39-17: Prostate Cancer

Prostate cancer is the most common noncutaneous cancer and the second leading cause of cancer-related death in American men with an estimated 174,650 new prostate cancer diagnoses and 31,620 prostate cancer deaths in 2019. The clinical incidence, however, does not match the prevalence of the disease since more than 40% of men over age 50 years are found to have prostatic carcinoma at autopsy. Further, its prevalence increases with age with 30% of men aged 60–69 years and 67% of men aged 80–89 years harboring the disease at autopsy. Most of these occult cancers are small and contained within the prostate gland with few representing regional or metastatic disease. Although the global prevalence of prostatic cancer at autopsy is relatively consistent, the clinical incidence varies considerably (high in North America and European countries, intermediate in South America, and low in the Far East), suggesting that environmental or dietary differences among populations may be important for prostatic cancer growth. A 50-year-old American man has a lifetime risk of 40% for latent cancer, a 16% risk for developing clinically apparent cancer, and a 2.9% risk of death due to prostatic cancer. African-American race, family history of prostatic cancer, and history of high dietary fat intake are risk factors for prostate cancer.

A. Symptoms and Signs

Prostate cancer may manifest as discrete nodules or areas of induration within the prostate on a DRE. However, most prostate cancers are currently detected because of elevations in serum PSA (not DRE findings).

Patients rarely present with signs of urinary retention or neurologic symptoms from epidural metastases and cord compression. Obstructive voiding symptoms are most often due to benign prostatic hyperplasia, which occurs in the same age group. Nevertheless, large or locally extensive prostatic cancers can cause obstructive voiding symptoms. Lymph node metastases can lead to lower extremity lymphedema. Because the axial skeleton is the most common site of metastases, patients may present with back pain or pathologic fractures.

B. Laboratory Findings

1. Serum tumor markers

PSA is a glycoprotein produced only by prostatic cells, either benign or malignant. The serum level is typically low and correlates with the total volume of prostate tissue and tends to increase with age. Measurement of serum PSA is useful in detecting and staging prostate cancer, monitoring response to treatment, and identifying recurrence before it becomes clinically evident. As a screening test, PSA is elevated (greater than 4.0 ng/mL [4.0 mcg/L]) in 10–15% of men. Prostate cancer will be diagnosed in approximately 18–30% of men with PSA 4.1–10 ng/mL (4.1–10 mcg/L) and 50–70% of men with PSA greater than 10 ng/mL (10 mcg/L). However, no PSA threshold excludes the diagnosis of prostate cancer.

In untreated patients with prostate cancer, the level of PSA correlates with the volume and stage of disease. Patients with PSA levels less than 10 ng/mL (10 mcg/L) usually have localized and therefore potentially curable cancers, while those with PSA levels in excess of 40 ng/mL (40 mcg/L) are more likely to have advanced disease (seminal vesicle invasion, lymph node involvement, or occult distant metastases). Approximately 98% of patients with metastatic prostate cancer will have an elevated PSA level. However, there are rare cancers that are localized despite substantial elevations in PSA. Therefore, initial treatment decisions cannot be made on the basis of PSA testing alone. A rising PSA after therapy is usually consistent with progressive disease, either locally recurrent or metastatic.

2. Miscellaneous laboratory testing

Patients with urinary retention or with ureteral obstruction due to loco-regionally advanced prostate cancers may present with elevations in blood urea nitrogen or serum creatinine. Patients with bony metastases may have elevations in serum alkaline phosphatase or calcium. Laboratory and clinical evidence of disseminated intravascular coagulation can occur in patients with advanced prostate cancers.

3. Prostate biopsy

Transrectal ultrasound-guided biopsy is the standard method for detection of prostate cancer. The use of a spring-loaded, 18-gauge biopsy needle has allowed transrectal biopsy to be performed with minimal patient discomfort and morbidity. Local anesthesia is routinely used and increases the tolerability of the procedure. Rising rates of post-biopsy infection/sepsis have led to increasing utilization of transperineal biopsies. The specimen preserves glandular architecture and permits accurate grading. Prostate biopsy specimens are taken from the apex, mid-portion, and base in men who have an abnormal DRE or an elevated serum PSA, or both. Extended-pattern biopsies, including a total of at least 10 biopsies, are associated with improved cancer detection and risk stratification of patients with newly diagnosed disease. In addition, suspicious hypoechoic prostatic lesions seen on transrectal ultrasound may be targeted for biopsy. Patients with abnormalities of the seminal vesicles can have these structures specifically biopsied to identify local tumor invasion.

C. Imaging

Use of staging imaging should be tailored to the likelihood of advanced disease in newly diagnosed cases. Asymptomatic patients with well to moderately differentiated cancers, thought to be localized to the prostate on DRE and transrectal ultrasonography and associated with modest elevations of PSA (ie, less than 10 ng/mL [10 mcg/L]), need no further imaging. CT of the abdomen and pelvis and radionuclide (99-technetium) bone scans are generally the first-line staging studies performed, when indicated, to assess for nodal and bony metastases, respectively.

MRI allows for evaluation of the prostate as well as regional lymph nodes. The positive predictive value for detection of both capsular penetration and seminal vesicle invasion is similar for transrectal ultrasound and MRI, although newer multi-parametric MRI techniques may better stage patients considering treatment or, alternatively, active surveillance. Additionally, there is a growing role for multi-parametric MRI in prostate cancer diagnosis, particularly among men with previous negative prostate biopsies, to evaluate for suspicious prostatic lesions. Such lesions may then be sampled via MR-Fusion or MRI-guided biopsy. Such an approach may improve not only overall cancer detection but discovery of clinically relevant disease, and its use in routine clinical practice has increased and continues to evolve.

Conventional radionuclide (99-technetium) bone scans are superior to conventional plain skeletal radiographs in detecting bony metastases. Prostate cancer bony metastases tend to be multiple and most commonly occur in the axial skeleton. Men with more advanced local lesions, symptoms of metastases (eg, bone pain), high-grade disease, or elevations in PSA greater than 20 ng/mL (20 mcg/L) should undergo radionuclide bone scan. PET (eg, ¹⁸F-sodium fluoride [¹⁸F-NaF] PET) and ¹⁸F-NaF PET/CT hybrid imaging are more sensitive than conventional bone scans. However, a high frequency of abnormal scans with ¹⁸F-NaF PET/CT resulting from degenerative joint disease has limited their usefulness. Fluciclovine (Axumin) PET imaging has been approved for suspected cancer recurrence based on elevated PSA after prior treatment. PSMA (prostate-specific membrane antigen) PET, using small molecules radiotracers targeting PSMA (eg, ¹⁸F-DCFBC (N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-4-¹⁸F-fluorobenzyl-L-cysteine) has shown significant promise as a next-generation imaging method and may replace traditional imaging modalities in the future. Intravenous urography and cystoscopy are not routinely needed to evaluate patients with prostate cancer.

Despite application of modern, sophisticated techniques, understaging of prostate cancer occurs in at least 20% of patients.

D. Genetic Testing

The role of genetics in prostate cancer diagnosis and management is evolving. A family history of prostate cancer increases the risk of prostate cancer. Additionally, prostate cancer has been associated with several hereditary cancer syndromes (eg, Lynch syndrome, hereditary breast and ovarian cancer syndrome, etc.) with approximately 11% of prostate cancer patients with at least one additional primary cancer carrying germline mutations. Consequently, some patients with prostate cancer and their families may have elevated risk for other cancers. Further, data suggest that some germline mutations, such as BRCA1/2, are associated with lower PSA at diagnosis and increased risk of progression and death; approximately 12% of patients with metastatic prostate cancer have germline mutations in homologous DNA repair genes. Finally, germline mutations in DNA repair genes can have implications for treatment and, as a result, play a role in personalized treatment.

Patients with prostate cancer should have a thorough review of their family history and those with a concerning family history should be referred for genetic counselling and possible testing. Additionally, patients with high-risk disease or metastatic disease should undergo genetic evaluation as well.

The impact of prostate cancer screening on mortality remains controversial. The screening tests currently available include DRE, PSA testing, and transrectal ultrasound. Prostate cancer detection rates using DRE alone vary from 1.5% to 7%, but unfortunately, most of these cancers are advanced (stage T3 or greater). Transrectal ultrasound should not be used as a first-line screening tool due to its expense, low specificity, and minimal improvement in detection rate versus the combined use of DRE and PSA testing.

PSA testing increases the detection rate of prostate cancers compared with DRE. Approximately 2–2.5% of men older than 50 years of age will be found to have prostate cancer using PSA testing compared with a rate of approximately 1.5% using DRE alone. PSA is not specific for cancer, and there is considerable overlap of values with men with benign prostate hyperplasia. The sensitivity, specificity, and positive predictive value of PSA and DRE are listed in Table 39–8. PSA-detected cancers are more likely to be localized compared with those detected by DRE alone. The Prostate Cancer Prevention Trial provided data demonstrating a significant risk of prostate cancer even in men with PSA less than 4.0 ng/mL (4.0 mcg/L) (Table 39–9) and a web-based calculator has been developed to estimate the risk of harboring both prostate cancer and high-grade cancer (http://riskcalc.org/PBCG).

To improve the performance of PSA as a screening test, several investigators have developed alternative methods for its use. These include establishment of age- and race-specific reference ranges, measurement of free serum and protein-bound levels of PSA (percent free PSA), and calculation of changes in PSA over time (PSA velocity). Generally, men with PSA free fractions exceeding 25% are unlikely to have prostate cancer, whereas those with free fractions less than 10% have an approximately 50% chance of having prostate cancer. Newer tests, including the Prostate Health Index (PHI) and 4kscore (https://4kscore.com), may better identify not only men at greater risk for prostate cancer but those with more aggressive disease. The frequency of PSA testing also remains a matter of debate. The traditional yearly screening approach may not be the most efficient; rather, earlier PSA testing at younger age may allow less frequent testing later as well as provide information regarding PSA velocity. Men with PSA above the age-based median when tested between 40 and 60 years are at significantly increased risk for subsequent cancer detection over 25 years. Men aged 40–50 with PSA below 0.6 ng/mL (0.6 mcg/L) and aged 50–60 with PSA below 0.71 ng/mL (0.71 mcg/L) may require less frequent PSA tests. In addition, men with PSA velocity greater than 0.35 ng/mL (0.35 mcg/L) per year measured 10–15 years before diagnosis had significantly worse cancer-specific survival compared with those with lower PSA velocity. The NCCN guidelines (https://www.nccn.org/professionals/physician_gls/f_guidelines.asp) for prostate cancer early detection incorporate many of these factors(eFigure 39–9). The European Association of Urology (EAU) recommends offering a baseline serum PSA to all men aged 40–45 years and subsequently initiating a risk-adapted strategy.

Two large, randomized trials have evaluated the benefit of PSA screening for early detection of prostate cancer. In the US Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, no mortality benefit was observed after combined screening with PSA testing and DRE during 15-year follow-up. Although screening resulted in a 12% increase in prostate cancer detection, the cancer-specific mortality rate was similar in the screening and control arms (2.55 and 2.44 deaths per 10,000 person-years, respectively). However, an estimated 86% of control patients received at least one screening PSA test and 46% of control patients received yearly PSA screening (versus 99% and 84%, respectively for the intervention arm) during the trial. Other criticisms of the negative PLCO study include use of a relatively high PSA threshold (4.0 ng/mL [4.0 mcg/L]) and significant screening of men in the 3 years prior to enrolling in the trial (44%). Conversely, the European Randomized Study of Screening for Prostate Cancer (ERSPC) trial demonstrated a significant 20% reduction in prostate cancer mortality with an absolute reduction of 1.75 deaths per 1000 men screened at 16 years. The number of men needed to be invited for screening to prevent one prostate cancer death was 570 at 16 years compared with 742 at 13 years, while the number of prostate cancers needing to be diagnosed to prevent one prostate cancer death was reduced from 26 to 18, underscoring the importance of adequate long-term follow-up for prostate cancer.

In 2018, the USPSTF issued a revised (Grade C) recommendation for men aged 55 to 69 years that the decision to undergo periodic PSA–based screening should be an individual one. Before deciding about screening, men should discuss its potential benefits and harms with their clinician, incorporating their own values and preferences in the decision. The revised recommendation acknowledges that, while screening offers some men a small potential benefit of reducing the chance of dying from prostate cancer, many other men will experience potential harms from screening. These include false-positive results that require additional testing and possible prostate biopsy; overdiagnosis and overtreatment; and treatment complications, such as incontinence and erectile dysfunction. In determining whether screening is appropriate in individual cases, the individual patient’s family history, race/ethnicity, comorbid medical conditions, values about the benefits and harms of screening and treatment-specific outcomes, and other health needs should be considered. Clinicians should not screen men who do not express a preference for screening. For men age 70 years and older, the USPSTF recommends against PSA-based screening (Grade D recommendation).

The majority of prostate cancers are adenocarcinomas. Most arise in the peripheral zone of the prostate, though a small percentage arise in the central (5–10%) and transition zones (20%) of the gland. Pathologists utilize the Gleason grading system whereby a “primary” grade is applied to the architectural pattern of malignant glands occupying the largest area of the specimen and a “secondary” grade is assigned to the next largest area of cancer. Grading is based on architectural rather than histologic criteria, and five “grades” are possible. Adding the score of the primary and secondary grades gives a Gleason score from 2 to 10. Gleason score correlates with tumor volume, pathologic stage, and prognosis (eFigure 39–10). A simplified five-grade group system has been introduced by the International Society of Urological Pathologists; it is based on Gleason score and has gained clinical traction and may help patients better understand their disease.

A. General Measures

The optimal management of localized prostate cancer remains controversial owing to the plethora of treatment options, side effects of the various options, and indolent nature of many prostate cancers. These factors have contributed to uncertainty regarding a definitive survival benefit of treating localized prostate cancer. To help guide treatment decision making, patients are risk stratified (very low, low, intermediate, and high-risk) according to their PSA level at diagnosis, DRE, and prostate cancer grade (Gleason score). Additionally, patients should have an assessment of life expectancy prior to treatment decision-making since all patients with low-risk disease and many with intermediate-risk disease with less than 10-year life expectancy will not benefit from treatment.

B. Active Surveillance

The goal of active surveillance is to avoid treatment in men who may never require it while recognizing and definitively treating men harboring higher-risk disease in order to balance cancer risk with the morbidity of treatment. Treatment decisions are made based on stage, PSA, and cancer grade (Gleason score) as well as the age and health of the patient. Active surveillance alone may be effective management for appropriately selected patients, typically those with low PSA, small volume, well-differentiated cancers, and life expectancy less than 10–15 years. For such patients, active surveillance involves serial PSA levels, DREs, and periodic prostate biopsies to reassess grade and extent of cancer. Endpoints for intervention in patients on active surveillance, particularly PSA changes, have not been clearly defined and surveillance regimens remain an active area of research. Nonetheless, they are increasingly accepted by patients and clinicians with contemporary series demonstrating freedom from definitive treatment in greater than half of patients at 5 years, and risk of developing metastases and suffering cancer-specific death in less than 3% and 2%, respectively, at 10 years. Active surveillance, which is distinguished from mere observation (watchful waiting), is featured prominently in the NCCN and EAU guidelines and is the preferred management in most men with very low risk prostate cancer. This approach is increasingly accepted and incorporated in routine clinical practice.

C. Radical Prostatectomy

During radical prostatectomy, the seminal vesicles, prostate, and ampullae of the vas deferens are removed. Refinements in technique have allowed preservation of urinary continence in most patients and erectile function in selected patients. Radical prostatectomy can be performed via open retropubic, transperineal, or laparoscopic (with or without robotic assistance) surgery. Local recurrence is uncommon after radical prostatectomy and related to pathologic stage. Organ-confined cancers rarely recur; however, cancers with adverse pathologic features (capsular penetration, seminal vesicle invasion) are associated with higher local (10–25%) and distant (20–50%) relapse rates.

Ideal candidates for radical prostatectomy include healthy patients with stages T1 and T2 prostate cancers. Patients with advanced local tumors (T4) or lymph node metastases are rarely candidates for prostatectomy alone, although the surgery is sometimes used in combination with hormonal therapy and postoperative radiation therapy for select high-risk patients.

D. Radiation Therapy

Radiation can be delivered by a variety of techniques including use of external beam radiotherapy and transperineal implantation of radioisotopes. Morbidity is limited, and the survival of patients with localized cancers (T1, T2, and selected T3) approaches 65% at 10 years. As with surgery, the likelihood of local failure correlates with technique and cancer characteristics. The likelihood of a positive prostate biopsy more than 18 months after radiation varies between 20% and 60%. Patients with local recurrence are at an increased risk of cancer progression and cancer death compared with those who have negative biopsies. Ambiguous target definitions, inadequate radiation doses, and understaging of the cancer may be responsible for the failure noted in some series. Newer techniques of radiation (implantation, conformal therapy using three-dimensional reconstruction of CT-based tumor volumes, heavy particle, charged particle, and heavy charged particle) may improve local control rates. Three-dimensional conformal radiation delivers a higher dose because of improved targeting and appears to be associated with greater efficacy as well as lower likelihood of adverse side effects compared with previous techniques. Brachytherapy—the implantation of permanent or temporary radioactive sources (palladium, iodine, or iridium) into the prostate—can be used as monotherapy in those with low-grade or low-volume malignancies or combined with external beam radiation in patients with higher-grade or higher-volume disease. The PSA may rise after brachytherapy because of prostate inflammation and necrosis. This transient elevation (PSA bounce) should not be mistaken for recurrence and may occur up to 20 months after treatment.

E. Focal Therapy

To reduce the morbidity of localized prostate cancer treatment, there has been a growing interest in focal therapy. Focal therapy delivers energy to the prostate, destroying the tumor(s) and a margin of normal prostate tissue while avoiding collateral damage to the neurovascular bundles, external urinary sphincter, bladder, and rectum. To date, several energy sources (cryotherapy, high intensity focused ultrasound, lasers, etc) have been evaluated and several others are under development. The multifocal nature and the difficulty of localizing the prostate cancer with contemporary imaging techniques combined with the prolonged disease course, lack of clearly defined endpoints, and randomized prospective data have limited the widespread adoption of focal therapies as well as a clear understanding of whom are the ideal candidates.

F. Localized Disease

Although selected patients may be candidates for active surveillance based on age or health and evidence of small-volume or well-differentiated cancers, most men with an anticipated life expectancy of longer than 10 years should be considered for treatment. Newly introduced genomic tests may provide important information to help guide treatment decisions. Both radiation therapy and radical prostatectomy result in acceptable levels of local control. A large, prospective, randomized trial compared watchful waiting with radical prostatectomy in 695 men with clinically localized and well-differentiated to moderately differentiated cancers. Radical prostatectomy significantly reduced disease-specific mortality, overall mortality, and risks of metastasis and local progression. The relative reduction in the risk of death at 23 years was 0.56 in the prostatectomy group, with the number needed to treat to avert one death (NNT) = 8 patients; the benefit was largest in men younger than age 65 years (relative risk [RR] = 0.45) and with intermediate-risk prostate cancer (RR = 0.38). Surgery also reduced the risk of metastases in older men (RR = 0.68). This trial accrued patients in Sweden between 1989 and 1999, thus likely including patients with greater cancer burden compared with that in patients currently diagnosed using PSA screening. Nevertheless, the survival benefit in the trials was still observed in men with low-risk prostate cancer. The ProtecT trial randomized 1632 men with clinically localized prostate cancer to either active monitoring, surgery, or radiotherapy. At 10 years follow-up, prostate-cancer-specific mortality was low in all three groups and differences were not significant, though both surgery and radiotherapy were associated with lower rates of disease progression and metastases (P < 0.001 and P = 0.004, respectively).

G. Locally and Regionally Advanced Disease

Patients with advanced pathologic stage or positive surgical margins are at an increased risk for local and distant tumor relapse. Such patients are candidates for adjuvant therapy (radiation for positive margins and seminal vesicle invasion or androgen deprivation and/or radiation for lymph node metastases). Two randomized clinical trials (EORTC 22911 and SWOG 8794) have demonstrated improved progression-free and metastasis-free survival with early radiotherapy in these men, and subsequent analysis of SWOG 8794 showed improved overall survival in men receiving adjuvant radiation therapy. Evidence suggests that salvage radiotherapy after radical prostatectomy, within 2 years of PSA relapse, increases prostate cancer-specific survival in men with shorter PSA doubling time (less than 6 months).

Those with locally extensive cancers, including seminal vesicle and bladder neck invasion, are at increased risk for both local and distant relapse despite conventional therapy. A variety of investigational regimens are being tested in an effort to improve cancer outcomes in such patients. Combination therapy (androgen deprivation combined with surgery or irradiation), newer forms of irradiation, and hormonal therapy alone are being tested, as is neoadjuvant and adjuvant chemotherapy. Neoadjuvant and adjuvant androgen deprivation therapy combined with external beam radiation therapy have demonstrated improved survival compared with external beam radiation therapy alone for patients with intermediate- and high-risk disease.

H. Metastatic Disease

Since death due to prostate carcinoma is almost invariably the result of failure to control metastatic disease, research has emphasized efforts to improve control of distant disease. Most prostate carcinomas are hormone dependent and approximately 70–80% of men with metastatic prostate carcinoma will respond to various forms of androgen deprivation. Androgen deprivation therapy may be effective at several levels along the pituitary–gonadal axis using a variety of methods or agents (Table 39–10). Use of luteinizing hormone-releasing hormone (LHRH) agonists (leuprolide, goserelin) achieves medical castration without orchiectomy and is the most common method of reducing testosterone levels. A single LHRH antagonist (degarelix) is FDA approved and has no short-term testosterone “flare” associated with LHRH agonists. Because of its rapid onset of action, ketoconazole should be considered in patients with advanced prostate cancer who present with spinal cord compression, bilateral ureteral obstruction, or disseminated intravascular coagulation. Although testosterone is the major circulating androgen, the adrenal gland secretes the androgens dehydroepiandrosterone, dehydroepiandrosterone sulfate, and androstenedione. This led to the development of abiraterone acetate (an inhibitor of CYP17, a key enzyme in androgen synthesis) to block both testicular and adrenal androgens. Nonsteroidal antiandrogen agents act by competitively binding the receptor for dihydrotestosterone, the intracellular androgen responsible for prostate cell growth and development. In addition to immediate side effects of androgen deprivation (sexual dysfunction and hot flashes), the chronic suppression of testosterone leads to osteoporosis and risk of fractures, cardiovascular disease and diabetes mellitus, and decreased muscle and increased fat. Bisphosphonates can prevent osteoporosis associated with androgen deprivation, decrease bone pain from metastases, and reduce skeletal-related events. Denosumab, a RANK ligand inhibitor, is approved for the prevention of skeletal-related events in patients with bone metastases from prostate cancer and also appears to delay the development of these metastases in patients with castration-resistant prostate cancer. In addition, enzalutamide definitively improves metastasis-free survival in men with nonmetastatic castrate-resistant prostate cancer and rapidly rising PSAs.

The management of advanced prostate cancer is rapidly evolving. Contemporary management consists of initiating androgen deprivation therapy with orchiectomy, LHRH agonist, or LHRH antagonist. A meta-analysis compared using an LHRH agonist or orchiectomy alone with an LHRH agonist or orchiectomy plus an antiandrogen agent; results showed little benefit of combination therapy. However, patients at risk for disease-related symptoms (bone pain, obstructive voiding symptoms) should receive concurrent antiandrogens due to the initial elevation of serum testosterone that accompanies LHRH agonists. For patients with elevated PSAs only (indicating recurrent, but nonmetastatic, cancer), nonsteroidal antiandrogen agents may be useful. Further androgen manipulations, initiation of cytotoxic chemotherapy, and local therapy (eg, radiation) is defined by the cancer’s androgen sensitivity status. For patients with hormone-sensitive metastatic prostate cancer, the addition of systemic cytotoxic chemotherapy with docetaxol to androgen deprivation therapy results in improved survival compared to androgen deprivation therapy alone, particularly in men with high-volume disease. Similarly, the addition, of abiraterone acetate plus prednisone to androgen deprivation therapy, results in superior survival compared to androgen deprivation therapy alone. Benefit of local therapy, in the form of external radiation, was demonstrated by STAMPEDE in which patients with low-volume metastatic disease who received external radiotherapy plus standard of care systemic therapy had improved overall survival compared to those who received only standard of care systemic therapy.

Patients with castrate-resistant disease or prostate cancer that demonstrates rising PSA or progression of disease despite castrate levels of serum testosterone (less than 50 ng/dL) should continue their LHRH agonist/antagonist regimen. Additional treatment options are stratified based on the presence of metastatic disease. Patients with nonmetastatic castrate-resistant disease and long PSA doubling time (longer than10 months) can simply be observed due to their relatively indolent disease. Conversely, nonmetastatic castrate-resistant patients with short doubling times (10 months or less) have demonstrated improved metastasis-free survival with the addition of the potent nonsteroidal androgen receptor antagonists enzalutamide, apalutamide, and darolutamide to androgen deprivation therapy. For patients with metastatic castrate-resistant prostate cancer, docetaxol was the first cytotoxic chemotherapy agent to improve survival. Enzalutamide and abiraterone improve overall survival in men with metastatic castrate prostate cancer in both the docetaxol naïve and non-naïve setting. Cabazitaxel is a second-line taxane chemotherapy that improves overall survival in men who have received docetaxel. Sipuleucel-T, an autologous cellular immunotherapy, is FDA approved in asymptomatic or minimally symptomatic men with metastatic castration-resistant prostate cancer. Radium-223 dichloride is approved for the treatment of men with castration-resistant, symptomatic bone metastases, with significant improvements in both overall survival and time to skeletal-related events (eg, fractures and spinal cord compression). Finally, patients who have undergone a genetics evaluation and are found to have specific germline or somatic mutations may benefit from personalized treatment strategies.

The likelihood of success of active surveillance or treatment can be predicted using risk assessment tools that usually combine stage, grade, PSA level, and number and extent of positive prostate biopsies. Several web-based tools are available (eg, https://www.mskcc.org/nomograms/prostate). Widely used nomograms include the Kattan nomogram and the CAPRA nomogram. CAPRA uses serum PSA, Gleason score, clinical stage, percent positive biopsies, and patient age in a point system to risk stratify and predict the likelihood of PSA recurrence 3 and 5 years after radical prostatectomy (Tables 39–11 and 39–12) as well as metastasis and prostate cancer-specific and overall survival. The CAPRA nomogram has been validated on large multicenter and international radical prostatectomy and radiation-treated cohorts.

The patterns of prostate cancer progression have been well defined. Small and well-differentiated cancers (Gleason grade 3) are usually confined within the prostate, whereas large-volume (greater than 4 mL) or poorly differentiated (Gleason grades 4 and 5) cancers are more often locally extensive or metastatic to regional lymph nodes or bone. Penetration of the prostate capsule by cancer is common and occurs along perineural spaces. Seminal vesicle invasion is associated with a high likelihood of regional or distant disease and disease recurrence. The most common sites of lymph node metastases are the obturator and internal iliac lymph node chains and of distant metastases, the axial skeleton.

• Refer all patients to a urologist for management of localized disease or for active surveillance.

• For metastatic disease, medical oncology should be consulted for consideration of systemic treatments.

• Active surveillance may be appropriate in selected patients with very low-volume, low-grade prostate cancer.

• Localized disease may be managed by active surveillance, surgery, or radiation therapy.

• Locally extensive, regionally advanced, and metastatic disease often require multimodal treatment strategies.