Prostate Cancer 

Updated: Aug 06, 2019
Author: Gerald W Chodak, MD; Chief Editor: Edward David Kim, MD, FACS 

Overview

Practice Essentials

Prostate cancer is the most common noncutaneous cancer in men in the United States. An estimated one in six white men and one in five African-American men will be diagnosed with prostate cancer in their lifetime, with the likelihood increasing with age.

The image below depicts the anatomy of the male pelvis and genitourinary tract.

Management of localized prostate cancer. This diag Management of localized prostate cancer. This diagram depicts the relevant anatomy of the male pelvis and genitourinary tract.

See Prostate Cancer: Diagnosis and Staging, a Critical Images slideshow, to help determine the best diagnostic approach for this potentially deadly disease.

See Advanced Prostate Cancer: Signs of Metastatic Disease, a Critical Images slideshow, for help identifying the signs of metastatic disease.

Signs and symptoms

Currently, most cases of prostate cancer are identified by screening in asymptomatic men. Symptoms of prostate cancer include the following:

  • Urinary complaints or retention
  • Back pain
  • Hematuria

However, such symptoms are often from diseases other than prostate cancer (eg, urinary complaints from benign prostatic hyperplasia [BPH]). Physical examination alone cannot reliably differentiate benign prostatic disease from cancer.

Findings in patients with advanced disease may include the following:

  • Cancer cachexia
  • Bony tenderness
  • Lower-extremity lymphedema or deep venous thrombosis
  • Adenopathy
  • Overdistended bladder due to outlet obstruction

See Presentation for more detail.

Diagnosis

Elevated prostate-specific antigen (PSA) level

  • No PSA level guarantees the absence of prostate cancer.

  • The risk of disease increases as the PSA level increases, from about 8% with PSA levels of ≤1.0 ng/mL[1] to about 25% with PSA levels of 4-10 ng/mL and over 50% for levels over 10 ng/mL[1]

Abnormal digital rectal examination (DRE) findings

  • DRE is examiner-dependent, and serial examinations over time are best

  • Most patients diagnosed with prostate cancer have normal DRE results but abnormal PSA readings

Biopsy

  • Biopsy establishes the diagnosis
  • False-negative results often occur, so multiple biopsies may be needed before prostate cancer is detected

Screening

The American Cancer Society (ACS) recommends that men decide whether to be screened for prostate cancer based on a discussion with their health care provider about the uncertainties, risks, and potential benefits of screening.[2]

The recommended age for starting screening is as follows:

  • 50 years of age for men at average risk who have at least a 10-year life expectancy
  • 40 or 45 years of age for African Americans and men who have had a first-degree relative diagnosed with prostate cancer before age 65 years
  • 40 years of age for men with several first-degree relatives who had prostate cancer at an early age

A guideline from the US Preventive Services Task Force (USPSTF), issued in May 2018, advises that in asymptomatic men aged 55 to 69 years, the decision to undergo periodic PSA-based screening for prostate cancer should be individualized and should include discussion with the clinician of the potential benefits and harms of screening (grade C recommendation). The USPSTF recommends against PSA screening in men aged 70 and older (grade D recommendation).[3]

See Workup for more detail.

Management

Localized prostate cancer

Standard treatments for clinically localized prostate cancer include the following:

  • Radical prostatectomy
  • Radiation therapy
  • Active surveillance
  • Androgen deprivation therapy (ADT)

Metastatic prostate cancer

Metastatic prostate cancer is rarely curable, and management of these cases typically involves the following:

  • Therapy directed at relief of particular symptoms (eg, palliation of pain)
  • Attempts to slow further progression of disease

See Treatment and Medication for more detail.

Background

Prostate cancer is the most common noncutaneous cancer in men. Although prostate cancer can be a slow-growing cancer, thousands of men die of the disease each year. It is the second most common cause of cancer death in males (see Epidemiology).

Marked variation in rates of prostate cancer among populations in different parts of the world suggests the involvement of genetic factors. Familial predisposition also occurs. Environmental factors, notably diet, are also important (see Etiology).

Currently, the majority of prostate cancers are identified in patients who are asymptomatic. Diagnosis in such cases is based on abnormalities in a screening prostate-specific antigen (PSA) level or findings on digital rectal examination (see Presentation and Workup).

Screening for prostate cancer is a controversial topic, in large part because of the conflicting findings from prospective, randomized studies (see Workup). Education about the risks and benefits is important to help men make informed decisions regarding screening and, in those diagnosed with prostate cancer, the various treatment options (see Treatment). (See the image below.)

The standard approach for grading prostate cancer The standard approach for grading prostate cancer depends on a Gleason score, which is based on pathologic evaluation of a prostatectomy specimen and is commonly estimated from prostate biopsy tissue. Prostate cancer patterns are assigned a number from 1-5; the score is created by adding the most common pattern and the highest-grade patterns. Courtesy of Wikimedia Commons.

See also the following Medscape articles:

Anatomy

The prostate lies below the bladder and encompasses the prostatic urethra. It is surrounded by a capsule and is separated from the rectum by a layer of fascia termed the Denonvilliers aponeurosis. (See the image below.)

Management of localized prostate cancer. This diag Management of localized prostate cancer. This diagram depicts the relevant anatomy of the male pelvis and genitourinary tract.

The inferior vesical artery, which is derived from the internal iliac artery, supplies blood to the base of the bladder and prostate. The capsular branches of the inferior vesical artery help to identify the pelvic plexus arising from the S2-4 and T10-12 nerve roots. The neurovascular bundle lies on either side of the prostate on the rectum. It is derived from the pelvic plexus and is important for erectile function.

Pathophysiology

Prostate cancer develops when the rates of cell division and cell death are no longer equal, leading to uncontrolled tumor growth. Following the initial transformation event, further mutations of a multitude of genes, including the genes for p53 and retinoblastoma, can lead to tumor progression and metastasis. Most prostate cancers (95%) are adenocarcinomas.

Approximately 4% of cases of prostate cancer have transitional cell morphology and are thought to arise from the urothelial lining of the prostatic urethra. The few cases that have neuroendocrine morphology are believed to arise from the neuroendocrine stem cells normally present in the prostate or from aberrant differentiation programs during cell transformation.

Squamous cell carcinomas constitute less than 1% of all prostate carcinomas. In many cases, prostate carcinomas with squamous differentiation arise after radiation or hormone treatment.

Of prostate cancer cases, 70% arise in the peripheral zone, 15-20% arise in the central zone, and 10-15% arise in the transitional zone. Most prostate cancers are multifocal, with synchronous involvement of multiple zones of the prostate, which may be due to clonal and nonclonal tumors.

Local spread and metastasis

When these cancers are locally invasive, the transitional-zone tumors spread to the bladder neck, while the peripheral-zone tumors extend into the ejaculatory ducts and seminal vesicles. Penetration through the prostatic capsule and along the perineural or vascular spaces occurs relatively late.

The mechanism for distant metastasis is poorly understood. The cancer spreads to bone early, often without significant lymphadenopathy. Currently, 2 predominant theories have been proposed for spread: the mechanical theory and the seed-and-soil theory.

The mechanical theory attributes metastasis to direct spread through the lymphatics and venous spaces into the lower lumbar spine. Advocates of the seed-and-soil theory, however, believe that tissue factors that allow for preferential growth in certain tissues, such as bone, must be present. Lung, liver, and adrenal metastases have also been documented. Specific tissue growth factors and extracellular matrices are possible examples.

The doubling time in early stage disease is variable. In the majority of cases, doubling time is longer than 4 years. Only a small percentage of prostate cancers double in less than 2 years. Doubling time tends to accelerate as the tumor grows and becomes more aggressive. Larger tumors usually have a higher Gleason grade and a faster doubling time.

The natural history of clinically localized disease varies, with lower-grade tumors having a more indolent course and some high-grade lesions progressing to metastatic disease with relative rapidity. Given the typically slow progression of localized disease, several studies have examined the strategy of active surveillance in selected groups of patients.[4]

Etiology

Marked variation in rates of prostate cancer among populations in different parts of the world suggests the involvement of genetic factors. For example, the risk of prostate cancer is particularly high in people of sub-Saharan African ancestry, while the risk tends to be low in many Asian populations. Increased risk in Asians who have migrated to the United States suggests the importance of environmental factors, notably diet.[5] Familial predisposition also occurs.

Prostate cancer is also found during autopsies performed in men with other causes of death. The rate of this latent or autopsy cancer is much greater than that of clinical cancer. In fact, it may be as high as 80% by age 80 years. Interestingly, the prevalence of the latent or autopsy form of the disease is similar worldwide. Together with migration studies, this suggests that environmental factors play a significant promoting role in the development of a clinical cancer from a latent precursor.

Genetics

Studies in different populations have identified several variants in the 8q24 region on chromosome 8 that are associated with increased risk of prostate cancer.[6] Gene alterations on chromosome 1, chromosome 17, and the X chromosome have been found in some patients with a family history of prostate cancer. The HPC1 (hereditary prostate cancer 1) gene and the PCAP (predisposing for cancer of the prostate) gene are on chromosome 1, while the human prostate cancer gene is on the X chromosome.

Genetic studies suggest that a strong familial predisposition may be responsible for as many as 5-10% of prostate cancer cases. Men with a family history of prostate cancer have a higher risk of developing prostate cancer and are also likely to present 6-7 years earlier. Several reports have suggested a shared familial risk (inherited or environmental) for prostate and breast cancer. BRCA-2 mutations increase the risk for prostate cancer that is more aggressive and develops at a younger age.[5]

A study by Ewing et al found that germline mutations in HOXB13 may be a risk factor for prostate cancer. HOXB13 is a homeobox transcription factor gene that is important in prostate development. The G84E variant of this gene, while rare, is significantly more common in men with early onset, familial prostate cancer than in those with late-onset, nonfamilial prostate cancer.[7]

An examination of cancer histories of 198 Lynch syndrome families, including probands and their first- through fourth-degree relatives, found that men with Lynch syndrome have a two-fold increased risk of prostate cancer compared to the general population. Of the 4127 men involved in the study, 97 had prostate cancer. Median age at diagnosis was 65, with 11.5% diagnosed before age 50. The cumulative risk of prostate cancer for men with Lynch syndrome was 6.3% at age 60 and 30% at age 80, vs a population risk of 2.6% and 17.8%, respectively.[8]

Diet

Diet may play a role in the development of prostate cancer. Epidemiologic studies have suggested a variety of dietary factors that may be associated with the disease, particularly fat intake and obesity. See Prostate Cancer and Nutrition for a complete discussion of this topic.

Hormones

Hormonal causes of prostate cancer have also been postulated. Androgen ablation causes a regression of prostate cancer. In addition, as indirect evidence of hormonal causes, eunuchs do not develop adenocarcinoma of the prostate.

Hsing and Comstock performed a large study comparing patients with prostate cancer with controls and found no significant difference in levels of testosterone, dihydrotestosterone, prolactin, follicle-stimulating hormone, or estrone. However, elevated levels of luteinizing hormone and of testosterone:dihydrotestosterone ratios were associated with mildly increased risk.[9]

5-alpha reductase

The Prostate Cancer Prevention Trial studied the prevalence of prostate cancer in a control group and in a group given a 5-alpha-reductase inhibitor (finasteride).[10] While the 5-alpha reductase inhibitor appeared to decrease the prevalence of tumors, some of those that did arise appeared histologically more aggressive. Only long-term follow-up of these patients will determine whether this more aggressive histology accurately reflects the underlying biology of these tumors or whether it is an artifact of the treatment.

A similar study was performed with dutasteride, a molecule that blocks not only D1 but also D2 receptors in the prostate. The investigators found a 22.8% relative risk reduction in the development of prostate cancer, but the study did not fully refute the concern that more aggressive cancers could arise in treated patients.

Possibly for this reason, when the concept of 5-alpha reductase for chemoprevention of prostate cancer was brought before the US Food and Drug Administration (FDA) in 2010, the FDA did not approve the drugs for this indication.[11, 12] Indeed, on June 9, 2011 the FDA announced revisions to the prescribing information for 5-alpha reductase inhibitors to include a warning regarding an increased incidence of high-grade prostate cancer in men taking dutasteride or finasteride compared with placebo.[13]

Epidemiology

Internationally, the incidence of prostate cancer varies by more than 50-fold, with the highest rates being in North America, Australia, and northern and central Europe and the lowest rates being in southeastern and south-central Asia and northern Africa.[5]

Occurrence in the United States

In the United States, prostate cancer is the most common noncutaneous cancer in men. An estimated one in six white men and one in five African American men will be diagnosed with prostate cancer in their lifetime, with the likelihood increasing with age. The American Cancer Society estimates that 174,650 new cases of prostate cancer will be diagnosed in 2019.[5] Prostate cancer is rarely diagnosed in men younger than 40 years, and it is uncommon in men younger than 50 years.

Between 1989 and 1992, incidence rates of prostate cancer increased dramatically in the United States, probably because of earlier diagnoses in asymptomatic men were being made as a result of the increased use of serum PSA testing. In addition, the incidence of organ-confined disease at diagnosis has increased because PSA testing and standard digital rectal examination are performed. Since 1992, incidence rates have declined markedly, decreasing from over 230 per 100,000 population to less than 120 per 100,000 population in 2014.[5, 14]

A review of almost 800,000 cases of prostate cancer diagnosed from 2004–2013 found that although the incidence of low-risk prostate cancer decreased from 2007-2013 to 37% less than that of 2004, the annual incidence of metastatic prostate cancer during those years increased to 72% more than that of 2004. The increase in metastatic prostate cancer was greatest (92%) in men aged 55–69 years.[15]

Racial demographics

Prevalence rates of prostate cancer remain significantly higher in African-American men than in white men, while the prevalence in Hispanic men is similar to that of white men. The prevalence in men of Asian origin is lower than in whites. Although mortality rates are continuing to decline among white and African-American men, mortality rates in African-American men remain more than twice as high as in any other racial group.[5]

Hispanic men and African-American men present with more advanced disease.[16] Studies have found that young African-American men have testosterone levels that are 15% higher than in young white men. Furthermore, evidence indicates that 5-alpha reductase may be more active in African Americans than in whites, implying that hormonal differences may play a role. However, the independent contribution of race is difficult to isolate from the effects of health-care access, income, education, and insurance status.

Prognosis

The most important and established indicators of prognosis for prostate carcinoma include the Gleason grade, the extent of tumor volume, and the presence of capsular penetration or margin positivity at the time of prostatectomy. High-grade prostate cancer, particularly the percentage of Gleason grades 4 and 5 that are present, is associated with adverse pathologic findings and disease progression. Conversely, low-grade prostate tumors are infrequently dangerous.

In a review of 11,521 patients treated with radical prostatectomy at 4 academic centers from 1987 to 2005, Eggener et al reported an overall 15-year prostate cancer–specific mortality rate of 7%. High-grade cancer and seminal vesicle invasion were the prime determinants of prostate cancer–specific mortality.[17]

Despite the steady decline in the incidence of newly diagnosed metastatic prostate cancer and microscopic lymph node metastasis, from 20% in the 1970s to 3.4% in the 1990s, the risk of extra-prostatic disease in patients with clinically localized disease remains high at approximately 30%. Depending on the PSA value, pathologic stage, and histologic grade of the tumor, approximately 30% of patients with clinically localized prostate cancer are estimated to progress despite initial treatment with intent to cure.

The Cancer of the Prostate Risk Assessment (CAPRA) score for predicting prognosis is calculated on the basis of the following:

  • PSA level
  • Gleason score
  • Percentage of biopsy cores positive for cancer
  • Clinical tumor stage
  • Age at diagnosis

In a study of 10,627 men with clinically localized prostate cancer who underwent primary radical prostatectomy, radiation therapy, androgen deprivation monotherapy, or watchful waiting/active surveillance, and had at least 6 months of follow-up after treatment, Cooperberg et al found that the CAPRA score was accurate for predicting metastases, cancer-specific mortality, and all-cause mortality.[18]

In a retrospective study of patients who underwent radical retropubic prostatectomies, researchers found an association between an opioid-sparing approach to anesthesia and reductions in prostate cancer progression and overall mortality. The investigators reviewed 1642 procedures performed with general anesthesia and 1642 prostatectomies performed with an opioid-sparing approach (general anesthesia supplemented with a neuraxial block), in patients diagnosed with prostate cancer between 1991 and 2005. Median follow-up in the study was 9 years.[19, 20] Results indicated that the risk of systemic progression of prostate cancer was almost 3 times greater and the mortality risk was 30% higher in the general anesthesia patients than in patients anesthetized with an opioid-sparing approach.[19, 20]

In a multivariate analysis, biochemical recurrence and disease-specific mortality were much higher in men who were smokers at the time of diagnosis versus those who had never smoked. A higher number of pack-years was associated with significantly increased risk for prostate cancer mortality but not for biochemical recurrence. Men who had quit smoking 10 years prior to diagnosis—or who had quit more recently but smoked for < 20 pack-years—had prostate cancer–mortality risks much like those of men who had never smoked.[21]

In a retrospective study at Johns Hopkins Medical Center in Baltimore, a greater connection between cigarette smoking and risk of prostate cancer recurrence was identified in men who had been treated with radical prostatectomy.[22] Without prospective studies, however, these relationships remain hypothetical.

In an analysis of two large cohort studies of health professionals, researchers found a significantly increased risk for melanoma among men with prostate cancer. In 42,372 participants in the Health Professionals’ Follow-Up Study, a history of prostate cancer was independently associated with an increased risk for melanoma (hazard ratio, 1.83). This association was confirmed in an analysis of 18,603 participants in the Physicians’ Health Study (hazard ratio, 2.17).[23]

Molecular prognostic markers

Several molecular markers have been shown to aid in determining the prognosis of patients undergoing treatment for localized and metastatic prostate cancers. Genetic changes associated with poor survival in prostate cancer include the following[24] :

  • Loss of one or both copies of the tumor suppressor gene PTEN

  • TMPRSS2–ERG chromosome fusion (fusion of an androgen-responsive promoter with the ERG transcription factor)

  • P53 mutations

  • Overexpression of MYC

Assessments of molecular alterations of gene products of RB, BCL2, cathepsin-D, and CDH1, among many others, have also been reported. Decreased expression of the cell cycle inhibitor p27 in prostate cancer cells has been associated with increased risk of prostate cancer recurrence.[25]

Prospective trials are needed to assess these markers more thoroughly before their implementation in clinical management is recommended. Currently, none of them are measured in routine practice.

Prognostic nomograms

The Partin tables are the best nomogram for predicting prostate cancer spread prior to therapy. The tables were updated by experts at Johns Hopkins in January 2013. Updates to the tool were based on a study of 5629 men who underwent radical prostatectomy and staging lymphadenectomy between 2006 and 2011. The updated tables show that certain categories of men who were previously not thought to have a good prognosis (eg, those with a Gleason score of 8) actually can be cured with surgery.[26, 27]

In addition, a series of nomograms has been developed from the Memorial Sloan-Kettering Cancer Center that is used to predict disease progression and survival after a variety of treatments.

Morbidity and mortality

Current prostate cancer treatments, including radical prostatectomy and radiation therapy, result in permanent side effects in many men. The most common ones are erectile dysfunction and urinary incontinence.[28]

A comparison of functional outcomes in African-American versus non–African-American patients found no statistically significant difference in urinary and sexual outcomes 6 months after robotic-assisted radical prostatectomy. At 12 months, however, African-American patients had lower rates of adequate erectile function (60% vs 76.4%) and urinary continence (55.7% vs 69.8% ) compared with non–African Americans.[29]

Margel et al found that radiation therapy for prostate cancer may be associated with slightly increased risk of secondary malignancy, such as rectal cancer and bladder cancer.[30] In this study, rectal cancer occurring after radiation therapy was diagnosed at a more advanced stage and resulted in lower disease-specific survival.

Prostate cancer is the second most common cause of cancer death in males, after lung cancer. The American Cancer Society estimates that 31,620 men will die from the disease in 2019.[5]  However, in contrast with lung cancer, which accounts for 13% of new cases but 24% of cancer deaths in men, prostate cancer accounts for 20% of new cases but only 10% of deaths.[5]

Death rates from prostate cancer rose steadily from 1975 to 1991, remained level from 1991 to 1994, and decreased subsequently, but rates appear to have stabilized from 2013 to 2015.[5] Although the decrease has been dismissed as an artifact of lead-time bias, earlier diagnosis of progressive disease and improvements in the treatment of advanced disease are the most likely driving force behind the mortality reduction.

In the United States, 5-year relative survival rates in men with local or regional prostate cancer at diagnosis are greater than 99%. In men with distant disease, however, survival is only 30%.[5]

Patient Education

With the advent of PSA screening, and in the absence of level I studies comparing the various options, a greater number of men require education about prostate cancer and how it is diagnosed, staged, and treated. Such education allows patients to make informed decisions about screening and, in men diagnosed with prostate cancer, to select the most appropriate treatment. Up-to-date information is available through the National Cancer Institute and the American Cancer Society, as well as Prostate Videos.com.

For patient education information, see the Men's Health Center and the Cancer Center, as well as Prostate Cancer, Enlarged Prostate (Benign Prostatic Hyperplasia or BPH), and Cancer: What You Need to Know.

 

Presentation

History

Currently, the majority of prostate cancers are identified in patients who are asymptomatic. Diagnosis in such cases is based on abnormalities in a screening prostate-specific antigen (PSA) level or findings on digital rectal examination (DRE). In addition, prostate cancer can be an incidental pathologic finding when tissue is removed during transurethral resection to manage obstructive symptoms from benign prostatic hyperplasia.

Symptoms of local disease

In the pre-PSA era, patients with prostate cancer commonly presented with symptoms that included urinary complaints or retention, back pain, and hematuria. Currently, with PSA screening, most prostate cancers are diagnosed at an asymptomatic stage. When symptoms do occur, diseases other than prostate cancer may be the cause. For example, urinary frequency, urinary urgency, and decreased urine stream often result from benign prostatic hyperplasia.

Symptoms of advanced disease

Advanced prostate cancer results from any combination of lymphatic, hematogenous, or contiguous local spread. Skeletal manifestations are especially common, because prostate cancer has a strong predilection for metastasizing to bone.

Manifestations of metastatic and advanced prostate cancer may include the following:

  • Weight loss and loss of appetite

  • Anemia

  • Bone pain, with or without pathologic fracture

  • Neurologic deficits from spinal cord compression

  • Lower extremity pain and edema due to obstruction of venous and lymphatic tributaries by nodal metastasis

Uremic symptoms can occur from ureteral obstruction caused by local prostate growth or retroperitoneal adenopathy secondary to nodal metastasis.

Physical Examination

Physical examination alone cannot reliably differentiate benign prostatic disease from cancer. Consequently, a biopsy is warranted to establish a diagnosis. Unfortunately, false-negative results often occur, so multiple biopsies may be needed before prostate cancer is detected.

If cancer is suspected, determining whether the disease is localized or extends outside the capsule is important for planning treatment. Obliteration of the lateral sulcus or involvement of the seminal vesical often indicates locally advanced disease.

Findings in patients with advanced disease may include the following:

  • Cancer cachexia
  • Bony tenderness
  • Lower-extremity lymphedema or deep venous thrombosis
  • Adenopathy
  • Overdistended bladder due to outlet obstruction

Neurologic examination, including determination of external anal sphincter tone, should be performed to help detect possible spinal cord compression. Findings such as paresthesias or wasting are uncommon, however.

Digital rectal examination

The DRE is examiner-dependent, and serial examinations over time are best. A nodule is suspicious for malignancy and warrants evaluation. In addition, findings such as asymmetry, difference in texture, and bogginess are important clues and should be considered in conjunction with the PSA level. Change in texture over time also suggests the need for a biopsy.

Cysts or stones cannot be accurately differentiated from cancer based on DRE findings alone. Therefore, maintain a high index of suspicion for noncancerous disorders if the DRE results are abnormal.

If cancer is detected, the DRE findings form the basis of clinical staging of the primary tumor (ie, tumor [T] stage in the tumor-node-metastases [TNM] staging system). In current practice, most patients diagnosed with prostate cancer have normal DRE results but abnormal PSA readings.

 

DDx

Diagnostic Considerations

In most cases, the differential diagnoses of advanced prostate cancer do not present any difficulty. However, certain caveats must be considered.

Radiologic findings of bony metastases can mimic Paget disease of the bone. Although bony metastases are blastic in nature, lytic lesions can occur, resulting in pathologic fractures. In men treated with luteinizing hormone-releasing hormone (LHRH), osteoporotic fractures must be distinguished from pathologic fractures.

Neurologic manifestations should be underscored. Sudden onset of weakness of the legs in an elderly man with a history of prostate cancer should raise the suspicion of spinal cord compression, necessitating emergency treatment (spinal cord decompression). Although brain metastases with associated neurologic manifestations are rare, they do occur with enough frequency to deserve recognition.

Lymphomas can manifest as pelvic masses and bone lesions. Although coexistence of lymphomas with prostate cancer has been reported, it is extremely rare.

Transitional cell carcinoma and sarcoma of the prostate are more common in men who have undergone prior pelvic radiation therapy for prostate cancer than in men who have not. Likewise, squamous cell carcinoma of the prostate may be observed in men treated with hormone therapy. All of these can present as a large pelvic mass with or without metastases.

Differential Diagnoses

 

Workup

Approach Considerations

Currently, most cases of prostate cancer are identified by screening in asymptomatic men. Digital rectal examination (DRE) and prostate-specific antigen (PSA) evaluation are the two components used in prostate cancer screening. Transrectal ultrasonography (TRUS) has been associated with a high false-positive rate, making it unsuitable as a screening tool, but it has an established role in directing prostatic biopsies.

Needle biopsy of the prostate is indicated for tissue diagnosis in patients whose screening shows elevated PSA levels or abnormal DRE findings. Pathologic evaluation of the biopsy specimen permits calculation of the Gleason score, which is used to help determine prognosis.

Blood studies beyond PSA offer little useful information for men with newly diagnosed early stage prostate cancer. For men with advanced disease, a chemistry profile (including serum creatinine and liver function tests) is warranted. Acid and alkaline phosphatase measurements do not provide helpful information in most cases.

Urinalysis should be performed. If results are abnormal (ie, indicating the presence of hematuria or infection), further workup is warranted before planning cancer therapy.

Computed tomography (CT) scanning is rarely helpful except in men who are at high risk for lymph node metastases or who are going to be treated with radiation. Chest radiography is no longer a routinely advisable staging test for prostate cancer.

 In patients with a family history of high-risk germline mutations (eg, BRCA 1/2, Lynch mutation), a suspicious family history, or intraductal carcinoma on prostate biopsy, National Comprehensive Cancer Network (NCCN) guidelines recommend germline testing, preferably with pre-test genetic counseling. If a genetic mutation is identified, the NCCN recommends post-test genetic counseling.[31]

Prostate Cancer Screening

DRE and PSA evaluation are the two components used in prostate cancer screening. Transrectal ultrasonography (TRUS) has been associated with a high false-positive rate, making it unsuitable as a screening tool, although it has an established role in directing prostatic biopsies.

A systematic review and meta-analysis that included 7 studies with 9,241 patients who underwent both DRE and prostate biopsy found that DRE performed by primary care physicians has poor diagnostic accuracy in screening for prostate cancer. The sensitivity of DRE in that setting was estimated to be 0.51, with a specificity of 0.59 and a positive predictive value of 0.41.[32]

Screening for prostate cancer is a controversial topic. Screening offers the opportunity to find cancers at a more curable stage. However, given the variable natural history of prostate cancer—with some cases progressing aggressively but many being indolent and posing little threat of significant morbidity or mortality—and the absence of a reproducible method for identifying patients in whom the disease will progress rapidly in the absence of therapy, screening inevitably results in some degree of overtreatment.

Many clinicians have argued that early intervention for prostate cancer does not offer a measurable survival advantage. The Prostate Intervention Versus Observation Trial (PIVOT), which randomized men with localized prostate cancer to watchful waiting or radical prostatectomy, found no significant difference in either all-cause or prostate cancer mortality between the two groups through a median 10 years of follow-up.[33]

Longer-term follow-up data from PIVOT (from 12.0 to 19.5 years; median follow-up, 12.7 years) confirmed that compared with observation, surgery does not reduce the risk of death for men with low-risk early-stage prostate cancer. Moreover, surgery was associated with a higher incidence of adverse events necessitating treatment.[34]

A systematic review and meta-analysis of five randomized controlled trials that enrolled 721,718 men concluded that "at best, screening for prostate cancer leads to a small reduction in disease-specific mortality over 10 years but does not affect overall mortality." The authors found moderate-quality evidence that PSA screening probably results in one fewer death from prostate cancer per 1000 men screened (95% confidence index [CI], with an incidence rate ratio of 0.79 (95% Ci, 0.69 to 0.91).[35, 36]  

This study also analyzed complications from biopsies and subsequent treatment. The authors estimated that for every 1000 men screened who undergo biopsy, 94 will experience hematospermia and one will require hospitalization, most likely for sepsis. Comparison of screened with unscreened men showed that for every 1000 men screened who undergo treatment, 3 more men would require pads for urinary incontinence and 25 more men would experience erectile dysfunction.[35]

Screening recommendations

Guidelines on prostate cancer screening have been issued by the following organizations:

  • American Cancer Society (ACS)
  • National Comprehensive Cancer Network (NCCN)
  • US Preventive Services Task Force (USPSTF)
  • American Urological Association (AUA)
  • American College of Physicians (ACP)

American Cancer Society guidelines

In 2010, the ACS recommended that men make an informed decision about whether to be screened for prostate cancer. The decision should be based on a discussion with their health care provider about the uncertainties, risks, and potential benefits of screening.[37, 2] Many critics have interpreted this to mean screening should not be done, which is incorrect.

If screening is done, it should be performed beginning at age 50 years in men at average risk who have a life expectancy of at least 10 years. Screening should be discussed at age 40 or 45 years for African Americans and men who have had a first-degree relative diagnosed with prostate cancer before age 65. For men with several first-degree relatives who had prostate cancer at an early age, the discussion should take place at age 40 years.[37, 2]

The ACS recommends that men who choose to be screened be tested with PSA measurement. DRE may also be done as a part of screening, but the 2010 ACS guideline notes that little evidence exists that the DRE adds significant benefit to the test unless the PSA level is in the borderline range.[37, 2]

The ACS advises that if the PSA level is less than 2.5 ng/mL, retesting may need to be done only every 2 years. Men whose PSA level is 2.5 ng/mL or higher should have annual testing.[37]

National Comprehensive Cancer Network guidelines

The NCCN recommends performing a baseline evaluation, with a history and physical examination that includes the following[38] :

  • Family history
  • Medications
  • History of prostate disease and screening, including prior PSA and/or isoforms, exams, and biopsies
  • Race
  • Family or personal history of BRC1/2 mutations

The clinician should then discuss of the risks and benefits of a baseline PSA test with the patient, and consider a baseline DRE to identify high-risk cancers associated with a seemingly normal PSA. In patients 45-75 years of age, subsequent evaluation is based on the results of those tests, as follows[38] :

  • PSA < 1 ng/mL, DRE normal (if done): Repeat testing at 2–4 year intervals
  • PSA 1-3 ng/mL, DRE normal (if done): Repeat testing at 1–2 year intervals
  • PSA >3 ng/mL or very suspicous DRE result: Evaluate for biopsy

Although very few men above the age of 75 years benefit from PSA testing, screening may be cautiously considered in selected cases of very healthy men with little or no comorbidity. If PSA is measured and is < 4 ng/mL, the DRE is normal (if done), and no other indications for biopsy are present, the NCCN recommends repeat testing in selected patients at 1–4 year intervals. If the PSA is >4 ng/mL or DRE results are very suspicious, the patient should be evaluated for biopsy.

The NCCN notes that men 60 years of age and older whose serum PSA is less than 1.0 ng/mL have a very low risk of metastasis or death from prostate cancer and may not benefit from further testing. The same is true of men age 75 years with a PSA of less than 3.0 ng/mL.

Evaluation for biopsy includes the following:

  • Repeat PSA
  • Perform DRE, if not done performed during initial risk assessment
  • Workup for benign disease

US Preventive Services Task Force guidelines

Controversially, in 2012 the USPSTF recommended against any routine PSA-based screening of men for prostate cancer, concluding that the harms of screening may outweigh the benefits or that the benefit is either too small or nonexistent.[39, 40]  In an updated recommendation issued in May 2018, the USPSTF advises that in men aged 55 to 69 years, the decision of whether or not to undergo screening should be individualized. This is a grade C recommendation, meaning that there is at least moderate certainty that the net benefit is small. For men aged 70 years and older, the USPSTF recommends against PSA-based screening for prostate cancer.[3]

The USPSTF concluded that currently available data are insufficient to assess whether the benefits of prostate cancer screening are different for African-American men or men with a family history of prostate cancer, or whether starting screening in those high-risk groups before age 55 years offers benefits.

While acknowledging the higher risk of prostate cancer in those groups, the USPSTF also notes the significantly higher risk of major infections after prostate biopsy in black men than white men, and the potential for harm in men with relatives whose prostate cancer was overdiagnosed. The USPSTF suggests that men with a positive family history who are most likely to benefit from screening are those with a first-degree relative who had advanced prostate cancer at diagnosis, who developed metastatic prostate cancer, or who died of prostate cancer.[3]

American Urological Association guidelines

In May 2013, the AUA released new guidelines supporting routine use of the PSA test in healthy men 55 to 69 years of age who are at average risk for prostate cancer and asymptomatic. The AUA recommends that men consult their physician about the risks and benefits before undergoing PSA testing. This recommendation is in direct contrast to the 2012 USPSTF guidelines discussed above.[41]

The AUA guidelines do not recommend testing in the following groups[41] :

  • Men 40 years of age or younger

  • Men 40 to 54 years old who are at average risk

  • Men 70 years of age or older

  • Men with a life expectancy of less than 10 - 15 years

American College of Physicians guidelines

The ACP published guidelines on prostate cancer screening in 2013.[42] The ACP recommends that clinicians inform men between the age of 50 and 69 years about the limited potential benefits and substantial harms of screening for prostate cancer. The ACP advises that the decision to screen for prostate cancer with PSA testing should be based on the patient’s risk for prostate cancer, his general health and life expectancy, his preferences.

The ACP advises against screening for prostate cancer with PSA testing in the following cases:

  • Patients who do not express a clear preference for screening

  • Average-risk men under the age of 50 years

  • Men over the age of 69 years

  • Men with a life expectancy of less than 10-15 years

Screening trials

The results of two large-scale, randomized, controlled PSA screening trials were published in 2009. Although designed to compare screening to no screening, the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial was actually a trial comparing high-intensity PSA screening to less-intensive screening. This trial found no reduction in mortality with screening after 10 years.[43]

Conversely, the European Randomized Study of Screening for Prostate Cancer (ERSPC) trial found that, over a median follow-up of 9 years, PSA-screening at an average of every 4 years resulted in a 20% reduction in the rate of death from prostate cancer. However, the risk of overdiagnosis was high.[44]

The ERSPC control group differed in terms of interval of screening amongst the 7 countries involved in the trial; 82% of patients underwent screening, although it is unclear how often. The longer screening interval, which might make it harder to show a screening effect, was offset by the lower PSA threshold used in this trial as compared with that of the PLCO Cancer Screening Trial.

The main flaw in this study was in the randomization strategy used by 3 of the 7 countries participating in the trial, whereby men identified from population registries were randomized before giving consent. Also, the screened group was more often treated at major medical centers, which could have affected the results. Nonetheless, this trial was twice as large as the PLCO Cancer Screening Trial, providing it with more power to detect a difference.

A Swedish study found that PSA screening reduced prostate cancer mortality almost by half over 14 years. In the ongoing prospective, randomized Göteborg trial, the risk of death from prostate cancer was 0.90% in the control group, versus 0.50% in the group that underwent PSA screening every 2 years.[45]

However, the risk of overdiagnosis was substantial. Overall, 293 men had to undergo screening and 12 had to be diagnosed and treated to prevent 1 prostate cancer death. (The number needed to treat was at least as high as in breast-cancer screening programs.)[45] Some of these men were part of the European trial and when they were excluded, the ESRPC study did not show a significant benefit.

Part of the reason for the variable results may be that the impact of treatment is unclear. A 2002 Scandinavian study randomized men to watchful waiting or radical prostatectomy and found a small, but statistically significant, reduction in prostate cancer mortality at 14 years. No difference in overall survival was noted, however.[46] The benefit was limited to men under 65 years. This study did not include men primarily diagnosed by screening.

In contrast, in the US PIVOT study (which, as noted above, showed no difference in mortality at 12 years), the patients were mostly from a screened population. The 2002 Scandinavian study and PIVOT did find a reduction in metastatic disease in treated patients. Also, in both studies, a portion of men did not comply with their assigned therapy, which could have affected the results.

Confounding these results is the observation from US data that prostate cancer mortality has decreased 1% per year since 1990, which coincides with the advent of PSA screening. Proponents of screening argue that this proves the benefit of screening. However, other theories have been proposed to account for the decrease, including changes in treatment practices and artifacts in mortality rates secondary to the changing incidence.

Prostate-Specific Antigen

When PSA testing was first developed, the upper limit of normal for PSA was thought to be 4 ng/mL. However, subsequent studies have shown that no PSA level guarantees the absence of prostate cancer. As the PSA level increases, so does the risk of this disease. When the PSA is 1 ng/mL, cancer can be detected in about 8% of men if a biopsy is performed. With a PSA level of 4-10 ng/mL, the likelihood of finding prostate cancer is about 25%; with a level above 10 ng/mL, the likelihood is much higher.[37]

Although cancer may be present even when the PSA level is less than 1 ng/mL, experts do not recommend a biopsy unless the PSA is higher. Some use 2.5 ng/mL as the cutoff, while others wait until it is 3 ng/mL or greater.

The European Randomized Study of Screening for Prostate Cancer (ERSPC) applied a PSA cutoff value of 3 ng/mL or higher as an indication for lateralized sextant biopsy.[47] For men with an initial PSA value of less than 3 ng/mL, the risk of developing aggressive prostate cancer and death has been found to significantly increase with PSA values in the 2-2.9 ng/mL range, although the overall risk of aggressive prostate cancer–related death remains limited.[48]

A review of data from the Surveillance, Epidemiology, and End Results (SEER) system of men with newly diagnosed prostate cancer from 2004 to 2006 by Shao et al found that most patients with a PSA threshold below 4.0 ng/mL had low-risk disease but underwent aggressive local therapy. Shao et al suggested that in the absence of the ability to distinguish indolent from aggressive cancers, lowering the biopsy threshold might increase the risk of overdiagnosis and overtreatment.[49]

A review by Preston and colleagues concluded that PSA levels in midlife correlate with future risk of lethal prostate cancer. The study population consisted of men who had PSA levels measured on enrollment in Physicians' Health Study, when they were 40-59 years old. In men with baseline PSA levels in the >90th percentile, versus those with levels at or below the median, the odds ratios for developing lethal prostate cancer (by age at baseline measurement) were as follows[50] :

  • Age 40-49 years: 8.7
  • Age 50-54 years: 12.6
  • Age 55-59 years: 6.9

A variety of approaches have been proposed for improving the accuracy of PSA for detecting prostate cancer. These include assessment of the velocity of PSA level increase and the percentage of free PSA.

See Prostate-Specific Antigen Testing for a complete discussion of this topic.

PSA velocity

PSA velocity is an important concept. To calculate velocity, at least 3 consecutive measurements on specimens drawn over at least 18-24 months should be used. Guidelines from the NCCN suggest that PSA velocity be considered in the context of the PSA level.[38] The following PSA velocities are suspicious for cancer:

  • PSA velocity of 0.35 ng/mL/y, when the PSA is ≤2.5 ng/mL
  • PSA velocity of 0.75 ng/mL/y, when the PSA is 4–10 ng/mL

However, a study by Vickers et al in 2011 called into question the concept of PSA velocity. In this study, PSA velocity cut points with a comparable specificity to PSA level cut points had a lower sensitivity, particularly for high-grade and clinically significant prostate cancer. The researchers concluded that “PSA velocity added little to the predictive accuracy of high PSA levels or positive DRE and would substantially increase the number of men recommended for a biopsy.”[51] This controversy has not been resolved.

Bound versus free PSA

The measurement of bound and free PSA can help to differentiate mildly elevated PSA levels due to cancer from elevated levels due to benign prostatic hyperplasia. Free PSA is calculated as a percentage of total PSA; the lower the percentage of free PSA, the higher the likelihood of cancer. For example, cancer is found at prostate biopsy in only 8% of men with greater than 25% free PSA, but in more than half of those with less than 10% free PSA.

The percentage of free PSA is generally used as an additional factor in making an informed recommendation for or against biopsy in patients with a PSA level of 4-10 ng/mL. Typically, a free PSA above 25% is considered normal. Some experts recommend biopsy when the free PSA is less than 18%; others advise a cutoff of 12%.

Free PSA percentage is most useful in men with very large glands and in patients in whom 1 biopsy result has already been negative. In healthy men with a PSA level of 4-10 ng/mL, many experts recommend biopsy without the additional free-PSA test. A common practice is to offer a course of antibiotics and anti-inflammatory drugs for a period of time and to then repeat the test to see if this treatment lowers the PSA level. However, no well-performed studies have established the value of this approach.

Fingerstick PSA testing

The Sangia Total PSA Test (OPKO Diagnostics) uses a fingerstick blood sample to measure PSA and provides results in 10 to 12 minutes, allowing its use at the point of care. In January 2019 the US Food and Drug Administration (FDA) approved the test for use with digital rectal examination (DRE) to screen for prostate cancer in men aged 50 years or older.[52]

In a trial in 434 men (median age 65 years), the test demonstrated a sensitivity of 85.4% and a specificity, 30.3%, at a total PSA cut-off value of 4 ng/mL. When combined with DRE, the test's sensitivity increased to 91% and the positive predicted value increased to approximately 70%.. Additionally, the test had a 95% correlation with an FDA-approved, laboratory-based PSA test.[52]  False negatives occur in about 36% of men who have a Gleason score of 6 or less and 18% of those with a Gleason score of 7 or higher.[52]

The test may have particular potential for use as part of active surveillance in patients with low-risk prostate cancer.  A possible risk, as with all PSA tests for prostate cancer screening, is that clinicians might fail to provide a discussion of the risks and benefits of PSA testing before performing the test.[52]

 

 

Prostate Biopsy

Needle biopsy of the prostate is indicated for tissue diagnosis in patients who present with elevated PSA levels or abnormal DRE findings. Transrectal ultrasonography (TRUS) is used to guide the biopsy, although MRI is being studied as an alternative. TRUS also permits measurement of the volume of the prostate. Hypoechoic areas on TRUS are commonly associated with cancers, but this finding is not specific enough for diagnostic purposes.

Ahmed et al reported that multi-parametric MRI (MP-MRI) may help men to avoid unnecessary TRUS-biopsy and improve diagnostic accuracy. In their study of 576 men with suspected prostate cancer, MP-MRI had greater sensitivity than TRUS-biopsy for detecting clinically significant cancers (93% vs 48%) but lower specificity (41% vs 96%). If follow-up biopsy were performed only in men with suspicious MP-MRI scores, then 27% would potentially avoid primary biopsy.[53]

See Transrectal Ultrasonography of the Prostate for a discussion of TRUS and prostate biopsy, as well as Imaging in Prostate Carcinoma and Techniques of Local Anesthesia for Prostate Procedures and Biopsies.

The number of biopsy samples that should be taken is debated. The former standard consisted of 6 samples taken in a sextant pattern. In extended-pattern biopsies, the sextant samples are supplemented with 2 lateral samples from each lobe for a 10-biopsy scheme, or 6 lateral peripheral zone samples for a 12-biopsy scheme; 18-core biopsy protocols are also used, especially for larger glands.

In addition, samples may be taken from palpable nodules or ultrasonographically suspicious areas. Color Doppler TRUS is being used to help identify suspicious areas.[54]

In patients with a persistently elevated PSA level in the face of negative biopsy results, the literature supports repeating the biopsy once or twice. Repeat biopsies may also include cores from the transition zone, which is not usually the case in initial biopsies.

In a retrospective study of 178 patients with elevated PSA levels, negative results on previous random biopsies, and positive results on multiparametric MRI, Cornelis et al found that the injection of sulfur hexafluoride microbubbles as an ultrasonographic contrast medium improved the prostate cancer detection rate. Transrectal biopsies guided by contrast-enhanced ultrasonography had a positive overall detection rate of 30.9%, compared with 6.9% for 12-core nontargeted biopsies.[55]

Saturation biopsies, in which more than 20 cores are taken under general or spinal anesthesia, are sometimes used in men who are at high risk and have had multiple negative biopsies. No studies have proved that saturation biopsies offer important advantages and they do pose a higher risk of bleeding, infection, and urinary retention. Also, the number of tissue samples obtained is a two-edged sword; more samples increase the chance of finding cancer but also increase the chance of finding non–life-threatening disease.

Patients should receive prophylactic antibiotics at least 20 minutes before prostate biopsy, to reduce the risk of infection. No studies have proved, however, that more than 1 or 2 doses of antibiotic offer advantages over longer-term use following biopsy. Serious infections with resistant organisms are increasing.

Patient comfort is greatly improved by injecting a local anesthetic into the nerves near the seminal vesicles, under ultrasonographic guidance. An enema is usually given prior to the biopsy.

The National Comprehensive Cancer Network (NCCN) has established guidelines for follow-up of patients who have benign biopsy results but other indications of high risk for prostate cancer (eg, positive DRE or elevated PSA).[38] However, these recommendations are not based on level I studies, so their reliability is uncertain.

Epigenetic changes induced by DNA methylation may serve as field-effect biomarkers for the presence of neighboring prostate cancer in tissue samples, and thereby help differentiate true-negative from false-negative biopsies. In the Methylation Analysis to Locate Occult Cancer (MATLOC) study, an assay that measures methylation of the genes GSTP1, APC, and RASSF1 correctly confirmed negative biopsies in approximately 64% of men without prostate cancer and identified occult cancer in 68% of patients who had initial false-negative biopsies.[56]

Complications

The National Cancer Institute (NCI) has observed that prostatic biopsies can have complications, including fever, pain, hematospermia, hematuria, positive urine cultures, and (rarely) sepsis. Also, the screening process itself can lead to adverse psychological effects in men who have a prostate biopsy but do not have identified prostate cancer.[28]

These risks are multiplied because a significant percentage of men will have more than 1 biopsy before cancer is detected or they are considered free of the disease. In a cohort study of asymptomatic men who underwent transrectal ultrasonography–guided biopsy because of elevated PSA levels, Rosario et al found that although prostate biopsy was well tolerated by most men, a minority experienced significant symptoms—most often pain, but also infection and bleeding—which were associated with the development of a negative attitude toward repeat biopsies.[57]

Transperineal prostate biopsy

Although transrectal prostate biopsy has been the standard technique, transperineal biopsy is increasingly used. In the United Kingdom, the National Health Service is supporting an innovation program to completely replace transrectal with transperineal biopsy. Elsewhere in Europe, multiple medical centers have switched over, and some centers in the United States are adopting the approach.[58]

In the past, transperineal biopsies have required general or spinal anesthesia to allow patients to tolerate multiple needle passes through the perineal tissue. However, a new tool, the PrecisionPoint Transperineal Access System (Perineologic), reduces the number of needle passes, allowing transperineal biopsy to be performed with local anesthesia. The tool can be used with or without MRI fusion technology. It was approved by the US Food and Drug Administration in 2016. For routine clinical use, transperineal biopsies could be performed as an office procedure, with no need for prophylactic antibiotics.[58]

In a UK feasibility study of a transperineal-only biopsy strategy in 678 consecutive men with suspected or actual prostate cancer, which used the PrecisionPoint Transperineal Access System, complication rates were low:sepsis requiring hospital admission and intravenous antibiotics, urinary tract infection, and hematuria with clot retention each occurred in a single patient (0.16%).  Four patients (0.5%) had urinary retention, but none required surgery. No complications were classified as Clavien 3 or higher. Local anesthesia was used for the biopsy in 58% of patients; of those, 42%) underwent the procedure in the outpatient clinic.

Histologic Findings

Although the change in glandular architecture represented by the Gleason score is currently the most widely used histologic parameter, it is not the only histologic change that can be observed in prostate cancers. Indeed, notable changes in cell and nuclear morphology, DNA ploidy, neuroendocrine differentiation, and vascularity can be observed and may have prognostic significance.

There is a continuum from normal prostatic epithelium to invasive carcinoma. Precursor lesions to carcinoma may include prostatic intraepithelial neoplasia (PIN) and atypical small acinar proliferation (ASAP). (See the images below.)

Micrograph of high-grade prostatic intraepithelial Micrograph of high-grade prostatic intraepithelial neoplasia
Prostate cancer. Adenocarcinoma around a small ner Prostate cancer. Adenocarcinoma around a small nerve (center). Courtesy of Thomas M. Wheeler, MD.
Prostate cancer. Small focus of adenocarcinoma on Prostate cancer. Small focus of adenocarcinoma on needle biopsy on right side of slide (normal glands on left side). Courtesy of Thomas M. Wheeler, MD.
Prostate cancer. Immunohistochemical stains showin Prostate cancer. Immunohistochemical stains showing normal basal cells (brown) in a benign gland with no basal cells in malignant glands (on right side with no brown staining). Malignant glands show increased expression of racemase (red cytoplasmic stain). Courtesy of Thomas M. Wheeler, MD.

The architecture of the gland remains normal but the epithelial layers become multi-layered and crowded. At a cellular level, the nucleus becomes large and nucleoli are visible. The term PIN is becoming less used in favor of atypical small acinar proliferation (ASAP), which is proliferation of usually small acini with features suggestive of but not diagnostic of cancer.

Clinical studies suggested that PIN predates a carcinoma by 10 or more years. This concept is less accepted in the modern era. PIN as a precursor of cancer has been replaced by ASAP. The identification of ASAP in prostate biopsy specimens warrants further searching for concurrent invasive carcinoma, with up to 30% having cancer identified on subsequent biopsy specimens. Repeat biopsies are recommended in such cases within 1-2 months.

See Precancerous Lesions of the Prostate for a complete discussion of this topic.

Selection Criteria for Imaging Studies

Imaging studies can be a valuable part of pretreatment staging of prostate cancer, helping to differentiate clinically localized disease (ie, stage T1 or T2), which is generally amenable to local therapy, from more advanced disease that may require multimodal therapy. The currently accepted staging system allows for inclusion of these studies in the assessment of disease, although the medical literature suggests that no single study can be used to reproducibly detect non–organ-confined disease.

Defining the best candidates for radiologic assessment depends on a clear understanding of the accuracy of the proposed study and on the expected prevalence of the anticipated finding in the population at risk. Understanding the relative prevalence of the suspected abnormality (eg, non–organ-confined disease, regional nodal involvement) is important in the decision algorithm.

Retrospective surgical data (eg, from Partin and colleagues) suggest that patients who present with early stage disease (T2a or lower), those with PSA values of less than 10, and those with a Gleason score of 6 or less are at low risk for non–organ-confined disease.[59] The presence of PSA levels of greater than 10 ng/mL, high-grade histology (Gleason score ≥7), or physical findings that suggest stage T3 disease may warrant some imaging studies for staging.

Comparisons of the accuracy of each imaging modality fail to provide a uniform consensus regarding the optimum study. For T staging, MRI is more accurate than CT scanning. Unfortunately, a significantly high inaccuracy rate limits the value of both of these tests. For example, if the test suggests extracapsular disease but the false-positive rate is about 30%, many men may be incorrectly advised to avoid prostatectomy.

MRI and CT scanning have equivalent accuracy for N staging. Neither is worthwhile unless the risk of nodal metastases is at least 15% or higher.

For M staging, bone scintigraphy with technetium-99m (99m Tc) is typically used. It is rarely indicated unless the PSA is above 10 or 20 ng/mL, however, because the likelihood of finding metastases is otherwise very low. Obtaining a baseline bone scan for aid in evaluating future tests makes little sense. See Imaging in Prostate Carcinoma for more information.

Ongoing work with 11C-choline positron-emission tomography (PET) scans may lead to its use in the future. In a study of 31 patients undergoing restaging of prostate cancer, an 11C-choline dual positron PET/MR protocol detected significantly more recurrences (12 patients), particularly small local recurrences, than dual imaging with PET and computed tomography (PET/CT) scanning (8 patients).[60]

The radiation dose delivered by PET/MR was about 80% lower and the imaging time was longer (41 min) than that delivered by PET/CT (23 min), and it was well tolerated by patients. However, the investigators cautioned that further research on the clinical impact of PET/MR is needed.[60]

The American College of Radiology (ACR) has developed guidelines for the selection of imaging studies for pretreatment staging.[61] These guidelines rate the appropriateness of particular imaging modalities on the basis of such findings as T stage, Gleason score, PSA level, and percentage of positive biopsy cores.

ProstaScint scan

ProstaScint scans are a form of immunoscintigraphy that involves a murine monoclonal antibody that reacts with prostate-specific membrane antigen to identify cancer in the prostate and in metastatic deposits. ProstaScint scans frequently yield false-negative results, but the specificity of the study may be improved when combined with single-photon emission CT (SPECT) imaging or CT scanning.[62]

The ACR suggests that routine use of ProstaScint scanning as an initial staging procedure is not currently justified. Some evidence supports its use in patients with postoperative treatment failure, especially to guide decisions regarding radiation therapy,[61] but no long-term studies have demonstrated the therapeutic benefits of administering salvage radiation based on ProstaScint scan results.

Investigational Studies

Certain molecular markers are being evaluated to help characterize disease progression. These include the following:

  • E-cadherin
  • p53 and p21
  • DNA ploidy analysis
  • Human kallikrein 2
  • Microvessel density - Histologic marker of tumor angiogenesis

Reverse transcriptase-polymerase chain reaction (RTPCR) testing may be able to find very small amounts of PSA nucleic acid in the bloodstream. This technique has been investigated as a method for identifying treatment failure (eg, residual tumor following surgery), but rates of false-positive results have been too high to support its use for making treatment decisions.

TNM Staging System

The tumor node metastases (TNM) staging system of the American Joint Committee on Cancer (AJCC) is used to stage prostate cancer. The current revision of the AJCC system, which took effect in January 2018, also uses both the Gleason score and the grade group for staging.[63]  See Prostate Cancer Staging.

T (primary tumor)

Clinical (cT) stages of primary tumor are as follows:

  • TX - Primary tumor cannot be assessed
  • T0 - No evidence of primary tumor
  • T1 - Clinically inapparent tumor not palpable or visible by imaging
  • T1a - Tumor incidental histologic finding in ≤5% of tissue resected
  • T1b - Tumor incidental histologic finding in >5% of tissue resected
  • T1c - Tumor identified by needle biopsy (because of elevated PSA level); tumors found in 1 or both lobes by needle biopsy but not palpable on digital rectal examination or reliably visible by imaging
  • T2 - Tumor confined within prostate (includes invasion into the prostatic apex or invasion into, but not beyond, the prostatic capsule)
  • T2a Tumor involves one-half or less of 1 lobe
  • T2b - Tumor involving more than half of a lobe but not more than 1 lobe
  • T2c - Tumor involving both lobes
  • T3 - Tumor extending through the prostatic capsule
  • T3a - Extracapsular extension (unilateral or bilateral)
  • T3b - Tumor invading seminal vesicle(s)
  • T4 - Tumor fixed to or invading adjacent structures other than seminal vesicles (eg, bladder neck, external sphincter, rectum, levator muscles, pelvic wall)

Pathologic (pT) stages of the primary tumor are as follows (there is no pT1 classification):

  • pT2–  Organ confined
  • pT3 –  Extraprostatic extension
  • pT3a – Extraprostatic extension or microscopic invasion of the bladder neck
  • pT3b – Seminal vesicle invasion
  • pT4 – Tumor is fixed or invades adjacent structures other than the seminal vesicles (eg, bladder, rectum)

N (nodes)

Clinical (cN) nodal stages are as follows:

  • NX - Regional lymph nodes were not assessed
  • N0 - No regional lymph node metastasis
  • N1 - Metastasis in regional lymph node or nodes

Regional lymph nodes are assessed via surgical removal or biopsy of the pelvic lymph nodes, including the obturator chain.

Pathologic (pN) nodal stages are as follows:

  • pNX –  Regional nodes not sampled
  • pN0 – No positive regional nodes
  • pN1 – Metastases in regional nodes(s)

M (metastasis)

Metastatic stages are as follows:

  • M0 - No distant metastasis
  • M1 - Distant metastasis
  • M1a - Nonregional lymph node(s)
  • M1b - Bone(s)
  • M1c - Other site(s), with or without bone disease

Gleason Score

The Gleason grading system is used to help determine prognosis in prostate cancer. It is based on histologic evaluation of tumor biopsy specimens.

Grades are based on the extent to which the epithelium has a normal glandular structure. Grades progress from less malignant to more malignant; a grade of 1 indicates a near-normal pattern, and grade 5 indicates the absence of any glandular pattern. This scheme of grading histologic features greatly depends on the skill and experience of the pathologist and is subject to some degree of individual variation.

The predominant pattern and the second most common pattern are given grades from 1-5 (see the images below). The sum of these 2 grades is referred to as the Gleason score. Scoring based on the 2 most common patterns is an attempt to factor in the considerable heterogeneity within cases of prostate cancer. In addition, this scoring method has been found to be superior for predicting disease outcomes, compared with using the individual grades alone.

The standard approach for grading prostate cancer The standard approach for grading prostate cancer depends on a Gleason score, which is based on pathologic evaluation of a prostatectomy specimen and is commonly estimated from prostate biopsy tissue. Prostate cancer patterns are assigned a number from 1-5; the score is created by adding the most common pattern and the highest-grade patterns. Courtesy of Wikimedia Commons.
Histologic scoring system showing the 2 most commo Histologic scoring system showing the 2 most common patterns seen on the biopsy specimen, termed the Gleason score.

Gleason score evaluations have changed considerably in recent years. Scores of 2-5 are rarely seen, while Gleason 7 is being reported more often.

The significance of the Gleason score is as follows:

  • A score of 2-6 indicates a low-grade or well-differentiated tumor

  • A score of 7 indicates a moderate-grade or moderately differentiated tumor

  • A score of 8-10 indicates a high-grade or poorly differentiated tumor

Prediction Models

Models have been developed that combine the clinical stage (as determined by DRE findings), Gleason score, and PSA level in an attempt to better predict which men have organ-confined cancer, as opposed to those who may have local extension. In addition, these models can be used to predict the time to biochemical failure and the time to the development of clinical metastatic disease in patients with rising PSA levels.

These models have been adapted to personal-computer and handheld-computer platforms and can be used with ease in clinical practice. One such program can be downloaded free of charge from the Prostate Nomogram section of the Memorial Sloan-Kettering Cancer Center Web site. The Partin tables, updated by experts at Johns Hopkins in January 2013, are another excellent nomogram for predicting prostate cancer spread and prognosis. Updates to the tool were based on a study of 5629 men who underwent radical prostatectomy and staging lymphadenectomy between 2006 and 2011. The updated tables show that certain categories of men who were previously not thought to have a good prognosis (eg, those with a Gleason score of 8) actually can be cured with surgery.[26, 27]

The Cancer of the Prostate Risk Assessment (CAPRA) score is calculated from the PSA level, the Gleason score, the percentage of biopsy cores positive for cancer, the clinical tumor stage, and the patient age at diagnosis. In a large cohort of patients with clinically localized prostate cancer, the CAPRA score proved accurate for predicting metastases, cancer-specific mortality, and all-cause mortality. No patient with a CAPRA score of 0 reached either metastasis or mortality endpoints, but each single-point increase in the CAPRA score was associated with increasing risk.[64]

From the results of the Prostate Cancer Prevention Trial (PCPT), an online risk calculator was created.[65, 66] The information needed includes age, PSA score, ethnicity, family history, positive or negative DRE findings, and positive or negative prior biopsy findings. After those values are entered, the calculator predicts the chances for no, low-grade, and high-grade prostate cancer. The intent is to help guide treatment decision-making. See the PCPT prostate cancer risk calculator.

Whitmore-Jewett classification

The Whitmore-Jewett classification divides prostate cancer into 4 stages, A-D, as follows:

  • Stage A - Tumor is present, but not detectable clinically

  • Stage B - The tumor can be felt on physical examination but has not spread outside the prostatic capsule

  • Stage C - The tumor has extended through the capsule

  • Stage D- The tumor has spread to other organs

The Whitmore-Jewett classification is no longer widely used, as prostate cancer does not necessarily progress in a sequential manner. However, further stratification of stage D by Crawford and Blumenstein[67] has been thought to improve classification and understanding of a subset of patients who have hormone-insensitive prostate cancer. The staging is as follows:

  • Stage D1 - Involvement of pelvic lymph nodes

  • Stage D1.5 - Rising PSA level after failure of local therapy (ie, biochemical failure)

  • Stage D2 - Metastatic disease to bone and other organs

  • Stage D2.5 - Rising PSA after nadir level

  • Stage D3 - Castrate-resistant prostate cancer

  • Stage D3.5 - Sensitive to hormones

  • Stage D4 - Insensitive to hormones

Surgical Staging

In patients undergoing radical prostatectomy, pathologic assessment of extracapsular disease extension and regional nodal involvement is readily available. Routine node dissection is not worthwhile unless the likelihood of finding disease is more than 15%, which can be determined from the Partin tables.

An unresolved controversy is whether removing the prostate in patients with lymph node metastases provides a survival benefit over alternative therapy. Uncontrolled studies are difficult to interpret and no randomized studies are available. In addition, the standard limited node dissection will miss metastases, while the more extensive dissection has a higher complication rate.

One approach to this situation is to perform pelvic lymph node dissection selectively, limiting the procedure to men at increased risk and performing a more extensive dissection in those men. Dissected lymph nodes are sent for frozen sections; if these disclose no metastasis, the surgeon proceeds to prostatectomy.

Performing pelvic lymph node dissection in men scheduled for radiation therapy may be warranted. However, studies have shown a benefit to radiating the pelvic nodes along with the prostate, so lymph node dissection is rarely done unless a prostatectomy is planned.

Investigators from Johns Hopkins University have validated this data. Their analysis of the Hamburg nomogram for surgically treated patients revealed a similar low risk for certain groups of patients (2.5% vs 2.2%). More importantly, their analysis further stratified patients into low, intermediate, and high risk for nodal involvement. These categories correspond to the number of sextant biopsy specimens that are positive with at least Gleason 4+3 disease, as follows[68] :

  • Very low risk (2.5% chance) of nodal involvement - No evidence of Gleason 4+3 disease or greater

  • Intermediate risk (20% chance) of nodal involvement - Patients with 1-3 biopsy specimens positive for Gleason 4+3 disease or greater

  • High risk (44.4%) for nodal involvement - Patients with 4-6 cores positive for Gleason 4+3 disease or greater

Although the Hamburg nomogram and the clinical validation by the Hopkins group highlight patient cohorts that may benefit from surgical exploration of regional nodal disease, neither addresses the importance of this finding in relation to patient outcome. One may reasonably conclude that the risk of regional nodal disease is very low in patients with a Gleason score of 6 or less. This result is not unlike information summarized in the Partin tables.

 

Treatment

Approach Considerations

Current guidelines on localized prostate cancer from the American Urological Association (AUA) strongly recommend that selection of a management strategy incorporate shared decision making and explicitly consider the following[69] :

  • Cancer severity (risk category)
  • Patient values and preferences
  • Life expectancy
  • Pretreatment general functional and genitourinary symptoms
  • Expected post-treatment functional status
  • Potential for salvage treatment

Standard treatments for clinically localized prostate cancer include the following:

  • Active surveillance
  • Watchful waiting
  • Radical prostatectomy
  • Radiation therapy
  • Hormone therapy

Whole-gland cryotherapy is also used, but its adverse effects are considerable and survival benefit compared with active surveillance has not been shown. Newer therapies, such as proton-beam radiation and high-intensity focused ultrasound are being used, but long-term survival and complication rates have not been presented in well-done studies.

For locally advanced prostate cancer, radiation therapy along with androgen ablation is generally recommended, although radical prostatectomy may be an appropriate alternative to radiation therapy in some cases. A combination of external radiation, brachytherapy, and hormone therapy is also being used, but it is unclear whether it offers advantages over hormone therapy and external radiation alone, and it does increase complications.

Metastatic prostate cancer is rarely curable.[70] Management of these cases typically involves therapy directed at relief of particular symptoms (eg, palliation of pain) and attempts to slow further progression of disease.

Comparisons between treatments for prostate cancer are complicated by the stage-migration and lead-time bias associated with the adoption of prostate-specific antigen (PSA)–based screening and the resultant increase in the detection of small, clinically localized cancers. In addition, treatment selection has become more complicated as options have increased.

Surgical treatment currently includes nerve-sparing techniques, laparoscopic procedures, robotically-assisted procedures, and the classic retropubic prostatectomy and perineal prostatectomy.

Multiple forms of radiation therapy are currently available. These include the following:

  • Conventional radiation therapy
  • Three-dimensional (3-D) conformal radiation therapy
  • Intensity-modulated radiation therapy
  • Temporary and permanent brachytherapy
  • Proton-beam radiation
  • Stereotactically guided radiation

Hormone therapy for prostate cancer is also known as androgen deprivation therapy (ADT). It may consist of surgical castration (orchiectomy) or medical castration. Agents used for medical castration include luteinizing hormone–releasing hormone (LHRH) analogues or antagonists, antiandrogens, and other androgen suppressants.

Localized Prostate Cancer

Whether one of the several different modalities used for treating localized prostate cancer offers survival benefits over the others remains controversial. The choice of definitive therapy has been suggested to make a significant difference in long-term survival in less than 10% of patients.

This means that most patients are cured either because the treatment was effective or because they had a non–life-threatening tumor and the treatment was unnecessary. The remainder of patients are not cured, either because they had unsuspected micrometastases or because the local therapy did not eradicate all of the malignant cells.

Current AUA guidelines (2017) consider active surveillance, radiation therapy, and radical prostatectomy to be acceptable treatment options for localized prostate cancer. However, the guidelines do not recommend any one of these therapies over the others. Instead, they advise that patients be informed of the benefits and drawbacks to the most commonly accepted interventions.[69]

One aspect of counseling that the AUA guidelines do not discuss is how to provide this information to patients. Rather than simply listing the potential side effects of each intervention, patients are likely to benefit from being given the odds of developing each complication and the odds that the treatment will result in recurrence of cancer, reduce the development of metastases, and improve overall survival.

The AUA guidelines do, however, emphasize that high-risk treatment should never be administered to low-risk patients. First-line hormone therapy is seldom indicated in patients with localized prostate cancer.

In a population-based cohort study of older patients with localized prostate cancer, Lu-Yao and colleagues found that primary ADT did not improve long-term overall or disease-specific survival. The study involved 66,717 men 66 years of age and older and was conducted in predefined geographical areas of the United States covered by the Surveillance, Epidemiology, and End Results (SEER) Program.[71]

A review of US Department of Veterans Affairs (VA) data by Loeb et al found that conservative management of low-risk prostate cancer increased significantly from 2005 to 2015. Over that decade, the use of conservative management in men younger than 65 years rose from 27% to 72%; in men 65 years or older, it rose from 35% to 79%. Conservative management consisted mostly of active surveillance; watchful waiting was more likely to be used in men older than 75 years and those with a higher PSA level and greater comorbidity.[72]

Intermediate-risk disease

In patients with intermediate-risk localized prostate cancer, appropriate treatment options include active surveillance, interstitial prostate brachytherapy, external beam radiation therapy, and radical prostatectomy. Cryotherapy should also be discussed.[69, 73] Treatment should be based in part on the patient’s preferences and functional status. A patient who chooses conventional external beam radiation therapy may have improved survival by combining it with 6 months of hormone therapy.[69]

Active surveillance

Active surveillance differs from watchful waiting. With watchful waiting, patients forgo close follow-up and primary treatment. Instead, palliative treatment is provided if local or metastatic progression occurs, as indicated by symptoms.

With active surveillance, the physician monitors the course of the disease over time and intervenes with treatment if the disease begins to progress.

Active surveillance is increasingly being recommended for men with very-low-risk disease (ie, T1c, 2 or fewer biopsy cores positive, no core with >50% involved, Gleason 3+3/grade group 1, and a PSA density < 0.15 ng/mL/g) or low-risk disease (T1-2a disease, a Gleason score of 2-6, and a PSA level below 10 ng/mL. The National Comprehensive Cancer Network (NCCN) notes that active surveillance is usually appropriate for men with very-low-risk and low-risk prostate cancer who have a life expectancy of 10 years or more.[74]

Progression of local disease may be indicated either by increased tumor volume or changes in the Gleason score. PSA doubling times are also being used, although some studies have questioned their reliability for this purpose.

The optimal management of men on active surveillance is evolving, although no randomized studies have yet been conducted. Monitoring typically consists of PSA testing every 3 months and repeat biopsy at 12- to 24-month intervals. Biopsy findings are the most important factor in deciding whether to pursue treatment. A rapid PSA level rise or patient choice can also prompt the physician to proceed to treatment.[75]

Current NCCN recommendations for active surveillance (based on lower-level evidence) include the following[31] :

  • PSA no more often than every 6 mo unless clinically indicated
  • DRE no more often than every 12 mo unless clinically indicated
  • Repeat prostate biopsy no more often than every 12 mo unless clinically indicated

However, the NCCN recommends a repeat biopsy within 6 months of diagnosis if the initial biopsy included fewer than 10 cores. Repeat biopsies are not indicated in patients whose life expectancy is less than 10 years.[31]

Watchful waiting

Watchful waiting is typically recommended to patients of advanced age and to those who have significant, life-limiting comorbidities or a life expectancy of less than 10 years. These patients will most likely experience worse quality of life if their cancer is treated than if they wait for disease progression. They have a very high chance of dying from another cause, and treatment of their prostate cancer could actually worsen comorbid (eg, cardiac) disease and hasten death.

In a 2009 study—the largest US study since the advent of PSA screening—Lu-Yao et al found that the prostate cancer–specific 10-year survival rate in patients managed with watchful waiting was 94%. Median age at diagnosis of the patients in this study was 78 years.[59]

Lu-Yao et al noted that outcomes in these patients, who were diagnosed from 1992-2002, were better than outcomes in patients diagnosed in the 1970s and 1980s. Possible explanations for the improvement include additional lead times, overdiagnoses related to PSA testing, grade migrations, and/or advances in medical care.

Radical prostatectomy versus watchful waiting

Since 1990, only 2 randomized studies comparing radical prostatectomy and watchful waiting have been conducted in men with clinically localized disease. In the first one, which was done in Sweden and included only a small percentage of cases diagnosed by screening PSA (3-5%), overall mortality at 15 years was 46.1% in the surgery group, compared with 52.7% in the watchful waiting group.[69, 76]

Prostate cancer mortality was 14.6% versus 20.7%, respectively, meaning that 1 cancer death was prevented for every 18 men treated with surgery.[76] In a subsequent analysis of the data, however, no mortality benefit was seen in men over 65 years.

Similarly, a 2008 research summary by the Agency for Healthcare Research and Quality (AHRQ) concluded that men with clinically localized prostate cancer detected by methods other than PSA testing who were treated with radical prostatectomy had fewer deaths from prostate cancer, marginally fewer deaths from any cause, and fewer distant metastases, than did men who underwent watchful waiting.[77]

As in the Swedish study, the AHRQ report noted that the advantage of radical prostatectomy with regard to lower cancer-specific and overall mortality rates appears to be limited to men younger than 65 years. The advantage was unrelated to baseline PSA level or histologic grade. The AHRQ found insufficient evidence to determine whether radiation or hormone therapy results in fewer deaths or cancer progressions than does watchful waiting.[77]

The AHRQ also pointed out that radical prostatectomy, radiation therapy, and hormone therapy result in more long-term adverse effects than watchful waiting. These include sexual, urinary, and bowel problems.[78]

PIVOT

Unlike the above reports, the Prostate Intervention Versus Observation Trial (PIVOT), the only such randomized study performed in screened men, showed no statistically significant difference between radical prostatectomy and watchful waiting with respect to either all-cause mortality (47% versus 49.9%, respectively) or prostate cancer–specific mortality (5.8% versus 8.4%, respectively) after a median follow-up of 10 years. PIVOT included 731 men aged 75 years or younger with localized prostate cancer, a PSA level below 50 ng/mL, and a life expectancy of at least 10 years.[33]

A subgroup analysis of PIVOT revealed a statistically significant reduction in overall mortality in men with a PSA greater than 10 ng/mL at diagnosis (61 of 126 men vs 77 of 125 men) but not in men with a PSA of 10 ng/mL or less (110 of 238 men vs 101 of 241 men). These results must be interpreted carefully, however. Age (< 65 vs ≥65 years), Gleason score, comorbidity, race, and performance score did not affect the efficacy of either treatment.[33]

Longer-term follow-up data from PIVOT confirmed the initial observation that for men with low-risk early-stage prostate cancer, surgery does not reduce the risk for death compared with observation. The 19.5-year cumulative incidence of death with surgeryversus observation was 61.3% versus 66.8%, respectively (hazard ratio [HR], 0.84; P = 0.06). Quality-of-life analysis in PIVOT subjects found that urinary incontinence and erectile and sexual dysfunction were each greater with surgery than with observation.[34]

Vascular-targeted photodynamic therapy

Vascular-targeted photodynamic therapy is an investigational technique being studied in Europe. In this technique, a light-responsive drug (padeliporfin) is infused intravenously; optical fibers are inserted into the prostate transcutaneously, to cover the desired treatment zone; and laser light is then used to activate the drug.

 A phase 3 randomized controlled trial in patients with low-risk, localized prostate cancer (Gleason grade 3) found that at a mean follow-up interval of 24 months, disease progression had occurred in 58 of the 206 men in the vascular-targeted photodynamic therapy group compared with 120 of the 207 men in the active surveillance group (28% versus 58%, respectively; adjusted risk ratio 3.67, P < 0.0001).[79]

The most common grade 3–4 adverse effects in the study were prostatitis, acute urinary retention, and erectile dysfunction, which occurred at similar rates (< 1% to 2%) in the vascular-targeted photodynamic therapy group and the active surveillance group. The most common serious adverse event in the vascular-targeted photodynamic therapy group, retention of urine occurred in 15 patients but resolved within 2 months in all cases.[79]

 

Radiation Therapy

External-beam radiation therapy

Radiation therapy also offers the potential for curative treatment of localized prostate cancer. It may be delivered in the form of external-beam radiation therapy (EBRT) or brachytherapy (ie, the insertion of radioactive seeds into the prostate gland). EBRT techniques include 3-dimensional conformal radiation therapy (3D-CRT) and intensity-modulated radiation therapy (IMRT). Higher-dose-rate therapy using stereotactic guidance is being used despite lack of data on long-term survival or complication rates.

In general, after 2 years, the quality-of-life profile for IMRT and surgery are similar, although radiation therapy does pose a slightly higher risk of persistent fecal urgency and incontinence of gas.[80]

Proton-beam therapy is theoretically an excellent modality for EBRT, providing an ideal dose distribution. In a phase 2 study in patients with organ-confined prostate cancer, Nihei et al found that acute, transient grade 2 rectal and bladder toxicity developed in 0.7% and 12% of patients, respectively, who underwent proton-beam therapy; at 2 years, late grade 2 or greater rectal and bladder toxicity developed in 2% and 4.1% of patients, respectively.[81]

A study of radiation therapy for primary prostate cancer treatment by Sheets et al found that, compared with patients undergoing conformal therapy, patients who received IMRT had less gastrointestinal (GI) morbidity and fewer hip fractures and were less likely to undergo additional cancer treatments. They were, however, more likely to develop erectile dysfunction. Patients who received proton therapy had more GI morbidity than did patients receiving IMRT and were more likely to undergo GI procedures.[82]

In a multi-center study, Briganti et al found that early salvage radiation therapy is comparable to adjuvant radiation therapy for improving biochemical recurrence–free survival in pT3pN0 prostate cancer patients after radical prostatectomy. Early salvage radiation therapy may reduce the overtreatment associated with adjuvant radiation therapy without compromising disease control in these patients.[83]

Complications of EBRT include cystitis, proctitis, enteritis, impotence, urinary retention, and incontinence. Rates depend on the total dose and the technique used.

A systematic review and meta-analysis of radiation therapy for prostate cancer found that EBRT, but not brachytherapy, was consistently associated with increased odds for a second malignancy of the bladder, colon, and rectum. Absolute rates were low, however: 0.1-3.8% for bladder, 0.3-4.2% for colorectal, and 0.3-1.2% for rectal cancers.[84]

Brachytherapy

In 2011, the American Society for Radiation Oncology (ASTRO) and the American College of Radiology (ACR) issued a practice guideline for transperineal permanent brachytherapy of prostate cancer. These guidelines established standards for the safe and effective performance of brachytherapy for patients with organ-confined prostate cancer.[85] See External Beam Radiation therapy in Prostate Cancer and Brachytherapy (Radioactive Seed Implantation Therapy) in Prostate Cancer for more information on these topics.

Radiation therapy plus androgen ablation therapy

Androgen ablation has been shown to improve survival in men with localized disease who are treated with external radiation. D’Amico et al reported higher overall survival with the combination of radiation therapy and 6 months of ADT in men with intermediate-risk prostate cancer. Median follow-up was 7.6 years.[86]

A study by Jones et al found that for patients with stage T1b, T1c, T2a, or T2b prostate cancer and a PSA level of 20 ng/mL or less, short-term ADT increased overall survival in intermediate-risk—but not low-risk—men. The 10-year rate of overall survival was 62% with combination therapy, versus 57% with radiation therapy alone; 10-year disease-specific mortality was 4% and 8%, respectively. In this study, ADT was given for 4 months, starting 2 months before radiation therapy.[87]

In a study by Pisansky et al of 1489 intermediate-risk prostate cancer patients, disease-specific survival in patients who underwent 28 weeks of preradiation total androgen suppression (TAS) was not significantly different from that achieved in patients with only 8 weeks of TAS prior to radiation therapy.[88]

Patients in the study were randomized to 8 or 28 weeks of TAS with LHRH agonist, along with a daily nonsteroidal antiandrogen, prior to radiation treatment. This was followed in both groups by an additional 8 weeks of androgen suppression, administered concurrently with radiotherapy.

Pisansky and colleagues found that the 10-year disease-specific survival rate in the study was 95% in the 8-week treatment group and 96% in the 28-week treatment group. The 10-year disease-free survival rates in the 8- and 28-week groups were 24% and 23%, respectively, and the 10-year cumulative incidences of clinical and biochemical relapse were 57% and 60%, respectively.[88]

Radiation therapy versus surgery

The AHRQ found insufficient evidence to determine whether any type of radiation therapy results in fewer deaths or cancer recurrences than radical prostatectomy does in patients with clinically localized prostate cancer.[78] The importance of dose escalation in disease control complicates the extraction of meaningful conclusions from current radiation therapy treatments (eg, 3D-CRT, IMRT).

Brachytherapy has also been compared with surgery in the management of early stage disease. Direct comparisons (ie, prospective, randomized trials) are not readily available, but preliminary data from most centers suggest that permanent prostate implants yield comparable local control and biochemical disease-free rates.

Valid comparisons of surgery and radiation therapy are impossible without data from randomized studies that look at long-term survival rather than PSA recurrence. Variation in radiation techniques and dosage administered; the variable use of androgen ablation, which improves survival in intermediate- and high-risk disease; and the variable impact on quality of life complicate comparison using uncontrolled studies.

Non–Organ-Confined Disease

When imaging studies provide clear evidence of non–organ-confined disease (eg, seminal vesicle or periprostatic involvement), the treatments offered may vary. Typically, some combination of modalities is involved.

Survival of men with locally advanced prostate cancer (T3-4N0M0) is improved by combining external radiation with androgen ablation for 6 months. If brachytherapy is used, it is often combined with EBRT and ADT, although studies demonstrating an improved outcome with combined radiation are also lacking. Because of the aggressive nature of these tumors, active surveillance is an option only in highly selected patients with life expectancies of less than 5 years.

Radical prostatectomy

Historically, radical prostatectomy for clinical stage T3 prostate cancer at initial presentation was not considered beneficial, because of the increased probability of incomplete resection of the cancer, the likelihood of micro-metastatic disease, and increased morbidity. For patients with T3a disease, however, current National Comprehensive Cancer Network guidelines recommend radical prostatectomy plus pelvic lymph node dissection as an option for initial therapy.[31]

Adjuvant therapy

Radical prostatectomy followed by adjuvant radiation is also an option, but the rate of adverse effects with this approach is higher than with external radiation and hormone therapy. In addition, proof is lacking as to whether it offers comparable survival to radiation and hormone therapy.

Neoadjuvant hormone therapy has been used to clinically down-stage patients before surgery; however, all randomized studies to date have failed to show a significant benefit in either disease recurrence or survival. See Neoadjuvant Androgen Deprivation in Prostate Cancer for more information on this topic.

One small, randomized study found that in men undergoing radical prostatectomy who had lymph node metastases detected, the addition of continuous androgen deprivation improved survival. However, it is unknown whether this combination also improves survival for T3-T4, N0 disease.[89]

In this study, Messing et al reported on results in 98 patients who underwent radical prostatectomy and lymphadenectomy and were found to have metastatic prostate cancer in the excised lymph nodes. Patients were randomized to receive immediate hormone blockade or to undergo observation. At a median follow-up of 7 years, the survival rate in the hormone blockade group was superior to that in the observation group (85% vs 65%, respectively).

This result becomes more impressive when only deaths from prostate cancer are considered (94% vs 68% survival rate, respectively). Not unexpectedly, the use of early hormone blockade was associated with a higher rate of grade I/II hematologic, genitourinary, and constitutional (eg, weight gain) toxicities.

The study by Messing et al supports the use of early hormone blockade in the setting of regionally advanced disease (ie, node-positive). However, quality of life may be compromised unless patients are carefully selected to balance the risks and benefits of therapy.

Unfortunately, the Messing study does not address the potential benefit of postoperative locoregional therapy (ie, radiation therapy). The benefit of radiation therapy following radical prostatectomy has been demonstrated in certain high-risk patients (eg, those with positive surgical margins) but not in men with node-positive disease.

Androgen ablation

Reports from the Memorial Sloan-Kettering Cancer Center suggest that long-term survival rates (ie, ≥15 y) are essentially zero in the setting of synchronous nodal involvement at diagnosis. In this group of patients, hormone blockade with or without EBRT is used. Patients in whom non–organ-confined disease is suspected or confirmed but metastases are absent typically receive radiation therapy with hormone manipulation (LHRH agonist or antagonist treatment). The effect of chemotherapy in this setting has not been well studied.

Several phase 3, randomized clinical trials have assessed the value of total androgen blockade in the treatment of patients with non–organ-confined disease. In each of these trials, patients exhibited longer disease-free intervals and PSA control of disease when total androgen suppression is used either during or after radiation therapy treatment. Few data suggest that the improved biochemical control of disease translates to improved survival, however.

A study by Bolla et al demonstrated increased survival with hormone blockade in conjunction with EBRT.[90] The authors reported 5-year disease-free survival rates of 74% with combination therapy versus 40% for EBRT alone. Moreover, overall 5-year survival rates improved, favoring patients who received 3 years of LHRH agonist treatment (78% vs 62%).

A subsequent study by Bolla et al found that when androgen suppression is given in combination with radiation therapy, 6 months of androgen suppression provides inferior survival compared with 3 years of androgen suppression.[91] These data suggest the importance of prolonged androgen ablation therapy in combination with EBRT.

Similarly, a meta-analysis by Bria et al suggests that the combination of androgen suppression and radiation therapy significantly decreases recurrence and mortality in patients with localized prostate cancer, without affecting toxicity.[92]

In men with high-risk prostate cancer managed with long-term ADT, including radiotherapy as part of initial treatment improved outcomes in a recent randomized study. During a median follow-up of 10.7 years, 118 of 439 patients treated with hormone therapy alone died of prostate cancer, compared with 45 of 436 patients treated with combination therapy (P< .0001). In the hormone-therapy-only group, the 10-year and 15-year prostate-cancer-specific mortality rates were 18.9% and 30.7%, compared with 8.3% and 12.4% in the combination therapy group.[93]

The AHRQ concluded that in high-risk patients (as defined by PSA levels >10 ng/mL or Gleason score >6), adding androgen ablation to EBRT may decrease overall and disease-specific mortality.[77] In contrast to Bria et al, however, the AHRQ found that the combination increases adverse effects.[77]

Androgen ablation commonly begins several months before radiation is initiated and continues for several months or years afterward. However, the optimum sequencing of androgen blockade and radiation therapy remains unclear. So far, the best results have occurred with 3 years of therapy, but those studies were performed when lower doses of radiation were used without IMRT techniques. Additional studies would be needed using higher doses of radiation to determine whether the same benefit would occur.

ADT produces a range of adverse effects, but these symptoms usually diminish or disappear after the hormone therapy is discontinued. However, awareness and treatment of the various side effects of this therapy are important for a man’s quality of life and for reducing the morbidity of this therapy.

Testosterone replacement therapy

In contrast to the established role of ADT, one study has demonstrated benefit of testosterone replacement therapy (TRT) in selected patients with prostate cancer. 

In a study of 824 patients who underwent robot-assisted radical prostatectomy (RARP) for the primary treatment of prostate cancer, Towe et al gave TRT for postoperative recovery of sexual function to the subset of patients (n = 152, 18%) who had low preoperative levels of free testosterone. Patients remained on TRT throughout follow-up or until biochemical recurrence. Surprisingly, after a median follow-up of 3.1 years, TRT was associated with a 53% relative reduction in risk for biochemical recurrence. In addition, TRT prolonged the time to recurrence by a median of 1.5 years (P = 0.005).[94]

Management of Advanced and Metastatic Disease

A rise in PSA after radical prostatectomy to greater than 0.2 ng/mL or three consecutive PSA increases after radiation therapy are evidence of impending disease progression. Not all men who have a rising PSA will develop metastases, and for that reason not all such men require treatment. The risk of metastases and death depend on the patient’s Gleason score, the length of time between the nadir PSA and the onset of the PSA’s rise, and the PSA doubling time.[95]

Patients who have PSA (biochemical) failure following radical prostatectomy and have no evidence of metastatic disease have the options of watchful waiting, radiation therapy, or hormone ablation as salvage therapy. Similarly, patients who have PSA failure following radiation therapy have the following options:

  • Watchful waiting
  • Brachytherapy
  • Prostatectomy
  • Cystoprostatectomy
  • Cryotherapy
  • Hormone ablation

The pretreatment Gleason score, clinical stage, PSA level, and percentage of positive core biopsy results have been found to be reliable predictors of failure following local therapy. Unfortunately, no means of identifying recurrences limited to the pelvis is reliable. Although a Gleason grade of 7 or less is associated with a better prognosis than a grade of 8 or more, the survival likelihood associated with a rise in the PSA level is greater if the rise occurs after 2 years following local treatment than if it occurs before 2 years.

The decision algorithm for the initiation of treatment for biochemical failure is controversial. Factors to consider include the following:

  • Type of local therapy previously instituted (if any)
  • Patient's life expectancy
  • Intention and likelihood of cure
  • Risk for increased morbidity
  • Patient's quality of life

Guidelines from the Naitonal Comprehensive Cancer Network (NCCN)[31] and the European Association of Urology[96] provide recommendations for treating patients with advanced prostate cancer in whom local therapy has failed.

Therapeutic options include the following:

  • LHRH agonists - Available in 1-month, 3-month, 6-month, and once-yearly depots
  • LHRH antagonist - Available in a 1-month depot
  • Complete androgen blockade - LHRH agonist or antagonist with an oral antiandrogen
  • Nonsteroidal antiandrogen monotherapy
  • Bilateral orchiectomy

A balance between disease control and minimization of the toxicity and intolerance of the treatment is difficult to maintain. Androgen blockade, while able to limit disease progression and reduce urinary outlet obstruction, produces a number of adverse effects. Intermittent hormone therapy, which has been studied in men with nonmetastatic disease, does enable some men to minimize their adverse effects without affecting overall survival, even though prostate cancer mortality is slightly higher.

An indication for immediate bilateral orchiectomy is spinal cord compression, because it avoids the potential flare response that can occur during the first 3 weeks of treatment with an LHRH agonist.

Although administering an antiandrogen just prior to starting the LHRH agonist can reduce the risk of a flare response, it does not completely eliminate that risk. One advantage of LHRH antagonist therapy is the avoidance of a flare response and a more immediate drop in testosterone than with LHRH agonists.

For full discussion, see Metastatic and Advanced Prostate Cancer.

Investigational therapies

Investigational therapies for recurrent prostate cancer include high-intensity focused ultrasound (HIFU) and gene therapy.[97] Other options include cellular immunotherapy,[98] tumor vaccines, or vaccination with tumor- or prostate-specific proteins such as PSA.

High-intensity focused ultrasound

HIFU is an acoustic ablation technique that uses ultrasound waves to destroy prostate tissue. Like cryotherapy, this is a transperineal procedure that does not involve ionizing radiation. (Among several cryotherapy studies that are currently under way is a multicenter national trial comparing the effectiveness of cryotherapy with HIFU.)

HIFU has been available since 1993 in Canada, Europe, and Mexico but is not yet approved for use by the US Food and Drug Administration (FDA). Patients who undergo the procedure require a catheter for about 10 days after therapy. Although urologists from the United States perform the procedure in Mexico and the Dominican Republic, patients should be counseled that the cure rates with this technique have not been proved, nor has the incidence of side effects been determined.[99]

Radiolabelled prostate-specific membrane antigen 

Treatment with prostate-specific membrane antigen 617 that is radiolabelled with lutetium-177 (177Lu–PSMA-617) is a promising approach to metastatic castration-resistant prostate cancer that has progressed after standard treatments. In this technique, after a screening PSMA and FDG-PET/CT to confirm high PSMA expression in the metastatic cells, the 177Lu–PSMA-617 is injected intravenously; the PSMA-16 binds with high affinity to PSMA, and the attached 177Lu then delivers high doses of beta particles to the metastatic cells. As beta particles travel only 1 millimeter, radiation exposure to normal cells is minimized.

Early studies of treatment with 177Lu–PSMA-617 have reported high response rates, low toxic effects, and pain reduction.[100, 101]  In an Australian trial, 22 of 49 patients (44.9%) showed a decline of ≥ 50% in PSA levels, and most adverse events were grade I (predominantly, dry mouth and transient nausea).[101]

Androgen Suppression in Advanced and Metastatic Disease

Androgen deprivation is considered the primary approach to the treatment of metastatic prostate cancer. However, ADT has been found to be palliative, not curative. Prior to the development of newer therapies, overall survival for patients with metastatic prostate cancer ranged from 24-36 months. In recent years, however, several new therapies have been approved that prolong survival in men whose disease progresses on ADT.

Early versus delayed treatment

In the years following the introduction by Huggins and Hodges of hormone therapy for prostate cancer,[102] early institution of such treatment was recommended, based on comparison with historical controls. Later, the Veterans Administration Cooperative Urology Research Group (VACURG) studies resulted in the recommendation to defer hormone therapy until symptomatic progression occurred; this was thought to avoid the promotion of early androgen resistance in prostate tumors.[103]

Subsequently, the controversy of the appropriate timing of ADT was renewed because of the advent of an LHRH antagonist and LHRH agonists. Laboratory studies demonstrated that early hormone therapy does not confer early resistance. Moreover, clinical trials found that it provided significantly longer survival with fewer complications (eg, pathologic fractures, spinal cord compression, ureteral obstruction) than did deferred treatment.[104, 105]

Intermittent androgen suppression

Intermittent androgen suppression has been assessed in prospective, randomized studies as a possible means of minimizing the side effects of ADT. Crook et al found that intermittent androgen suppression was noninferior to continuous therapy with respect to overall survival.[106] In a Spanish study, a greater number of cancer deaths in the intermittent treatment arm was balanced by a greater number of cardiovascular deaths in the continuous treatment arm.[107]

In both studies, intermittent therapy resulted in better quality of life. Indeed, this benefit might be more pronounced than was seen in these studies, because the testosterone level does not return to baseline in about one third of men on intermittent therapy.

However, survival in men with metastatic hormone-sensitive prostate cancer may be shorter when androgen deprivation therapy is given intermittently rather than continuously, according to a large study of 770 men treated with intermittent therapy and 765 men treated with continuous therapy, who were followed for a median of almost 10 years (average survival, 5.1 vs 5.8 years, a 10% higher relative risk for death). Intermittent therapy was associated with better erectile function and mental health at month 3 but not thereafter.[108]

National Comprehensive Cancer Network (NCCN) guidelines advise that for men with nonmetastatic prostate cancer, intermittent ADT is considered as safe as continuous ADT. The NCCN recommends that intermittent ADT be considered in men with metastatic disease.[109]  

Combined androgen blockade

Combined androgen blockade (CAB; also known as maximal androgen blockade [MAB]) recognizes the 5-10% contribution of adrenal androgens to total body testosterone. The concept was originally studied by Huggins and then by Labrie and colleagues after the development of medications that allowed CAB to be accomplished pharmacologically rather than surgically.[110, 111]

Considerable controversy has surrounded this approach despite a total of 27 prospective, randomized studies. Most of these studies showed no benefit from CAB, but 3 showed significant 3-6 month increases in survival with the use of an LHRH agonist combined with an antiandrogen.[112]

One explanation for many of the negative studies is the antiandrogen withdrawal phenomenon, in which a tumor that has started to grow despite antiandrogen treatment regresses when antiandrogen treatment is stopped. This phenomenon was highlighted by the advent of PSA testing; it was observed that when the PSA increased in a patient who was receiving antiandrogen treatment, withdrawing the antiandrogen resulted in a decline in PSA in 20-40% of patients, with some also having objective improvement.

The antiandrogen withdrawal phenomenon apparently results from alterations in the tumor’s androgen receptor, which causes the antiandrogen to stimulate growth. The phenomenon was not known at the time the studies were conducted. Since the study protocols called for continuing the antiandrogen until objective progression occurred, many men may have been made worse by not stopping the antiandrogen sooner.[110]

Although meta-analyses have shown that overall improvement in survival with antiandrogen treatment is small, it remains the best option for maximizing survival. Current American Society of Clinical Oncology (ASCO) guidelines recommend either orchiectomy or an LHRH agonist for initial hormonal management of androgen-sensitive, metastatic, recurrent, or progressive prostate cancer. However, the guidelines state that CAB should be considered in these patients.[113]

The addition of an antiandrogen to LHRH agonist treatment can minimize the risk of the flare response (ie, temporary rise in testosterone levels) that can occur with LHRH treatment. Giving the antiandrogen for only 1-3 months reduces, but does not eliminate, the risk of a flare response; instead, the antiandrogen should continue to be given unless PSA progression occurs.

If the PSA level begins to rise in a patient who is receiving CAB, the antiandrogen should be discontinued before other therapy is initiated. Generally, 1-2 months are needed following antiandrogen withdrawal to see whether the patient will improve. The optimal interval varies with different antiandrogens.

Androgen suppression plus docetaxel

Early results from a randomized, controlled study of 790 men with hormone-sensitive metastatic prostate cancer indicated that patients treated with the chemotherapy drug docetaxel at the beginning of standard hormone therapy with androgen deprivation therapy (ADT) have improved survival compared with those treated with hormone therapy alone.[114]

Patients were treated with either ADT alone or ADT combined with docetaxel, every 3 weeks for 18 weeks. Patients who received docetaxel had a significant improvement in overall 3-year survival, as compared with those treated with ADT alone (69.0% vs. 52.5%). In patients with a high extent of metastatic disease, 3-year survival rates were 63.4% for ADT plus docetaxel treatment versus 43.9% for ADT alone.[114]

Androgen suppression plus abiraterone

In February 2018, the FDA approved abiraterone acetate (Zytiga) in combination with prednisone for patients with metastatic high-risk castration-sensitive prostate cancer, based on findings from the LATITUDE trial. In this double-blind, placebo-controlled, phase 3 trial in 1199 men with metastatic, castration-sensitive prostate cancer, the addition of abiraterone acetate and prednisone to ADT significantly increased overall survival and radiographic progression-free survival. Median overall survival was significantly longer in the abiraterone group versus the placebo group (not reached vs. 34.7 months). Median radiographic progression-free survival was 33 months in the abiraterone group versus 14.8 months in the placebo group.[115]

In addition, the abiraterone group had significantly better outcomes in all secondary end points, including the time until pain progression, next subsequent therapy for prostate cancer, initiation of chemotherapy, and prostate-specific antigen progression (P< 0.001 for all), along with next symptomatic skeletal events.[115]

In the STAMPEDE trial, the addition of abiraterone acetate and prednisolone at the initiation of primary ADT was associated with a 71% relative improvement in the time to treatment failure, which translated into a 37% difference in overall survival. Three-year  survival rates were 83% with combination therapy, versus 76% with ADT alone, and treatment failure–free survival rates at 3 years were 75% vs 45%, respectively. STAMPEDE included 1917 men with newly diagnosed, locally advanced or metastatic prostate cancer, or relapsed disease with high-risk features.[116]

Adverse effects of androgen suppression

Surgical and medical castration lead to a number of side effects, including the following, that can have a significant impact on a man’s quality of life:

  • Anemia
  • Breast enlargement
  • Cognitive impairment
  • Decreased libido
  • Decreased muscle mass
  • Erectile dysfunction
  • Fatigue
  • Fractures
  • Gastrointestinal tract disturbances
  • Gynecomastia
  • Hot flashes
  • Osteoporosis
  • Metabolic syndrome
  • Pulmonary edema
  • Psychological changes
  • Weight gain

In addition, in men with prostate cancer receiving ADT, lean body mass decreases significantly after 12-36 months of treatment.[117]

Uncertainty remains about the impact of androgen ablation on cardiovascular morbidity and mortality. However, the combination of weight gain and anemia in men with asymptomatic cardiovascular disease could adversely affect survival in some cases.

The FDA has advised that manufacturers of gonadotropin-releasing hormone (GnRH) agonists, which are approved for palliative treatment of advanced prostate cancer, must add safety warnings about the increased risk of diabetes and certain cardiovascular diseases (eg, myocardial infarction, sudden cardiac death, stroke) in men receiving these medications. The FDA notes that although the risk for these complications appears to be low, patients should be evaluated for risk factors for these diseases before prescribing these agents.[118]

Patients receiving GnRH agonists should be actively monitored for diabetes and cardiovascular disease and treated when possible. Periodic measurement of fasting glucose, cholesterol, triglycerides, and blood counts should be performed. In addition, the package inserts for all LHRH medications recommend periodically measuring serum testosterone, because levels above 50 ng/dL do occur and may adversely affect long-term survival.

Long-term androgen blockade for prostate cancer may also increase a patient’s risk for colorectal cancer. An observational study by Gillessen et al of men with prostate cancer—identified through the Surveillance, Epidemiology, and End Results (SEER) database of the National Cancer Institute—found that after adjustment for confounding variables such as age, socioeconomic status, and the use of radiation therapy, the rate of colorectal cancer was 30-40% higher in men treated with androgen blockade than in those who were not.[119]

In a study of the bone density differences between African-American and Caucasian men who were receiving androgen deprivation therapy for prostate cancer, Morgans et al found that African-American men had a greater hip bone mineral density and tended to have fewer prevalent vertebral fractures than Caucasian men. However, African-American men experience a decrease in bone mineral density similar to that of Caucasian men despite a lower baseline risk for osteoporosis and fracture.[120]

Acute kidney injury

In a case-control analysis of more than 10,000 men with prostate cancer, ADT was significantly associated with an increased risk for acute kidney injury (AKI). Current use of any ADT more than doubled the risk for AKI, compared with such risk in patients who had never undergone ADT. The risk was especially heightened for combination therapies and estrogens.[121, 122]

In the study, researchers reviewed data from the UK Clinical Practice Research Datalink on 10,250 men newly diagnosed between 1997 and 2008 with nonmetastatic prostate cancer. The overall incidence rate of AKI in the study population was 5.5 per 1000 person-years, compared with 1.8 per 1000 person-years in the general population. The odds of developing AKI with current ADT use, compared with that for persons who never used the therapy, were highest during the first year of treatment. The odds decreased with longer durations but remained statistically significant for up to 3 years, as well as for 3 years and beyond.

Bone protection in patients receiving androgen blockade

Two drugs, zoledronic acid [Reclast] and denosumab [Prolia], have been approved to treat osteoporosis secondary to androgen deprivation. These drugs are given along with supplemental vitamin D and calcium. Both agents are associated with a low incidence of osteonecrosis of the jaw.

A double-blind, placebo-controlled, multicenter study in men with primary or hypogonadism-associated osteoporosis found that over a 14-month period, treatment with zoledronic acid reduced the risk of vertebral fractures by 67%. New morphometric vertebral fracture occurred in 1.6% of men taking zoledronic acid and in 4.9% taking placebo. Patients receiving zoledronic acid had significantly higher bone mineral density and lower bone-turnover markers. However, the rate of myocardial infarction was higher in the treatment group (1.5% vs 0.3%)[123]

A double-blind, placebo-controlled, multicenter study in men undergoing ADT for nonmetastatic, hormone-sensitive prostate cancer found that patients receiving denosumab had a decreased incidence of new vertebral fractures at 36 months (1.5% vs 3.9% with placebo). Patients receiving denosumab also had significant increases in bone mineral density in the total hip, femoral neck, and distal third of the radius.[124]

Radiation Therapy in Metastatic Disease

In a study of men with newly diagnosed metastatic prostate cancer, treatment with prostate radiation and androgen deprivation therapy (ADT) led to substantially longer survival compared with treatment with ADT alone. In the study, which included 6,382 men, combination therapy yield superior median survival (55 v 37 months) and 5-year overall survival (49% versus 33%) (P < 0.001).[125]

In patients with metastatic prostate cancer, radiation is also applied for palliative purposes. It is used in patients with castrate-resistant disease with painful bone metastases, in patients at risk for fracture, and in patients with impending spinal cord compression.

A meta-analysis of the use of radioisotopes to relieve pain from bone metastases found that over 1-6 months, pain may be reduced without an increase in analgesic use; however, severe effects such as leukocytopenia and thrombocytopenia frequently surface.[126]

Radium-223 dichloride (Xofigo), formerly alpharadin, is an alpha–particle-emitting radioactive therapeutic agent that was approved by the FDA in May 2013.[127] It is approved for men with castration-resistant prostate cancer (CRPC), symptomatic bone metastases, and no known visceral metastatic disease. Approval was based on the ALSYMPCA trial (ALpharadin in SYMptomatic Prostate CAncer), which is the first randomized phase III trial to demonstrate improved survival of CRPC with a bone-seeking radioisotope.[128, 129, 130] The multinational trial was conducted in 19 countries and included 921 patients with prostate cancer that had progressed with symptomatic bone metastases and no known visceral metastases. The trial was halted early after a planned interim analysis found a survival benefit in favor of radium-223. Updated analysis has demonstrated a 3.6-month survival advantage compared with placebo (14.9 vs 11.3 months, respectively).

Surgical Management of Metastatic Disease

There is no evidence that radical prostatectomy conveys any benefits to patients with documented metastatic disease. However, transurethral resection is sometimes needed in men who develop obstruction secondary to local tumor growth.

Bilateral orchiectomy can be used to produce androgen deprivation in patients with widely advanced and metastatic prostate cancer. Since the introduction of LHRH agonist and antagonist therapies, surgical intervention has been practiced less often. An indication for immediate bilateral orchiectomy is spinal cord compression, because it avoids the potential flare response that can occur during the first 3 weeks of treatment with an LHRH agonist.

Management of Castrate-Resistant Prostate Cancer

Eventually, almost all patients with metastatic disease become resistant to androgen ablation. In patients with castrate serum testosterone levels (less than 50 ng/dL), castrate-resistant prostate cancer is defined as 2-3 consecutive rises in PSA levels obtained at intervals of greater than 2 weeks and/or documented disease progression based on findings from computed tomography (CT) scan and/or bone scan, bone pain, or obstructive voiding symptoms.

Rarely, a rise in PSA may reflect failure of LHRH treatment to control testosterone secretion, rather than the development of castrate-resistant disease. Therefore, the testosterone level should be measured when the PSA rises. If the serum testosterone level exceeds castrate levels, changing the antiandrogen therapy may drop the PSA and delay the need for other therapy.

Prior to the development of the most recent therapies, the median time to symptomatic progression after a rise in the PSA level of more than 4 ng/mL was approximately 6-8 months, with a median time to death of 12-18 months. Since then, however, the latter figure has increased.

Little information is available about the impact of maintaining hormone suppression when androgen-independent progression occurs, but the general consensus among specialists is that the treatment should continue. The reasoning is that tumor cells are still hormone sensitive and may grow faster if the testosterone is permitted to rise.

Nonchemotherapy options that provide palliation and improve quality of life include the following:

  • Megestrol
  • Nonsteroidal antiandrogens
  • Corticosteroids
  • Ketoconazole
  • Radiation therapy
  • Bisphosphonates
  • Suramin
  • Estrogen

None of these have been shown to improve survival, although few of them have been properly assessed for that endpoint.

Docetaxel

Therapeutic options for patients with castrate-resistant prostate cancer have changed significantly in the past 7 years, beginning with the approval of docetaxel chemotherapy. Two randomized studies have shown that this drug improves survival.[131] In the Southwestern Oncology group trial SWOG 99-16, median survival was 2 months longer with docetaxel plus estramustine than with mitoxantrone plus prednisone (17.5 vs 15.6 months).[132] Gastrointestinal and cardiovascular side effects were more common in the group receiving docetaxel, however.

In the TAX 327 trial, median survival was 16.5 months in patients given mitoxantrone, 17.4 months in those given weekly docetaxel, and 18.9 months in those given docetaxel every 3 weeks. All 3 groups also received prednisone.[133]

A follow-up analysis confirmed these findings, with median survival of 16.3 months in the mitoxantrone arm, 17.8 months in the weekly docetaxel arm, and 19.2 months in the every-3-weeks arm.[134]

Other therapies now approved for androgen-independent prostate cancer include the following:

As previously mentioned, early results from a randomized, controlled trial indicated that in patients with hormone-sensitive metastatic prostate cancer, those who are treated with docetaxel at the beginning of standard hormone therapy with ADT have improved survival compared with those treated with hormone therapy alone.[114]

In the phase 3 COMET-1 study, the tyrosine kinase inhibitor cabozantinib did not significantly improve overall survival compared with prednisone in heavily treated patients with metastatic castration-resistant prostate cancer who had progressive disease after docetaxel and abiraterone and/or enzalutamide. Cabozantinib had some activity in improving bone scan response, which was the secondary trial end point. However, grade 3 to 4 adverse events and discontinuations because of adverse events were higher with cabozantinib than with prednisone.[135]

Sipuleucel-T

Sipuleucel-T is a therapeutic vaccine that was approved by the FDA in April 2010 for asymptomatic or minimally symptomatic prostate cancer with metastases resistant to standard hormone treatment. The NCCN supports its use in men with good performance status, a life expectancy of more than 6 months, no hepatic metastases, and no or minimal symptoms.[136]

Sipuleucel-T must be prepared individually for each patient. To create Sipuleucel-T, peripheral blood mononuclear cells, including antigen-presenting cells (APCs), are extracted from the patient using leukapheresis and are incubated with prostatic acid phosphatase, an antigen expressed in prostate cancer tissue. The product, which now contains activated APCs, is then reinfused into the patient.

An updated report of a randomized, placebo-controlled study by Kantoff et al showed median survival of 25.8 months versus 21.7 months and a survival probability at 36 months of 32.1% versus 23% in the sipuleucel-T and placebo arms, respectively.[137] The study included a crossover design, which means the true benefit is likely to be higher. A subset analysis found that survival in men with a PSA level below 22 ng/mL was 13 months longer in the sipuleucel-T group than in the control group.

One aspect of sipuleucel-T treatment that has made its acceptance difficult is that it does not appear to produce either a PSA or objective disease response; the benefit is limited to overall survival. Consequently, other therapies can be instituted after the sipuleucel-T treatment regimen has been completed.

Adverse events that have been reported more often with sipuleucel-T than with placebo include chills, pyrexia, headache, influenza- like illness, myalgia, hypertension, hyperhidrosis, and groin pain. The majority of these were low grade and resolved within 1-2 days.[137]

Abiraterone acetate

Abiraterone acetate (Zytiga), an inhibitor of androgen biosynthesis, was approved by the FDA in April 2011 for use in combination with prednisone for the treatment of patients with metastatic, castrate-resistant prostate cancer who have received prior chemotherapy containing docetaxel. Abiraterone blocks CYP17A1, an enzyme that is important in the synthesis of testosterone by the adrenal gland and by prostate cancer cells. This results in blocking all testosterone production.

Approval of abiraterone was based on the results of a randomized, controlled trial that showed improved survival in 1195 patients with castrate-resistant prostate cancer who were treated with this combination.[138] More recently, a large, international, randomized trial found a median overall survival period of 15.8 months in men receiving abiraterone, compared with 11.2 months in the placebo group.[139]

Men receiving abiraterone also had a significantly longer time to PSA progression, a longer progression-free survival, and a higher PSA response. The side effects occurring more frequently in the treated group were related to decreased mineralocorticoid effects and included hypertension, fluid retention, and hypokalemia.[139]

An ultramicronized abiraterone tablet (Yonsa) was approved in May 2018 for CRPC in combination with methylprednisolone. The ultramicronized formulation may be administered with or without food, whereas, the original tablet formulation (Zytiga) must be administered 1 hour before or 2 hours after meals.

In December 2012 the FDA expanded the approved use of abiraterone to treatment of men with late-stage (metastatic), castrate-resistant prostate cancer prior to receiving chemotherapy. The expanded indication was based on a study in which patients who received abiraterone had a median overall survival period of 35.3 months, compared with 30.1 months for patients receiving placebo, and had better radiographic progression–free survival.[140]

Enzalutamide

Enzalutamide acts by inhibiting the binding of androgens to the androgen receptor and inhibits translocation of the androgen receptor into the nucleus. The results of a large, randomized trial showed a median overall survival period of 18.4 months in the enzalutamide group, versus 13.6 months in the placebo group.[141]

Patients receiving the active drug also had a higher PSA and quality-of-life response and a longer time to PSA progression, longer radiographic progression-free survival, and longer time to first skeletally related event. Fatigue, diarrhea, and hot flashes were more common in the enzalutamide group. Seizures were reported in five patients (0.6%) receiving enzalutamide.[141]

Enzalutamide proved superior to bicalutamide in the TERRAIN clinical trial, a double-blind, randomized phase II study in 375 asymptomatic or minimally symptomatic men with prostate cancer progression on ADT. Patients in the group had Median progression-free survival was significantly longer with enzalutamide than bicalutamide (15.7 versus 5.8 months; HR, 0.44; P< 0.0001). However, 68% of patients in the enzalutamide group and 88% of those in the bicalutamide group discontinued their assigned treatment before study end, mainly due to progressive disease.[142]

In July 2018, the FDA approved an expanded indication for enzalutamide in CRPC to include patients with nonmetastatic disease. Approval was based on the PROSPER trial. In the 1401-patient trial, enzalutamide decreased the risk for distant metastasis or death by 71% (hazard ratio, 0.29; 95% confidence interval, 0.24 - 0.35; P < 0.0001), with a median metastasis-free survival of 36.6 compared with 14.7 months in the placebo group (an improvement of 21.9 months).[143]

Cabazitaxel

Cabazitaxel is another taxane that acts as a microtubular inhibitor. In a study of 755 men with metastatic, castrate-resistant prostate cancer that had progressed despite docetaxel treatment, the median overall survival period was 15.1 months in patients receiving cabazitaxel, versus 12.7 months in those receiving mitoxantrone. Median progression-free survival was also longer with cabazitaxel. Both groups also received prednisone. The most common clinically significant grade 3 or higher adverse events with cabazitaxel were neutropenia and diarrhea. Febrile neutropenia was also more common with cabazitaxel.[144]

Apalutamide

Apalutamide, an androgen receptor inhibitor, was approved by the FDA in February 2018 for treatment of nonmetastatic, castration-resistant prostate cancer (NM-CRPC). The FDA based its approval on safety and efficacy data from the phase 3 SPARTAN (Selective Prostate Androgen Receptor Targeting With ARN-509) trial, in which median metastasis-free survival (the primary endpoint), was 40.5 months in the apalutamide group as compared with 16.2 months in the placebo group (P < 0.001). That translated into a 72% reduction in the relative risk for metastasis or death with apalutamide (hazard ratio, 0.28; 95% confidence interval [CI], 0.23 - 0.35).[145] .

In the SPARTAN trial, 806 men were randomized to receive treatment with apalutamide (240 mg per day) and 401 to receive placebo; all participants also received hormone therapy, either gonadotropin-releasing hormone analogue therapy or surgical castration. All the participants had undergone previous definitive treatment, either surgery or radiotherapy, for prostate cancer, but their PSA scores doubled within 10 months or less following treatment, despite hormone therapy.[145]

Darolutamide

Similar to apalutamide, darolutamide was approved for patients with nonmetastatic castration-resistant prostate cancer.

Approval was based on the phase 3 ARAMIS trial which evaluated metastasis-free survival, with the presence of metastasis determined by independent central review of radiographic imaging every 16 weeks. Patients (n=1509) received either darolutamide or placebo while continuing androgen-deprivation therapy. In the planned primary analysis, the median metastasis-free survival was 40.4 months with darolutamide, as compared with 18.4 months with placebo. Darolutamide was also associated with benefits to all secondary end points, including overall survival, time to pain progression, time to cytotoxic chemotherapy, and time to a symptomatic skeletal event. Among men with nonmetastatic, castration-resistant prostate cancer, metastasis-free survival was significantly longer with darolutamide than with placebo.[146]

Drug sequencing for androgen-independent prostate cancer

The availability of the above new agents presents a challenge for physicians and patients, who must decide on the best sequence and timing for each of them. So far, no studies have been done to determine the best approach. Studies in progress are likely to result in some change to the sequencing of these drugs.

As of October 2012, and excluding cost considerations, men with asymptomatic or minimally symptomatic progressive disease can start with immunotherapy using sipuleucel-T. Since no objective responses are expected, patients can then be given abiraterone acetate.

On September 11, 2014 the FDA expanded the approved use of enzalutamide for the treatment of men with late-stage (metastatic), castrate-resistant prostate cancer prior to receiving chemotherapy. The expanded indication was based on a study in which patients who received enzalutamide reduced the risk of radiographic progression or death by 83% versus placebo, while significantly reducing the risk of death by 29%.[147]

Without formal studies to guide recommendations, either drug may be used next, although enzalutamide does not require prednisone, and for that reason it may be most suitable. Hopefully, studies will be done to determine whether men are better off receiving either enzalutamide or abiraterone first or second. Men showing progression on those drugs should then be offered docetaxel followed by cabazitaxel.

Bone Protection in Metastatic Disease

Use of a bone-protective therapy is an important aspect of managing men with metastatic disease. Two agents are now approved for this indication: zoledronic acid, a bisphosphonate, and denosumab, an antibody that inhibits osteoclastic activity in bone. Both drugs delay the risk of skeletally related events by relieving bone pain, preventing fractures, decreasing the need for surgery and radiation to the bones, and lowering the risk of spinal cord compression.

Zoledronic acid is administered as an intravenous infusion. Denosumab is administered subcutaneously. In a double-blind, randomized, comparative trial performed in men with hormone-refractory disease, the time to first skeletally related event was significantly longer with denosumab than with zoledronic acid (20.7 mo vs 17.1 mo, respectively). Hypocalcemia was more common in the denosumab group than in the zoledronic acid group (13% vs 6%, respectively). Osteonecrosis of the jaw occurred infrequently in both groups (2% vs 1%, respectively).[148]

Vitamin D and calcium should be taken as supplements with this therapy. In addition, patients should be monitored regularly for hypocalcemia.

Palliative Therapy

Despite the availability of new therapies, most men with metastatic prostate cancer will eventually experience progression of disease. For these patients, palliative care is important, and early consultation with hospice may provide for a smoother transition.

The combination of mitoxantrone and prednisone is an approved treatment for symptoms of metastatic disease but does not improve survival. Bone pain due to metastatic disease requires narcotics, awareness of fractures, and, possibly, palliative radiation.

Urinary retention

Urinary retention may occur secondary to urethral strictures, bladder outlet obstruction, or a blood clot. Cystoscopy or a retrograde urethrogram should be performed to identify the cause. Strictures can be either dilated or treated endoscopically. Outlet obstruction can be managed by transurethral resection. Ureteral obstruction due to lymphadenopathy may be treated with a ureteral stent or percutaneous nephrostomy.

Long-term urinary retention or malignant urinary obstruction due to untreated prostate cancer can lead to chronic renal failure, which manifests as uremic symptoms and an elevated serum creatinine level. Patients on watchful-waiting protocols are at risk for this if they are not closely monitored.

Hematuria

This may manifest as a small element of prostate venous bleeding or it may lead to large clots. Hematuria is more common in patients who have undergone radiation therapy.

Vigorously irrigate the bladder with copious amounts of fluid to remove all evidence of clots. Sterile water is best because it helps to lyse the clot. Use care, however, because absorption of the fluid may occur in situations in which prostatic venous channels are open.

Prostatic bleeding may be treated first with transurethral resection and cauterization. If that is unsuccessful, medications can be attempted. Androgen ablation can be tried if not already in use. Otherwise, aminocaproic acid and megestrol may help some men.

Urinary incontinence

Incontinence from bladder spasm or irritation is common immediately after various prostate treatments. While patients have urinary catheters in place, oxybutynin, tolterodine, belladonna and opium suppositories, and phenazopyridine (Pyridium) may be used to decrease symptoms.

Patients with incontinence secondary to radical prostatectomy or radiation may benefit from placement of a urinary sphincter. In rare occasions, urinary diversion may be considered.

Rectal complications

Although uncommon, a urethrorectal fistula may occur after surgery or radiation. Manage the fistula with urinary and fecal diversion using appropriate treatment options.

Rectal bleeding and tenesmus are observed in patients treated with radiation. Steroid enemas and in some cases focal cauterization can alleviate the problem.

Fractures

Patients receiving ADT and those with bone metastasis should receive preventive therapy for fractures. Patients diagnosed with impending paralysis due to spinal cord compression or patients with pathologic fractures should be immediately hospitalized and treated emergently with spinal cord decompression, steroids, and orchiectomy or an LHRH antagonist.

Prevention

Possible preventive measures for prostate cancer include lifestyle modification and chemoprevention with 5-alpha-reductase inhibitors (5-ARIs). Use of 5-ARIs, however, has proved problematic. Lifestyle measures such as weight loss in obese patients and physical activity can be recommended unequivocally because of their multiple benefits.

Lifestyle measures

Diets associated with a reduced risk of prostate cancer in epidemiologic studies are composed mainly of vegetables, fruits, grains, and fish. Tomatoes (because of their lycopene content), broccoli, green tea, and soy have all been hypothesized to be beneficial.

Increased risk has been shown with high-fat diets, excessive intake of estrogens and phytoestrogens, and the consumption of burned or charred foods. Obesity appears to be the diet-related factor most strongly associated with prostate cancer, so overall energy intake is important.

Because a high-fat diet is linked with a higher incidence of prostate cancer, a low-fat diet may be beneficial for men at high risk of developing prostate cancer (ie, those with a positive family history, African Americans) and for patients undergoing treatment for advanced prostate cancer. However, no prospective studies have proved that dietary modification provides a benefit.

Nutritional supplements also have not proved beneficial in research studies. The Physicians' Health Study II, a long-term, randomized, controlled trial involving male physicians, found that neither vitamin E nor vitamin C supplementation reduced the risk of prostate or other cancers.[149]

Similarly, the Selenium and Vitamin E Cancer Prevention Trial (SELECT), a randomized placebo-controlled trial involving 35,533 relatively healthy study participants from 427 US sites, found that neither selenium nor vitamin E (alone or in combination), at the doses and formulations used, prevented prostate cancer.[150] See Prostate Cancer and Nutrition for more information on this topic.

Physical activity appears to lower prostate cancer risk. A meta-analysis by Liu et al found a small, but significant, association between physical activity and prostate cancer in men aged 20-45 years.[151]

Improving diet and increasing physical activity to reduce prostate cancer risk will also reduce cardiovascular risk. This is a significant benefit, as cardiovascular disease is the cause of death in many men with prostate cancer.

5-alpha-reductase inhibitors

The 5-ARIs, approved by the FDA for benign prostatic hyperplasia (BPH) and alopecia, include finasteride (Proscar, Propecia) and dutasteride (Avodart, Jalyn).

The use of 5-ARIs to prevent prostate cancer was studied in 2 large, randomized, controlled trials, the Prostate Cancer Prevention Trial (PCPT) and the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial. In both of these studies, men taking dutasteride or finasteride had a decreased incidence of prostate cancer overall, but they also had an increased incidence of high-grade prostate cancer over participants who received placebo.[10, 11]

The American Society of Clinical Oncology (ASCO) Health Services Committee (HSC), the ASCO Cancer Prevention Committee, and the American Urological Association Practice Guidelines Committee jointly convened a panel of experts who used the results from a systematic review of the literature to develop evidence-based recommendations on the use of 5-ARIs for prostate cancer chemoprevention.[152]

The panel concluded that asymptomatic men with a PSA level of 3 ng/mL or less who are undergoing regular PSA screening or who are planning to undergo such screening annually may be aided by a discussion of the benefits of using 5-ARIs for prostate cancer prevention and of the risks associated with the drugs, such as the development of high-grade prostate cancer.

On June 9, 2011, the FDA announced revisions to the prescribing information for 5-ARIs to include a warning regarding a possible increased risk of high-grade prostate cancer with these agents.[13] The revised prescribing information recommends that prior to initiating therapy with 5-ARIs, an appropriate evaluation be performed to rule out other urologic conditions, including prostate cancer, that might mimic BPH. Finasteride and dutasteride were denied approval for prostate cancer prevention.

In contrast, a 2012 placebo-controlled study of dutasteride on prostate cancer progression in men with low-risk disease who chose to be followed up with active surveillance found that at 3-year follow-up, 38% of men in the dutasteride group and 48% of controls had prostate cancer progression. No prostate cancer-related deaths or metastatic disease occurred; 5% of patients in both groups experienced cardiovascular adverse events. The investigators concluded that dutasteride could be a beneficial supplement to active surveillance.[153]

Consultations

Consultation with a radiation oncologist should be obtained for palliative radiation therapy for bone metastases, for locally extensive tumors, and, on an emergent basis, for spinal cord compression. Consultations with a neurosurgeon for spinal cord compression and an orthopedic surgeon for pathologic fractures are appropriate. Consultation with a medical oncologist may also be considered for chemotherapy when a patient with metastatic disease begins to show disease progression on hormone therapy.

Long-Term Monitoring

Follow-up is not standardized; however, practitioners use general guidelines that are derived mainly from publications report outcomes on various methods of treatment. In addition, the NCCN, an alliance of 19 cancer centers, publishes follow-up guidelines for the various treatment modalities discussed below.

Watchful waiting

Patients on watchful waiting are treated only if they develop symptomatic progression of their disease. No curative therapy is administered. A digital rectal examination (DRE) and PSA test are performed periodically to determine when a bone scan and CT scan might be warranted and if hormone therapy is necessary. The results can also be used to determine when bone-directed treatments are appropriate to avoid serious morbidity.

Radical prostatectomy

PSA testing is performed every 3-4 months for the first 2 years after radical prostatectomy, every 6 months for the third and fourth years, and yearly thereafter. DRE has not been shown to offer any added advantage in the detection of local recurrence beyond PSA testing, but most physicians continue to do it.

Radiation therapy

In patients who have been treated with EBRT, DRE and PSA are performed every 3-6 months for 5 years and then annually thereafter. Evidence is lacking that periodic prostate biopsies following radiation therapy are beneficial.

After brachytherapy, PSA testing is performed every 3-6 months for 2 years and then annually thereafter. Here too, no studies have proved that there is a benefit to performing a prostate biopsy unless the PSA begins to rise and the patient is considered a candidate for salvage prostatectomy.

Biochemical recurrence

A biochemical recurrence (ie, measurable PSA) is considered to have occurred following radical prostatectomy if the PSA level is greater than 0.2 ng/mL or is above the minimal detectable level of the assay. For example, using ultrasensitive PSA assays, a cutoff of 0.01 ng/mL or 0.05 ng/mL can be used.

The definition of a biochemical recurrence following radiation is more complex, and significant debate still surrounds this topic. Options for determining biochemical recurrence include the following:

  • 2-3 consecutive rises in the PSA level following a nadir (ASTRO definition)

  • Rise of 2 ng/mL or more above the nadir PSA level (Phoenix definition[154] )

  • An absolute cutoff of 0.2, 0.5, or 1 ng/mL

Biochemical recurrence should prompt closer follow-up and consideration of alternative therapies. When the PSA level begins doubling every 10-12 months or reaches some minimal level ranging from 10-20 ng/mL, imaging studies may be performed, as follows:

  • Bone scan

  • CT scan of the abdomen and pelvis

  • Potentially, transrectal ultrasonography–guided rebiopsy of the prostate or prostatic fossa in patients treated with radical prostatectomy

  • ProstaScint scan

The ProstaScint scan is most commonly used in patients who have biochemical recurrence without evidence of metastases and who may be candidates for EBRT. The ProstaScint scan is especially useful for identifying localized recurrence and lymphatic spread.

Other imaging studies include positron emission tomography (PET) scanning and magnetic resonance imaging (MRI) spectroscopy. PET scanning uses cancer metabolism to illuminate cancer spread to other organs. MRI spectroscopy combines anatomic information with metabolic activity to detect residual cancer in the gland.

Multiparametric MRI (mpMRI) may have a role in detecting clinically significant prostate cancer in men with elevated PSA levels.[155] Recommendations on a standardized method for the conduct, interpretation, and reporting of prostate MRI for cancer detection and localization have been agreed on, using formal consensus methods.

Followup by primary care physicians

The American Cancer Society has released evidence- and expert-based guidelines for the management of prostate cancer survivors by primary care physicians (PCPs), a response to the fact that as the number of men surviving prostate cancer has increased, reliance on PCPs for their care has grown as well. The new guidelines address promotion of healthy lifestyles, surveillance for disease recurrence, screening for second primary cancers, and evaluation and management of adverse physical and psychosocial effects caused by the disease and its treatment. Recommendations include the following[156, 157] :

  • Oncologists should provide PCPs with treatment summaries, as well as recommendations for posttreatment follow-up

  • Serum prostate-specific antigen (PSA) levels should be assessed every 6-12 months during the first five years of follow-up and then should be rechecked annually

  • Patients should undergo an annual digital rectal examination

  • Patients undergoing androgen deprivation therapy (ADT) should be periodically monitored for treatment-associated anemia, but routine anemia therapy for asymptomatic patients receiving ADT is not necessary

  • Owing to the risks for metabolic syndrome, obesity, and bone loss and fracture associated with ADT, baseline assessments of calcium and vitamin D levels and bone-density scanning should be performed in men undergoing this treatment, and patients should receive dietary counseling, supplements (if needed), and other therapeutic interventions

  • Physicians should, during routine care, inquire about the patient’s ability to function sexually; treatment options for sexual dysfunction include phosphodiesterase type 5 (PDE-5) inhibitors

  • Patients may suffer from depression and anxiety as a result of sexual dysfunction or bowel and urinary problems, necessitating a counseling referral

 

Guidelines

Guidelines Summary

Guidelines Contributor: Bagi RP Jana, MD Associate Professor of Medicine (Genitourinary Oncology), Division of Hematology and Oncology, University of Texas Medical Branch

Prostate Cancer Screening

Guidelines on prostate cancer screening have been issued by the following organizations:

  • American Cancer Society (ACS)
  • National Comprehensive Cancer Network (NCCN)
  • American Urological Association (AUA)
  • U.S. Preventive Services Task Force (USPSTF)
  • American College of Physicians (ACP)
  • European Society for Medical Oncology (ESMO)
  • European Association of Urology/European Society for Radiotherapy and Oncology/International Society of Geriatric Oncology (EAU/ESTRO/SIOG)

The guidelines differ in their recommendations regarding whether or not to provide routine prostate-specific antigen (PSA)–based prostate cancer screening, in what age groups and life expectancies, and at what intervals. The guidelines agree that PSA-based prostate cancer screening requires an informed, shared decision-making process, and that the decision should reflect the patient’s understanding of the possible benefits and risks and should respect the patient’s preferences and values.[2, 39, 38, 42, 158, 159, 160]

ACS Screening Guidelines

The ACS guidelines for early detection of prostate cancer were last updated in 2010.[2]  The ACS does not recommend routine screening in any age group. Instead, asymptomatic men with at least a 10-year life expectancy should be given an opportunity to make an informed decision with their health care provider after receiving information on the uncertainties, risks and benefits of screening

Men should receive the information starting at the following ages:

  • Age 50 for those at average risk of developing prostate cancer

  • Age 45 for those at high risk, including African Americans and men with a first-degree relative (father, brother, son) diagnosed with prostate cancer before age 65

  • Age 40 for those at higher risk (more than one first-degree relative diagnosed with prostate cancer at an early age)

For men who are unable to decide whether they wish to be screened, the ACS advises that the patient’s health care provider can make the screening decision, taking into account the patient’s general health preferences and values.

Men who decide to be screened should be tested with a PSA test. A digital rectal exam (DRE) may also be done as a part of screening.

If screening does not detect cancer, the time between subsequent screenings depends on the results of the blood test, as follows:

  • PSA < 2.5 ng/ml – Retesting may be done every 2 years

  • PSA ≥2.5 ng/ml – Retesting should be done annually

Even after the decision to screen has been made, the discussion about the risks and benefits of testing should be repeated as new information becomes available.

NCCN Screening guidelines

The NCCN recommends performing a baseline evaluation, with a history and physical examination that includes the following:

  • Family history
  • Medications
  • History of prostate disease and screening, including prior PSA and/or isoforms, exams, and biopsies
  • Race
  • Family or personal history of BRC1/2 mutations

The clinician should then discuss of the risks and benefits of a baseline PSA test with the patient, and consider a baseline DRE to identify high-risk cancers associated with a seemingly normal PSA. In patients 45-75 years of age, subsequent evaluation is based on the results of those tests, as follows[38] :

  • PSA < 1 ng/mL, DRE normal (if done): Repeat testing at 2–4 year intervals
  • PSA 1-3 ng/mL, DRE normal (if done): Repeat testing at 1–2 year intervals
  • PSA >3 ng/mL or very suspicous DRE result: Evaluate for biopsy

For men above the age of 75 years, screening may be cautiously considered in selected cases of very healthy men with little or no comorbidity. If PSA is measured and is < 4 ng/mL, the DRE is normal (if done), and no other indications for biopsy are present, the NCCN recommends repeat testing in selected patients at 1–4 year intervals. If the PSA is >4 ng/mL or DRE results are very suspicious, the patient should be evaluated for biopsy.

The NCCN notes that men ≥60 years of age with serum PSA < 1.0 ng/mL have a very low risk of metastasis or death from prostate cancer and may not benefit from further testing. The same is true of men age 75 years with a PSA of < 3.0 ng/mL.

Evaluation for biopsy includes the following:

  • Repeat PSA
  • Perform DRE, if not done performed during initial risk assessment
  • Workup for benign disease

AUA screening guidelines

The current recommendations of the AUA date from 2013 and update the Association’s 2009 Best Practice Statement on Prostate-Specific Antigen (PSA).[160]  The guidelines do not recommend routine screening for the following groups:

  • Any man with a life expectancy less than 10-15 years

  • Men under 40 years

  • Men between ages 40 to 54 years at average risk

  • Men over age 70

For men 55 to 69 years of age, the decision to undergo PSA screening involves weighing the benefits and risks. The guidelines strongly recommend:

  • Shared decision-making for men age 55-69 years who are considering PSA screening, and proceeding based on patients’ values and preferences

  • A routine screening interval of two years or more in those men who have participated in shared decision-making and decided on screening.

USPSTF screening guidelines

USPSTF guidelines from 2012 recommended against PSA-based screening for prostate cancer, while recognizing that some men will continue to request screening.[39]  In such cases, screening should not be ordered prior to shared decision making that weighs the benefits and risks and takes into account the patient’s preferences and values.

However, in an updated recommendation issued in May 2018, the USPSTF advises that in men aged 55 to 69 years, the decision of whether or not to undergo screening should be individualized. This is a grade C recommendation, meaning that there is at least moderate certainty that the net benefit is small. For men aged 70 years and older, the USPSTF recommends against PSA-based screening for prostate cancer.[3]

The USPSTF concluded that currently available data are insufficient to assess whether the benefits of prostate cancer screening are different for African-American men or men with a family history of prostate cancer, or whether starting screening in those high-risk groups before age 55 years offers benefits.

While acknowledging the higher risk of prostate cancer in those groups, the USPSTF also notes the significantly higher risk of major infections after prostate biopsy in black men than white men, and the potential for harm in men with relatives whose prostate cancer was overdiagnosed. The USPSTF suggests that men with a positive family history who are most likely to benefit from screening are those with a first-degree relative who had advanced prostate cancer at diagnosis, who developed metastatic prostate cancer, or who died of prostate cancer.

ACP screening guidelines

The ACP 2013 guidelines recommend that clinicians base the decision to screen for prostate cancer, using the PSA test, on the following:

  • The patient's risk for prostate cancer
  • A discussion of the benefits and harms of screening
  • The patient's general health and life expectancy
  • Patient preference

The ACP advises that clinicians should not screen for prostate cancer in patients who do not express a clear preference for screening. In addition, the ACP recommends against screening in the following[42] :

  • Average-risk men under the age of 50 years
  • Men over the age of 69 years
  • Men with a life expectancy of less than 10 to 15 years

ESMO screening guidelines

Likie USPSTF, ESMO guidelines recommend against population-based PSA screening for prostate cancer, as well as screening of asymptomatic men over 70 years old.[158]

EAU/ESTR/SIOG screening guidelines

In 2016, revised joint guidelines were issued by EAU/ESTRO/SIOG with the recommendation that men who are informed and request an early diagnosis should be given a PSA test and undergo a digital rectal examination (DRE). PSA testing should be offered to the following groups at elevated risk for developing prostate cancer[159] :

  • Men > age 50 
  • Men > age 45 and a family history of prostate cancer
  • African-American men > age 45 
  • Men with a PSA level of > 1 ng/mL at age 40
  • Men with a PSA level of > 2 ng/mL at age 60 

Follow-up testing at intervals of 2 years for the following at risk groups:

  • Men with a PSA level of > 1 ng/mL at age 40 
  • Men with a PSA level of > 2 ng/mL at age 60 

Postpone follow-up to 8 years in those not at risk.

Discontinue testing based on life expectancy and performance status; men who have a life expectancy of < 15-years are unlikely to benefit.

Genetic Testing

National Comprehensive Cancer Network (NCCN) guidelines[109] recommend that at the time of initial diagnosis of prostate cancer, clinicians should inquire about family and personal history of cancer. The NCCN recommends germline genetic testing, with or without pretest genetic counseling, for patients with prostate cancer and any of the following:

  • A positive family history of cancer (eg, prostate, breast)
  • High-risk, very-high-risk, regional or metastatic prostate cancer, regardless of family history
  • Ashkenazi Jewish ancestry
  • Intraductal histology

Germline testing, when performed, should include the following:

  • MLH1, MSH2, MSH6, and  PMS2 (for Lynch syndrome)
  • The homologous recombination genes  BRCA2, BRCA1, ATM, PALB2,and  CHEK2

Clinicians may also consider a next-generation sequencing (NGS) panel to test for cancer predisposition. At minimum, the panel should include the following:

  • BRCA2
  • BRCA1
  • ATM
  • CHEK2
  • PALB2
  • MLH1
  • MSH2
  • MSH6
  • PMS2

​Testing of additional genes may be appropriate, depending on the clinical context. For example, HOXB13 is a prostate cancer risk gene; although its presence does not currently have clear therapeutic implications in the advanced disease setting, testing for it may be valuable for family counseling.

Somatic tumor testing based on risk groups

NCCN recommendations for testing of prostate cancer tumors are as follows:

  • Tumor testing for somatic homologous recombination gene mutations (eg, BRCA1, BRCA2, ATM, PALB2, FANCA, RAD51D, CHEK2) can be considered in patients with regional or metastatic prostate cancer.

  • Tumor testing for microsatellite instability (MSI) or mismatch repair deficiency (dMMR) can be considered in patients with regional or metastatic prostate cancer.

  • Multigene molecular testing can be considered for patients with low- and favorable-intermediate risk prostate cancer and life expectancy ≥10 years.

  • The Decipher molecular assay can be considered as part of counseling for risk stratification in patients with PSA resistance/recurrence after radical prostatectomy.

  • If mutations in BRCA2, BRCA1, ATM, CHEK2,  or PALB2  are found, the patient should be referred for genetic counseling to assess for the possibility of hereditary breast and ovarian cancer (HBOC) syndrome.

  • If MSI testing is performed, testing using an NGS assay validated for prostate cancer is preferred. If high MSI (MSI-H) or dMMR is found, the patient should be referred for genetic counseling to assess for the possibility of Lynch syndrome. MSI-H or dMMR indicate eligibility for pembrolizumab in second and subsequent lines of treatment of castration-resistant prostate cancer.

Multiparametric Magnetic Resonance Imaging

The National Comprehensive Cancer Network (NCCN) advises that although standard MRI techniques can be considered for initial evaluation of high-risk patients, multiparametric magnetic resonance imaging (mpMRI) can be used in the staging and characterization of prostate cancer. mpMRI images are defined as those acquired with at least one more sequence in addition to the anatomic T2-weighted images, such as diffusion-weighted imaging and dynamic contrast images. In addition, the NCCN guidelines recommend considering mpMRI in patients undergoing active surveillance if anterior and/or aggressive cancer is suspected when PSA increases and systematic prostate biopsies are negative.[31]

The 2016 EAU/ESTR/SIOG guidelines recommend mpMRI prior to performing a repeat biopsy when clinical suspicion of prostate cancer persists in spite of negative biopsies. During repeat biopsy, target any mpMRI lesions seen. Additionally, the guidelines recommend performing mpMRI for local staging and metastatic screening in predominantly Gleason pattern 4 intermediate risk patients and for local staging in high-risk localised prostate cancer.[159]

 

Management of Clinically Localized Prostate Cancer

American Urological Association

Guidelines from the American Urological Association, the American Society for Radiation Oncology (ASTRO) and the Society of Urologic Oncology (SUO) for management of clinically localized prostate cancer include the following recommendations for very-low-risk and low-risk disease[1, 161] :

  • Abdominal-pelvic CT or routine bone scans hsould not be performed as part of the staging of asymptomatic patients with very-low-risk or low-risk prostate cancer. (Strong Recommendation; Evidence Level: Grade C)
  • Clinicians should recommend active surveillance as the best available care option for patients with very-low-risk localized prostate cancer. (Strong Recommendation; Evidence Level: Grade A)
  • Clinicians should recommend active surveillance as the preferable care option for most patients with low-risk localized prostate cancer. (Moderate Recommendation; Evidence Level: Grade B)
  • Clinicians may offer definitive treatment (ie, radical prostatectomy or radiotherapy) to select low-risk localized prostate cancer patients who may have a high probability of progression on active surveillance. (Conditional Recommendation; Evidence Level: Grade B)
  • Clinicians should not add androgen deprivation therapy (ADT) to radiotherapy for low-risk localized prostate cancer, except to reduce the size of the prostate for brachytherapy. (Strong Recommendation; Evidence Level: Grade B)
  • Clinicians should inform low-risk prostate cancer patients considering whole gland cryosurgery that consequent side effects are considerable and survival benefit has not been shown in comparison with active surveillance. (Conditional Recommendation; Evidence Level: Grade C)
  • Clinicians should inform low-risk prostate cancer patients who are considering focal therapy or high-intensity focused ultrasound (HIFU) that these interventions are not standard care options because comparative outcome evidence is lacking. (Expert Opinion)
  • Clinicians should recommend observation or watchful waiting for men with a life expectancy ≤5 years with low-risk localized prostate cancer. (Strong Recommendation; Evidence Level: Grade B)
  • In most cases of low-risk localized prostate cancer, tissue-based genomic biomarkers have not shown a clear role in the selection of candidates for active surveillance. (Expert Opinion)

For patients with intermediate-risk disease, care recommendations are as follows:

  • Clinicians should consider staging unfavorable intermediate-risk localized prostate cancer with cross-sectional imaging (CT or MRI) and bone scan. (Expert Opinion)
  • Clinicians should recommend radical prostatectomy or radiotherapy plus ADT as standard treatment options for patients with intermediate-risk localized prostate cancer. (Strong Recommendation; Evidence Level: Grade A)
  • Clinicians should inform patients that favorable intermediate-risk prostate cancer can be treated with radiation alone, but that the evidence basis is less robust than for combining radiotherapy with ADT. (Moderate Recommendation; Evidence Level: Grade B)
  • In select patients with intermediate-risk localized prostate cancer, clinicians may consider other treatment options such as cryosurgery. (Conditional Recommendation; Evidence Level: Grade C)
  • Active surveillance may be offered to select patients with favorable intermediate-risk localized prostate cancer; however, patients should be informed that this comes with a higher risk of developing metastases compared with definitive treatment. (Conditional Recommendation; Evidence Level: Grade C)
  • Clinicians should recommend observation or watchful waiting for men with a life expectancy ≤5 years with intermediate-risk localized prostate cancer. (Strong Recommendation; Evidence Level: Grade A)
  • Clinicians should inform patients with intermediate-risk prostate cancer who are considering focal therapy or HIFU that these interventions are not standard care options because comparative outcome evidence is lacking. (Expert Opinion)

For high-risk patients the guideline recommendations include the following:

  • Clinicians should stage high-risk localized prostate cancer patients with cross-sectional imaging (CT or MRI) and bone scan. (Clinical Principle)
  • Clinicians should recommend radical prostatectomy or radiotherapy plus ADT as standard treatment options for patients with high-risk localized prostate cancer. (Strong Recommendation; Evidence Level: Grade A)
  • Clinicians should not recommend active surveillance for patients with high-risk localized prostate cancer. Watchful waiting should be considered only in asymptomatic men with limited life expectancy (≤5 years). (Moderate Recommendation; Evidence Level: Grade C)
  • Cryosurgery, focal therapy, and HIFU treatments are not recommended for men with high-risk localized prostate cancer outside of a clinical trial. (Expert Opinion)
  • Clinicians should not recommend primary ADT for patients with high-risk localized prostate cancer unless the patient has both limited life expectancy and local symptoms. (Strong Recommendation; Evidence Level: Grade
  • Clinicians may consider referral for genetic counseling for patients (and their families) with high-risk localized prostate cancer and a strong family history of specific cancers (eg, breast, ovarian, pancreatic, other gastrointestinal tumors, lymphoma). (Expert Opinion)

European Society of Medical Oncology

The 2015 ESMO guidelines recommend watchful waiting with delayed hormone therapy as an option for localized disease or as an alternative for men with localized or locally advanced disease who are unwilling or unsuited for radical therapy.[4]

Other recommended treatment options include[158] :

  • Active surveillance for men with low-risk disease 

  • Radical prostatectomy (RP) or radiotherapy (external beam or brachytherapy) for men with low- or intermediate-risk disease 

  • Primary androgen deprivation therapy (ADT)  alone is not recommended for treatment of non-metastatic disease 

  • For patients with high-risk or locally advanced prostate cancer, external beam RT plus hormone treatment or RP plus pelvic lymphadenectomy 

Cancer Care Ontario/American Society of Clinical Oncology

In 2016, the American Society of Clinical Oncology (ASCO) endorsed Cancer Care Ontario’s guideline on active surveillance for the management of localized prostate cancer.[162] The recommendations include the following:

  • Active surveillance is the recommended disease management strategy for most patients with low‐risk (Gleason score ≤6) localized prostate cancer.
  • Because of heterogeneity within this population, factors such as younger age, high-volume Gleason 6 cancer, patient preference, and/or African American ethnicity should be taken into account in the decision to use active surveillance.
  • Young patients (under age 55) with high-volume Gleason 6 cancer should be closely scrutinized for the presence of higher‐grade cancer; definitive therapy may be warranted for select patients.
  • For patients with limited life expectancy (< 5 years) and low‐risk cancer, watchful waiting may be more appropriate than active surveillance.
  • Active treatment (radical prostatectomy or radiotherapy) is recommended for most patients with intermediate‐risk (Gleason score 7) localized prostate cancer, but active surveillance may be offered to select patients with low‐volume, intermediate‐risk (Gleason 3+4=7) localized prostate cancer.

The guidelines recommend that the active surveillance protocol include the following tests:

  • Prostate-specific antigen (PSA) testing every 3 to 6 months
  • Digital rectal examination (DRE) at least every year
  • At least a 12-core confirmatory transrectal ultrasound (TRUS)–guidedbiopsy (including anterior directed cores) within 6 to 12 months, then serial biopsy every 2 to 5 years thereafter, or more frequently if clinically warranted; men with limited life expectancy may transition to watchful waiting and avoid further biopsies.
  • Ancillary tests that are still under investigation but may be included in the protocol could include  multiparametric MRI (mpMRI) and/or genomic testing. Such tests may beindicated when a patient’s clinical findings are discordant with the pathologic findings

Bone Scan for Diagnosis of Metastatic Disease

Current NCCN guidelines include scanning technology utilizing fluorine-18 sodium fluoride (18 F-NaF) as the tracer for the subsequent positron-emission tomography (PET) scan as an option for men with prostate cancer who undergo a bone scan to search for metastatic disease. PET and hybrid imaging bone scans appear more sensitive than conventional 99-technetium bone scans.[31]

Castration-Resistant Prostate Cancer

The following organizations have published guidelines for the treatment of castration-resistant prostate cancer (CRPC):

  • American Society of Clinical Oncology (ASCO)/Cancer Care Ontario (CCO)

  • American Urology Association (AUA)

  • National Comprehensive Cancer Network (NCCN)

  • European Association of Urology/European Society for Radiotherapy and Oncology/International Society of Geriatric Oncology (EAU/ESTRO/SIOG)

American Society of Clinical Oncology/Cancer Care Ontario recommendations

ASCO and CCO released a joint clinical practice guideline for treatment of men with metastatic CRPC in 2014. The guideline recommendations include the following[163] :

  • Pharmacologic androgen deprivation therapy (ADT) should be continued indefinitely

  • Offer patients one of three treatment options—abiraterone/prednisone, enzalutamide, or radium-223 (if cancer has spread to bone)—in addition to hormone deprivation

  • When considering chemotherapy, docetaxel/prednisone should be an option but side effects must be discussed

  • Offer cabazitaxel to men whose disease worsens even if docetaxel has been tried, but again, discuss side effects

  • Offer sipuleucel-T to men with no symptoms or minimal symptoms of cancer

  • Offer mitoxantrone, but include a discussion of the drug's limited clinical benefit and side effect risk

  • Offer ketoconazole or the anti-androgen therapies bicalutamide, flutamide or nilutamide but discuss the limited clinical benefit for these three medications

  • Do not offer the drugs bevacizumab (Avastin), estramustine, or sunitinib

  • Begin discussion of palliative care early on while discussing treatment options

American Urological Association recommendations

American Urological Association guidelines for the management of CRPC describe six index-patient scenarios for which recommendations could be formulated.[163]

Index patient no. 1: Asymptomatic non-metastatic CRPC

Recommendations are as follows:

  • Observation with continued ADT

  • First-generation antiandrogens (flutamide, bicalutamide, and nilutamide) or first-generation androgen-synthesis inhibitors (ketoconazole plus steroid) to patients unwilling to accept observation.

  • Systemic chemotherapy or immunotherapy should not be offered to patients with non-metastatic CRPC outside the context of a clinical trial

Index patient no. 2: Asymptomatic or minimally-symptomatic, metastatic CRPC with good performance status and without prior docetaxel chemotherapy

Recommendations are as follows:

  • Abiraterone plus prednisone, enzalutamide, docetaxel, or sipuleucel-T

  • First-generation antiandrogen therapy or ketoconazole plus steroid or observation to patients who do not want or cannot have one of the standard therapies

Index patient no. 3: Symptomatic, metastatic CRPC with good performance status and no prior docetaxel chemotherapy

Recommendations are as follows:

  • Docetaxel

  • Abiraterone plus prednisone, enzalutamide, or docetaxel

  • Ketoconazole plus steroid, mitoxantrone, or radionuclide therapy for patients who do not want or cannot have one of the standard therapies

  • Radium-223 to patients with symptoms from bony metastases and without known visceral disease

  • Treatment with either estramustine or sipuleucel-T should not be offered

Index patient no. 4: Symptomatic, metastatic CRPC with poor performance status and no prior docetaxel chemotherapy

Recommendations are as follows:

  • Abiraterone plus prednisone or enzalutamide

  • Ketoconazole plus steroid or radionuclide therapy to patients who are unable or unwilling to receive abiraterone plus prednisone

  • Docetaxel or mitoxantrone chemotherapy in select cases, specifically when performance status is directly related to the cancer

  • Radium-223 to patients with symptoms from bony metastases and without known visceral disease in select cases, specifically when the performance status is directly related to symptoms related to bone metastases.

  • Treatment with sipuleucel-T should not be offered

Index patient no. 5: Symptomatic, metastatic CRPC with good performance status and prior docetaxel chemotherapy

Recommendations are as follows:

  • Abiraterone plus prednisone, cabazitaxel, or enzalutamide

  • If the patient received abiraterone plus prednisone prior to docetaxel chemotherapy, offer cabazitaxel or enzalutamide

  • Ketoconazole plus steroid if abiraterone plus prednisone, cabazitaxel, or enzalutamide is unavailable

  • Re-treatment with docetaxel for patients who were benefiting from but discontinued treatment with docetaxel because of reversible adverse effects

  • Radium-223 to patients with symptoms from bony metastases and without known visceral disease

Index patient no. 6: Symptomatic, metastatic CRPC with poor performance status and prior docetaxel chemotherapy

Recommendations are as follows:

  • Palliative care

  • For selected patients, offer treatment with abiraterone plus prednisone, enzalutamide, ketoconazole plus steroid, or radionuclide therapy

  • Systemic chemotherapy or immunotherapy should not be offered

Bone health recommendations

Because the skeletal system is the most common site for prostate cancer metastasis, the guideline also makes recommendations regarding bone health not specific to any index patient group:

  • Offer preventive treatment (eg, supplemental calcium, vitamin D) for fractures

  • Choose either denosumab or zoledronic acid as preventative treatment for skeletal-related events

National Comprehensive Cancer Network recommendations

The NCCN guidelines for prostate cancer include treatment recommendations for CRPC based on the presence or absence of visceral metastases. For the most part, these recommendations are based on high-level evidence and are supported by uniform NCCN consensus (category 1 recommendations).[31]

CRPC without distant metastasis

  • Enrollment in clinical trial is preferred

  • Observation is acceptable

  • Secondary hormone therapy can be considered for patients with prostate-specific antigen (PSA) doubling < 10 months; anti-androgen therapy is acceptable for patients who previously received medical or surgical castration, ketoconazole, corticosteroids, diethylstilbestrol or other estrogens

CRPC with bone metastases

Measures to promote bone health include the following:

  • Zoledronic acid or denosumab

  • Avoidance of invasive dental surgery during treatment

  • Calcium and vitamin D supplements to prevent hypocalcemia during treatment

Radium-233 can be used to treat symptomatic bone metastases without visceral metastases.

Metastatic CRPC with no visceral metastases

  • Sipuleucel-T for asymptomatic or minimally symptomatic patients

  • Abiraterone plus prednisone or enzalutamide for asymptomatic patients

  • Docetaxel with prednisone for symptomatic patients; may also be considered in a symptomatic patients with signs of rapid progression

  • Radium-233 for symptomatic patients

  • Secondary hormone therapy or enrollment in clinical trial may be considered

Second-line treatment for patients with no visceral metastases who experience progression of disease after treatment with enzalutamide or abiraterone is as follows:

  • Docetaxel with prednisone

  • Abiraterone, if the patient had previously taken enzalutamide

  • Enzalutamide, if the patient had previously taken abiraterone

  • Radium-233 for bone-predominant disease

  • Sipuleucel-T for asymptomatic or minimally symptomatic patients with no liver metastases, life expectancy > 6 mo, and ECOG performance status 0-1

  • Clinical trial

  • Other secondary hormone therapy (eg, antiandrogen, antiandrogen withdrawal, ketoconazole, corticosteroids, diethylstilbestrol or other estrogen)

  • Best supportive care

Second-line treatment for patients with no visceral metastases who experience progression of disease after treatment with docetaxel is as follows:

  • Enzalutamide

  • Abiraterone with prednisone

  • Radium-233 for bone-predominant disease

  • Cabazitaxel with prednisone

  • Sipuleucel-T for asymptomatic or minimally symptomatic patients with no liver metastases, life expectancy > 6 mo, and ECOG performance status 0-1

  • Clinical trial

  • Docetaxel rechallenge

  • Alternative chemotherapy (mitoxantrone)

  • Other secondary hormone therapy (eg, antiandrogen, antiandrogen withdrawal, ketoconazole, corticosteroids, diethylstilbestrol or other estrogen)

  • Best supportive care

Metastatic CRPC with visceral metastases

  • Docetaxel with prednisone (preferred treatment)

  • Addition of estramustine to docetaxel not recommended

  • Enzalutamide (category 1)

  • Abiraterone for men who decline chemotherapy

Second-line treatment for patients with visceral metastases who experience progression of disease after treatment with enzalutamide or abiraterone is as follows:

  • Docetaxel with prednisone

  • Clinical trial

  • Abiraterone, if the patient had previously taken enzalutamide

  • Enzalutamide, if the patient had previously taken abiraterone

  • Other secondary hormone therapy (eg, antiandrogen, antiandrogen withdrawal, ketoconazole, corticosteroids, diethylstilbestrol or other estrogen)

  • Best supportive care

Second-line treatment for patients with visceral metastases who experience progression of disease after treatment with docetaxel is as follows:

  • Enzalutamide

  • Abiraterone with prednisone

  • Cabazitaxel with prednisone

  • Clinical trial

  • Docetaxel rechallenge

  • Alternative chemotherapy (mitoxantrone)

  • Other secondary hormone therapy (eg, antiandrogen, antiandrogen withdrawal, ketoconazole, corticosteroids, diethylstilbestrol or other estrogen)

  • Best supportive care

European Association of Urology/European Society for Radiotherapy and Oncology/International Society of Geriatric Oncology recommendations

EAU, ESTRO and SIOG released a joint clinical practice guideline for prostate cancer in 2016. The guideline recommendations for patients with mCRPC  include the following[159] :

  • Treat with life prolonging agents (alphabetical order: abiraterone, docetaxel, enzalutamide, radium-223, sipuleucel-T). Base the choice of first line treatment on the performance status, symptoms, comorbidities and extent of disease.

  • Candidates for cytotoxic therapy should be offered docetaxel with 75 mg/m2 every 3 weeks.

  • In patients with progression following docetaxel chemotherapy, offer further life-prolonging treatment options, which include cabazitaxel, abiraterone, enzalutamide and radium-223.

  • Offer bone protective agents to patients with skeletal metastases to prevent osseous complications. However, the benefits must be balanced against the toxicity of these agents, and jaw necrosis, in particular, must be avoided.

  • Offer calcium and vitamin D supplementation when prescribing either denosumab or bisphosphonates.

  • Treat painful bone metastases early on with palliative measures such as EBRT, radionuclides, and adequate use of analgesics.

  • In patients with spinal cord compression, start immediate high-dose corticosteroids and assess for spinal surgery followed by irradiation. Offer radiation therapy alone if surgery is not appropriate.

 

Medication

Medication Summary

The goals of pharmacotherapy for prostate cancer are to induce remission, reduce morbidity, and prevent complications. Agents used include the following:

  • Androgen antagonists
  • Gonadotropin-releasing hormone (GnRH) agonists
  • Bisphosphonates
  • Antifungal agents
  • Chemotherapeutic agents
  • Corticosteroids
  • Immunologic agents

Antineoplastics, GnRH Agonist

Class Summary

GnRH agonists provide medical castration in patients with prostate cancer. They are used early and late in the course of the disease.

GnRH agonists bind to the GnRH receptors on pituitary gonadotropin-producing cells, causing an initial release of luteinizing hormone (LH) and follicle stimulating hormone (FSH) and consequently a rise in testosterone levels for a few weeks. However, sustained use of these agents causes a decrease in the production of LH and FSH, which in turn leads to a decrease in testosterone production in the testes, reducing testosterone to castrate levels or to below the castrate threshold (50 ng/dL).

Leuprolide (Lupron Depot, Lupron Depot-Ped, Eligard)

Leuprolide is indicated as palliative treatment for advanced prostate cancer when orchiectomy or estrogen administration is not indicated or is unacceptable to the patient. It is a potent inhibitor of gonadotropin secretion when given continuously in therapeutic doses.

Leuprolide can be administered as a depot at doses of 3.75 mg every 4 weeks, 11.25 mg every 12 weeks, or 30 mg every 24 weeks. Lupron should be administered intramuscularly, and Eligard should be administered subcutaneously.

Triptorelin (Trelstar, Trelstar Mixject)

Triptorelin is indicated for palliative treatment of advanced prostate cancer. The recommended dosage is 3.75 mg intramuscularly once every 4 weeks, 11.25 mg intramuscularly once every 12 weeks, or 22.5 mg intramuscularly once every 24 weeks.

Triptorelin is a synthetic decapeptide agonist analogue of GnRH. It decreases LH and FSH secretion when administered long-term and thus decreases testosterone and estrogen levels. The serum testosterone concentration drops to a level typically seen in surgically castrated men.

Goserelin (Zoladex)

Goserelin is used in the palliative treatment of advanced prostate cancer. It is available as a 3.6 mg and 10.8 mg subcutaneous implant. The usual dose is 3.6 mg every 4 weeks or 10.8 mg every 12 weeks.

Goserelin is a synthetic decapeptide analogue of GnRH that inhibits pituitary gonadotropin secretion if administered long-term. Like other GnRH agonists, goserelin provides a medical castration that deprives hormonally-dependent tumors of testosterone or estrogen. Decreased testosterone production leads to a decrease in prostatic size and improves associated symptoms.

Histrelin (Vantas, Supprelin LA)

Histrelin is indicated for the palliative treatment of advanced prostate cancer. It is available in a 50 mg subcutaneous implant designed to provide continuous release of histrelin at a nominal rate of 50-60 mcg/day over 12 months. This agent is not active when given orally. The recommended dose is 1 implant inserted subcutaneously every 12 months.

Histrelin is a potent inhibitor of gonadotropin secretion. It desensitizes the responsiveness of pituitary gonadotropin, which in turn causes a reduction in testicular steroidogenesis.

Antineoplastics, Antiandrogen

Class Summary

Antiandrogens bind to androgen receptors and competitively inhibit their interaction with testosterone and dihydrotestosterone. Unlike medical castration, antiandrogens do not decrease LH levels and androgen production; testosterone levels are normal or increased. Antiandrogens are not commonly used as monotherapy. Rather, these agents are generally used in combination with a GnRH agonist.

Antiandrogen therapy appears to be less effective than medical or surgical castration, except possibly in patients without overt metastases (M0).[29]

Abiraterone (Zytiga)

Abiraterone is indicated in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC) and metastatic high-risk castration-sensitive prostate cancer (CSPC. The usual dosage is 1000 mg once daily in combination with prednisone 5 mg twice daily for metastatic CRPC. For metastatic high-risk CSPC, the usual dosage is 1000 mg once daily in combination with prednisone 5 mg once daily.

Abiraterone is an androgen biosynthesis inhibitor that inhibits 17-alpha-hydroxylase/C17,20-lyase (CYP17); this enzyme is expressed in testicular, adrenal, and prostatic tumor tissues and is required for androgen biosynthesis.

Bicalutamide (Casodex)

Bicalutamide is indicated for the treatment of stage D2 metastatic carcinoma of the prostate, in combination with an LHRH analogue. It is a nonsteroidal androgen receptor inhibitor that competitively inhibits the action of androgens by binding to cytosol androgen receptors. The usual dosage is 50 mg orally once daily in the morning or evening.

Degarelix (Firmagon)

Degarelix is a GnRH receptor antagonist indicated for patients with advanced prostate cancer. A single dose of degarelix 240 mg causes a decrease in the plasma concentrations of LH and FSH and subsequently of testosterone. Degarelix is effective in achieving and maintaining testosterone suppression below the castration level of 50 ng/dL. Unlike GnRH agonists, degarelix does not cause any short-term increase in testosterone; testosterone suppression to castrate concentrations is achieved within 1-3 days of administration.

The initial dose is 240 mg subcutaneous injection (given as 2 injections of 120 mg at a concentration of 40 mg/mL). The maintenance dose is 80 mg subcutaneous injection (at a concentration of 20 mg/mL) every 28 days. The first maintenance dose should be given 28 days after the starting dose.

Flutamide

Flutamide is approved by the US Food and Drug Administration (FDA) for use in combination with LHRH agonists for the management of locally confined stage B2-C and stage D2 metastatic prostate cancer. The usual dosage is 250 mg every 8 hours. The antiandrogenic effects of flutamide are mediated by the inhibition of the uptake and/or nuclear binding of testosterone and dihydrotestosterone by prostatic tissue. Flutamide-induced inhibition of androgens at the cellular level complements the castration effects of LHRH agonists.

Nilutamide (Nilandron)

Nilutamide is not suitable for inducing chemical castration since, by blocking the feedback mechanism for control of testosterone secretion, it increases testosterone concentrations. Instead, it is indicated for use in combination with surgical castration for the treatment of metastatic prostate cancer (stage D2). The initial dose is 300 mg once daily for 30 days. The maintenance dose for nilutamide is 150 mg once daily.

Enzalutamide (Xtandi)

Androgen receptor inhibitor; competitively inhibits androgen binding to androgen receptors; also inhibits androgen receptor nuclear translocation and interaction with DNA resulting in decreased proliferation and induced cell death.

Major metabolite, N-desmethyl enzalutamide, exhibited similar in vitro activity to enzalutamide. It is indicated for treatment of nonmetastatic or metastatic castration-resistant prostate cancer (mCRPC).

Apalutamide (Erleada)

Androgen receptor (AR) inhibitor that binds directly to the ligand-binding domain of the AR. Inhibits AR nuclear translocation, inhibits DNA binding, and impedes AR-mediated transcription. This results in decreased tumor cell proliferation and increased apoptosis, leading to decreased tumor volume. It is indicated for nonmetastatic, castration-resistant prostate cancer (nmCRPC).

Darolutamide (Nubeqa)

Darolutamide is an androgen receptor (AR) inhibitor. Darolutamide competitively inhibits androgen binding, AR nuclear translocation, and AR-mediated transcription. Keto-darolutamide, a major metabolite, exhibited similar in vitro activity to darolutamide. In addition, darolutamide functioned as a progesterone receptor (PR) antagonist in vitro. Darolutamide decreased prostate cancer cell proliferation in vitro and tumor volume in mouse xenograft models of prostate cancer. It is indicated for patients with nonmetastatic castration-resistant prostate cancer.

Antineoplastics, Antimicrotubular

Class Summary

Antimicrotubule chemotherapy agents such as docetaxel and cabazitaxel have demonstrated improvements in overall survival in patients with metastatic, castrate-resistant prostate cancer.

Docetaxel (Docefrez, Taxotere)

Docetaxel is indicated in combination with prednisone for the treatment of patients with androgen-independent (hormone-refractory), metastatic prostate cancer. The usual dose is 75 mg/m2 every 3 weeks as a 1-hour infusion in combination with prednisone 5 mg orally twice daily.

Cabazitaxel (Jevtana)

Cabazitaxel is indicated in combination with prednisone for hormone-refractory, metastatic prostate cancer previously treated with a docetaxel-containing regimen. The usual dosage is 25 mg/m2 administered as a 1-hour intravenous infusion every 3 weeks in combination with oral prednisone 10 mg administered daily throughout cabazitaxel treatment. Dosage can be reduced to 20 mg/m2 if patients experience adverse reactions. Caution should be used, since neutropenic deaths and severe hypersensitivity reactions have been reported.

Antineoplastics, Anthracenedione

Class Summary

For symptomatic patients who cannot tolerate docetaxel, mitoxantrone may provide palliative benefit.[29] Mitoxantrone is a palliative treatment option for patients who may not be candidates for taxane-based regimens.

Mitoxantrone

Mitoxantrone is indicated as initial chemotherapy for the treatment of patients with pain related to advanced, hormone-refractory prostate cancer. This agent is a palliative treatment that improves quality of life in these cases but does not improve survival. It is given in combination with corticosteroids such as prednisone. The recommended dose is 12-14 mg/m2 given as a short intravenous infusion every 21 days.

Antineoplastics, Hormones

Class Summary

Estramustine is a conjugate of an alkylating agent to estradiol. As a single agent, estramustine showed some activity in men with castrate-resistant prostate cancer, which led to its evaluation in various combination regimens.[164]

Estramustine (Emcyt)

Estramustine combines estradiol and nitrogen mustard. It is a relatively weak alkylating agent with weak estrogenic activity.

Estramustine is used in combination with vinblastine, etoposide, paclitaxel, docetaxel, mitoxantrone, or corticosteroids to achieve synergistic effects. It is indicated for palliative treatment of metastatic and/or progressive carcinoma of the prostate. The usual dose is 14 mg/kg/day given in 3 or 4 divided doses. Treat patients for 30-90 days before assessing the possible benefits of continued therapy. Therapy should be continued as a favorable response is seen.

Chemotherapy Modulating Agents

Class Summary

Autologous cellular immunotherapy is designed to stimulate a patient’s own immune system to respond against the cancer. Sipuleucel-T was developed to induce an immune response targeted against prostatic acid phosphatase (PAP), an antigen that is expressed in most prostate cancers.

Sipuleucel-T (Provenge)

Sipuleucel-T is a cellular immunotherapy indicated for the treatment of asymptomatic or minimally symptomatic metastatic prostate cancer that is resistant to standard hormone treatment. It is an autologous treatment, and thus must be prepared individually for each patient.

The usual regimen consists of the administration of 3 complete doses, given at intervals of approximately 2 weeks. Each dose contains a minimum of 50 million autologous CD54+ cells activated with prostatic acid phosphatase (PAP), an antigen expressed in more than 95% of prostate cancers, and granulocyte-macrophage colony-stimulating factor (GM-CSF), an immune-cell activator, suspended in 250 mL of lactated Ringer solution.

Antifungals, Systemic

Class Summary

Antifungal agents such as ketoconazole produce a response similar to that of antiandrogens. These agents provide an alternative option that may produce clinical benefit if initial androgen deprivation therapy fails. These agents inhibit various cytochrome P-450 enzymes, including 11-beta-hydroxylase and 17-alpha-hydroxylase, which in turn inhibit steroid synthesis.

Ketoconazole

Ketoconazole is an imidazole broad-spectrum antifungal agent that acts on several of the P-450 enzymes, including the first step in cortisol synthesis, cholesterol side-chain cleavage, and conversion of 11-deoxycortisol to cortisol. It may inhibit adrenocorticotropic hormone (ACTH) secretion when used at therapeutic doses. Ketoconazole in dosages of 400 mg every 8 hours has been used in the treatment of advanced prostate cancer, although it is not FDA approved for this indication.

Bisphosphonate Derivatives

Class Summary

In men with castrate-resistant prostate cancer and bone metastases, zoledronic acid is recommended to help prevent or delay disease-associated, skeletally related events. Skeletally related events can include pathologic fractures or spinal cord compression, which may require surgery or radiation therapy to bone.[136]

Zoledronic acid (Zometa)

Zoledronic acid is an intravenous bisphosphonate that is indicated for patients with documented bone metastases from solid tumors treated with standard chemotherapy. Prostate cancer should have progressed after treatment with at least 1 hormonal therapy. It inhibits bone resorption, possibly by acting on osteoclasts or osteoclast precursors, and thus reduces the risk of skeletally related events. Adverse effects include osteonecrosis of the jaw.

General dosing recommendations include administering 4 mg infused intravenously over no less than 15 minutes every 3 or 4 weeks for patients with a creatinine clearance (CrCl) of more than 60 mL/min. Treatment is continued for 9-15 months. Oral calcium supplementation of 500 mg and a multiple vitamin containing vitamin D 400 units daily are also recommended.

Monoclonal Antibodies, Endocrine

Class Summary

Monoclonal antibodies such as denosumab have been shown to decrease the incidence of skeletally related events (fractures, spinal cord compression, need for radiation therapy) in men with known bone metastases from prostate cancer.

Denosumab (Prolia, Xgeva)

Denosumab is a human immunoglobulin G2 (IgG2) monoclonal antibody that binds to the receptor activator of nuclear factor kappaB ligand (RANKL), which acts as the primary signal to promote bone removal. By inhibiting the development and activity of osteoclasts, denosumab decreases bone resorption and increases bone density.

Under the brand name Prolia, denosumab is indicated for increasing bone mass in men who are at high risk for fracture because they are receiving androgen deprivation therapy for nonmetastatic prostate cancer. In these patients the dosage is 60 mg subcutaneously every 6 months.

Under the brand name Xgeva, denosumab is indicated for the prevention of skeletally related events in men with bone metastases from prostate cancer. In these patients the dosage is 120 mg subcutaneously every 4 weeks.

With both indications, all patients should receive calcium supplementation of 1000 mg and at least 400 units of vitamin D daily.

Corticosteroids

Class Summary

Corticosteroids have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli. They are used in combination with agents such as mitoxantrone, abiraterone, and docetaxel.

Prednisone (Rayos)

Prednisone provides significant subjective palliation and reduces prostate-specific antigen (PSA) levels. Higher doses may be used in patients with spinal cord compression or cerebral edema.

Hydrocortisone (A-Hydrocort, Cortef, Solu-Cortef)

Hydrocortisone decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing increased capillary permeability.

Dexamethasone (Dexamethasone Intensol)

Dexamethasone may provide palliative benefits in patients with prostate cancer. Dexamethasone can prevent or suppress inflammation and immune responses when administered at pharmacologic doses.

Radiopharmaceuticals

Class Summary

The bone-seeking isotope, radium-223 dichloride, has been shown to improve survival of castration-resistant prostate cancer in men with symptomatic bone metastases.

Radium-223 dichloride (Xofigo)

Radium-223 dichloride is an alpha–particle-emitting radiopharmaceutical. This heavy metal mimics calcium and forms complexes with the bone mineral hydroxyapatite at areas of increased bone turnover, such as bone metastases. The complexes cause the double-strand DNA breaks that are lethal to the prostate cancer cell at the site of increased bone turnover induced by the cancer. It is indicated for men with castration-resistant prostate cancer with symptomatic bone metastases and no known visceral metastatic disease.

 

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