What Is Prostate Cancer? – Causes, Symptoms, Treatment

Causes of Prostate Cancer

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

The overall incidence increases as people get older; but fortunately, cancer aggressiveness decreases with age.[rx] Prostate cancer risk factors include male gender, older age, positive family history, increased height, obesity, hypertension, lack of exercise, persistently elevated testosterone levels, Agent Orange exposure, and ethnicity.[rx]

5-Alpha-Reductase Inhibitors

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

Genetics

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

Diet

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

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

Chemical Exposure

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

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

Gender

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

Infections

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

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

Vasectomy and Prostate Cancer

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

Symptoms of Prostate Cancer

Symptoms of prostate cancer can include

• needing to pee more frequently, often during the night
• needing to rush to the toilet
• difficulty in starting to pee (hesitancy)
• straining or taking a long time while peeing
• weak flow
• feeling that your bladder has not emptied fully
• blood in urine or blood in semen

Males who do experience symptoms may notice

• difficulty starting and maintaining urination
• a frequent urge to urinate, especially at night
• blood in the urine or semen
• painful urination
• in some cases, pain on ejaculation
• difficulty getting or maintaining an erection
• pain or discomfort when sitting, if the prostate is enlarged

Advanced symptoms

Advanced prostate cancer can involve the following symptoms

• bone fracture or bone pain, especially in the hips, thighs, or shoulders
• edema, or swelling in the legs or feet
• weight loss
• tiredness
• changes in bowel habits
• back pain

Diagnosis of Prostate Cancer

Histopathology

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

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

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

Pre-Malignant Lesions

• High-Grade Prostatic Intraepithelial Neoplasia (High-Grade PIN) – The Gleason system is a very good way of grading prostate cancers, but there are situations where the microscopic appearance of prostatic tissue is not malignant even though the individual cells appear very abnormal and dysplastic; similar to how most cancer cells in other tissues would typically appear.  In high-grade PIN, cells will usually show very large nucleoli, but marked pleomorphism is not present.  The prostatic ducts and glandular patterns appear normal with a normal peripheral basal cell layer. This condition is considered pre-malignant and is called high grade prostatic intraepithelial neoplasia (high-grade PIN). A low-grade PIN is considered benign and is usually not reported.[rx]
• Atypical Small Acinar Proliferation (ASAP) – Also considered a premalignant lesion, atypical small acinar proliferation indicates that there are small foci or atypical prostatic glands that are suspicious for cancer but there is insufficient overall evidence of malignancy to diagnose cancer. There is a 40 to 50% chance of finding overt prostate cancer on repeat biopsy, so the consensus recommendation is to repeat the prostatic biopsy with or without MRI image guidance 3 to 6 months after the initial diagnosis of atypical small acinar proliferation.[rx]
• Atypical Adenomatous Hyperplasia (Adenosis) – First described in 1941, atypical adenomatous hyperplasia is defined as a well-circumscribed nodule or lobule of small prostatic glands that are closely packed. What sets it apart from a diagnosis of prostate cancer is the presence of basal cells and the absence of significant cytologic atypia. There is some controversy regarding whether atypical adenomatous hyperplasia is a premalignant lesion or not, but the consensus suggests that it has relatively low malignant potential by itself and does not routinely warrant a repeat biopsy.[rx][rx]

History and Physical

• Early prostate cancer is usually asymptomatic. However, it may sometimes cause symptoms similar to benign prostatic hyperplasia including frequent urination, nocturia, difficulty starting and maintaining a steady stream, hematuria, and dysuria.[rx]
• Prostate cancer may also be associated with problems involving sexual function and performance, such as difficulty achieving an erection or painful ejaculation.[rx]
• Metastatic prostate cancer can cause severe bone pain, often in the vertebrae, pelvis, hips or ribs. Spread into the femur is usually to the proximal part of the bone.[rx]
• Prostate cancer can result in spinal cord compression; causing tingling, leg weakness, pain, paralysis, and urinary as well as fecal incontinence.[rx]

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

• Palpation (feeling) – Here the doctor gently inserts a finger into the anus to feel the size, hardness and surface of the prostate (digital rectal exam, or DRE).
• PSA test – The PSA test is a blood test that looks for a certain protein known as “prostate-specific antigen.” This protein is produced inside the prostate. Small amounts of it enter the bloodstream. Having high levels of PSA might – but doesn’t necessarily – mean that someone has prostate cancer. Other things can lead to an increase in PSA levels too.
• Transrectal ultrasound (TRUS) – Ultrasound is used to check the size and shape of the prostate gland. This involves gently inserting an ultrasound device about as wide as a finger into the rectum (the end part of the bowel).
• A tissue sample (biopsy) – The only way to find out whether there actually is cancerous tissue in the prostate is by taking a tissue sample. Ten to twelve tissue samples are usually taken to be examined under a microscope. The most commonly used approach is called fine-needle aspiration. This also involves inserting an ultrasound device into the rectum. The device has a fine hollow needle that can puncture the prostate through the wall of the rectum in order to take a sample of the prostate tissue. This procedure is done using a local anesthetic, or – in some rare cases – a brief general anesthetic.

PSA and Other Pre-Biopsy Prostate Cancer Predictive Tests

• Elevated Prostate-Specific Antigen (PSA) – levels (usually greater than 4 ng/ml) in the blood is how 80% of prostate cancers initially present even though elevated PSA levels alone correctly identify prostate cancer only about 25% to 30% of the time. We recommend at least 2 abnormal PSA levels or the presence of a palpable nodule on DRE to justify a biopsy and further investigation.[rx] The value of PSA screenings remains controversial due to concerns about possible overtreatment of low-risk cancers, overdiagnosis, complications from “unnecessary biopsies,” the presumed “limited” actual survival benefit from early diagnosis and treatment, and the true value of definitive therapy intended to cure.[rx]
• Free and Total PSA – The percentage of free PSA in the blood can be a useful indicator of malignancy.  If the total PSA is between 4 and 10 ng/ml, a free PSA percentage is considered valid.  The free PSA percentage is calculated by multiplying the free PSA level by 100 and dividing by the total PSA value.

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

• PSA Density – is the total PSA divided by the prostatic volume as determined by MRI or ultrasound (US). The formula for the volume of the prostate is prostate volume = width x height x length x pi/6. For most purposes, Pi/6 can be estimated as 0.52 to make the calculations easier. The PSA density is intended to minimize the effect of benign prostatic enlargement. In general, if the PSA density is greater than 0.15, it is considered suggestive of malignancy.[rx]
• PSA Velocity – compares serial, annual PSA serum levels. An annual PSA increase of greater than 0.75 ng/ml or greater than 25% suggests a potential cancer of the prostate (total PSA 4 to 10 ng/ml). If the total PSA is 2.6 to 4 ng/ml, then an annual increase of 0.35 ng/ml would be considered suspicious.[rx]
• Prostate Cancer Antigen 3 (PCA3) – is an RNA based genetic test performed from a urine sample obtained immediately after a prostatic massage. PCA3 is a long, non-coding RNA molecule that is overexpressed exclusively in prostatic malignancies. It is upregulated 66 fold in prostate cancers. If PCA3 is elevated, it suggests the presence of prostate cancer.  It is more reliable than PSA as it is independent of prostate volume. PCA3 is best used to determine the need for a repeat biopsy after initial negative histology. Serial PCA3 testing may also be helpful in monitoring patients with low-grade prostate cancers on active surveillance. [rx]
• The Prostate Health Index (PHI) – is a blood test that includes free PSA, total PSA, and the [-2] pro PSA isoform of free PSA. A formula is used to combine these test results mathematically to give the PHI score. This PHI score appears to be superior to PSA, free and total PSA, and PCA3 in predicting the presence of prostate cancer.[rx]
• Mi-Prostate Score – is a predictive algorithm developed at the University of Michigan.  It includes PSA, PCA3, and urine TMPRSS2: ERG (a genetic fusion found in about 50% of all prostate cancers).  While better than PSA alone, it is currently uncertain if this algorithm significantly outperforms PCA3 alone.[rx]
• The “4K” Test – measures serum total PSA, free PSA, intact PSA, and human kallikrein antigen 2. It includes clinical DRE results as well as information from any prior biopsies. These results are compared to a very large, age-matched database, and a percentage risk of “significant” prostate cancer is calculated. Clinically significant prostate cancer is usually defined as Gleason 3 + 4 = 7 or higher disease. A risk analysis of 10% or more would typically suggest proceeding with a biopsy.  Interestingly, the “4K” test has not been shown to be any better than PSA testing alone when used for tracking active surveillance patients. [rx]
• Exod Prostate Intelliscore (EPI) – uses PCA3 and urinary TMPRSS2: ERG to detect clinically significant prostate cancer.  The test analyzes exosomal RNA for three biomarkers known to be expressed in the urine of men with high-grade prostate cancer. A proprietary algorithm is then used to assign a risk score that predicts the presence of high-grade (Gleason Score = 7 or higher, or any Gleason Grade = 4 or 5) prostate cancer. Unlike other urine-based tests for prostate cancer, no digital rectal examination or prostatic massage is required.  Negative predictive value is  91.3% with a sensitivity rating of 91.9%. [rx]

Results are reported very straight-forwardly as either

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

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

Prostate Imaging

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

• Transrectal ultrasound (TRUS) during prostate biopsies can sometimes see a potentially “suspicious hypoechoic area,” but ultrasound alone is not a reliable diagnostic test for prostatic malignancy. TRUS is best used for directing the needle for prostate biopsies.
• Prostate MRI has much better soft tissue resolution than ultrasound and can identify areas in the gland that are truly “suspicious” with a high degree of accuracy and reliability (positive predictive value greater than 90%).
• In Europe, a positive MRI finding is sometimes sufficient to make a diagnosis of prostate cancer without necessarily requiring histological confirmation.
• Prostate MRI is also used for surgical planning in men considering radical prostatectomy and for improved biopsies, instead of saturation biopsies, when cancer is strongly suspected despite a negative initial TRUS-guided biopsy.
• MRI of the prostate may also have a role in active surveillance as an alternative to periodic or repeated biopsies.
• Prostatic MRI is becoming a standard imaging modality for the diagnosis of prostate cancer. It can identify and grade suspicious prostate nodules to help with staging and localization, check for extracapsular extension, evaluate the seminal vesicles for possible tumor involvement and determine enlargement of regional lymph nodes that might indicate early metastatic disease.[rx][rx]

Prostate Imaging, Reporting and Data System (PIRADS)

• MRI imaging, unlike CT or x-rays – typically shows denser tissue as dark areas.  Standard MRI imaging of the prostate usually requires a 3 Tesla (3T) MRI machine and optimally uses intravenous (IV) contrast, although non-contrast (bi-parametric) MRI tests are quicker, cheaper, and still quite useful. IV contrast will demonstrate early vascular entry (faster inflow) and quicker washout from cancerous lesions or nodules compared to normal prostatic tissue. Various MRI tissue characteristics ultimately determine the relative cancer risk which is documented in the final report as a PIRADS score. A PIRADS score of 1 or 2 is highly unlikely to be cancer. A PIRADS score of 4 or 5 is highly suspicious for clinically significant disease (Gleason 3 + 4 = 7 and higher). PIRADS 3 is equivocal. Histological confirmation with a biopsy is recommended for all PIRADS 3, 4, and 5 lesions.[rx]
• PIRADS 3 – lesions usually demonstrate benign histology on biopsy, but low-grade prostate cancer is possible and it cannot reliably exclude intermediate or high-grade pathology. About 20% (17% to 25%) of all PIRADS 3 patients biopsied will show intermediate or high-grade prostate cancer pathology.[rx] Recent studies of PIRADS 3 lesions have identified several clinical risk factors that were clearly associated with significant, higher-grade disease (Gleason score 3 + 4 = 7 and higher).[rx]

Risk Factors Identified for PIRADS 3 Lesions Including

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

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

Controversies in MRI use for men with elevated PSA levels

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

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

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

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

Prostate-Specific Membrane Antigen PET/CT Imaging (PSMA PET/CT)

• Prostate-specific membrane antigen (PSMA) based positron emission tomography (PET) correlated with computed tomography (CT) is rapidly emerging as the gold standard imaging modality for staging of intermediate and advanced prostate cancer.
• It has been suggested by the International Society of Urological Pathology, that PSMA PET/CT could potentially be used in all newly diagnosed prostate cancer patients with significant Gleason grade 4 or any Gleason grade 5 histology, PSA > 20 or clinical T3 or higher disease. [rx]

Biopsy

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

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

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

Staging

Clinical Tumor Staging

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

Pathologic Tumor Staging

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

Stages are used for prostate cancer

Stage I

Stage I prostate cancer – Cancer is found in the prostate only. The cancer is not felt during a digital rectal exam and is found by needle biopsy done for high prostate-specific antigen (PSA) level or in a sample of tissue removed during surgery for other reasons. The PSA level is less than 10 and the Grade Group is 1; OR the cancer is felt during a digital rectal exam and is found in one-half or less of one side of the prostate. The PSA level is less than 10 and the Grade Group is 1.

In stage I

• cancer is found in the prostate[rx] only. Cancer is not felt during a digital rectal exam[rx] and is found by needle biopsy[rx] (done for a high PSA[rx] level) or in a sample of tissue removed during surgery for other reasons (such as benign prostatic hyperplasia).
• The PSA level is lower than 10 and the Grade Group is 1, or is felt during a digital rectal exam and is found in one-half or less of one side of the prostate. The PSA level is lower than 10 and the Grade Group is 1.

Stage II

• In stage II, cancer is more advanced than in stage I but has not spread outside the prostate[rx]. Stage II is divided into stages IIA, IIB, and IIC.

• Stage IIA prostate cancer – Cancer is found in the prostate only. Cancer is found in one-half or less of one side of the prostate. The prostate-specific antigen (PSA) level is at least 10 but less than 20 and the Grade Group is 1; OR cancer is found in more than one-half of one side of the prostate or in both sides of the prostate. The PSA level is less than 20 and the Grade Group is 1.
• In stage IIA, cancer[rx] is found in one-half or less of one side of the prostate. The PSA[rx] level is at least 10 but lower than 20 and the Grade Group is 1 or found in more than one-half of one side of the prostate or in both sides of the prostate. The PSA level is lower than 20 and the Grade Group is 1.

Stage IIB prostate cancer. Cancer is found in the prostate only. Cancer is found in one or both sides of the prostate. The prostate-specific antigen level is less than 20 and the Grade Group is 2.

In stage IIB, cancer

• is found in one or both sides of the prostate. The PSA[rx] level is lower than 20 and the Grade Group is 2.

Stage IIC prostate cancer. Cancer is found in the prostate only. Cancer is found in one or both sides of the prostate. The prostate-specific antigen level is less than 20 and the Grade Group is 3 or 4.

In stage IIC, cancer

• is found in one or both sides of the prostate. The PSA[rx] level is lower than 20 and the Grade Group is 3 or 4.

Stage III

Stage III[rx] is divided into stages IIIA, IIIB, and IIIC.

Stage IIIA prostate cancer – Cancer is found in the prostate only. Cancer is found in one or both sides of the prostate. The prostate-specific antigen level is at least 20 and the Grade Group is 1, 2, 3, or 4.

In stage IIIA, cancer[rx] is found in one or both sides of the prostate. The PSA level is at least 20 and the Grade Group is 1, 2, 3, or 4.

Stage IIIB prostate cancer – Cancer has spread from the prostate to the seminal vesicles or to nearby tissue or organs, such as the rectum, bladder, or pelvic wall. The prostate-specific antigen can be any level and the Grade Group is 1, 2, 3, or 4.

In stage IIIB – cancer has spread from the prostate to the seminal vesicles[rx] or to nearby tissue or organs[rx], such as the rectum, bladder[rx], or pelvic wall. The PSA can be any level and the Grade Group is 1, 2, 3, or 4.

Stage IIIC prostate cancer – Cancer is found in one or both sides of the prostate and may have spread to the seminal vesicles or to nearby tissue or organs, such as the rectum, bladder, or pelvic wall. The prostate-specific antigen can be any level and the Grade Group is 5.

In stage IIIC – cancer is found in one or both sides of the prostate and may have spread to the seminal vesicles[rx] or to nearby tissue or organs, such as the rectum, bladder[rx], or pelvic wall. The PSA can be any level and the Grade Group is 5.

Stage IV

Stage IV is divided into stages IVA and IVB.

Stage IVA prostate cancer – Cancer is found in one or both sides of the prostate and may have spread to the seminal vesicles or to nearby tissue or organs, such as the rectum, bladder, or pelvic wall. Cancer has spread to nearby lymph nodes. The prostate-specific antigen can be any level and the Grade Group is 1, 2, 3, 4, or 5.

In stage IVA – cancer is found in one or both sides of the prostate and may have spread to the seminal vesicles[rx] or to nearby tissue or organs, such as the rectum, bladder, or pelvic wall. Cancer has spread to nearby lymph nodes[rx].

Stage IVB prostate cancer – Cancer has spread to other parts of the body, such as the bones or distant lymph nodes. In stage IVB, cancer has spread to other parts of the body, such as the bones or distant lymph nodes. Prostate cancer[rx] often spreads to the bones.

Testing For Evidence of Tumor Spread

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

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

Treatment / Management

Depending on the situation, each man can choose one of the following options:

• Active surveillance – The prostate is checked at regular intervals. The cancer is treated only if the tumor starts growing. This strategy is an option for what is known as “low-risk” prostate cancer. It is based on the fact that low-risk prostate cancer usually grows very slowly or doesn’t grow at all. This type of cancer often doesn’t progress even years after it was diagnosed. The advantage: Many men can avoid the side effects of treatment. The disadvantage: If the cancer does progress, that is sometimes discovered too late. Many men find the checks to be distressing as well.
• External radiotherapy – The cancer is exposed to radiation from outside of the body (through the skin) in order to destroy the cancer cells. The most common side effects include erection problems and bowel trouble such as diarrhea, unintentional bowel movements and blood in the stool (poo).
• Internal radiotherapy (brachytherapy) – The cancer is exposed to radiation from slightly radioactive “seeds” that are implanted inside the body. The side effects of brachytherapy are similar to those of external radiotherapy. Bowel problems are a little less common. There may also be problems with urination (peeing) in the first 1 to 2 years.
• Removal of the prostate gland (prostatectomy) – The prostate and cancer are surgically removed. Common side effects include urinary incontinence, erection problems and impotence.

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

Active Surveillance

• Many low-risk cases can now be followed with active surveillance. In active surveillance, patients are usually required to have regular, periodic PSA testing and at least one additional biopsy 12 to 18 months after the original diagnosis. Active surveillance is appropriate for men with low-grade prostate cancer (Gleason 3+3=6 or less with a PSA less than 20) and limited sized cancers. Genomic testing can be considered in these cases but may be most helpful when the PSA is in the 10 to 20 ng/ml range, or there is increased tumor volume.[rx]
• It is estimated that only 32% to 49% of eligible low-risk prostate cancer patients are currently on an active surveillance protocol in the United States.

Focal Ablation Therapy for Localized Prostate Cancer

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

Focal ablative therapies for localized prostate cancer are currently considered investigational in the United States.

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

Hormone Therapy

• Initial therapy with leuprolide, goserelin and similar luteinizing hormone-releasing hormone (LHRH) agonists should be preceded by anti-androgen therapy, such as bicalutamide when the PSA level is greater than 10 ng/ml to prevent any clinical response to the temporary testosterone surge that typically accompanies the initiation of hormonal therapy with these agents. This prophylactic anti-androgen therapy is not necessary with degarelix because it is a direct LHRH antagonist and there is no testosterone surge with this drug.
• The hormonal therapy is usually continued for at least one year and optimally for at least two years after radiation. Intermittent hormone therapy is another option in selected cases to minimize the side effects of sustained, very low testosterone levels. Castration levels of testosterone have historically been considered <50 ng/dL, but newer data suggest that optimal results are obtained when testosterone levels are maintained at less than 20 ng/dL.
• Patients with high volume of prostate cancer and metastases who are being started on hormonal therapy will benefit from initiating docetaxel at the same time.  There appears to be no similar survival advantage in low volume of prostate cancers with metastases.

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

Surgical Oncology

Radical Prostatectomy

• Radical prostatectomy offers the greatest potential for a definitive cure for localized prostate cancer and a significant improvement in overall survival, cancer-specific survival and the development of distant metastases. These benefits over other definitive, curative therapies are not evident before 10 years after treatment for localized disease and are most pronounced in men younger than 65 years at the time of diagnosis. Radical prostatectomy is not an appropriate therapy if the tumor is fixed to surrounding structures or there are distant metastases.[rx
• The majority of such surgeries are now being done robotically or laparoscopically. There does not appear to be much of a difference overall in side effects or survival between minimally invasive (robotic) or open surgical approaches. The experience of the surgeon appears to be the most critical factor associated with a successful outcome regardless of which technique is used.[rx]

Lymph Node Dissections

• Performing a lymph node dissection is based on the expected incidence of finding malignant involvement. In general, it can be safely omitted in selected patients with low-risk disease (smaller tumors with lower PSA levels and favorable Gleason scores).[rx]
• The optimal extent of the lymph node dissection is uncertain. A greater and more extensive lymph node dissection is obviously likely to find a larger number of positive lymph nodes. In the past, a pelvic lymph node dissection was sufficient, but it is now known that metastases will often go directly to the common iliac, paraaortic, perirectal or presacral nodes, so a more extended dissection is recommended; particularly in higher-risk disease.[rx]
• No improvement in overall longevity from lymph node dissections has been clearly demonstrated, although some men with the microscopic lymphatic disease have had prolonged survival which suggests the possibility of a benefit from the procedure.[rx]

Salvage Radiation Therapy After Radical Prostatectomy

The serum PSA should become and remain undetectable after successful radical prostatectomy surgery. If this cannot be achieved or if there are positive margins after surgery, salvage radiation therapy should be considered.[142]

• This is recommended based on the likelihood that the supplemental radiation may control the relatively small amount of cancer that might remain in the vicinity of the resected prostate. Typically, salvage radiation therapy is 60 to 70 Gy, which is substantially less than for primary definitive radiation therapy.[rx]
• Without treatment, the metastatic disease can develop from microscopic cancer remnants after radical prostate surgery in about 8 years, and overall survival averages about 10 to 13 years.[rx]
• Early data suggest that everolimus at 10 mg/day can be safe, helpful and effective when combined with salvage radiation therapy for post-prostatectomy biochemical failures or recurrences.[rx]

Cryotherapy

• Cryotherapy provides good tissue ablation and destruction, but has some complications and is very technology-dependent. An early use was delayed due to the size of the original Nitrogen probes, urethral injuries and the inability to monitor the exact location of the probes and ice-ball in real-time. These problems were solved by technological advances including the use of transrectal ultrasound to visualize the size and shape of the ice-ball, more precise freezing probe placement, use of multiple strategically placed interstitial temperature sensors to prevent over-freezing, utilizing multiple smaller probes simultaneously based on Argon gas for freezing instead of the harder to use liquid nitrogen, adding a thaw cycle to the protocol, and the standard placement of urethral warming catheters to protect the urethra from injury.[rx]
• The use of two freeze/thaw cycles instead of just one, rapid freezing to -40 C with slow thawing, and appropriate use of hormonal therapy to shrink larger prostates (greater than 60 gm) before treatment appears to improve the cancer-free results.  Hormonal therapy can help reduce prostate size but does not otherwise improve survival outcomes with cryotherapy.[rx] Focal or limited cryotherapy is a possible experimental option in selected patients.[rx]

Radiation Oncology

• The goal of radiation therapy is to provide a lethal dose of radiation to the tumor without harming the surrounding normal tissue of the bladder and rectum. No post-radiation prostate biopsies are recommended unless additional local therapy is being considered. After radiation therapy, the PSA is expected to decrease for about 18 months. Treatment failure is usually noted by a rise in PSA level of 2 ng/ml or more above the baseline level before initiation of radiation therapy.[rx]

External Beam Radiation Therapy

• Treatment fields are calculated and individualized from MRIs or CT scans, as some patients will need treatment for the seminal vesicles and/or regional lymph nodes. These other areas are included in the radiation field when there is direct evidence of tumor involvement, or the calculated likelihood of malignancy is 15% or more.[rx][rx]
• The current standard of care is to use conformal techniques, such as intensity-modulated radiation therapy (IMRT), and image-guided radiation therapy (IGRT). Such conformal techniques allow for higher dosages to be given to the prostate and tumor while not significantly increasing exposure to the surrounding tissues to minimize late side effects.[rx][rx]
• Treatment usually consists of daily exposures (5 days a week) for up to 8 weeks. This typically amounts to a minimum of 38 to 45 fractions of 1.8 to 2 Gy.  The American College of Radiology recommends a total dose of 75 to 78 Gy. (At our institution, our radiation oncologists use a total dose of 77.4 Gy.)  Doses higher than 81 Gy are not recommended due to increased risks of radiation cystitis and proctitis.[rx]

Stereotactic Ablative Radiotherapy (SABR)

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

Brachytherapy (Radioactive Seed Implants)

• Brachytherapy is another form of radiation therapy that involves surgically implanting tiny radioactive seeds into the prostate. Conceptually, this allows for a higher total dose to be delivered to the prostate without increasing exposure to surrounding structures. It also allows for optimal treatment in patients where transportation and other issues would make standard external beam therapy more difficult. Most prostates will accept from 75 to 125 seeds.[rx]
• Hormonal therapy can be used to shrink the prostate if it is too large for therapy (greater than 60 gm). Three months of hormonal therapy will decrease the size of the prostate by about 30%.[rx]
• When combined with brachytherapy, hormonal therapy has been shown to improve survival outcomes so it is usually recommended.[rx] Seeds are placed transperineally using TRUS and a template plan that has been previously worked out by a radiation therapist or physicist.[rx] Radioactive materials used include iodine 125, palladium 103, and cesium 131. Cesium has the shortest half-life.[rx]

High-Dose Rate Brachytherapy

• High-Dose Rate Brachytherapy can also be done, using hollow needles placed through the perineum which are then loaded with iridium 192 or similar. These typically are left in place for 24 to 40 hours during which time the patient is admitted to a hospital. The newer trend is to treat with only 2 fractions per day, allowing the patient to go home at night.[rx]
• External beam radiation can then be used to treat regional lymph nodes and other areas outside the prostate not adequately controlled by the seeds alone.[rx]

[stextbox id=’custom’]

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

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

[/stextbox]

Proton Beam Therapy

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

Carbon Ion Therapy

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

Treatment Selection: Radiation Therapy versus Radical Prostatectomy

• Radiation therapy and radical prostatectomy surgery are both highly effective for controlling most cases of localized prostate cancer.  Treatment selection is then based on other factors such as patient preference, co-morbidities, age, availability of high-quality therapy, and transportation issues.[190]

Medical Oncology

Aggressive Prostate Cancer

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

Castrate-Resistant Disease

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

PSMA and Choline PET Scans

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

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

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

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

• Bisphosphonates like zoledronic acid –  and rank ligand inhibitors like denosumab (Xgeva), have been shown to improve quality of life and reduce pathological fractures in CRPC patients. Unfortunately, these agents have not been shown to improve survival.  Before use of either of these agents, a dental checkup is recommended due to their association with osteonecrosis of the jaw.  They should always be used with supplemental oral calcium and Vitamin D.[rx]
• Radium Ra 223 dichloride – is a radiopharmaceutical that works particularly well on bone metastases from prostate cancer. It has been shown to improve overall survival in CRPC patients by 30% which sounds good but is only about 3 to 4 months for most recipients. Xofigo specifically targets the bone and is ineffective in visceral, soft tissue, and nodal disease.  Therefore it should be used in CRPC with bone metastases but without significant organ, soft tissue or lymph node involvement. Xofigo improves the quality of life, reduces bone fracture rates, and extends survival even if only for a relatively short time. It can be used with all other prostate cancer therapies. However, some data suggested that there may be an increased risk of fractures and deaths associated with the use of Ra-223 together with abiraterone and prednisone. [rx][rx]
• Sipuleucel-T – a prostate cancer vaccine, has been found to result in a tangible survival benefit for men with metastatic, castrate-resistant prostate cancer but it is quite expensive and provides only a relatively limited improvement in life expectancy. (Note: The drug remains available even though its manufacturer, Dendreon, has declared bankruptcy.)  It is an autologous, dendritic cell-based vaccine that targets prostatic acid phosphatase.  It is the only vaccine-based therapy currently available for prostate cancer in the U.S. but a number of others are in various stages of development. We need to develop reliable prostate cancer biomarkers to help determine which future immunotherapy will offer the most benefit for each individual patient.[rx][rx]

Life Expectancy

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

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

Palliative Care and Hospice

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

• Cancer pain related to bone metastases may be treated with bisphosphonates, rank ligand inhibitors, opioids, radiopharmaceuticals, and palliative radiation therapy.
• Spinal cord compression can be treated with steroids, surgery, or radiation therapy.
• A common mistake is failing to get palliative care and Hospice services involved early enough in the course of the disease so they can start patient assistance immediately when needed, without undue delays.[rx]

PSA Testing: The Pros and the Cons

• Prostate-Specific Antigen (PSA) is a protein produced by the prostate and is abundant in semen. Its natural function is to divide seminogelin in the semen, which helps in liquefaction. The expression of PSA is androgen-regulated.
• It was originally used as a prostatic tissue stain to help determine the etiology of tumors of unknown origin. Later, serum levels of PSA were used as a prostate cancer screening tool because serum PSA levels start to increase significantly about seven to nine years before the clinical diagnosis of malignancy.  While a good indicator of prostatic disorders, PSA elevation is not specific for cancer as it is also elevated in benign prostatic hyperplasia, infection, infarction, inflammation (prostatitis) and after prostatic manipulation.  It also cannot reliably distinguish between low risk/low-grade disease and high risk/high-grade cancers.

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

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

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

The Current USPSTF Recommendation

• For men 55 to 69 years of age, the decision regarding whether to be screened for prostate cancer by PSA should be an individual one after a full discussion about the benefits, harms, and limitations of such screening.[rx]
• Routine PSA screenings are not recommended in men 70 years or over, based on the conclusion that definitive treatment of localized cancers for most older men has minimal effect on overall survival while adding significant treatment side effects and morbidities to many.
• Many professional organizations now have guidelines and recommendations regarding PSA screening for prostate cancer. Most include a recommendation for an informed discussion with patients about the benefits and potential risks of screenings, biopsies, definitive therapy, and possible overtreatment.

Prostate Cancer Screening: The Pros and Cons

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

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

Against PSA Screenings

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

In Favor of PSA Screenings

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

Recommended General Guide to PSA Testing

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

Summary of Genomic Prostate Cancer Tests (Beyond PSA)

Pre-biopsy

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

Post-biopsy

• A patient with a negative initial tissue biopsy being considered for a repeat prostatic biopsy can best be further analyzed and risk-stratified by tissue-based gene assay, the “4K” test or PCA3.
• Patients with low grade or intermediate grade disease being considered for either active surveillance or definitive therapy would benefit most from either genomic test.
• Men on active surveillance can be tracked and followed with genomic testing or serial PCA3 testing in addition to standard PSA levels.
• Patients who are post-radiation therapy or who were diagnosed with prostate cancer after TURP surgery can be tracked with the genomic tests.

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

References