Prostate Cancer

Most cancers today are found by screening with serum PSA levels (and sometimes DRE). Screening recommendations can vary, but screening is commonly done annually in men > 50 years old and is sometimes begun earlier for men at high risk (eg, those with a family history of prostate cancer, Black men). Screening is not usually recommended for men with a life expectancy < 10 to 15 years.

Abnormal findings are further investigated based on clinician and patient preferences. Multiparametric MRI can detect suspect lesions, and various urine and blood tests may help determine the need for prostate biopsy.

It is still not certain whether screening decreases morbidity; decreases in mortality appear likely (1), but the number needed to screen is high. It remains unclear if 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 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 (2, 3). As a result, in 2017, the United States Preventive Services Task Force (USPSTF) reconsidered their 2012 recommendation against screening for prostate cancer (Level D) with a possible benefit (Level C) in men less than 70 years of age. Based on recent data (4), the decrease in prostate cancer-specific mortality associated with screening appears likely, but the number needed to screen is high.

The current USPSTF recommendation is that for men aged 55 to 69 years, the decision to undergo periodic prostate-specific antigen (PSA)–based screening for prostate cancer should be an individual one after discussing the potential benefits and harms of screening with a clinician (4). 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 or prostate manipulation (catheter, cystoscopy, prostate biopsy). Rarely, other activities such as sexual activity or extreme bicycle riding falsely elevate PSA.

A level of ≥ 4 ng/mL (4 micrograms [mcg]/L) is often 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 (4 to 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 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 are 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). Similarly, PSA density (PSA relative to prostate volume) can help guide need for biopsy; biopsy should be considered if values are ≥ 0.15 (or sometimes ≥ 0.10 ng/mL).

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 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, metastatic or high-grade localized prostate cancer, a strong family history of prostate cancer, or a known family history of BRCA1/2 mutations/Lynch syndrome/hereditary breast and ovarian cancer.

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 the tumor and the better 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 Gleason Grade Group is a newer score to help communicate this to patients, and also to simplify pathologic grading. This new scoring system was accepted by the World Health Organization (WHO) in 2016:

Grade Group 1 = Gleason score 6 (3+3)

Grade Group 2 = Gleason score 7 (3+4)

Grade Group 3 = Gleason score 7 (4+3)

Grade Group 4 = Gleason score 8

Grade Group 5 = Gleason score 9 and 10

Gleason Grade Group, 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) or MRI of the prostate 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 current guidelines (1) now suggest that PSMA-PET and that PSMA-PET/CT or PSMA-PET/MRI can be effective first-line imaging studies (instead of conventional imaging studies) for intermediate or high-risk patients.

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); it may also be slightly elevated after vigorous prostatic massage and in the presence of 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.

Risk of cancer spread can be estimated by tumor stage, Gleason score (Gleason Grade Group), and PSA level:

• Low risk: Stage ≤ T2a, Gleason score = 6 (Gleason Grade Group 1), and PSA level ≤ 10 ng/mL (10 mcg/L)

• Intermediate risk: Stage T2b-c, Gleason score = 7 (Gleason Grade Group 2-3), or PSA level ≥ 10 (10 mcg/L) and ≤ 20 ng/mL (20 mcg/L)

• High risk: Stage ≥ T3, Gleason score ≥ 8 (Gleason Grade Group 4-5), or PSA ≥ 20 ng/mL (20 mcg/L)

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.

1. 1. de Vos II, Meertens A, Hogenhout R, et al: A detailed evaluation of the effect of prostate-specific antigen-based screening on morbidity and mortality of prostate cancer: 21-year follow-up results of the Rotterdam section of the European Randomised Study of Screening for Prostate Cancer. Eur Urol 84(4):426-434, 2023. doi: 10.1016/j.eururo.2023.03.016

2. 2. European Randomized Study of Screening for Prostate Cancer. Accessed September 10, 2023.

3. 3. Shoag JE, Mittal S, Hu JC: Reevaluating PSA testing rates in the PLCO trial. N Engl J Med 374(18):1795-1796, 2016. doi: 10.1056/NEJMc1515131

4. 4. U.S. Preventive Services Task Force: Prostate cancer: Screening. Final recommendation statement. Accessed September 6, 2023.

Active surveillance is appropriate for many asymptomatic patients 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 older 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 < 75 years old with a life expectancy of > 10 to 15 years and a tumor confined to the prostate. Prostatectomy is appropriate for some older men, based on life expectancy, coexisting disorders, and ability to tolerate surgery and anesthesia. Prostatectomy was historically done through an incision in the lower abdomen. Now, most prostatectomies are done via a robot-assisted laparoscopic approach that minimizes blood loss and hospital stay but has not been shown to alter morbidity or mortality. Complications of radical prostatectomy include urinary incontinence (which is severe 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.

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 external radiation therapy such as proton therapy cost more, an expense that may not be justifiable given that the benefits in men with prostate cancer have not been 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 (2) also supports the use of radiation to the prostate in men with low-volume metastatic disease, often called oligometastatic disease, commonly defined as less than 3 to 5 metastatic sites. Recent advances in prostate cancer radiation therapy include the use of fiducial markers placed around the prostate to improve targeting. Hydrogel spacers can be placed by transrectal needle placement to help reduce rectal toxicity. The hydrogel spacers resorb with time. Hypofractionation is an evolving concept in radiation treatment, in which the total dose of radiation is divided into large doses and treatments are given once a day or less often. Hypofractionated radiation therapy is given over a shorter period of time (fewer days or weeks) than standard radiation therapy.

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.

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 United States but may be used if radiation therapy is unsuccessful.

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 more widely available in the United States. 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 or low-risk cancer with individual tumors that can be treated by focal therapy. Several other investigational therapies to treat focal lesions are under study, such as laser ablation and catheter electroporation.

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 for periods varying from 6 months to 2 to 3 years).

If cancer has spread beyond the prostate gland, cure is unlikely; systemic treatment aimed at decreasing or limiting tumor extent is usually given (3).

testosterone level more rapidly than LHRH agonists. LHRH agonists and LHRH antagonists usually reduce serum testosterone

All androgen-deprivation treatments cause loss of libido and erectile dysfunction and may cause hot flushes

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 [1.74 nmol/L]) 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 testosteronetestosterone suppression include

• Radium-233 (which emits alpha radiation, recently found to prolong survival as well as prevent complications due to bone metastases in men with CRPC)

• External beam radiation therapy (EBRT)

• Lutetium Lu 177 vipivotide tetraxetan, which specifically targets a molecule on the surface of prostate cancer cells and is given with a PSMA-positive PET/CT scan.

To help treat and prevent complications due to bone metastases

1. 1. Hamdy FC, Donovan JL, Lane JA, et al: 10-year outcomes after monitoring, surgery, or radiotherapy for localized prostate cancer. N Engl Med 375(15):1415-1424, 2016. doi: 10.1056/NEJMoa1606220

2. 2. Parker CC, James ND, Brawley CD, et al: Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): A randomised controlled phase 3 trial. Lancet 392(10162):2353-2366, 2018. doi: 10.1016/S0140-6736(18)32486-3

3. 3. Posdzich P, Darr C, Hilser T, et al: Metastatic prostate cancer—A review of current treatment options and promising new approaches. Cancers 15(2):461, 2023. https://doi.org/10.3390/cancers15020461