in clinical trials in those with CRPC who have not previously received chemotherapy.[160][161]

Prostate cancer that persists when testosterone levels are lowered by hormonal therapy is called castrate-resistant prostate cancer (CRPC).[162][163] Many early-stage cancers need normal levels of testosterone to grow, but CRPC does not. Previously considered "hormone-refractory prostate cancer" or "androgen-independent prostate cancer", the term CRPC emerged because these cancers show reliance upon hormones, particularly testosterone, for androgen receptor activation.[164][165]

The cancer chemotherapeutic docetaxel has been used as treatment for CRPC with a median survival benefit of 2 to 3 months.[166][167] A second-line chemotherapy treatment is cabazitaxel.[168] A combination of bevacizumab, docetaxel, thalidomide and prednisone appears effective in the treatment of CRPC.[169]

Not all patients respond to androgen signaling-blocking drugs. Certain cells with characteristics resembling stem cells remain unaffected.[170][171] Therefore, the desire to improve CRPC outcomes resulted in increasing doses or combination therapy with synergistic androgen-signaling blocking agents.[172] But even these combination will not affect stem-like cells that do not exhibit androgen signaling.[173]

For patients with metastatic prostate cancer that has spread to their bones, doctors use a variety of bone-modifying agents to prevent skeletal complications and support the formation of new bone mass.[174] Zoledronic acid (a bisphosphonate) and denosumab (a RANK-ligand-inhibitor) appear to be effective agents, but are associated with more frequent and serious adverse events.[174]

Complications

The two main complications encountered after prostatectomy and prostate radiotherapy are erectile dysfunction and urinary incontinence, mainly stress-type. Most men regain continence within 6 to 12 months after the operation, so doctors usually wait at least one year before resorting to invasive treatments.[175]

Stress urinary incontinence usually happens after prostate surgery or radiation therapy due to factors that include damage to the urethral sphincter or surrounding tissue and nerves.[176] The prostate surrounds the urethra, a muscular tube that closes the urinary bladder.[177] Any of the mentioned reasons can lead to incompetent closure of the urethra and hence incontinence.[178] Initial therapy includes bladder training, lifestyle changes, kegel exercises, and the use of incontinence pads. More invasive surgical treatment can include the insertion of a urethral sling or an artificial urinary sphincter, which is a mechanical device that mimics the function of the urethral sphincter, and is activated manually by the patient through a switch implanted in the scrotum.[179] The latter is considered the gold standard in patients with moderate or severe stress urinary incontinence.[180]

Erectile dysfunction happens in different degrees in nearly all men who undergo prostate cancer treatment, including radiotherapy or surgery; however, within one year, most of them will notice improvement. If nerves were damaged, this progress may not take place. Pharmacological treatment includes PDE-5 inhibitors such as viagra or cialis, or injectable intracavernous drugs injected directly into the penis (prostaglandin E1 and vasoactive drug mixtures). Other nonpharmacological therapy includes vacuum constriction devices and penile implants.[181]

Psychological

Psychological interventions such as psychoeducation, cognitive behavioural therapy (CBT) and mindfulness are recommended for the management of mental and emotional complications of disease symptoms and those associated with active treatment.[182][183] Due to limited research and inadequate methodological rigor of published literature, solid recommendations cannot be made on the effectiveness of mindfulness in men with prostate cancer.[184]

Prognosis

The prognosis of diagnosed prostate cancer varies widely based on the cancer's grade and stage at the time of diagnosis; those with lower stage disease have vastly improved prognoses. Around 80% of prostate cancer diagnoses are in men whose cancer is still confined to the prostate. These men often survive long after diagnosis, with as many as 99% still alive 10 years from diagnosis.[185] Men whose cancer has metastasized to a nearby part of the body (around 15% of diagnoses) have poorer prognoses, with five-year survival rates of 60–80%.[186] Those with metastases in distant body sites (around 5% of diagnoses) have relatively poor prognoses, with five-year survival rates of 30–40%.[186]

Mortality varies widely across geography and other elements. In the United States, five-year survival rates range from 29% (distant metastases) to 100% (local or regional tumors).[187] In Nigeria, 2% of men develop prostate cancer, and 64% of them are dead after 2 years.[188] Most Nigerian men present with metastatic disease with a typical survival of 40 months.[189]

In patients who undergo treatment, the most important clinical prognostic indicators of disease outcome are the stage, pretherapy PSA level, and Gleason score.[190] The higher the grade and the stage, the poorer the prognosis. Nomograms can be used to calculate the estimated risk of the individual patient. The predictions are based on the experience of large groups of patients.[191]

Between 50 and 75% of patients die from other causes without experiencing prostate symptoms.[192]

An important aspect of decision making on the value of treatment is how to balance prognosis from prostate cancer with other causes of mortality and the morbidity of treatment. The PREDICT Prostate algorithm[193] is a multivariable prognostic model that provides individualised cancer-specific and overall long-term survival estimates in early stage non-metastatic PCa patients.[194] In addition to the use of routinely available preoperative clinical-pathological variables such as PSA, biopsy Gleason score (ISUP grade group), and clinical T-stage, the PREDICT Prostate tool also includes the impact of patient characteristics (age and comorbidity status) and radical treatment (radical prostatectomy or radiotherapy) on survival. The tool provides patients with estimated survival rates after treatment in the context of absolute mortality rate, which allows patients to make an informed decision as to the value of treatment and its potential side effects. Predict Prostate is endorsed for use as a decision aid for prostate cancer by the UK National Institute for Health and Care Excellence [195]

No evidence shows that either surgery or beam radiation has an advantage over the other in this regard. The lower death rates reported with surgery appear to occur because surgery is more likely to be offered to younger men with less severe cancers. Insufficient information is available to determine whether seed radiation extends life more readily than the other treatments, but data so far do not suggest that it does.[196]

Older men (age 70–75) with low-grade disease had a roughly 20% overall survival at 15 years due to deaths from competing causes. Men with high-grade disease (Gleason 8–10) experienced high mortality within 15 years of diagnosis, regardless of their age.[197]

Classification systems
Micrograph of prostate adenocarcinoma, acinar type, the most common type of prostate cancer. Needle biopsy, H&E stain

Several tools are available to help predict outcomes, such as pathologic stage and recurrence after surgery or radiation therapy. Most combine stage, grade, and PSA level, and some include the number or percentage of biopsy cores positive, age, and/or other information.

  • The D'Amico classification stratifies men by low, intermediate, or high risk based on stage, grade and PSA. It is used widely in clinical practice and research settings.[198] The major downside to the three-level system is that it does not account for multiple adverse parameters (e.g., high Gleason score and high PSA) in stratifying patients.
  • The Partin tables[199] predict pathologic outcomes (margin status, extraprostatic extension, and seminal vesicle invasion) based on the same three variables and are published as lookup tables.
  • The Kattan nomograms predict recurrence after surgery and/or radiation therapy, based on data available at the time of diagnosis or after surgery.[200] The Kattan score represents the likelihood of remaining free of disease at a given time interval following treatment.
  • The UCSF Cancer of the Prostate Risk Assessment (CAPRA) score predicts both pathologic status and recurrence after surgery. It offers accuracy comparable to the Kattan preoperative nomogram and can be calculated without tables or a calculator. Points are assigned based on PSA, grade, stage, age, and percentage of cores positive; the sum yields a 0–10 score, with every two points representing roughly a doubling of risk of recurrence. The CAPRA score was derived from community-based data in the CaPSURE database.[201] It has been validated among over 10,000 prostatectomy patients, including patients from CaPSURE;[202] the SEARCH registry, representing data from several Veterans Health Administration and military medical centers;[203] a multi-institutional cohort in Germany;[204] and the prostatectomy cohort at Johns Hopkins University.[205] More recently, it has been shown to predict metastasis and mortality following prostatectomy, radiation therapy, watchful waiting, or androgen deprivation therapy.[206]
  • The UK National Institute for Health and Care Excellence guidelines recommends use of the Cambridge Prognostic Groups (CPG) 5-tier model when determining treatment options. The rationale for the change related to recent evidence, which suggests that 5-tier risk stratification model was better at predicting prostate cancer specific mortality than older 3-tier models [207] The CPG model has been tested and validated in studies including >80,000 men [208][209][210] The NICE CPG model and treatment recommendations can be viewed at the NICE guideline website.[211]

Epidemiology
Age-standardized death from prostate cancer per 100,000 inhabitants in 2004.[212]
  no data
  <4
  4–8
  8–12
  12–16
  16–20
  20–24
  24–28
  28–32
  32–36
  36–40
  40–44
  >44

Prostate cancer is the second-most frequently diagnosed cancer in men (after lung cancer), with 1.2 million new cases diagnosed each year and over 350,000 annual deaths.[213] Rates of prostate cancer rise with age. Disease is rare in those under 40;[214] with the overwhelming majority of cases in those over 60 years.[213] Due to this, prostate cancer rates are generally higher in parts of the world with higher life expectancy, which also tend to be areas with higher gross domestic product and higher human development index.[213] Australia, Europe, North America, New Zealand, and parts of South America have the highest incidence. South Asia, Central Asia, and sub-Saharan Africa have the lowest incidence of prostate cancer; though incidence is increasing in these regions at among the fastest rates in the world.[213]

Prostate cancer is least common among Asian men and most common among Black men, with white men in between.[215][216]

A minority of men with prostate cancer will ever have symptoms of the disease or have their prostate cancer diagnosed. More than 70% of men autopsied in their 70s have cancer in their prostate; however, 1 in 8 men are diagnosed with prostate cancer. Of those with prostate cancer, around 2% die of the disease.[217]

United States
New cases and deaths from prostate cancer in the United States per 100,000 males between 1975 and 2014

Prostate cancer is the third-leading cause of cancer death in men, exceeded by lung cancer and colorectal cancer. It accounts for 19% of all male cancers and 9% of male cancer-related deaths.[218]

Cases ranged from an estimated 230,000 in 2005[219] to an estimated 164,690 In 2018.[220]

Deaths held steady around 30,000 in 2005[219] and 29,430 in 2018.

Age-adjusted incidence rates increased steadily from 1975 through 1992, with particularly dramatic increases associated with the spread of PSA screening in the late 1980s, later followed by a fall in incidence. A decline in early-stage incidence rates from 2011 to 2012 (19%) in men aged 50 years and older persisted through 2013 (6%).

Declines in mortality rates in certain jurisdictions may reflect the interaction of PSA screening and improved treatment.[221] The estimated lifetime risk is about 14.0%, and the lifetime mortality risk is 2.6%.[222]

Between 2005 and 2011, the proportion of disease diagnosed at a locoregional stage was 93% for whites and 92% for African Americans;[223] the proportion of disease diagnosed at a late stage was 4% for European Americans and 5% for African Americans.[223]

Prostate cancer is more common in the African American population than the European American population.[3] An autopsy study of White and Asian men also found an increase in occult prostate cancer with age,[224] reaching nearly 60% in men older than 80 years. More than 50% of cancers in Asian men and 25% of cancers in White men had a Gleason score of 7 or greater,[225] suggesting that Gleason score may be an imprecise indicator of clinically insignificant cases.[226]

Canada

Prostate cancer is the third-leading type of cancer in Canadian men. In 2016, around 4,000 died and 21,600 men were diagnosed with prostate cancer.[227]

Europe

In Europe in 2012, it was the third-most diagnosed cancer after breast and colorectal cancers at 417,000 cases.[228]

In the United Kingdom, it is the second-most common cause of cancer death after lung cancer, where around 35,000 cases are diagnosed every year, of which around 10,000 are fatal.[229]

History

The prostate was first described by Venetian anatomist Niccolò Massa in 1536, and illustrated by Flemish anatomist Andreas Vesalius in 1538.[230] Prostate cancer was identified in 1853.[231][232] It was initially considered a rare disease, probably because of shorter life expectancies and poorer detection methods in the 19th century. The first treatments were surgeries to relieve urinary obstruction.[233]

Removal of the gland was first described in 1851,[234] and radical perineal prostatectomy was first performed in 1904 by Hugh H. Young at Johns Hopkins Hospital.[235][231]

Surgical removal of the testes (orchiectomy) to treat prostate cancer was first performed in the 1890s, with limited success.[236] Transurethral resection of the prostate (TURP) replaced radical prostatectomy for symptomatic relief of obstruction in the middle of the 20th century because it could better preserve penile erectile function. Radical retropubic prostatectomy was developed in 1983 by Patrick Walsh.[237] This surgical approach allowed for removal of the prostate and lymph nodes with maintenance of penile function.

In 1941, Charles B. Huggins published studies in which he used estrogen to oppose testosterone production in men with metastatic prostate cancer. This discovery of "chemical castration" won Huggins the 1966 Nobel Prize in Physiology or Medicine.[238] The role of the gonadotropin-releasing hormone (GnRH) in reproduction was determined by Andrzej W. Schally and Roger Guillemin, who shared the 1977 Nobel Prize in Physiology or Medicine for this work. GnRH receptor agonists, such as leuprorelin and goserelin, were subsequently developed and used to treat prostate cancer.[239][240]

Radiation therapy for prostate cancer was first developed in the early 20th century and initially consisted of intraprostatic radium implants. External beam radiotherapy became more popular as stronger [X-ray] radiation sources became available in the middle of the 20th century. Brachytherapy with implanted seeds (for prostate cancer) was first described in 1983.[241]

Systemic chemotherapy for prostate cancer was first studied in the 1970s. The initial regimen of cyclophosphamide and 5-fluorouracil was quickly joined by regimens using other systemic chemotherapy drugs.[242]

Enzalutamide gained FDA approval in 2012 for the treatment of castration-resistant prostate cancer (CRPC).[160][161] Alpharadin won FDA approval in 2013, under the priority review program.[243]

In 2006, a previously unknown retrovirus, Xenotropic MuLV-related virus (XMRV), was associated with human prostate tumors,[244] but PLOS Pathogens retracted the article in 2012.[244]

Society and culture

Men with prostate cancer generally encounter significant disparities in awareness, funding, media coverage, and research—and therefore, inferior treatment and poorer outcomes—compared to other cancers of equal prevalence.[245] In 2001, The Guardian noted that Britain had 3,000 nurses specializing in breast cancer, compared to a single nurse for prostate cancer.[246] Waiting time between referral and diagnosis was two weeks for breast cancer but three months for prostate cancer.[247]

A 2007 report by the U.S.-based National Prostate Cancer Coalition stated that prostate cancer drugs were outnumbered seven to one by breast cancer drugs.[248] The Times also noted an "anti-male bias in cancer funding" with a four-to-one discrepancy in the United Kingdom by both the government and by cancer charities such as Cancer Research UK.[245][249] Critics cite such figures when claiming that women's health is favored over men's health.[250]

Disparities extend into detection, with governments failing to fund or mandate prostate cancer screening while fully supporting breast cancer programs. For example, a 2007 report found 49 U.S. states mandate insurance coverage for routine breast cancer screening, compared to 28 for prostate cancer.[251]

Prostate cancer experiences significantly less media coverage than other, equally prevalent cancers, outcovered 2.6:1 by breast cancer.[245]

Prostate Cancer Awareness Month takes place in September in a number of countries. A light blue ribbon is used to promote the cause.[252][253]

Research

Castration-resistant prostate cancer

Castration-resitant prostate cancer is prostate cancer that progresses despite androgen depletion therapy.[254]

Enzalutamide is a nonsteroidal antiandrogen (NSAA).[160][161] It has been used with abiraterone in studies involving Whole genome sequencing that have shown how androgen receptors acquire resistance to them, which determines the use of new therapies against this pathology such as degraders of the protein or of the N-terminal domain of this receptor. This has been seen thanks to the sequencing of circulating tumor DNA in patients.[255]

Alpharadin uses bone targeted Radium-223 isotopes to kill cancer cells by alpha radiation.[256]

PARP inhibitor olaparib is an approved breast/ovarian cancer drug that is undergoing clinical trials.[257] Also in trials for CRPC are : checkpoint inhibitor ipilimumab, CYP17 inhibitor galeterone (TOK-001), and immunotherapy PROSTVAC.[257]

All medications for CRPC block androgen receptor (AR) signaling via direct or indirect targeting of the AR ligand binding domain (LBD). AR belongs to the steroid nuclear receptor family.[258] Development of the prostate is dependent on androgen signaling mediated through AR, and AR is also important for disease progression.[259] Molecules that could successfully target alternative domains have emerged.[258] Such therapies could provide an advantage; particularly in treating prostate cancers that are resistant to current therapies.[258]

Evolution

Sequencing techniques, in addition to reflecting the mechanisms of resistance to treatment, through the circulating tumor DNA, distinguish between the evolutionary history of this cancer when it metastasizes and the temporal subclonal dynamics, determining how the tumor is found when it is diagnosed.[255]

Pre-clinical

Arachidonate 5-lipoxygenase has been identified as playing a significant role in the survival of prostate cancer cells.[260][261][262] Medications that target this enzyme are undergoing development.[260][261][262] In particular, arachidonate 5-lipoxygenase inhibitors produce massive, rapid programmed cell death in prostate cancer cells.[260][261][262]

Galectin-3 is another potential target.[263] Aberrant glycan profiles have been described in prostate cancer,[264][265] and studies have found specific links between the galectin signature and prostate cancer.[266][267]

The PIM kinase family is another potential target for selective inhibition. A number of related drugs are under development. It has been suggested the most promising approach may be to co-target this family with other pathways including PI3K.[18]

Cancer models

Scientists have established prostate cancer cell lines to investigate disease progression. LNCaP, PC-3 (PC3), and DU-145 (DU145) are commonly used prostate cancer cell lines.[268] The LNCaP cancer cell line was established from a human lymph node metastatic lesion of prostatic adenocarcinoma. PC-3 and DU-145 cells were established from human prostatic adenocarcinoma metastatic to bone and to brain, respectively. LNCaP cells express AR, but PC-3 and DU-145 cells express very little or no AR.

The proliferation of LNCaP cells is androgen-dependent but the proliferation of PC-3 and DU-145 cells is androgen-insensitive. Elevation of AR expression is often observed in advanced prostate tumors in patients.[269][270] Some androgen-independent LNCaP sublines have been developed from the ATCC androgen-dependent LNCaP cells after androgen deprivation for study of prostate cancer progression. These androgen-independent LNCaP cells have elevated AR expression and express prostate specific antigen upon androgen treatment. Paradoxically, androgens inhibit the proliferation of these androgen-independent prostate cancer cells.[271][272][273]

Diagnosis

One active research area and non-clinically applied investigations involves non-invasive methods of tumor detection.[274] A molecular test that detects the presence of cell-associated PCA3 mRNA in fluid obtained from the prostate and first-void urine sample is under investigation. PCA3 mRNA is expressed almost exclusively by prostate cells and has been shown to be highly over-expressed in prostate cancer cells. The test result is currently reported as a specimen ratio of PCA3 mRNA to PSA mRNA.[275]

The PCA3 test attempts to help decide whether, in men suspected of having prostate cancer (especially if an initial biopsy fails to explain the elevated serum PSA), a biopsy/rebiopsy is needed. The higher the expression of PCA3 in the sample, the greater the likelihood of a positive biopsy.[276] The CDC's Evaluation of Genomic Applications in Practice and Prevention Working Group discourages clinical use.[277]

See also

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