Adenocarcinoma of the prostate is the most common nondermatologic cancer in men > 50 in the US. In the US, about 174,650 new cases and about 31,620 deaths (2019 estimates) occur each year (1). Incidence increases with each decade of life; autopsy studies show prostate cancer in 15 to 60% of men aged 60 to 90 years old, with incidence increasing with age. The lifetime risk of being diagnosed with prostate cancer is 1 in 6. Median age at diagnosis is 72, and > 75% of prostate cancers are diagnosed in men > 65. Risk is highest for black men.
Sarcoma of the prostate is rare, occurring primarily in children. Undifferentiated prostate cancer, squamous cell carcinoma, and ductal transitional carcinoma also occur infrequently. Prostatic intraepithelial neoplasia is considered a possible premalignant histologic change.
Hormonal influences contribute to the course of adenocarcinoma but almost certainly not to other types of prostate cancer.
Prostate cancer usually progresses slowly and rarely causes symptoms until advanced. In advanced disease, hematuria and symptoms of bladder outlet obstruction (eg, straining, hesitancy, weak or intermittent urine stream, a sense of incomplete emptying, terminal dribbling) may appear. Bone pain, pathologic fractures, or spinal cord compression may result from osteoblastic metastases to bone (commonly pelvis, ribs, vertebral bodies).
Screening by digital rectal examination (DRE) and prostate-specific antigen (PSA)
Assessment of abnormalities by transrectal needle biopsy
Grading by histology
Staging by CT and bone scanning
Sometimes stony-hard induration or nodules are palpable during DRE, but the examination is often normal; induration and nodularity suggest cancer but must be differentiated from granulomatous prostatitis, prostate calculi, and other prostate disorders. Extension of induration to the seminal vesicles and lateral fixation of the gland suggest locally advanced prostate cancer. Prostate cancers detected by DRE tend to be large, and > 50% extend through the capsule.
Diagnosis of prostate cancer requires histologic confirmation, most commonly by transrectal ultrasound (TRUS)–guided needle biopsy, which can be done in an office with use of local anesthesia. Hypoechoic areas are more likely to represent cancer. Occasionally, prostate cancer is diagnosed incidentally in tissue removed during surgery for benign prostatic hyperplasia (BPH). Multiparametric MRI is under investigation as a way to determine which patients need a biopsy, but its use is not widespread. Multiparametric MRI is useful for follow-up of men with a negative initial biopsy or following men who are on active surveillance.
Most cancers today are found by screening with serum prostate-specific antigen (PSA) levels (and sometimes DRE). Screening is commonly done annually in men > 50 years old but is sometimes begun earlier for men at high risk (eg, those with a family history of prostate cancer and black men). Screening is not usually recommended for men with a life expectancy < 10 to 15 years. Abnormal findings are further investigated with TRUS-guided needle biopsy.
It is still not certain whether screening decreases morbidity or mortality or whether any gains resulting from screening outweigh the decreases in quality of life resulting from treatment of asymptomatic cancers. Screening is recommended by some professional organizations and discouraged by others. A recent pooled analysis of ERSPC (European Randomized Study of Screening for Prostate Cancer) and PLCO (Prostate, Lung, Colorectal, and Ovarian) trial data suggests that screening in both trials demonstrated a reduction in prostate cancer mortality when controlling for differences in screening intensity despite the high rate of contamination in the control arm of PLCO (1,2). As a result, in 2017, the United States Preventive Services Task force reconsidered their 2012 recommendation completely against screening for prostate cancer (Level D) with a possible benefit (Level C) in men less than 70 years of age. Most patients with newly diagnosed prostate cancers have a normal DRE, and serum PSA measurement is not ideal as a screening test. Although PSA is elevated in 25 to 92% of patients with prostate cancer (depending on tumor volume), it also is moderately elevated in 30 to 50% of patients with benign prostatic hyperplasia (depending on prostate size and degree of obstruction), in some smokers, and for several weeks after prostatitis.
A level of ≥3 ng/mL (3 micrograms [mcg]/L) is considered an indication for biopsy in men > 50 years old. Although very high levels are significant (suggesting extracapsular extension of the tumor or metastases) and likelihood of cancer increases with increasing PSA levels, there is no cut-off below which there is no risk.
In asymptomatic patients, positive predictive value for cancer is 67% for PSA > 10 ng/mL (10 mcg/L) and 25% for PSA 4 to 10 ng/mL (10 mcg/L); recent evidence indicates a 15% prevalence of cancer in men≥ 55 years old with PSA < 4 ng/mL (4 mcg/L) and a 10% incidence with PSA between 0.6 and 1.0 ng/mL (0.6 and 1.0 mcg/L). However, cancer present in men with lower levels tends to be smaller (often < 1 mL) and of lower grade, although high-grade cancer (Gleason score 7 to 10) can be present at any level of PSA; perhaps 15% of cancers manifesting with PSA < 4 ng/mL (4 mcg/L) are high grade. Although it appears that a cut-off of 4 ng/mL (4 mcg/L) will miss some potentially serious cancers, the cost and morbidity resulting from the increased number of biopsies necessary to find them is unclear.
The decision whether to biopsy may be helped by other PSA-related factors, even in the absence of a family history of prostate cancer. For example, the rate of change in PSA (PSA velocity) should be < 0.75 ng/mL/yr (0.75 mcg/L/yr; lower in younger patients). Biopsy is usually recommended for PSA velocities > 0.75 ng/mL/yr (0.75 mcg/L/yr).
Assays that determine the free-to-total PSA ratio and complex PSA are more tumor specific than standard total PSA measurements and may reduce the frequency of biopsies in patients without cancer. Prostate cancer is associated with less free PSA; no standard cut-off has been established, but generally, levels < 10 to 20% warrant biopsy. Other isoforms of PSA and new markers for prostate cancer are being studied. None of these other uses of PSA answers all of the concerns about possibly triggering too many biopsies. Many new tests (eg, urinary prostate cancer antigen 3 [PCA-3], Prostate Health Index, 4Kscore, urinary SelectMDX, and others) are available commercially and may be useful aids in screening decisions.
Clinicians should discuss the risks and benefits of PSA testing with patients. Some patients prefer to eradicate cancer at all costs no matter how low the potential for progression and possible metastasis and may prefer annual PSA testing. Others may value quality of life highly and can accept some uncertainty; they may prefer less frequent (or no) PSA testing.
Men with newly diagnosed prostate cancer should be offered germline testing and genetic counseling if they have intraductal histology, a strong family history of prostate cancer, or a known family history of BRCA1/2 mutations/Lynch syndrome.
Grading, based on the resemblance of tumor architecture to normal glandular structure, helps define the aggressiveness of the tumor. Grading takes into account histologic heterogeneity in the tumor. The Gleason score is commonly used. The most prevalent pattern and the next most prevalent pattern are each assigned a grade of 1 to 5, and the two grades are added to produce a total score. Most experts consider a score ≤ 6 to be well differentiated, 7 moderately differentiated, and 8 to 10 poorly differentiated. The lower the score, the less aggressive and invasive is the tumor and the better is the prognosis. For localized tumors, the Gleason score helps predict the likelihood of capsular penetration, seminal vesicle invasion, and spread to lymph nodes. Gleason grades 1 and 2 have now been eliminated; as a result, the lowest score possible (3 + 3) is 6. However, a Gleason score of 6 does not sound low on a scale previously ranging from 2 to 10.
The grade group is a newer score to help communicate this to patients, and also to simplify pathological grading. This new scoring system was accepted by the World Health Organization (WHO) in 2016:
Grade group 1 = Gleason 3+3
Grade group 2 = Gleason 3+4
Grade group 3 = Gleason 4+3
Grade group 4 = Gleason 8
Grade group 5 = Gleason 9 and 10
Gleason score, clinical stage, and PSA level together (using tables or nomograms) predict pathologic stage and prognosis better than any of them alone.
Prostate cancer is staged to define extent of the tumor (see tables AJCC/TNM Staging of Prostate Cancer and TNM Definitions for Prostate Cancer ). Transrectal ultrasonography (TRUS) may provide information for staging, particularly about capsular penetration and seminal vesicle invasion. Patients with clinical stage T1c to T2a tumors, low Gleason score (≤ 7), and PSA < 10 ng/mL (10 mcg/L) usually get no additional staging tests before proceeding to treatment. Radionuclide bone scans are rarely helpful for finding bone metastases (they are frequently abnormal because of the trauma of arthritic changes) until the PSA is > 20 ng/mL (20 mcg/L) or unless the Gleason score is high (ie, ≥ 8 or [4 +3]). CT (or MRI) of the abdomen and pelvis is commonly done to assess pelvic and retroperitoneal lymph nodes if the Gleason score is 8 to 10 and the PSA is > 10 ng/mL (10 mcg/L), or if the PSA is > 20 ng/mL (20 mcg/L) with any Gleason score. Suspect lymph nodes can be further evaluated by using needle biopsy. An MRI may also help define the local extent of the tumor in patients with locally advanced prostate cancer (stage T3). The role of PSMA (prostate-specific membrane antigen) and fluciclovine F18 PET scanning for staging is evolving but is certainly not needed for early, localized disease.
Elevated serum acid phosphatase—especially the enzymatic assay—correlates well with the presence of metastases, particularly in lymph nodes. However, this enzyme may also be elevated in benign prostatic hyperplasia (BPH)—and is slightly elevated after vigorous prostatic massage—multiple myeloma, Gaucher disease, and hemolytic anemia. It is rarely used today to guide treatment or to follow patients after treatment, especially because its value when done as a radioimmune assay (the way it is usually done) has not been established. Reverse transcriptase–polymerase chain reaction assays for circulating prostate cancer cells are being studied as staging and prognostic tools.
AJCC/TNM* Staging of Prostate Cancer
TNM Definitions for Prostate Cancer
Risk of cancer spread is considered low if
T2b tumor, Gleason score 7, or PSA > 10 ng/mL (10 mcg/L) are considered intermediate risk by most experts. T2c tumor, Gleason score ≥ 8, or PSA > 20 ng/mL (20 mcg/L; or 2 intermediate risk factors) are generally high risk.
Risk of cancer spread can be estimated by tumor stage, Gleason score, and PSA level:
Both acid phosphatase and PSA levels decrease after treatment and increase with recurrence, but PSA is the most sensitive marker for monitoring cancer progression and response to treatment and has virtually replaced acid phosphatase for this purpose.
Shoag JE: Reevaluating PSA testing rates in the PLCO trial. N Engl J Med 374:1795-1796, May 5, 2016. doi: 10.1056/NEJMc1515131.
Prognosis for most patients with prostate cancer, especially when it is localized or regional, is very good. Life expectancy for elderly men with prostate cancer may differ little from age-matched men without prostate cancer, depending on their age and comorbidities. For many patients, long-term local control, or even cure, is possible. Potential for cure, even when cancer is clinically localized, depends on the tumor’s grade and stage. Without early treatment, patients with high-grade, poorly differentiated cancer have a poor prognosis. Undifferentiated prostate cancer, squamous cell carcinoma, and ductal transitional carcinoma respond poorly to conventional therapies. Metastatic cancer has no cure. Median life expectancy with metastatic disease is 1 to 3 years, although some patients live for many years.
Treatment is guided by prostate-specific antigen (PSA) level, grade and stage of tumor, patient age, coexisting disorders, and life expectancy. The goal of therapy can be
Most patients, regardless of age, prefer definitive therapy if cancer is life-threatening and potentially curable. However, therapy is palliative rather than definitive if cancer has spread outside the prostate because cure is unlikely. Watchful waiting can be used for men unlikely to benefit from definitive therapy (eg, because of older age or comorbidity); these patients are treated with palliative measures if symptoms develop.
Active surveillance is appropriate for many asymptomatic patients > 70 with low-risk, or possibly even intermediate-risk, localized prostate cancer or if life-limiting disorders coexist; in these patients, risk of death due to other causes is greater than that due to prostate cancer. This approach requires periodic digital rectal examination (DRE), PSA measurement, and monitoring of symptoms. In healthy younger men with low-risk cancer, active surveillance also requires periodic repeat biopsies. The optimal interval between biopsies has not been established, but most experts agree that it should be ≥ 1 year, possibly less frequently if biopsies have been repeatedly negative. If the cancer progresses, treatment is required. About 30% of patients undergoing active surveillance eventually require therapy. In elderly men, active surveillance results in the same overall survival rate as prostatectomy; however, patients who had surgery have a significantly lower risk of distant metastases and disease-specific mortality.
Local therapy is aimed at curing prostate cancer and may thus also be called definitive therapy. Radical prostatectomy, some forms of radiation therapy, and cryotherapy are the primary options. Careful counseling concerning the risks and benefits of these treatments and considerations of patient-specific characteristics (age, health, tumor characteristics) are critical in decision making.
Radical prostatectomy (removal of prostate with seminal vesicles and regional lymph nodes) is probably best for patients < 70 years old with a tumor confined to the prostate. Prostatectomy is appropriate for some elderly men, based on life expectancy, coexisting disorders, and ability to tolerate surgery and anesthesia. Prostatectomy is done through an incision in the lower abdomen. More recently, a robot-assisted laparoscopic approach has been developed that minimizes blood loss and hospital stay but has not been shown to alter morbidity or mortality. Complications include urinary incontinence (in about 5 to 10%), bladder neck contracture or urethral stricture (in about 7 to 20%), erectile dysfunction (in about 30 to 100%—heavily dependent on age and current function), and rectal injury (in 1 to 2%). Nerve-sparing radical prostatectomy reduces the likelihood of erectile dysfunction but cannot always be done, depending on tumor stage and location.
Cryotherapy (destruction of prostate cancer cells by freezing with cryoprobes, followed by thawing) is less well established; long-term outcomes are unknown. Adverse effects include bladder outlet obstruction, urinary incontinence, erectile dysfunction, and rectal pain or injury. Cryotherapy is not commonly the therapy of choice in the US but may be used if radiation therapy is unsuccessful.
Standard external beam radiation therapy usually delivers 70 grays (Gy) in 7 weeks, but this technique has been supplanted by conformal 3-dimensional radiation therapy and by intensity-modulated radiation therapy (IMRT), which safely deliver doses approaching 80 Gy to the prostate; data indicate that the rate of local control is higher, especially for high-risk patients. Some decrease in erectile function occurs in at least 40%. Other adverse effects include radiation proctitis, cystitis, diarrhea, fatigue, and possibly urethral strictures, particularly in patients with a prior history of transurethral resection of the prostate. Results with external-beam radiation therapy, radical prostatectomy, and active monitoring were shown to be comparable at a median of 10 years after treatment for localized prostate cancer, as demonstrated in the ProtecT trial (1). Newer forms of radiation therapy such as proton therapy are more costly, and the benefits in men with prostate cancer are not clearly established. External beam radiation therapy also has a role if cancer is left after radical prostatectomy or if the PSA level begins to rise after surgery and no metastasis can be found. Recent evidence also supports the use of radiation to the prostate in men with low volume metastatic disease.
Brachytherapy involves the implantation of radioactive seeds into the prostate through the perineum. These seeds emit a burst of radiation over a finite period (usually 3 to 6 months) and are then inert. Research protocols are examining whether high-quality implants used as monotherapy or implants plus external beam radiation therapy are superior for intermediate-risk patients. Brachytherapy also decreases erectile function, although onset may be delayed and patients may be more responsive to phosphodiesterase type 5 inhibitors than patients whose neurovascular bundles are resected or injured during surgery. Urinary frequency, urgency, and, less often, retention are common but usually subside over time. Other adverse effects include increased bowel movements; rectal urgency, bleeding, or ulceration; and prostatorectal fistulas.
HIFU (high-intensity focused ultrasound) uses intense ultrasound energy administered transrectally to ablate prostate tissue. It has been used for many years in Europe and Canada and has recently become available in the US. The role of this technology in the management of prostate cancer is evolving; presently, it appears to be best suited for radiation-recurrent prostate cancer.
If cancer localized to the prostate is high risk, various therapies may need to be combined (eg, for high-risk prostate cancer treated with external beam radiation, addition of hormonal therapy).
If cancer has spread beyond the prostate gland, cure is unlikely; systemic treatment aimed at decreasing or limiting tumor extent is usually given.
Patients with a locally advanced tumor or metastases may benefit from androgen deprivation by castration, either surgically with bilateral orchiectomy or medically with luteinizing hormone-releasing hormone (LHRH) agonists, such as leuprolide, goserelin, triptorelin, histrelin, and buserelin, with or without radiation therapy. LHRH antagonists (eg, degarelix) can also lower the testosterone level, usually more rapidly than LHRH agonists. LHRH agonists and LHRH antagonists usually reduce serum testosterone almost as much as bilateral orchiectomy. The LATITUDE and STAMPEDE trials (2,3) showed that adding abiraterone and prednisone (or prednisolone) to standard therapy prolonged survival in patients with hormone-sensitive metastatic prostate cancer. If patients have high volume, hormone-sensitive metastatic cancer, first-line chemotherapy with docetaxel may also be considered instead of abiraterone (4).
All androgen-deprivation treatments cause loss of libido and erectile dysfunction and may cause hot flushes. LHRH agonists may cause PSA levels to increase temporarily. Some patients benefit from adding antiandrogens (eg, flutamide, bicalutamide, nilutamide, cyproterone acetate [not available in US]) for total androgen blockade. Combined androgen blockade usually refers to LHRH agonists plus antiandrogens, but its benefits appear minimally better than those of an LHRH agonist (or degarelix or orchiectomy) alone. Another approach is intermittent androgen blockade, which purports to delay emergence of androgen-independent prostate cancer and helps to limit some adverse effects of androgen deprivation. Total androgen ablation is given until PSA levels are reduced (usually to undetectable levels), then stopped. Treatment is started again when PSA levels rise above a certain threshold, although the ideal threshold is not yet defined. The optimal schedules for treatment and time-off treatment have not been determined and vary widely among practitioners.
Androgen deprivation may impair quality of life significantly (eg, self-image, attitude toward the cancer and its treatment, energy levels) and cause osteoporosis, anemia, and loss of muscle mass with long-term treatment. Exogenous estrogens are rarely used because they have a risk of cardiovascular and thromboembolic complications.
Hormonal therapy is effective in metastatic prostate cancer for a limited amount of time. Cancer that progresses (indicated by an increasing PSA level) despite a testosterone level consistent with castration (< 50 ng/dL) is classified as castrate-resistant prostate cancer. Castrate-resistant prostate cancer (CRPC) can be further classified as M0 (nonmetastatic) CRPC or M1 (metastatic) prostate cancer. An increasing PSA despite low testosterone and absence of lesions on CT or bone scan is nonmetastatic prostate cancer. Risk of metastases is high. Apalutamide (5) and enzalutamide (6) are now available and can slow progression from M0 to M1 CRPC. Treatments that prolong survival in metastatic CRPC (many identified since 2010) include
Docetaxel (a taxane chemotherapy drug)
Sipuleucel-T (a patient-derived vaccine designed to induce immunity against prostate cancer cells)
Abiraterone (which blocks androgen synthesis in the tumor as well as in the testes and adrenal glands)
Enzalutamide (which blocks binding of androgens to their receptors)
Cabazitaxel (a taxane chemotherapy drug that may have activity in tumors that have become resistant to docetaxel)
Radium-233 (which emits alpha radiation, recently found to prolong survival as well as prevent complications due to bone metastases in men with CRPC)
PARP (poly [ADP-ribose]) inhibitors appear active in mCRPC patients with BRCA1/2 mutations
Some data suggest that sipuleucel-T should be used at the earliest sign of CRPC. In general, treatments for castrate-resistant prostate cancer are being tried earlier during the course of prostate cancer and are now showing benefit in hormone-sensitive metastatic prostate cancer. However, choice of treatment may involve many factors, and few data may be available to help predict results; thus patient education and shared decision-making are recommended.
To help treat and prevent complications due to bone metastases (eg, pathologic fractures, pain, spinal cord compression), an osteoclast inhibitor (eg, denosumab, zoledronic acid) can be used. Traditional external beam radiation therapy has been used to treat individual bone metastases.
Hamdy FC, Donovan JL, Lane JA, et al: 10-year outcomes after monitoring, surgery, or radiotherapy for localized prostate cancer. N Engl J Med 375:1415-1424, 2016. doi: 10.1056/NEJMoa1606220.
Fizazi K, Tran N, Fein L, et al: Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. N Engl J Med 377(4):352-360, 2017. doi: 10.1056/NEJMoa1704174.
James ND, de Bono JS, Spears MR, et al: Abiraterone for prostate cancer not previously treated with hormone therapy. N Engl J Med 377(4):338-351, 2017. doi: 10.1056/NEJMoa1702900.
Sweeney CJ, Chen Y-H, Carducci M, et al: Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med 373(8):737-746, 2015. doi: 10.1056/NEJMoa1503747.
Saad F, Cella D, Basch E, et al: Effect of apalutamide on health-related quality of life in patients with non-metastatic castration-resistant prostate cancer: An analysis of the SPARTAN randomised, placebo-controlled, phase 3 trial. Lancet Oncol 19(10):1404-1416, 2018.
Hussain M, Fizazi K, Saad F, et al: Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer. N Engl J Med Jun 28;378(26):2465-2474, 2018.
Prostate cancer develops very commonly with aging but is not always clinically important.
Symptoms develop only after the cancer has enlarged enough to be more difficult to cure.
Complications due to bone metastases are common and consequential.
Diagnose prostate cancer by transrectal ultrasound-guided needle biopsy.
Discuss advantages and disadvantages of screening in men > age 50 with life expectancy > 10 or 15 years.
For localized prostate cancer, consider local, curative treatment (eg, prostatectomy, radiation therapy) and active surveillance.
For cancer that has spread beyond the prostate, consider systemic treatments (eg, various hormonal therapies, sipuleucel-T, taxane chemotherapy).
For bone metastases, consider radium-233 and osteoclast inhibitors.