prostate cancer

{{Infobox medical condition

| name = Prostate cancer

| synonyms = Prostate carcinoma

| image = Diagram showing prostate cancer pressing on the urethra CRUK 182.svg

| caption = Diagram of prostate tumor pressing on urethra

| field = Oncology, urology

| symptoms = Typically none. Sometimes trouble urinating, erectile dysfunction, or pain in the back/pelvis.

| complications =

| onset = Age over 40

| duration =

| types =

| causes =

| risks = Older age, family history, race

| diagnosis = PSA test followed by tissue biopsy

| differential = Benign prostatic hyperplasia

| prevention =

| treatment = Active surveillance, prostatectomy, radiation therapy, hormone therapy, chemotherapy

| medication =

| prognosis = Five-year survival rates range from 30–99%, depending on stage.{{sfn|Rebello|Oing|Knudsen|Loeb|2021|loc="Figure 3: Prostate cancer stages and progression."}}

}}

Prostate cancer is the uncontrolled growth of cells in the prostate, a gland in the male reproductive system below the bladder. Abnormal growth of the prostate tissue is usually detected through screening tests, typically blood tests that check for prostate-specific antigen (PSA) levels. Those with high levels of PSA in their blood are at increased risk for developing prostate cancer. Diagnosis requires a biopsy of the prostate. If cancer is present, the pathologist assigns a Gleason score; a higher score represents a more dangerous tumor. Medical imaging is performed to look for cancer that has spread outside the prostate. Based on the Gleason score, PSA levels, and imaging results, a cancer case is assigned a stage 1 to 4. A higher stage signifies a more advanced, more dangerous disease.

Most prostate tumors remain small and cause no health problems. These are managed with active surveillance, monitoring the tumor with regular tests to ensure it has not grown. Tumors more likely to be dangerous can be destroyed with radiation therapy or surgically removed by radical prostatectomy. Those whose cancer spreads beyond the prostate are treated with hormone therapy which reduces levels of the androgens (male sex hormones) that prostate cells need to survive. Eventually cancer cells can grow resistant to this treatment. This most-advanced stage of the disease, called castration-resistant prostate cancer, is treated with continued hormone therapy alongside the chemotherapy drug docetaxel. Some tumors metastasize (spread) to other areas of the body, particularly the bones and lymph nodes. There, tumors cause severe bone pain, leg weakness or paralysis, and eventually death. Prostate cancer prognosis depends on how far the cancer has spread at diagnosis. Most men diagnosed have low-risk tumors confined to the prostate; 99% of them survive more than 10 years from their diagnoses. Tumors that have metastasized to distant body sites are most dangerous, with five-year survival rates of 30–40%.

The risk of developing prostate cancer increases with age; the average age of diagnosis is 67. Those with a family history of any cancer are more likely to have prostate cancer, particularly those who inherit cancer-associated variants of the BRCA2 gene. Each year 1.2 million cases of prostate cancer are diagnosed, and 350,000 die of the disease,{{sfn|Rebello|Oing|Knudsen|Loeb|2021|loc="Epidemiology"}} making it the second-leading cause of cancer and cancer death in men. One in eight men are diagnosed with prostate cancer in their lifetime and one in forty die of the disease.{{sfn|Scher|Eastham|2022|loc="Prostate cancer"}} Prostate tumors were first described in the mid-19th century, during surgeries on men with urinary obstructions. Initially, prostatectomy was the primary treatment for prostate cancer. By the mid-20th century, radiation treatments and hormone therapies were developed to improve prostate cancer treatment. The invention of hormone therapies for prostate cancer was recognized with the 1966 Nobel Prize to Charles B. Huggins and the 1977 Prize to Andrzej W. Schally.

Signs and symptoms

Early prostate cancer usually causes no symptoms. As the cancer advances, it may cause erectile dysfunction, blood in the urine or semen, or trouble urinating – commonly including frequent urination and slow or weak urine stream. More than half of men over age 50 experience some form of urination problem,{{sfn|Merriel|Funston|Hamilton|2018|loc="Symptoms and signs"}} typically due to issues other than prostate cancer such as benign prostatic hyperplasia (non-cancerous enlargement of the prostate).

Advanced prostate tumors can metastasize to nearby lymph nodes and bones, particularly in the pelvis, hips, spine, ribs, head, and neck.{{sfn|Rebello|Oing|Knudsen|Loeb|2021|loc="Figure 3: Prostate cancer stages and progression"}} There they can cause fatigue, unexplained weight loss, and back or bone pain that does not improve with rest.{{sfn|Coleman|Croucher|Padhani|Clézardin|2020|loc="Prevalence of SREs"}}{{cite web |url=https://www.cancerresearchuk.org/about-cancer/prostate-cancer/symptoms |access-date=21 May 2023 |title=Symptoms of Prostate Cancer |publisher=Cancer Research UK |date=15 March 2022 |archive-date=21 May 2023 |archive-url=https://web.archive.org/web/20230521153936/https://www.cancerresearchuk.org/about-cancer/prostate-cancer/symptoms |url-status=live }} Metastases can damage the bones around them, and around a quarter of those with metastatic prostate cancer develop a bone fracture.{{sfn|Coleman|Croucher|Padhani|Clézardin|2020|loc="Prostate cancer"}} Growing metastases can also compress the spinal cord causing weakness in the legs and feet, or limb paralysis.{{sfn|Clinical Overview|2022|loc="Clinical presentation"}}{{sfn|Scher|Eastham|2022|loc="Metastatic disease: noncastrate"}}

Screening

Most cases of prostate cancer are diagnosed through screening tests, when tumors are too small to cause any symptoms.{{cite web |title=Prostate Cancer Signs and Symptoms |url=https://www.cancer.org/cancer/prostate-cancer/detection-diagnosis-staging/signs-symptoms.html |access-date=21 May 2023 |publisher=American Cancer Society |date=1 August 2019 |language=en}} This is done through blood tests to measure levels of the protein prostate-specific antigen (PSA), which are elevated in those with enlarged prostates, whether due to prostate cancer or benign prostatic hyperplasia.{{sfn|Rebello|Oing|Knudsen|Loeb|2021|loc="Screening and early detection"}}{{cite web |url=https://www.cdc.gov/cancer/prostate/basic_info/screening.htm |access-date=17 May 2023 |title=What Is Screening for Prostate Cancer? |publisher=U.S. Centers for Disease Control and Prevention |date=25 August 2022 |archive-date=7 September 2017 |archive-url=https://web.archive.org/web/20170907151112/https://www.cdc.gov/cancer/prostate/basic_info/screening.htm |url-status=live }} The typical man's blood has around 1 nanogram (ng) of PSA per milliliter (mL) of blood tested.{{sfn|Carlsson|Vickers|2020|loc="3. Tailor screening frequency based on PSA-level"}} Those with PSA levels below average are very unlikely to develop dangerous prostate cancer over the next 8 to 10 years.{{sfn|Carlsson|Vickers|2020|loc="3. Tailor screening frequency based on PSA-level"}} Men with PSA levels above 4 ng/mL are at increased risk – around 1 in 4 will develop prostate cancer – and are often referred for a prostate biopsy.{{cite web|url=https://www.cancer.org/cancer/types/prostate-cancer/detection-diagnosis-staging/tests.html |accessdate=11 December 2023 |title=Screening Tests for Prostate Cancer |publisher=American Cancer Society |date=4 January 2021}}{{sfn|Scher|Eastham|2022|loc="Prostate-specific antigen"}} PSA levels over 10 ng/mL indicate an even higher risk: over half of men in this group develop prostate cancer. Men with high PSA levels are often recommended to repeat the blood test four to six weeks later, as PSA levels can fluctuate unrelated to prostate cancer.{{sfn|Carlsson|Vickers|2020|loc="4. For men with elevated PSA (≥3 ng/mL), repeat PSA."}} Benign prostatic hyperplasia, prostate infection, recent ejaculation, and some urological procedures can increase PSA levels; taking 5α-reductase inhibitors can decrease PSA levels.

Those with elevated PSA may undergo secondary screening blood tests that measure subtypes of PSA and other molecules to better predict the likelihood that a person will develop aggressive prostate cancer. Many measure "free PSA" – the fraction of PSA unbound to other blood proteins, usually around 10% to 30%. Men who have a lower percentage of free PSA are more likely to have prostate cancer.{{sfn|Duffy|2020|loc="Percent free PSA"}} Several common tests more accurately detect prostate cancer cases by also measuring subtypes of free PSA, including the Prostate Health Index (measures a fragment called −2proPSA) and 4K score (measures intact free PSA).{{sfn|Duffy|2020|loc="Prostate Health Index (PHI)"}}{{sfn|Duffy|2020|loc="4K score"}} Other tests measure blood levels of additional prostate-related proteins such as kallikrein-2 (also measured by 4K score), or urine levels of mRNA molecules common to prostate tumors like PCA3 and TMPRSS2 fused to ERG.{{sfn|Duffy|2020|loc=Table 2}}

Several large studies have found that men screened for prostate cancer have a reduced risk of dying from the disease;{{sfn|Rebello|Oing|Knudsen|Loeb|2021|loc="Box 1: Screening for prostate cancer in different regions"}} however, detection of cancer cases that would not have otherwise impacted health can cause anxiety, and lead to unneeded biopsies and treatments, both of which can cause unwanted complications.{{sfn|Rebello|Oing|Knudsen|Loeb|2021|loc="Screening and early detection"}} Major national health organizations offer differing recommendations, attempting to balance the benefits of early diagnosis with the potential harms of treating people whose tumors are unlikely to impact health.{{sfn|Rebello|Oing|Knudsen|Loeb|2021|loc="Screening and early detection"}} Most medical guidelines recommend that men at high risk of prostate cancer (due to age, family history, ethnicity, or prior evidence of high blood PSA levels) be counseled on the risks and benefits of PSA testing, and be offered access to screening tests.{{sfn|Rebello|Oing|Knudsen|Loeb|2021|loc="Screening and early detection"}} Medical guidelines generally recommend against screening for men over age 70, or with a life expectancy of less than 10 years, as a newly diagnosed prostate cancer is unlikely to impact their natural lifespan.{{sfn|Rebello|Oing|Knudsen|Loeb|2021|loc="Screening and early detection"}}{{sfn|Rebello|Oing|Knudsen|Loeb|2021|loc="Box 1: Screening for prostate cancer in different regions"}} Uptake of screening 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 a low Human Development Index.{{sfn|Rebello|Oing|Knudsen|Loeb|2021|loc="Box 1: Screening for prostate cancer in different regions"}}

Diagnosis

File:Digital rectal exam nci-vol-7136-300.jpg

Men suspected of having prostate cancer may undergo several tests to 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.{{cite web |url=https://www.cancer.org/cancer/types/prostate-cancer/detection-diagnosis-staging/how-diagnosed.html |access-date=18 May 2023 |title=Tests to Diagnose and Stage Prostate Cancer |publisher=American Cancer Society |date=21 February 2023 |archive-date=18 May 2023 |archive-url=https://web.archive.org/web/20230518160203/https://www.cancer.org/cancer/types/prostate-cancer/detection-diagnosis-staging/how-diagnosed.html |url-status=live }}{{sfn|Rebello|Oing|Knudsen|Loeb|2021|loc="Diagnosis"}} 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.{{sfn|Scher|Eastham|2022|loc="Physical examination"}} Several urological societies' guidelines recommend magnetic resonance imaging (MRI) to evaluate the prostate for potential tumors in men with high PSA levels. MRI results can help distinguish those who have potentially dangerous tumors from those who do not.{{sfn|Maffei|Giganti|Moore|2023|loc="MRI as a test for clinically referred men with a raised PSA or abnormal digital rectal exam}}

A definitive diagnosis of prostate cancer requires a biopsy of the prostate. Prostate biopsies are typically taken by a needle passing through the rectum or perineum, guided by transrectal ultrasonography, MRI, or a combination of the two.{{sfn|Scher|Eastham|2022|loc="Prostate biopsy"}}{{sfn|Rebello|Oing|Knudsen|Loeb|2021|loc="Diagnosis"}} Ten to twelve samples are taken from several regions of the prostate to improve the chances of finding any tumors.{{sfn|Rebello|Oing|Knudsen|Loeb|2021|loc="Diagnosis"}} Biopsies are sent for a histopathologic diagnosis of prostate cancer, wherein they 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).{{sfn|Scher|Eastham|2022|loc="Pathology"}}

File:Gallium PSMA PET scan.png (left) and PSMA scan (right) showing prostate cancer metastases in the bone (red arrows). The dye used for PSMA scans is also absorbed by the kidneys, liver, and spleen (large dark objects at right). |alt=Medical images of a man's torso. Arrows indicate tumor metastases, visible as dots in the man's spine and pelvis, in both scans.]]

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 numbers ranging from 3 (most similar to healthy prostate tissue) to 5 (least similar) to different regions of the biopsied tissue. They then calculate a "Gleason score" by adding the two numbers that represent the largest areas of the biopsy sample.{{sfn|Scher|Eastham|2022|loc="Pathology"}} The lowest possible Gleason score of 6 represents a biopsy most similar to healthy prostate; the highest Gleason score of 10 represents the most severely cancerous.{{efn|group=note|The original 1966 Gleason grading system allowed pathologist scores of 1 to 5, resulting in Gleason scores of 2 to 10; however, a 2005 update by the International Society of Urological Pathology largely eliminated the pathologist scores 1 and 2. In common practice, tumors are now scored 3 to 5, resulting in Gleason scores of 6 to 10.{{sfn|Epstein|2018|loc="Historical background", "2005 and 2014 ISUP grading conferences", and "Gleason patterns"}}}} Gleason scores are commonly grouped into "Gleason grade groups", which predict disease prognosis: a Gleason score of 6 is Gleason grade group 1 (best prognosis). A score of 7 (with Gleason scores 4 + 3, or Gleason scores 3 + 4, with the most prominent listed first) can be grade group 2 or 3; it is grade group 2 if the less severe Gleason score (3) covered more area; grade group 3 if the more severe Gleason score (4) covered more area. A score of 8 is grade group 4. A score of 9 or 10 is grade group 5 (worst prognosis).{{sfn|Scher|Eastham|2022|loc="Pathology"}}

The extent of cancer spread is assessed by MRI or PSMA scan – a positron emission tomography (PET) imaging technique where a radioactive label that binds the prostate protein prostate-specific membrane antigen is used to detect metastases distant from the prostate.{{sfn|Scher|Eastham|2022|loc="Prostate cancer staging"}}{{sfn|Rebello|Oing|Knudsen|Loeb|2021|loc="Diagnosis"}} 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.{{sfn|Scher|Eastham|2022|loc="Prostate cancer staging"}}

= Staging =

File:Diagram showing T1-3 stages of prostate cancer CRUK 278.svg

After diagnosis, the tumor is staged to determine the extent of its 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).{{cite web |url=https://www.cancer.org/cancer/types/prostate-cancer/detection-diagnosis-staging/staging.html |title=Prostate Cancer Staging |date=8 October 2021 |publisher=American Cancer Society |access-date=14 May 2023 |archive-date=15 May 2023 |archive-url=https://web.archive.org/web/20230515034626/https://www.cancer.org/cancer/types/prostate-cancer/detection-diagnosis-staging/staging.html |url-status=live }} 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.{{sfn|Scher|Eastham|2022|loc="Table 87-1 TNM classification"}} T3 is for tumors that grow beyond the prostate – T3a for tumors with any extension outside the prostate; T3b for tumors that invade the adjacent seminal vesicles. T4 is for tumors that have grown into organs beyond the seminal vesicles.{{sfn|Scher|Eastham|2022|loc="Table 87-1 TNM classification"}} The N and M scores are binary (yes or no). N1 represents any spread to the nearby lymph nodes. M1 represents any metastases to other body sites.{{sfn|Scher|Eastham|2022|loc="Table 87-1 TNM classification"}}

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 and PSA between 10 and 20 ng/mL are designated 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).

{| class="wikitable floatright" style="text-align:center;font-size:90%;margin-left:1em;"

|+AJCC stage for prostate cancer

!AJCC Stage

!TNM scores

!Gleason grade group

!PSA

|Stage I

|T1 or T2, N0, M0

|<10 ng/mL

|Stage IIA

| rowspan="3" |T1 or T2, N0, M0

| rowspan="3" |10-20 ng/mL

|Stage IIB

|Stage IIC

|3 or 4

|Stage IIIA

|T1 or T2, N0, M0

| rowspan="2" |3 or 4

|> 20 ng/mL

|Stage IIIB

|T3 or T3, N0, M0

| rowspan="2" |10–20 ng/mL

|Stage IIIC

|T1 or T2, N0, M0

|Stage IVA

|Any T, N1

| rowspan="2" |Any group

| rowspan="2" |Any PSA

|Stage IVB

|Any T, M1

The United Kingdom National Institute for Health and Care Excellence recommends a five-stage system based on disease prognosis called the Cambridge Prognostic Group, with prognostic groups CPG 1 to CPG 5.{{cite web |title=Prostate Cancer: Diagnosis and Management. NICE Guideline [NG131] |url=https://www.nice.org.uk/guidance/ng131/chapter/Recommendations#assessment-and-diagnosis |access-date=3 October 2022 |website=National Institute for Health and Care Excellence (NICE) |date=9 May 2019 |archive-date=11 August 2023 |archive-url=https://web.archive.org/web/20230811131224/https://www.nice.org.uk/guidance/ng131/chapter/Recommendations#assessment-and-diagnosis |url-status=live }} CPG 1 is the same as AJCC stage I. Cases with localized tumors (T1 or T2) and either Gleason grade group 2 or higher PSA levels (10 to 20 ng/mL) are designated CPG 2. CPG 3 represents either Gleason grade group 3, or the combination of the CPG 2 criteria. CPG 4 is similar to AJCC stage 3 – any of Gleason grade group 4, PSA levels above 20 ng/mL, or a tumor that has grown beyond the prostate (T3). CPG 5 is for the highest risk cases: either a T4 tumor, Gleason grade group 5, or any two of the CPG 4 criteria.{{cite web |url=https://www.cancerresearchuk.org/about-cancer/prostate-cancer/stages/cambridge-prognostic-group-cpg |access-date=25 June 2023 |title=Prostate Cancer Risk Groups and the Cambridge Prognostic Group (CPG) |publisher=Cancer Research UK |date=24 May 2022 |archive-date=11 August 2023 |archive-url=https://web.archive.org/web/20230811132255/https://www.cancerresearchuk.org/about-cancer/prostate-cancer/stages/cambridge-prognostic-group-cpg |url-status=live }}

Prevention

No drug or vaccine is approved by regulatory agencies for the prevention of prostate cancer. Several studies have shown 5α-reductase inhibitors – both finasteride and dutasteride, which are used to treat non-cancerous enlarged prostate – to reduce the total incidence of prostate cancer; however, it is unclear {{as of|2022|lc=y}} whether they reduce any cases of dangerous disease.{{sfn|Scher|Eastham|2022|loc="No cancer diagnosis"}}

Management

Treatment of prostate cancer varies based on how advanced the cancer is, the risk it may spread, and the affected person's health and personal preferences.{{sfn|Rebello|Oing|Knudsen|Loeb|2021|loc="Management"}} Those with localized disease at low risk for spread are often more likely to be harmed by the side effects of treatment than the disease itself, and so are regularly tested for a worsening of their disease.{{sfn|Scher|Eastham|2022|loc="Active surveillance"}} Those at higher risk may receive treatment to eliminate the tumor – typically prostatectomy (surgery to remove the prostate) or radiation therapy, sometimes alongside hormone therapy.{{cite web |url=https://www.cancer.org/cancer/types/prostate-cancer/treating/by-stage.html |access-date=28 May 2023 |title=Initial Treatment of Prostate Cancer, by Stage and Risk Group |publisher=American Cancer Society |date=9 August 2022 |archive-date=28 May 2023 |archive-url=https://web.archive.org/web/20230528155727/https://www.cancer.org/cancer/types/prostate-cancer/treating/by-stage.html |url-status=live }} Those with metastatic disease are treated with chemotherapy, as well as radiation or other agents to alleviate the symptoms of metastatic tumors. Blood PSA levels are monitored every few months to assess the effectiveness of treatments, and whether the disease is recurring or advancing.{{cite web |url=https://www.cancer.org/cancer/types/prostate-cancer/treating/psa-levels-after-treatment.html |title=Following PSA Levels During and After Prostate Cancer Treatment |access-date=28 May 2023 |publisher=American Cancer Society |date=1 August 2019 |archive-date=28 May 2023 |archive-url=https://web.archive.org/web/20230528155727/https://www.cancer.org/cancer/types/prostate-cancer/treating/psa-levels-after-treatment.html |url-status=live }}

= Localized disease =

File:External beam radiotherapy NCI.jpg

Men diagnosed with low-risk cases of prostate cancer often defer treatment and are monitored regularly for cancer progression by active surveillance, which involves testing for tumor growth at fixed intervals by PSA tests (around every six months), digital rectal exam (annually), and MRI or repeat biopsies (every one to three years).{{cite web |url=https://www.cancer.org/cancer/types/prostate-cancer/treating/watchful-waiting.html |accessdate=16 April 2024 |title=Observation or Active Surveillance for Prostate Cancer |publisher=American Cancer Society |date=22 November 2023 |archive-date=16 April 2024 |archive-url=https://web.archive.org/web/20240416172559/https://www.cancer.org/cancer/types/prostate-cancer/treating/watchful-waiting.html |url-status=live }} This program continues until increases in PSA levels, Gleason grade, or tumor size indicate a higher-risk tumor that may require intervention.{{sfn|Liu|Patel|Haney|Epstein|2021|loc="Reclassification and progression"}} At least half of men remain on active surveillance, never requiring more direct treatment for their prostate tumors.{{sfn|Liu|Patel|Haney|Epstein|2021|loc="Abstract"}}

Those who elect to have therapy receive radiation therapy or a prostatectomy; these have similar rates of cancer control, but different side effects.{{sfn|Rebello|Oing|Knudsen|Loeb|2021|loc="Localized Disease"}}{{sfn|Scher|Eastham|2022|loc="Clinically localized prostate cancer"}} Radiation can be delivered by intensity-modulated radiation therapy (IMRT), which allows for high doses (greater than 80 Gy) to be delivered to the prostate with relatively little radiation to other organs, or by brachytherapy, where a radioactive source is surgically inserted into the prostate.{{sfn|Scher|Eastham|2022|loc="External beam radiation therapy"}}{{sfn|Scher|Eastham|2022|loc="Brachytherapy"}} IMRT is given over several sessions, with treatments repeated five days per week for several weeks. Brachytherapy is typically performed in a single session, with the radioactive source permanently implanted into the prostate, where it expends its radioactivity within the next few months.{{cite web |url=https://www.cancer.org/cancer/types/prostate-cancer/treating/radiation-therapy.html |accessdate=5 December 2023 |title=Radiation Therapy for Prostate Cancer |publisher=American Cancer Society |date=13 February 2023 |archive-date=5 December 2023 |archive-url=https://web.archive.org/web/20231205211228/https://www.cancer.org/cancer/types/prostate-cancer/treating/radiation-therapy.html |url-status=live }} With either technique, radiation damage to nearby organs can increase the risk of subsequent bladder cancer and cause erectile dysfunction, infertility, irreversible lumbar plexopathy{{cite journal |last1=Brejt |first1=Nick |last2=Berry |first2=Jonathan |last3=Nisbet |first3=Angus |last4=Bloomfield |first4=David |last5=Burkill |first5=Guy |title=Pelvic radiculopathies, lumbosacral plexopathies, and neuropathies in oncologic disease: a multidisciplinary approach to a diagnostic challenge |journal=Cancer Imaging |date=December 30, 2013 |volume=13 |issue=4 |pages=591–601 |doi=10.1102/1470-7330.2013.0052 |pmid=24433993 |pmc=3893894}} and radiation proctitis – damage to the rectum that can cause diarrhea, bloody stools, fecal incontinence, and pain.{{sfn|Brawley|Mohan|Nein|2018|loc="Radiation therapy"}}

File:Surgeon performing robot-assisted surgery.jpg

Radical prostatectomy aims to surgically remove the cancerous part of the prostate, along with the seminal vesicles, and the end of the vas deferens (the duct that delivers sperm from the testes).{{sfn|Dall'Era|2023|loc="Radical prostatectomy"}} In wealthier countries, this is typically done by robot-assisted surgery, where robotic tools inserted through small holes in the abdomen allow a surgeon to make small and exact movements during surgery.{{sfn|Costello|2020|loc="The rise of robotic surgery"}} This method results in shorter hospital stays, less blood loss, and fewer complications than traditional open surgery.{{sfn|Costello|2020|loc="The rise of robotic surgery"}} In places where robot-assisted surgery is unavailable, prostatectomy can be performed laparoscopically (using a camera and hand tools through small holes in the abdomen), or through traditional open surgery with an incision above the penis (retropubic approach) or below the scrotum (perineal approach).{{sfn|Scher|Eastham|2022|loc="Radical prostatectomy"}}{{sfn|Costello|2020|loc="The rise of robotic surgery"}} The four approaches result in similar rates of cancer control.{{sfn|Scher|Eastham|2022|loc="Radical prostatectomy"}} Damage to nearby tissue during surgery can result in erectile dysfunction and urinary incontinence. Erectile dysfunction is more likely in those who are older or had previous erectile issues.{{sfn|Scher|Eastham|2022|loc="Radical prostatectomy"}} Incontinence is more common in those who are older and have shorter urethras.{{sfn|Scher|Eastham|2022|loc="Radical prostatectomy"}} Both for cancer progression outcomes and surgical side effects, the skill and experience of the individual surgeon doing the procedure are among the greatest determinants of success.{{sfn|Scher|Eastham|2022|loc="Radical prostatectomy"}}

After prostatectomy, PSA levels drop rapidly, reaching very low or undetectable levels within two months. Radiotherapy also substantially reduces PSA levels, but more slowly and less completely, with PSA levels reaching their nadir two years after radiotherapy.{{cite web |url=https://www.cancer.org/cancer/types/prostate-cancer/treating/psa-levels-after-treatment.html |accessdate=5 December 2023 |title=Following PSA Levels During and After Prostate Cancer Treatment |publisher=American Cancer Society |date=1 August 2019 |archive-date=7 December 2023 |archive-url=https://web.archive.org/web/20231207065408/https://www.cancer.org/cancer/types/prostate-cancer/treating/psa-levels-after-treatment.html |url-status=live }} After either treatment, PSA levels are monitored regularly. Up to half of those treated will eventually have a rise in PSA levels, suggesting the tumor or small metastases are growing again.{{sfn|Rebello|Oing|Knudsen|Loeb|2021|loc="Biochemical recurrence and residual disease"}} People with high or rising PSA levels are often offered another round of radiation therapy directed at the former tumor site. This reduces risk for further progression by 75%.{{sfn|Rebello|Oing|Knudsen|Loeb|2021|loc="Biocehmical recurrence and residual disease"}} Those suspected of metastases can undergo PET scanning with sensitive radiotracers C-11 choline, F-18 fluciclovine, and F-18 or Ga-68 attached to a PSMA-targeting drug, each of which is able to detect small metastases more sensitively than alternative imaging methods.{{sfn|Scher|Eastham|2022|loc="Rising PSA after definitive local therapy"}}{{sfn|Rebello|Oing|Knudsen|Loeb|2021|loc="Biocehmical recurrence and residual disease"}}

= Metastatic disease =

File:Verlauf Prostatakrebs 2011-01 Posttherapie-Szintigramm cropped.jpg

For those with metastatic disease, the standard of care is androgen deprivation therapy (also called "chemical castration"), drugs that reduce levels of androgens (male sex hormones) that prostate cells require to grow.{{sfn|Rebello|Oing|Knudsen|Loeb|2021|loc="Metastatic hormone-sensitive prostate cancer"}} Various drugs are used to lower androgen levels by blocking the synthesis or action of testosterone, the primary androgen. The first line of treatment typically involves GnRH agonists like leuprolide, goserelin, or triptorelin by injection monthly or less frequently as needed.{{cite web |url=https://www.cancer.org/cancer/types/prostate-cancer/treating/hormone-therapy.html |access-date=15 May 2023 |title=Hormone Therapy for Prostate Cancer |date=9 August 2022 |publisher=American Cancer Society |archive-date=15 May 2023 |archive-url=https://web.archive.org/web/20230515212541/https://www.cancer.org/cancer/types/prostate-cancer/treating/hormone-therapy.html |url-status=live }}{{sfn|Rebello|Oing|Knudsen|Loeb|2021|loc="Metastatic hormone-sensitive prostate cancer"}} GnRH agonists cause a brief rise in testosterone levels at treatment initiation, which can worsen disease in people with significant symptoms of metastases.{{sfn|Scher|Eastham|2022|loc="Testosterone-lowering agents"}} In these people, GnRH antagonists like degarelix or relugolix are given instead, and can also rapidly reduce testosterone levels.{{sfn|Scher|Eastham|2022|loc="Testosterone-lowering agents"}} Reducing testosterone can cause various side effects, including hot flashes, reduction in muscle mass and bone density, reduced sex drive, fatigue, personality changes, and an increased risk of diabetes, cardiovascular disease, and depression.{{sfn|Scher|Eastham|2022|loc="Testosterone-lowering agents"}} Hormone therapy halts tumor growth in more than 95% of those treated,{{sfn|Achard|Putora|Omlin|Zilli|2022|loc="Introduction"}} and PSA levels return to normal in up to 70%.{{sfn|Scher|Eastham|2022|loc="Outcomes of androgen deprivation"}}

Despite reduced testosterone levels, metastatic prostate tumors eventually continue to grow – manifested by rising blood PSA levels, and metastases to nearby bones.{{sfn|Scher|Eastham|2022|loc="Metastatic disease: castrate"}}{{sfn|Rebello|Oing|Knudsen|Loeb|2021|loc="Metastatic castration-resistant prostate cancer"}} This is the most advanced stage of the disease, called castration-resistant prostate cancer (CRPC). CRPC tumors continuously evolve resistance to treatments, necessitating several lines of therapy, each used in sequence to extend survival. The standard of care is the chemotherapy docetaxel along with antiandrogen drugs, namely the androgen receptor antagonists enzalutamide, apalutamide, and darolutamide, as well as the testosterone production inhibitor abiraterone acetate.{{sfn|Teo|Rathkopf|Kantoff|2019|loc="Management of metastatic castration-resistant prostate cancer"}}{{sfn|Scher|Eastham|2022|loc="Metastatic disease: castrate"}}{{sfn|Teo|Rathkopf|Kantoff|2019|loc="Abiraterone acetate"}} An alternative is the cell therapy procedure Sipuleucel-T, where the affected person's immune cells are removed, treated to more effectively target prostate cancer cells, and re-injected.{{sfn|Scher|Eastham|2022|loc="Metastatic disease: castrate"}} Tumors that evolve resistance to docetaxel may receive the second-generation taxane drug cabazitaxel.{{sfn|Scher|Eastham|2022|loc="Metastatic disease: castrate"}}

Some CRPC treatments are used only in men whose tumors have certain characteristics that make the therapy more likely to be effective. Men whose tumors express the protein PSMA may receive the radiopharmaceutical Lu-177 PSMA, which binds to and destroys PSMA-positive cells.{{cite web |url=https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pluvicto-metastatic-castration-resistant-prostate-cancer |accessdate=9 January 2024 |title=FDA Approves Pluvicto for Metastatic Castration-Resistant Prostate Cancer |publisher=U.S. Food & Drug Administration |date=23 March 2022 |archive-date=24 March 2022 |archive-url=https://web.archive.org/web/20220324031828/https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pluvicto-metastatic-castration-resistant-prostate-cancer |url-status=live }}{{sfn|Scher|Eastham|2022|loc="Metastatic disease: castrate"}} Those whose tumors have defective DNA damage repair benefit from treatment with the immune checkpoint inhibitor drug pembrolizumab and PARP inhibitors, namely olaparib, rucaparib, or niraparib.{{sfn|Scher|Eastham|2022|loc="Metastatic disease: castrate"}}

= Supportive care =

Bone metastases – present in around 85% of those with metastatic prostate cancer – are the primary cause of symptoms and death from metastatic prostate cancer.{{sfn|Coleman|Croucher|Padhani|Clézardin|2020|loc="Prevalence of bone metastases"}}{{sfn|Coleman|Croucher|Padhani|Clézardin|2020|loc="Prevalence of SREs"}} Those with constant pain are prescribed nonsteroidal anti-inflammatory drugs.{{sfn|Coleman|Croucher|Padhani|Clézardin|2020|loc="Analgesics used in CIBP"}} However, people with bone metastases can experience "breakthrough pain", sudden bursts of severe pain that resolve within around 15 minutes, before pain medications can take effect.{{sfn|Coleman|Croucher|Padhani|Clézardin|2020|loc="Analgesics used in CIBP"}} Single sites of pain can be treated with external beam radiation therapy to shrink nearby tumors.{{sfn|Scher|Eastham|2022|loc="Pain management"}} More dispersed bone pain can be treated with radioactive compounds that disproportionately accumulate in bone, like radium-223 and samarium-153-EDTMP, which help reduce the size of bone tumors. Similarly, the systemic chemotherapeutics used for metastatic prostate cancer can reduce pain as they shrink tumors.{{sfn|Scher|Eastham|2022|loc="Pain management"}} Other bone modifying agents like zoledronic acid and denosumab can reduce prostate cancer bone pain, even though they have little effect on tumor size.{{sfn|Scher|Eastham|2022|loc="Pain management"}} Metastases compress the spinal cord in up to 12% of those with metastatic prostate cancer causing pain, weakness, numbness, and paralysis.{{sfn|Thompson|Wood|Feuer|2007|loc="Cord compression"}}{{cite web |url=https://prostatecanceruk.org/prostate-information-and-support/advanced-prostate-cancer/metastatic-spinal-cord-compression-mscc?scrollTo=symptoms-of-MSCC |access-date=25 June 2023 |title=What is Metastatic Spinal Cord Compression (MSCC)? |publisher=Prostate Cancer UK |date=June 2022 |archive-date=26 June 2023 |archive-url=https://web.archive.org/web/20230626033230/https://prostatecanceruk.org/prostate-information-and-support/advanced-prostate-cancer/metastatic-spinal-cord-compression-mscc?scrollTo=symptoms-of-MSCC |url-status=live }} Inflammation in the spine can be treated with high-dose steroids, as well as surgery and radiotherapy to shrink spinal tumors and relieve pressure on the spinal cord.{{sfn|Thompson|Wood|Feuer|2007|loc="Cord compression"}}

Those with advanced prostate cancer suffer fatigue, lethargy, and a generalized weakness. This is caused in part by gastrointestinal problems, with loss of appetite, weight loss, nausea, and constipation all common. These are typically treated with appetite-increasing drugs – megestrol acetate or corticosteroids – antiemetics, or treatments that focus on underlying gastrointestinal issues.{{sfn|Thompson|Wood|Feuer|2007|loc="Gastrointestinal symptoms"}} General weakness can also be caused by anemia, itself caused by a combination of the disease itself, poor nutrition, and damage to the bone marrow from cancer treatments or bone metastases.{{sfn|Thompson|Wood|Feuer|2007|loc="General debility"}} Anemia can be treated in various ways depending on the cause, or can be addressed directly with blood transfusions.{{sfn|Thompson|Wood|Feuer|2007|loc="General debility"}} Organ damage and metastases in the lymph nodes can lead to uncomfortable accumulation of fluid (called lymphedema) in the genitals or lower limbs. These swellings can be extremely painful, curtailing an affected person's ability to urinate, have sex, or walk normally. Lymphedema can be treated by applying pressure to aid drainage, surgically draining pooled fluid, and cleaning and treating nearby damaged skin.{{sfn|Thompson|Wood|Feuer|2007|loc="Lymphoedema"}}

People with prostate cancer are around twice as likely to experience anxiety or depression compared to those without cancer.{{sfn|Mundle|Afenya|Agarwal|2021|loc="Estimates of anxiety, depression, and distress"}} When added to normal prostate cancer treatments, psychological interventions such as psychoeducation and cognitive behavioral therapy can help reduce anxiety, depression, and general distress.{{sfn|Mundle|Afenya|Agarwal|2021|loc="Abstract"}}

As those severely ill with metastatic prostate cancer approach the end of their lives, most experience confusion and may hallucinate or have trouble recognizing loved ones.{{sfn|Thompson|Wood|Feuer|2007|loc="Delirium"}}{{cite web|url=https://prostatecanceruk.org/prostate-information-and-support/advanced-prostate-cancer/dying-from-prostate-cancer/what-to-expect |access-date= 25 June 2023 |title=Dying from Prostate Cancer – What to Expect |publisher=Prostate Cancer UK |date=July 2018}} Confusion is caused by various conditions, including kidney failure, sepsis, dehydration, and as a side effect of various drugs, especially opioids.{{sfn|Thompson|Wood|Feuer|2007|loc="Delirium"}} Most people sleep for long periods, and some feel drowsy when awake. Restlessness is also common, sometimes caused by physical discomfort from constipation or urinary retention, sometimes caused by anxiety. In their last few days, affected men's breathing may become shallow and slow, with long pauses between breaths. Breathing may be accompanied by a rattling noise as fluid lingers in the throat, but this is not uncomfortable for the affected person.{{cite web |url=https://www.cancer.net/navigating-cancer-care/advanced-cancer/care-through-final-days |access-date=25 June 2023 |title=Care Through the Final Days |date=November 2022 |publisher=American Society of Clinical Oncology |archive-date=26 June 2023 |archive-url=https://web.archive.org/web/20230626033230/https://www.cancer.net/navigating-cancer-care/advanced-cancer/care-through-final-days |url-status=live }} Their hands and feet may cool to the touch, and skin become blotchy or blue due to weaker blood circulation. Many stop eating and drinking, resulting in dry-feeling mouth, which can be aided by moistening the mouth and lips. The person becomes less and less responsive, and eventually the heart and breathing stop.

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 can survive long after diagnosis, with as many as 99% still alive 10 years from diagnosis.{{sfn|Rebello|Oing|Knudsen|Loeb|2021|loc="Prognosis and survival"}} 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%.{{sfn|Rebello|Oing|Knudsen|Loeb|2021|loc="Figure 3: Prostate cancer stages and progression."}} Those with metastases in distant body sites (around 5% of diagnoses) have relatively poor prognoses, with five-year survival rates of 30–40%.{{sfn|Rebello|Oing|Knudsen|Loeb|2021|loc="Figure 3: Prostate cancer stages and progression."}}

Those who have low blood PSA levels at diagnosis, and whose tumors have a low Gleason grade and less-advanced clinical stage tend to have better prognoses.{{sfn|Pilié|Viscuse|Logothetis|Corn|2022|loc=Table 45-2}} After prostatectomy or radiotherapy, those who have a short time between treatment and a subsequent rise in PSA levels, or quickly rising PSA levels are more likely to die from their cancers.{{sfn|Rebello|Oing|Knudsen|Loeb|2021|loc="Biochemical recurrence and residual disease"}} Castration-resistant metastatic prostate cancer is incurable,{{sfn|Rebello|Oing|Knudsen|Loeb|2021|loc="Abstract"}} and kills a majority of those whose disease reaches this stage.{{sfn|Scher|Eastham|2022|loc="Metastatic disease: castrate"}}

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, replication, cell death, and DNA damage repair.{{sfn|Rebello|Oing|Knudsen|Loeb|2021|loc="Genetics"}} With these processes dysregulated, some cells replicate abnormally, forming a clump of cells called a tumor.{{cite web |url=https://www.cancer.org/cancer/types/prostate-cancer/causes-risks-prevention/what-causes.html |access-date=17 May 2023 |title=What Causes Prostate Cancer? |publisher=American Cancer Society |date=1 August 2019 |archive-date=17 May 2023 |archive-url=https://web.archive.org/web/20230517173538/https://www.cancer.org/cancer/types/prostate-cancer/causes-risks-prevention/what-causes.html |url-status=live }} As the tumor grows, its cells accumulate more mutations, allowing it to stimulate the growth of new blood vessels to support further growth.{{sfn|Rebello|Oing|Knudsen|Loeb|2021|loc="Disease progression"}} Eventually, a tumor can grow large enough to invade nearby organs such as the seminal vesicles or bladder.{{cite web |url=https://www.cancerresearchuk.org/about-cancer/prostate-cancer/stages/locally-advanced-prostate-cancer |access-date=21 May 2023 |title=Locally Advanced Prostate Cancer |publisher=Cancer Research UK |date=31 May 2022 |archive-date=21 May 2023 |archive-url=https://web.archive.org/web/20230521192139/https://www.cancerresearchuk.org/about-cancer/prostate-cancer/stages/locally-advanced-prostate-cancer |url-status=live }} In advanced tumors, cells can develop the ability to detach from their original tissue site, and evade the immune system.{{sfn|Rebello|Oing|Knudsen|Loeb|2021|loc="Disease progression"}} These cells can spread through the lymphatic system to nearby lymph nodes, or through the bloodstream to the bone marrow and (more rarely) other body sites.{{sfn|Rebello|Oing|Knudsen|Loeb|2021|loc="Disease progression"}} 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 can eventually kill the affected person.{{sfn|Rebello|Oing|Knudsen|Loeb|2021|loc="Disease progression"}}

Pathophysiology

Most prostate tumors begin in the peripheral zone – the outermost part of the prostate.{{sfn|Sandhu|Moore|Chiong|Beltran|2021|loc="The biology of prostate cancer"}} As cells begin to grow out of control, they form a small clump of disregulated cells called a prostatic intraepithelial neoplasia (PIN).{{cite web|url=https://www.cancer.org/cancer/diagnosis-staging/tests/understanding-your-pathology-report/prostate-pathology/high-grade-prostatic-intraepithelial-neoplasia.html |access-date=25 May 2023 |title=Understanding Your Pathology Report: Prostatic Intraepithelial Neoplasia (PIN) and Intraductal Carcinoma |publisher=American Cancer Society}} Some PINs continue to grow, forming layers of tissue that stop expressing genes common to their original tissue location – p63, cytokeratin 5, and cytokeratin 14 – and instead begin expressing genes typical of cells in the innermost lining of the pancreatic duct – cytokeratin 8 and cytokeratin 18.{{sfn|Sandhu|Moore|Chiong|Beltran|2021|loc="The biology of prostate cancer"}} These multilayered PINs also often overexpress the gene AMACR, which is associated with prostate cancer progression.{{sfn|Sandhu|Moore|Chiong|Beltran|2021|loc="The biology of prostate cancer"}}

Some PINs can eventually grow into tumors. This is commonly accompanied by large-scale changes to the genome, with chromosome sequences being rearranged or copied repeatedly. Some genomic alterations are particularly common in early prostate cancer, namely gene fusion between TMPRSS2 and the oncogene ERG (up to 60% of prostate tumors), mutations that disable SPOP (up to 15% of tumors), and mutations that hyperactivate FOXA1 (up to 5% of tumors).{{sfn|Sandhu|Moore|Chiong|Beltran|2021|loc="The biology of prostate cancer"}}

Metastatic prostate cancer tends to have more genetic mutations than localized disease.{{sfn|Rebello|Oing|Knudsen|Loeb|2021|loc="Metastatic disease"}} 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).{{sfn|Rebello|Oing|Knudsen|Loeb|2021|loc="Metastatic disease"}} 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.{{sfn|Rebello|Oing|Knudsen|Loeb|2021|loc="Metastatic disease"}}

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 (for example, FOXA1), or inactivating mutations in its negative regulators (for example, ZBTB16 and NCOR1).{{sfn|Rebello|Oing|Knudsen|Loeb|2021|loc="Metastatic disease"}} These androgen receptor disruptions are only found in up to 6% of biopsies of castrate-sensitive metastatic disease.{{sfn|Rebello|Oing|Knudsen|Loeb|2021|loc="Metastatic disease"}} Similarly, deletions of the tumor suppressor PTEN are harbored by 12–17% of castrate-sensitive tumors, but over 40% of castrate-resistant tumors.{{sfn|Rebello|Oing|Knudsen|Loeb|2021|loc="Metastatic disease"}} Less commonly, tumors have aberrant activation of the Wnt signaling pathway via disruption of members APC (9% of tumors) or CTNNB1 (4% of tumors); or dysregulation of the PI3K pathway via PI3KCA/PI3KCB mutations (6% of tumors) or AKT1 (2% of tumors).{{sfn|Rebello|Oing|Knudsen|Loeb|2021|loc="Metastatic disease"}}

Epidemiology

File:US PC Inc by age 2016.tif

Prostate cancer is the second-most frequently diagnosed cancer in men, and the second-most frequent cause of cancer death in men (after lung cancer).{{sfn|Rebello|Oing|Knudsen|Loeb|2021|loc="Epidemiology"}}{{sfn|Scher|Eastham|2022|loc="Prostate cancer"}} Around 1.2 million new cases of prostate cancer are diagnosed each year, and over 350,000 people die of the disease, annually.{{sfn|Rebello|Oing|Knudsen|Loeb|2021|loc="Epidemiology"}} One in eight men are diagnosed with prostate cancer in their lifetime, and around one in forty die of the disease.{{sfn|Scher|Eastham|2022|loc="Prostate cancer"}} Rates of prostate cancer rise with age. 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.{{sfn|Rebello|Oing|Knudsen|Loeb|2021|loc="Epidemiology"}} 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 quickly in these regions.{{sfn|Rebello|Oing|Knudsen|Loeb|2021|loc="Epidemiology"}} Prostate cancer is the most diagnosed cancer in men in over half of the world's countries, and the leading cause of cancer death in men in around a quarter of countries.{{sfn|Bergengren|Pekala|Matsoukas|Fainberg|2023|loc="3.1 Epidemiology"}}

Prostate cancer is rare in those under 40 years old,{{sfn|Pernar|Ebot|Wilson|Mucci|2018|loc="Risk factors for total prostate cancer"}} and most cases occur in those over 60 years,{{sfn|Rebello|Oing|Knudsen|Loeb|2021|loc="Epidemiology"}} with the average person diagnosed at 67.{{sfn|Stephenson|Abouassaly|Klein|2021|loc="Age at diagnosis"}} The average age of those who die from prostate cancer is 77.{{sfn|Stephenson|Abouassaly|Klein|2021|loc="Age at diagnosis"}} Only a minority of prostate cancer cases are diagnosed. Autopsies of men who died at various ages have shown cancer in the prostates of over 40% of men over age 50. Incidence rises with age, and nearly 70% of men autopsied at age 80–89 had cancer in their prostates.{{sfn|Dall'Era|2023|loc="General considerations"}}

= Genetics =

Prostate cancer is more common in families with a history of any cancer.{{sfn|Rebello|Oing|Knudsen|Loeb|2021|loc="Genetic predisposition"}} 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.{{sfn|Scher|Eastham|2022|loc="Epidemiology"}} Increased risk also runs in some ethnic groups, with men of African and African-Caribbean ancestry at particularly high risk – having prostate cancer at higher rates, and having more-aggressive prostate cancers that develop at earlier ages.{{sfn|McHugh|Saunders|Dadaev|McGrowder|2022|loc="Introduction"}} Large genome-wide association studies have identified over 100 gene variants associated with increased prostate cancer risk.{{sfn|Rebello|Oing|Knudsen|Loeb|2021|loc="Genetic predisposition"}} 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.{{sfn|Rebello|Oing|Knudsen|Loeb|2021|loc="Genetic predisposition"}} 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.{{sfn|Rebello|Oing|Knudsen|Loeb|2021|loc="Genetic predisposition"}} Additionally, variants in the genome near the oncogene MYC are associated with increased risk.{{sfn|Rebello|Oing|Knudsen|Loeb|2021|loc="Genetic predisposition"}} 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.{{sfn|Scher|Eastham|2022|loc="Epidemiology"}} Together, known gene variants are estimated to cause around 25% of prostate cancer cases, including 40% of early-onset prostate cancers.{{sfn|Scher|Eastham|2022|loc="Epidemiology"}}

= Body and lifestyle =

Men who are taller are at a slightly increased risk for developing prostate cancer, as are men who are obese.{{sfn|Pernar|Ebot|Wilson|Mucci|2018|loc="Risk factors for advanced and fatal prostate cancer"}} High levels of blood cholesterol are also associated with increased prostate cancer risk; consequently, those who take the cholesterol-lowering drugs, statins, have a reduced risk of advanced prostate cancer.{{sfn|Pernar|Ebot|Wilson|Mucci|2018|loc="Statins"}} Chronic inflammation can cause various cancers. Potential links between infection (or other sources of inflammation) and prostate cancer have been studied but none definitively found, and one large study found no link between prostate cancer and a history of gonorrhea, syphilis, chlamydia, or infection with various human papillomaviruses.{{sfn|Stephenson|Abouassaly|Klein|2021|loc="Inflammation and infection"}}

Regular vigorous exercise may reduce one's chance of developing advanced prostate cancer, as can several dietary interventions.{{sfn|Pernar|Ebot|Wilson|Mucci|2018|loc="Exercise"}} Those with a diet rich in cruciferous vegetables (certain leafy greens, broccoli, and cauliflower), fish, genistein (found in soy), or lycopene (found in tomatoes) are at a reduced risk of symptomatic prostate cancer.{{sfn|Scher|Eastham|2022|loc="Epidemiology"}}{{sfn|Pernar|Ebot|Wilson|Mucci|2018|loc="Fish"}} Conversely, those who consume high levels of dietary fats, polycyclic aromatic hydrocarbons (from cooking red meats), or calcium may be at an increased risk of developing advanced prostate cancer.{{sfn|Scher|Eastham|2022|loc="Epidemiology"}}{{sfn|Pernar|Ebot|Wilson|Mucci|2018|loc="Calcium, dairy products, and vitamin D"}} Several dietary supplements have been studied and found not to impact prostate cancer risk, including selenium, vitamin C, vitamin D, and vitamin E.{{sfn|Scher|Eastham|2022|loc="No cancer diagnosis"}}{{sfn|Pernar|Ebot|Wilson|Mucci|2018|loc="Calcium, dairy products, and vitamin D"}}

Special populations

Transgender women and gender non-conforming people who have prostates can develop prostate cancer. Those who have undergone gender-affirming hormone therapy or gender-affirming surgery have reduced risk of developing prostate cancer, relative to cisgender men of similar age.{{sfn|Bertoncelli Tanaka|Sahota|Burn|Falconer|2022|loc="Conclusions"}} Screening tests in this group are complicated, as transgender women may have lower PSA levels than cisgender men due to their reduced testosterone levels.{{sfn|Bertoncelli Tanaka|Sahota|Burn|Falconer|2022|loc="Interpretation of PSA in transgender women on GAHT"}} PSA levels greater than 1 ng/mL are generally considered above normal by gender care specialists.{{sfn|Bertoncelli Tanaka|Sahota|Burn|Falconer|2022|loc="Screening for prostate cancer in transgender women"}} Digital rectal exams of the prostate are often impossible in transgender women who have undergone vaginoplasty, as the length and rigidity of the new vagina can obstruct access to the prostate from the rectum.{{sfn|Bertoncelli Tanaka|Sahota|Burn|Falconer|2022|loc="Screening for prostate cancer in transgender women"}}

History

File:Charles_Brenton_Huggins_nobel.jpg

A prostate mass was first described in 1817 by the English surgeon George Langstaff, following the autopsy of a man who had died at age 68 with lower-body pain and urinary issues.{{sfn|Valier|2016|pp=15–18}}{{cite journal |vauthors=Lawrence W |title=Cases of Fungus Hæmatodes, with Observations, by George Langstaff, Esq. and an Appendix, Containing two Cases of Analogous Affections |journal=Med Chir Trans |volume=8 |issue= |pages=272–314 |date=1817 |pmid=20895322 |pmc=2129005 |doi=10.1177/095952871700800114 }} In 1853, London Hospital surgeon John Adams described another prostate tumor from a man who had died with urinary issues; Adams had a pathologist examine the tumor, providing the first confirmed case of a cancerous tumor in the prostate.{{sfn|Valier|2016|pp=15–18}}{{cite journal | vauthors = Adams J | title = The Case of Scirrhous of the Prostate Gland with Corresponding Affliction of the Lymphatic Glands in the Lumbar Region and in the Pelvis | journal = Lancet | volume = 1 | issue = 1547 | pages = 393–94 | year = 1853 | doi = 10.1016/S0140-6736(02)68759-8 }} The disease was initially rarely described; an 1893 report found only 50 cases described in the medical literature.{{sfn|Lytton|2001|p=1859}} Around the turn of the 19th century, prostate surgery to relieve urinary obstruction became more common, allowing surgeons and pathologists to examine the removed prostate tissue. Two studies around the time found cancer in as many as 10% of surgical specimens, suggesting prostate cancer was a fairly common cause of prostate enlargement.{{sfn|Lytton|2001|p=1859}}

For much of the 20th century, the primary therapy for prostate cancer was surgery to remove the prostate. Perineal prostatectomy was first performed in 1904 by Hugh H. Young at Johns Hopkins Hospital.{{sfn|Denmeade|Isaacs|2002|loc="Prostatectomy"}}{{cite journal | vauthors = Young HH | title = Four Cases of Radical Prostatectomy | journal = Johns Hopkins Bull. | volume = 16 | year = 1905 }} Young's method became the widespread standard, initially done primarily to relieve symptoms of urinary blockage.{{sfn|Denmeade|Isaacs|2002|loc="Prostatectomy"}} In 1931 a new surgical method, transurethral resection of the prostate, became available, replacing perineal prostatectomy for symptomatic relief of obstruction.{{sfn|Lytton|2001|p=1859}} In 1945, Terence Millin described a retropubic prostatectomy approach, which provided easier access to pelvic lymph nodes to assist in staging the extent of disease, and was easier for surgeons to learn.{{sfn|Denmeade|Isaacs|2002|loc="Prostatectomy"}} This was improved upon by Patrick C. Walsh's 1983 description of a retropubic prostatectomy approach that avoided damage to the nerves near the prostate, preserving erectile function.{{sfn|Denmeade|Isaacs|2002|loc="Prostatectomy"}}{{cite journal | vauthors = Walsh PC, Lepor H, Eggleston JC | title = Radical Prostatectomy with Preservation of Sexual Function: Anatomical and Pathological Considerations | journal = The Prostate | volume = 4 | issue = 5 | pages = 473–485 | year = 1983 | pmid = 6889192 | doi = 10.1002/pros.2990040506 | s2cid = 30740301 }}

Radiation therapy for prostate cancer was used occasionally in the early 20th century, with radium implanted into the urethra or rectum to reduce the tumor size and associated symptoms.{{sfn|Denmeade|Isaacs|2002|loc="Radiation therapy"}} In the 1950s the advent of more powerful radiation machines allowed for external beam radiotherapy to reach the prostate. By the 1960s, this was often combined with hormone therapy to improve the potency of therapy.{{sfn|Denmeade|Isaacs|2002|loc="Radiation therapy"}} In the 1970s, Willet Whitmore pioneered an open surgery technique where needles of Iodine-125 were placed directly into the prostate. This was improved upon by Henrik H. Holm in 1983 by using transrectal ultrasound to guide the implantation of radioactive material.{{sfn|Denmeade|Isaacs|2002|loc="Radiation therapy"}}

The observation that the testicles (and the hormones they secrete) influence prostate size was made as early as the late 18th century via castration experiments in animals. However, occasional experimentation over the next century bore mixed results, likely due to the inability to separate prostate tumors from prostates enlarged due to benign prostatic hyperplasia. In 1941, Charles B. Huggins and Clarence V. Hodges published two studies using surgical castration or oral estrogen to reduce androgen levels and improve prostate cancer symptoms. Huggins was awarded the 1966 Nobel Prize in Physiology or Medicine for this discovery, the first systemic therapy for prostate cancer.{{sfn|Denmeade|Isaacs|2002|loc="Androgen-ablation therapy"}}{{cite journal | vauthors = Huggins CB, Hodges CV | title = Studies on Prostate Cancer: 1. The Effects of Castration, of Estrogen and Androgen Injection on Serum Phosphatases in Metastatic Carcinoma of the Prostate | journal = Cancer Res | volume = 1 | issue = 4 | pages = 293 | year = 1941 | url = http://cancerres.aacrjournals.org/content/1/4/293 | archive-url = https://web.archive.org/web/20170630121943/http://cancerres.aacrjournals.org/content/1/4/293 | archive-date = 30 June 2017 | access-date = 2 September 2015 }} In the 1960s, large studies showed estrogen therapy to be as effective as surgical castration at treating prostate cancer, but that those on estrogen therapy were at increased risk of suffering blood clots.{{sfn|Denmeade|Isaacs|2002|loc="Androgen-ablation therapy"}} Through the 1980s, Andrzej W. Schally's studies of GnRH led to the development of GnRH agonists, which were found to be as effective as estrogen without the increased risk of clotting.{{sfn|Denmeade|Isaacs|2002|loc="Androgen-ablation therapy"}}{{cite journal | vauthors = Tolis G, Ackman D, Stellos A, Mehta A, Labrie F, Fazekas AT, Comaru-Schally AM, Schally AV | title = Tumor Growth Inhibition in Patients with Prostatic Carcinoma Treated with Luteinizing Hormone-Releasing Hormone Agonists | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 79 | issue = 5 | pages = 1658–1662 | date = March 1982 | pmid = 6461861 | pmc = 346035 | doi = 10.1073/pnas.79.5.1658 | doi-access = free | title-link = doi | bibcode = 1982PNAS...79.1658T }} Schally was awarded the 1977 Nobel Prize in Physiology or Medicine for his work on GnRH and prostate cancer.{{sfn|Denmeade|Isaacs|2002|loc="Androgen-ablation therapy"}}

Systemic chemotherapy for prostate cancer has been studied since the 1950s but clinical trials failed to show benefits in most people who receive the drugs.{{sfn|Denmeade|Isaacs|2002|loc="Cytotoxic chemotherapy"}} In 1996, the US Food and Drug Administration approved the systemic chemotherapy mitoxantrone for those with castration-resistant prostate cancer based on trials showing that it improved symptoms even though it failed to enhance survival.{{sfn|Desai|McManus|Sharifi|2021|loc="Evolution of treatment"}} In 2004, docetaxel was approved as the first chemotherapy to increase survival in those with castration-resistant prostate cancer.{{sfn|Desai|McManus|Sharifi|2021|loc="Evolution of treatment"}} After additional trials in 2015, docetaxel use was extended to those with castration-sensitive prostate cancer.{{sfn|Teo|Rathkopf|Kantoff|2019|loc="Figure 1"}}

Society and culture

Prostate cancer screening and awareness have been widely promoted since the early 2000s by Prostate Cancer Awareness Month in September and Movember in November.{{sfn|Patel|Halpern|Desai|Keeter|2020|p=64}} However, an analysis of internet searches suggests neither event changes the level of prostate cancer interest or discussion much, in contrast to the more established Breast Cancer Awareness Month.{{sfn|Patel|Halpern|Desai|Keeter|2020|p=64}}

Research

Prostate cancer is a major topic of ongoing research. From 2016 to 2020, over $1.26 billion was invested in prostate cancer research, representing around 5% of global cancer research funds.{{sfn|McIntosh|Alam|Adams|Boon|2023|loc=Table 1}} This places prostate cancer 10th among 18 common cancer types in funding per cancer death, and 9th in funding per disability-adjusted life year lost.{{sfn|McIntosh|Alam|Adams|Boon|2023|loc=Table 2}}

Research into prostate cancer relies on a number of laboratory models to test aspects of the disease. Several prostate immortalized cell lines are widely used, namely the classic lines DU145, PC-3, and LNCaP, as well as more recent cell lines 22Rv1, LAPC-4, VCaP, and MDA-PCa-2a and −2b.{{sfn|Mai|Chin|Foong|Pang|2022|loc="2.1 Human prostate cancer cell lines"}} Research requiring more complex models of the prostate uses organoids – clusters of prostate cells that can be grown from human prostate tumors or stem cells.{{sfn|Mai|Chin|Foong|Pang|2022|loc="2.4. Organoids"}} Modeling tumor growth and metastasis requires a model organism, typically a mouse. Researchers can either surgically implant human prostate tumors into immunocompromised mice (a technique called a patient derived xenograft),{{sfn|Mai|Chin|Foong|Pang|2022|loc="2.2 PDX lines"}} or induce prostate tumors in mice with genetic engineering.{{sfn|Mai|Chin|Foong|Pang|2022|loc="2.3 Genetically engineered mouse model (GEMM)"}} These genetically engineered mouse models typically use a Cre recombinase system to disrupt tumor suppressors or activate oncogenes specifically in prostate cells.{{sfn|Ittmann|Huang|Radaelli|Martin|2013|loc="Introduction"}}

{{as of|2024}} studies exploring the relationship between ejaculation frequency and prostate cancer risk are inconclusive and age, urinary health, and lifestyle are important factors to consider.{{sfn|Kokori|Olatunji|Isarinade|Aboje|2024|loc="Abstract"}}{{sfn|Gandaglia|Leni|Bray|Fleshner|2021|loc="3.3.3. Ejaculation frequency and sexual activity"}}

Notes

References

= Works cited =

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{{cite journal |vauthors=Maffei D, Giganti F, Moore CM |title=Seminar: Revisiting the Value of PSA-Based Prostate Cancer Screening Essay No 5: Should Men Undergo MRI Before Prostate Biopsy? (Pro) |journal=Urol Oncol |volume=41 |issue=2 |pages=88–91 |date=February 2023 |pmid=35871993 |doi=10.1016/j.urolonc.2022.04.016 |url=https://discovery.ucl.ac.uk/id/eprint/10157007/}}
{{cite journal |vauthors=Mai CW, Chin KY, Foong LC, Pang KL, Yu B, Shu Y, Chen S, Cheong SK, Chua CW |title=Modeling Prostate Cancer: What Does it Take to Build an Ideal Tumor Model? |journal=Cancer Lett |volume=543 |issue= |pages=215794 |date=September 2022 |pmid=35718268 |doi=10.1016/j.canlet.2022.215794 |s2cid=249831438 }}
{{cite journal |vauthors=McHugh J, Saunders EJ, Dadaev T, McGrowder E, Bancroft E, Kote-Jarai Z, Eeles R |title=Prostate Cancer Risk in Men of Differing Genetic Ancestry and Approaches to Disease Screening and Management in these Groups |journal=Br J Cancer |volume=126 |issue=10 |pages=1366–1373 |date=June 2022 |pmid=34923574 |pmc=9090767 |doi=10.1038/s41416-021-01669-3 }}
{{cite journal |vauthors=McIntosh SA, Alam F, Adams L, Boon IS, Callaghan J, Conti I, Copson E, Carson V, Davidson M, Fitzgerald H, Gautam A, Jones CM, Kargbo S, Lakshmipathy G, Maguire H, McFerran K, Mirandari A, Moore N, Moore R, Murray A, Newman L, Robinson SD, Segaran A, Soong CN, Walker A, Wijayaweera K, Atun R, Cutress RI, Head MG |title=Global Funding for Cancer Research Between 2016 and 2020: a Content Analysis of Public and Philanthropic Investments |journal=Lancet Oncol |volume=24 |issue=6 |pages=636–645 |date=June 2023 |pmid=37269844 |doi=10.1016/S1470-2045(23)00182-1 |url=https://eprints.ncl.ac.uk/fulltext.aspx?url=291767/C1967B92-EEE6-42F7-97E9-B4641C8A5D2D.pdf&pub_id=291767}}
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{{cite journal |vauthors=Sandhu S, Moore CM, Chiong E, Beltran H, Bristow RG, Williams SG |title=Prostate cancer |journal=Lancet |volume=398 |issue=10305 |pages=1075–1090 |date=September 2021 |pmid=34370973 |doi=10.1016/S0140-6736(21)00950-8 |s2cid=236941733 |doi-access = free | title-link = doi }}
{{cite journal |vauthors=Teo MY, Rathkopf DE, Kantoff P |title=Treatment of Advanced Prostate Cancer |journal=Annu Rev Med |volume=70 |issue= |pages=479–499 |date=January 2019 |pmid=30691365 |pmc=6441973 |doi=10.1146/annurev-med-051517-011947 }}
{{cite journal |vauthors=Thompson JC, Wood J, Feuer D |title=Prostate Cancer: Palliative Care and Pain Relief |journal=Br Med Bull |volume=83 |issue= |pages=341–354 |date=2007 |pmid=17628024 |doi=10.1093/bmb/ldm018 |doi-access = free | title-link = doi }}
{{cite book|title=A History of Prostate Cancer |vauthors=Valier H |isbn=978-1-4039-8803-4 |date=2016 |publisher=Springer Nature |chapter=The Problematic Prehistory of Prostate Cancer |pages=15–42}}

External links

{{Medical resources

| ICD11 = {{ICD11|2C82}}

| ICD10 = {{ICD10|C61}}

| ICD9 = {{ICD9|185}}

| ICDO =

| OMIM = 176807

| DiseasesDB = 10780

| MedlinePlus = 000380

| eMedicineSubj = radio

| eMedicineTopic = 574

| MeshID = D011471

}}

Category: Men's health

Category:Male genital neoplasia

Category:Neoplastic and hyperplastic prostate disorders

Category:Types of cancer

prostate cancer

Signs and symptoms

Screening

Diagnosis

= Staging =

Prevention

Management

= Localized disease =

= Metastatic disease =

= Supportive care =

Prognosis

Cause

Pathophysiology

Epidemiology

= Genetics =

= Body and lifestyle =

Special populations

History

Society and culture

Research

Notes

See also

References

= Works cited =

External links