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The following module was designed to supplement medical students’ learning in the clinic. Please take the time to read through each module by clicking the headings below. Information on epidemiology, classification, signs & symptoms, diagnosis, pathology, staging, management, treatment and prognosis of prostate cancer is provided. By the end of the tutorial, the following objectives should be addressed:
The prostate gland is a walnut-sized exocrine gland that makes up a part of the male reproductive system. It is located between the bladder & external urethral sphincter, and anterior to the rectum. It surrounds the prostatic urethra below the urinary bladder and is palpable on digital rectal exam (DRE). The cavernous nerves run posterior and lateral to the prostate gland from the pelvic plexus to the corpus cavernosum muscles. Prostate cancer and some of its treatment modalities can damage these nerves, thereby contributing to erectile dysfunction.
The prostate gland secretes an alkaline fluid that aids in sperm survival in the vaginal tract. This fluid is secreted during ejaculation, and consists of proteolytic enzymes, including the prostate-specific antigen (PSA), and prostatic acid phosphatase.
The prostate can be divided into 4 zones for pathological classification. The majority of prostate cancers occur in the peripheral zone, which makes up the vast majority of the gland. In comparison, benign prostatic hypertrophy, or BPH, occurs in the transitional zone, which makes up only 5% of prostatic tissue.
Prostate cancer is the most commonly diagnosed cancer in Canadian men, accounting for more than 1 in 5 new cases (1). According to the Canadian Cancer Statistics from 2020, approximately 1 in 9 men develop prostate cancer every year, whereas 1 in 29 die from it (2).
It is the second most common malignancy in men worldwide and also the 5th leading cause of death from cancer (3).
Nonetheless, prostate cancer is a slower-growing disease. It has one of the highest five-year survival rates of all cancers in Canada (95%) (4). The mortality rate for prostate cancer has been declining since 1994, likely due to earlier screening and detection, and improved treatment including the introduction of hormonal therapy and further advances in radiation therapy (5).
Age
The number one risk factor for prostate cancer is age; in fact, its incidence is more strongly correlated with age than most other human malignancies. According to the data in the American National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) program, the percentage of new cases of prostate cancer was highest for men within the age range of 65 to 74 years (1). The percentage of new cases was 0.5% for men aged 35 to 44, 9.0% for men ages 45 to 54, 33% for men ages 55 to 64, and declined for age groups 75 to 84, and for men >85 years, at 15% and 4% respectively (1).
Ethnicity
Black North Americans have a higher risk of developing prostate cancer and are more likely to develop a more aggressive clinical course (2). In the United States, black men are also more likely to have an earlier age of onset and a higher than expected rate of biochemical recurrence (2). In comparison, white North American men have intermediate rates of developing prostate cancer and Asian North American men have relatively lower rates (2).
There is a greater prevalence of prostate cancer in North America than in Asia, however, an increasing frequency of prostate cancer in Asian immigrants may suggest that the correlation is related to environmental rather than genetic causes (2).
Genetics
Approximately 10% of prostate cancer is attributed to genetic heritability. In those who are diagnosed before the age of 55, heritability plays a greater role. Having a first degree relative with prostate cancer increases the relative risk by 2-fold and having 2 first degree relatives increases the risk by 4-5 fold (3).
Some genes that may be involved in prostate cancer development are HOXB13, c-myc (growth regulation), bcl-2 (anti-apoptosis), 5-alpha-reductase, and telomerase (4-9). Tumour suppressor genes such as p53, Rb, CDKN2, and TGF-β may also be affected in those who have prostate cancer (4-9). The BRCA-1 and BRCA-2 genes involved in breast and ovarian cancer, also predisposes men to developing prostate cancer (10).
Testosterone
Serum testosterone levels, or other endogenous sex hormones were found not to be associated with an increased risk of prostate cancer according to some studies conducted in 2008 (11).
Diet
Diets high in fat may be associated with a greater risk of prostate cancer (12). This is more likely the case with saturated fats that are present in foods such as red meat and butter, while plant fats may actually decrease risk (12). The soybean isoflavinoid compound genistein and vitamin E may reduce the risk and slow progression of prostate cancer (12). Further research is required into the role of dietary intake on the prevention and treatment of prostate cancer.
A high body mass index (BMI) has also been associated with increased risk of high-grade prostate cancer and mortality (12). For now, the best dietary advice involves following a healthy diet rich in fruits and vegetables, reducing total and saturated fats, as well as refined carbohydrates.
Summary
Prostate cancer is the most commonly-diagnosed cancer in males in North America. Prostate cancers are often slow-growing and many men with histological disease may die of other causes; that is, they may die with prostate cancer rather than from it.
Age is the most significant risk factor, while black race/ethnicity and family history are other important risk factors. Smoking and alcohol are not directly associated with an increased risk for prostate cancer. Maintaining a healthy BMI and diet may reduce the risk of prostate cancer.
History of Screening
Prostate specific antigen (PSA) is a glycoprotein that was identified as a serum marker for adenocarcinoma of the prostate in the 1980s (1). Its function is to liquefy semen coagulum, aiding in fertility (1). PSA is a prohormone protease that is specific to the prostate gland and produced in prostate acinar glands (1). After entering the glandular lumen, it is cleaved by an enzyme and then enters the bloodstream where it has a half-life of 2 days (1).
After the introduction of PSA as a screening test in Canada, the incidence of prostate cancer increased from 1984 to 1993, levelled off, and started to decline after 2001 (3). It is established that the rate of prostate cancer diagnosis is linked to PSA screening (3).
Indications for Screening
Screening in men aged 55-69 has been shown to increase the detection rate of early-stage cancer. Whether PSA screening reduces overall mortality is controversial. The two largest PSA Screening Trials, PLCO and ERSPC, produced conflicting results with the ERSPC showing a 20% reduction in prostate cancer mortality with PSA screening. (4). In 2014, the Canadian Task Force on Preventive Health Care recommended against routinely screening men of ages 55-69 for prostate cancer (5). These recommendations primarily apply to men in the general population, including those with lower urinary tract symptoms (e.g. urgency, weak stream, nocturia) and BPH.
The United States Preventive Services Task Force released updated recommendations in 2018 for men of ages 55-69 based on longer follow-up from the screening trials upgrading their recommendation from Grade D (recommend against screening) to Grade C (6). Thus, the Task Force concluded that the decision to proceed with PSA screening should be individualized and eligible patients should discuss the relative risks and benefits of PSA screening with their providers and engage in a shared-decision making process. Clinicians and patients should discuss the potential benefits and harms of screening in the context of the patient’s personal risk factors, comorbid conditions, and values (Table 1). Most guidelines currently recommend limiting screening to men aged 55 to 69 as they are more likely to derive benefit from screening compared to younger or older men.
Additionally, digital rectal exams (DREs) are also no longer recommended for screening as there is a lack of evidence on the benefits (6).
Screening Methods
Serum PSA Values
The serum PSA test is used for screening for prostate cancer and for diagnosis in conjunction with other clinical parameters (3). Prostate cancer cells generate less PSA per cell than normal tissue, however, prostate cancer lacks basal cells (1). This results in changes to the normal lumen architecture and breaks in the basement membrane, leading to proPSA along with other truncated forms of the PSA protein leaking out into normal circulation (1). Thus, more ‘PSA’ is present in the blood, and a larger fraction of the PSA, that is produced by cancer cells, escapes the proteolytic processing pathways that convert proPSA into PSA and degrade active PSA to form inactive PSA (1).
Serum PSA levels are used to plan treatment, prognosticate and determine if treatments are working, and predict if there is extraprostatic spread (3). This is done with serial PSAs measurements and monitoring of trends over time to determine the extent of their disease before, during, and after treatment (7,9).
However, it is important to note that serum PSA levels can be elevated due to a multitude of reasons other than prostate cancer, as displayed in Table 2.
Normal PSA ranges can also be characterized by age, and are presented in Table 3:
Further investigations are generally recommended when the PSA values are >4ng/ml (3). A value of 4-10ng/ml has a positive predictive value (PPV) for cancer of 20%, whereas values >10ng/ml have a PPV of 45% (3).
Free PSA Ratio
A free PSA ratio blood test can provide further information and can be ordered after a high total PSA (7). Prostate cancer can cause disruption of the acinar gland basement membranes which causes more PSA (bound state) to enter the bloodstream before it is cleaved in the glandular lumen to become free PSA (unbound state) (1). When it enters the bloodstream uncleaved, it is bound to the protein carrier alpha-1-chymotrypsin (1). Thus, in prostate cancer the ratio of free to total PSA decreases (unbound PSA/total PSA) (7).
PSA Density (PSAD)
PSA values can be expressed as a ratio relative to the size of the prostate which is approximated by transrectal ultrasound (TRUS) (11). This may be done to correct for increased PSA values due to BPH (11). In general, there is a 10x greater increase in PSA levels per gram of tissue with cancer than with BPH (11). PSAD is a relatively new parameter and is currently being evaluated for its sensitivity and specificity (11).
PSA Velocity
The PSA velocity measures the increase in PSA values over time. It can also be reported as PSA doubling time, and may be used to predict the need for screening, treatment response, and survival rates post-treatment. A PSA velocity of greater than 0.75 ng/ml/year is suggestive of prostate cancer (7). This is sometimes considered when assessing for cancer because a PSA that is high but stable over time is unlikely to represent cancer, versus a PSA that is high, and continuing to increase over time (12).
Digital Rectal Examination (DRE)
Digital rectal examination can be used to detect prostate enlargement and asymmetry. DRE has a low sensitivity and specificity for detecting prostate cancer but may be used as an adjunct with PSA testing. Malignant prostate masses will often feel hard, nodular, and irregular. 95% of prostate cancers are located in the peripheral zone which is palpable by DRE (13). According to a study in the Journal of National Cancer Institute, up to 50% of nodules palpable on DRE do tend to be malignant (14).
DIFFERENTIAL DIAGNOSES FOR PROSTATE MASS DETECTABLE BY DRE
Summary
Historically, prostate cancer screening through serum PSA testing and DRE was common for men aged 50-70 years. While screening may lead to a small reduction in prostate cancer mortality, there is insufficient evidence that screening reduces all-cause mortality. The risks involved with screening include false-positive results and harms from treatment including erectile dysfunction and urinary incontinence. Clinicians should discuss the potential benefits and harms of PSA screening with men aged 55 to 69 years to support them in making an individualized decision based on their values.
Signs & Symptoms
Common Presenting Symptoms
Prostate cancer is most commonly detected by PSA screening or abnormal findings on DRE. This is because many prostate cancer patients are asymptomatic at earlier stages of their disease. However, some patients may present with urinary tract obstruction, bleeding or bone pain and these symptoms warrant further investigation. This is because, often, prostate cancer is found incidentally when being assessed for lower urinary tract symptoms secondary to other conditions, such as BPH. Nonetheless, listed below are some of the common presenting symptoms in prostate cancer::
Voiding symptoms can occur in locally advanced prostate cancer when the prostatic urethra is obstructed; however, these symptoms are more likely to be due to benign prostatic hyperplasia (BPH). Urinary tract obstruction can present as urinary hesitancy, straining to void, dribbling, decreased flow or weak stream, and incomplete bladder emptying. In fact, severe urinary tract outlet obstruction can cause severe hydronephrosis. Nonetheless, it is important to note BPH and prostate cancer have different etiologies and BPH is not a precancerous lesion (1).
Hematospermia, hematuria, and hematochezia may occur with prostate cancer. It is important to rule out other more common causes of these symptoms (e.g. hematuria caused by renal calculi, bladder tumours, etc).
Symptoms of Advanced Prostate Cancer
Metastatic prostate cancer can spread to the bones and cause bone pain, most commonly in the lumbar spine, pelvis and femurs. Bone pain is often characterized as deep, penetrating and dull, and may be present at rest. Bone metastases can also cause pathological fractures in late stages.
In rare cases, prostate cancer may present with advanced bone metastasis and spinal cord compression. These patients could present with back pain, sensory or motor changes and bowel and bladder dysfunction (see spinal cord compression module).
Occasionally, patients may have metastases to lymph nodes in the pelvis. While mostly asymptomatic, they can result in abdominal or pelvic pain and potential peripheral lymphedema.
Visceral metastases to other sites (i.e. lung, brain) are uncommon.
Summary
Prostate cancer is most commonly asymptomatic in early stages and is often diagnosed through PSA screening or abnormalities on DRE. In some cases, patients can present with advanced prostate cancer and have symptoms arising from urinary tract obstruction, bone pain, or other symptoms due to local invasion or metastasis.
Information about past investigations such as PSA, DRE, and biopsy should be elicited on initial evaluation. These are all important components of the patient’s history and help to determine the cancer stage.
In addition to the PSA, one should acquire a thorough focused history, by specifically asking questions about urinary obstruction, bowel movement frequency, sexual dysfunction, genitourinary bleeding and bone or low back pain. Performance status and other medical comorbidities are relevant as well.
The International Prostate Symptom Score (IPSS) is a questionnaire that is often used for assessment of voiding symptoms. Although it is usually used to assess baseline urinary function, which is mostly important for treatment decisions and side-effect counselling, it may also be helpful for identifying potential symptoms associated with prostate cancer. To determine the IPSS, patients can fill out the survey independently, and a score out of 35 is calculated to assess voiding symptom severity and frequency.
A family history of prostate and other types of cancer should also be investigated, particularly amongst first-degree relatives. It is also very important to inquire about a family history of breast and ovarian cancers and about past genetic testing to look for any BRCA mutations.
A digital rectal examination (DRE) should be performed to assess for nodules, enlargement, or indurations of the peripheral zone of the prostate. It can also give a good indication of a patient’s baseline prostate size and shape, to compare with at follow-up visits, in order to look for improvement or recurrence. On initial assessment, the exam may reveal the presence of prostate nodules, and/or asymmetrical enlargement of one or both lobes, where either one or both lobes are biopsy positive. It can also give an indication of how much of each lobe is involved. This information can be utilized for more accurate staging. For instance, T1 tumours are not palpable, thus, there is no pathological T1 classification. T2 tumours, however, are palpable and confined to the organ, and are subclassified based on whether there is unilateral or bilateral involvement of the prostate.
A DRE can also allow the clinician to determine if there is extracapsular extension. Despite MRIs being more sensitive, DREs allow for a more specific evaluation of extracapsular extension and these findings can be used to determine prognosis. This is because, extracapsular extension is not only grossly-palpable on DREs, but is also indicative of a poorer prognosis with either surgical resection or brachytherapy. Thus, extracapsular extension is classified as T3 or higher, depending on the structures affected.
Inguinal node enlargement (a rare finding) and external genitalia should also be examined for signs of locally-advanced disease. In recent years, pelvic lymph node involvement on initial presentation has decreased and not all patients will undergo lymph node dissection (1). This is most likely because of increased PSA screening and earlier detection of cancers. Calculations based on the tumour (T) stage, PSA levels and Gleason scores can provide an estimated risk of nodal involvement.
CT scans, if done at the time of workup, can also show the presence of enlarged lymph nodes. If this is not seen on imaging, and overall the risk is low, lymph node dissection is not performed. If dissection is performed due to higher risk of disease spread, it is often performed laparoscopically.
Finally, a physical examination of the axial and appendicular skeletons and of the abdomen should be completed to assess for signs of distant metastasis.
Although PSA levels should be followed in low-risk disease, there are a number of other laboratory tests that may be ordered and assessed as part of the complete prostate cancer workup (Table 1).
Prostate gland biopsies provide information on the type of cancer, degree of atypia, presence of PIN, Gleason score, and involvement of rectal, fibrous/adipose tissue (1). A total of 12 cores are taken during the biopsy procedure, and the number of cores found to have prostate cancer cells can provide some information about the presence of low- vs. high-risk disease.
If radical prostatectomy is performed, the surgical specimen provides information on histology, size, proportion of prostate gland involved by the malignancy, Gleason score, extra-prostatic involvement, seminal vesicle invasion, margin status, vascular invasion and lymph node involvement (1). Thus, both biopsies and radical prostatectomy can provide important pathological information used for staging and determination of disease prognosis.
A transrectal ultrasound (TRUS) is used to guide biopsies and assess the prostate size, which may be helpful in evaluating if certain treatments, e.g. brachytherapy, would be appropriate. On ultrasound, malignant lesions often appear hyperechoic (higher amplitude and density of echoes on ultrasound) with poorly-defined margins, while benign lesions appear hypoechoic (lower amplitude and density of echoes on ultrasound) with well-defined margins (1). However, these findings are not specific for prostate cancer, and a tissue diagnosis is required through a biopsy if prostate cancer is suspected.
Core needle biopsy is the gold standard in prostate cancer diagnosis. Indications for prostate biopsy include PSA >4.0 ng/ml, or above age-specific ranges, or the presence of nodules, asymmetry or indurations found on DRE. In many cases, it is not possible to establish whether a patient does or does not have prostate cancer based on a PSA value, and the decision to proceed with biopsy must be individualized. Nomograms and predictive models can be used to assist in this decision. Standard practice involves performing a systematic 12-core prostate biopsy, although some studies have indicated that they may not be very reliable due to an increased risk of false-negatives (2,3).
Although poorly-visualized on CT scans, prostate cancer lesions are better identified on MRI scans, which makes them particularly useful for investigating a discordant PSA and biopsy result, or for ensuring that all suspicious lesions have been biopsied, before proceeding with active surveillance. A PI-RADS (Prostate Imaging Reporting and Data System) score can be calculated based on the MRI interpretation, to provide some information on prostate cancer diagnosis, staging and prognosis. Recent studies have also shown that the MRI/US fusion-guided prostate biopsy offers equal prostate cancer detection, relative to the systematic TRUS-guided biopsy. However, the MRI/US fusion-guided biopsy requires comparatively fewer tissue core samples than a systematic TRUS-guided biopsy (4).
Core biopsy provides information on location, percent of each individual core that is positive, and the number of positive cores. Tissue samples are evaluated for histological type and a Gleason grade is calculated (see pathology section for more information). Vascular, lymphatic, and perineural invasion may be assessed, as well as invasion beyond the prostate capsule.
Summary
Prostate cancer is commonly asymptomatic in early stage disease and is often detected by PSA screening or abnormal findings on DRE. The work-up of prostate cancer involves performing a thorough history and physical exam, laboratory tests including PSA and possibly imaging, such as bone scans in patients with suspicion for metastatic disease. The PSA is important for staging, especially in T1 tumours that do not have a pathological classification. The DRE, on the other hand, provides information on the ‘T’ stage, as well as on extraprostatic extension and seminal vesicle invasion. However, neither test is highly specific nor sensitive, and the DRE findings come with significant interobserver variation. Thus, further testing may be required with TRUS-guided prostate biopsy to accurately diagnose and stage the patient’s cancer. This is a systematic 12-core biopsy procedure done transrectally, under ultrasound guidance, and it is currently standard practice for the diagnosis of prostate cancer. As availability and expertise increases, the role of MRI for staging and diagnosis is expanding.
95% of all prostate malignancies are adenocarcinomas of the prostate, which makes it the most common subtype (1). However, multiple other forms, including several aggressive subtypes do exist and are shown in the table below.
With respect to adenocarcinoma, early signs of prostate gland atypia are called prostatic intraepithelial neoplasia (PIN). PIN is a precursor for prostate cancer consisting of atypical and dysplastic cells that are present within normal glands (1). The basal cell layer of prostate gland cells may be lost and signs of anaplasia may also be seen (1). These lesions are typically located adjacent to areas of proliferative inflammatory atrophy, which consists of focal hyperplasia in association with inflammation (1). PIN appears as early as ten years before prostate cancer, but not all lesions become cancerous.
PIN is graded based on the amount of atypia. Grades I & II are not readily associated with cancer. Grade III PIN is an indication for additional biopsies to assess for cancer in other areas of the prostate.
Prostate cancer histopathology is evaluated using the Gleason Scoring System (Table 1). The Gleason grade evaluates architectural features of prostate cancer cells, and is closely associated with clinical behaviour. Each biopsy core is graded from 1-5. The two most common patterns, the primary (most common) and secondary (second most common) grades, are added to give a Gleason score out of 10. If only one pattern is present, it is doubled to give the Gleason score (Table 2). Higher scores indicate more aggressive cancers, worse prognosis, and a less favourable post-treatment outcome. 85% of cancers are Gleason Grades 5-7 (1). Transitional zone cancers are usually assigned a higher grade and extend outside of the prostate (1).
Table 2 shows the scoring summary:
It is important to note that a Gleason Score of 7 with a Grade 4 primary and Grade 3 secondary (4+3) pattern has a worse prognosis than the same score with a Grade 3 primary and Grade 4 secondary (3+4) pattern (2). Thus, a Gleason 3+4 is considered to be favourable, intermediate-risk prostate cancer, whereas a Gleason 4+3 is considered to be unfavourable. The classification of favourable vs. unfavourable has implications for treatment modalities that should be considered for patients with both Gleason patterns.
Gleason scores were therefore organized into grade groups in order to simplify categorization. There are a total of 5 grade groups, where groups 2 and 3 both lead to an overall score of 7, but the pattern of spread in group 3 is of higher risk. Groups are listed in Table 3 as follows:
Patterns of Spread
1. Local
Prostate cancer is often multifocal with numerous heterogeneous tumours. Apex tumours spread earlier in their course as the prostatic capsule is less defined at this location (1). Local spread is common via thinner, weaker capsular walls, i.e., those closest to the bladder neck, ejaculatory duct insertion, and especially to the seminal vesicles. In fact, extension into the seminal vesicles is especially important for prostate cancer staging - it subclassifies T3 tumours into T3b. In locally-advanced disease, there may be extension to the bladder or rectum, but this is rare.
2. Lymphatic
Prostate cancer can spread to the obturator, hypogastric, presacral and external iliac lymph nodes.(1)
3. Hematogenous
The most common location for distant metastases is the bone. Very rarely, the liver or lungs may be involved (1).
Summary
Prostate adenocarcinoma is the most common form of prostate cancer. Other more aggressive variants exist. The Gleason grading system is calculated based on microscopic examination of biopsy cores and assessment of the degree of glandular atypia. Together with other parameters, it is used to guide treatment and prognosis for men diagnosed with prostate cancer. Prostate cancer can spread locally, via the lymphatic system, or hematogenously (most commonly to bone).
Prostate cancer staging involves classifying the extent and progression of disease using the TNM system. The standardized system allows different healthcare professionals to communicate and provides international consistency. The clinical stage, along with initial PSA and Gleason score are used to stratify prostate cancers into low, intermediate and high-risk categories (1). This classification system is essential to informing treatment decisions and prognostication.
Imaging for staging
CT scans and MRIs of the abdomen and pelvis are performed as indicated, particularly when there is a suspicion for lymph node positive disease or invasion into other organs. MRI can identify suspicious lesions, extraprostatic extension, seminal vesicle involvement, and invasion into adjacent organs, but is typically done for biopsy reasons or surgical planning, rather than for staging. The role of PET/CT and PET/MRI, which combine anatomic information with functional and metabolic data, is currently being evaluated. FDG-PET is not commonly used because of its low sensitivity and specificity. This is due to the slow proliferation of prostate cancer, and the fact that excreting the tracer via the bladder and the urinary system tends to obscure the prostate gland.
Instead, radiotracers directed to prostate-specific membrane antigen (PSMA), expressed in prostate cancer, metastatic lymph nodes and bony metastases, have been developed (3). These show promising preliminary results for accurate diagnostic, staging and therapeutic applications (3).
According to the 2019 Canadian Urological Association Guidelines for prostate cancer staging, there are strong (Level 3) recommendations to use a CT of the abdomen and pelvis, and a bone scan (99mTc-MDP) for men who are newly-diagnosed with prostate cancer and present with high risk features such as a PSA >20 ng/mL, a Gleason score >7, or a clinical stage of T3 or greater (1).
PET/CT
Staging of metastatic prostate cancer using integrated positron emission tomography/computed tomography (PET/CT), with radiotracers targeting prostate-specific membrane antigen (PSMA), is currently being investigated. The FDA approved the first a PSMA-targeted PET imaging drug in Dec 2020 after a recently-published randomized crossover study of 302 men with high-risk localized prostate cancer demonstrated that higher accuracy by 27% when using the radiotracer Gallium-68 (Ga-68) for PSMA PET/CT, before curative intent surgery or radiotherapy instead of the conventional CT/bone scan imaging (3). In this study, the aforementioned technique was especially effective for detecting metastases to pelvic and distant lymph nodes, and was also found to have higher sensitivity (85% versus 38%) and specificity (98 versus 91 percent), compared to conventional CT imaging and bone scans (3).
In fact, the use of PSMA PET/CT has led to twice as many patients changing their initial management compared to when conventional imaging was utilized for staging, where half of the group chose to undergo treatment with palliative- instead of curative-intent (3).
Bone Scan
A bone scan, or bone scintigraphy, is performed if the patient is symptomatic, has a PSA greater than 20 ng/ml, stage is ≥T3 as per TNM staging or a Gleason score ≥8 (Figure 1). This is done to assess for bone involvement, since bones are the most common sites for prostate cancer metastasis.
Bone scans use radiopharmaceuticals which collect in rapidly-proliferating tissue (such as in groups of cancerous cells) and are visible on the scan. The National Comprehensive Cancer Network recommends a bone scan in patients with prostate cancer with PSA levels >20 ng/mL, as this is one criteria for patients to be considered high-risk for metastatic disease (1). Bone scans may be considered in patients with PSA levels between 10-20 ng/mL, if the tumour is Gleason ≥8 on biopsy, if the stage is ≥T3, or if the symptoms and signs identified on the patient’s history and physical exam suggest bony metastases (1). False positives on bone scan may occur with concurrent healing fractures, arthritis or Paget’s disease (6).
Tumor Node Metastasis (TNM) System
Prostate cancer is staged worldwide using the TNM system which was updated by the American Joint Committee on Cancer in 2017 (4). Below is a table explaining TNM criteria for each stage category, and the associated 10-year survival.
T – Tumour extent
N – Nodal involvement
M – Metastasis
Stage Categories
The TNM classification can be grouped into Stage categories I through IV. While the stages are important and may have some prognostic value, they are not commonly used in clinical settings. It is the classification of low, intermediate and high-risk disease that is used to make most treatment decisions.
Note that, when either PSA or Grade Group is unavailable, grouping is determined by the ‘T’ category, and/or, by either PSA or Grade Group, as available.
Risk Stratification of Prostate Cancer
Prostate cancers are categorized into low, intermediate and high-risk groups based on clinical stage, Gleason score and initial PSA. This risk stratification system assists in therapeutic decision-making, clinical trial design and outcome reporting.
Summary
Prostate cancer staging involves assessment of the extent of prostate cancer. This is done using clinical exam, laboratory testing, biopsy, imaging, and/or surgery. Imaging is used to assess for local invasion, lymph node disease, and distant metastasis, which most commonly spreads to bone. The TNM system is used for staging and risk classification systems can help guide treatment recommendations.
The treatment for localized prostate cancer can be divided into three categories: low risk, intermediate risk, and high risk. This classification, along with patient performance status and preference, provides guidance for physicians and patients in selecting treatment options. Appropriate specialists will discuss the advantages and disadvantages of treatment options with the patient to support their decision-making. Active surveillance, watchful waiting, and curative, or palliative treatment options may be explored either individually, or in combination with each other.
A ‘cure’ for prostate cancer can be defined in numerous ways, i.e., in terms of overall survival (OS), metastasis-free survival, biochemical recurrence-free survival, etc (1).
Curative treatment may be recommended depending on an individual patient’s estimated life expectancy, and their disease context (e.g., adverse features, node positive disease, etc.) (2). Prostate cancer is initially asymptomatic and may take over 10 years to progress (2). If a patient’s life expectancy is less than 10 years, the morbidity from treatment may be greater than the expected benefit of cure (2).
The following table summarizes potential treatment modalities for prostate cancer stratified as either low, intermediate or high-risk. Treatment modalities are discussed further in detail later in this section. It is important to note that patients are frequently presented with individual modalities in combination with one another, based on their individual management plans.
Expectant management where treatment is delayed until the disease progresses or symptoms appear is also always an option, as discussed below.
1. Active Surveillance
Active surveillance is defined as the postponement of immediate definitive therapy (radical prostatectomy or radiotherapy), with the initiation of curative-intent treatment if there is clinical evidence of disease progression. The goal is to avoid treatment-related complications for men whose cancers are not likely to progress. The National Comprehensive Cancer Network (NCCN) guidelines recommend treatment with active surveillance for appropriate patients with low-risk prostate cancer and an estimated life expectancy of >10 years (2). Periodic serum PSA and DRE assessments and biopsies are performed to monitor cancer extent. Follow-up is done by urologists or radiation oncologists depending on the future treatment option of either surgery or radiotherapy, as selected by the patient.
2. Watchful Waiting
In comparison, watchful waiting refers to monitoring men who are unlikely to benefit from curative treatment of their localized prostate cancer, typically due to older age, comorbidities/frailty, patient preference, etc. Watchful waiting is an appropriate option for (2):
These patients are monitored for symptomatic progression, at which time palliative treatment is initiated, typically with androgen deprivation therapy (ADT) (3). Serial PSA levels and DREs are done for monitoring, typically once or twice per year.
3. Radical Prostatectomy
This treatment is commonly used if the entire extent of malignant tissue can be surgically excised, with minimal effect on the patient’s urinary and sexual functions (2,4). Patients are evaluated by laboratory tests, including CBC, creatinine, and urinalysis, chest X-ray and electrocardiogram to ensure that they are appropriate candidates for surgery.
A radical prostatectomy can be performed using an open approach (open retropubic or perineal prostatectomy) or a minimally-invasive (laparoscopic or robotic) technique. There are several advantages and disadvantages to pursuing this treatment option (Table 1).
Patients are followed up with serial serum PSAs, as this value should become, and remain undetectable in the blood and is usually first checked 6 weeks - 3 months post surgery (1). Previous randomized trials showed a benefit for adjuvant radiation for patients with adverse pathological features (positive margins, extracapsular extension, seminal vesicle invasion) for progression-free survival with one trial showing an overall survival advantage. Salvage radiotherapy and routine postoperative PSA monitoring was variably used in the control arms. More recent trials have compared adjuvant radiotherapy to early salvage radiation with results suggesting that they are equivalent. The reappearance of PSA in the bloodstream indicates biochemical relapse but not necessarily clinical relapse.
Follow-up visits are then scheduled, to re-assess the pathology reports, and if needed, to perform bone scintigraphy in order to assess for distant metastases. The faster the PSA doubling time, the greater the risk for clinical relapse (which, unlike biochemical relapse, is defined by signs and symptoms of recurring cancer) (1).
4. Radiation Therapy
Radiation therapy is the other modality commonly used for curative treatment of low risk, localized prostate cancer. Radiation therapy includes external beam radiation therapy (EBRT, Figure 1) and/or brachytherapy (Figure 2). Treatment with EBRT targets the prostate with or without targeting pelvic lymph node groups. In general, it is used when patients have severe urinary symptoms pre-treatment, or significant comorbidities that make both brachytherapy and surgery more risky. In these cases, the anesthetic risk, the possibility of worsening symptoms post-brachytherapy, and the potential high risk of extraprostatic extension, e.g. in the lymph nodes, prevent adequate treatment of the prostate cancer with surgery or brachytherapy, and thus EBRT is deemed most appropriate.
Brachytherapy is done via two methods:
Table 2 discusses the advantages, and disadvantages of EBRT and brachytherapy.
Follow up is done at the one-month mark, and every 3 months for the first year. This is followed by reassessments every 6 months, with physical examination and serial PSAs on bloodwork (1).
5. Androgen Deprivation Therapy
Androgens stimulate prostate cancer growth, so Androgen Deprivation Therapy (ADT) is used to block the effects of androgens systemically to slow prostate cancer growth . Androgen deprivation therapy is also known as hormone therapy and can be used for prostate cancer treatment in several ways. It can be used as neoadjuvant therapy, which is provided before radiation or prostatectomy. ADT can also be given concurrently with radiotherapy in the salvage setting after surgery and in cases of recurrent cancer after another therapy has been used.
ADT can also be the primary therapy and is the first-line treatment for advanced metastatic cancer.
ADT includes anti-androgens and Luteinizing Hormone Releasing Hormone (LHRH) analogues. LHRH is a hormone released by the hypothalamus, which then stimulates Luteinizing hormone (LH) production and release from the anterior pituitary gland. LH circulates through the bloodstream, and acts on the testes, stimulating release of testosterone. Testosterone then acts on prostate cells, by binding to androgen receptors and activating them. Androgen receptor activation initiates a signalling cascade that leads to an upregulation of genes promoting cell growth, and downregulation of genes promoting apoptosis.
LHRH analogues are utilized in androgen-targeted therapy because these synthetic agents prevent pulsatile LHRH release, thereby preventing LH and FSH release. This leads to less androgen (testosterone) being released into the bloodstream. When LHRH agonists are first given, there is a surge in testosterone levels, and anti-androgen medications are required to block the effects of the surge. The surge may cause an increase in symptoms such as bone pain, obstruction, or rarely, spinal cord compression. It is recommended to use an anti-androgen agent for 4 weeks to prevent this flare-up. Once the LHRH agonist has been given continuously for several weeks, the surge normalizes and anti-androgen agents can be discontinued.
Listed below are the potential side effects of anti-androgen treatment:
Treatment: Metastatic Prostate Cancer
Metastatic prostate cancer can manifest through elevated or rising PSA after definitive local treatment. In other cases, patients may have overt metastases, which are predominantly bone lesions. Metastatic prostate cancer can be divided into castration-sensitive and castration-resistant prostate cancer. The initial approach to disseminated prostate cancer includes the use of androgen-deprivation therapy (ADT). Men who relapse after initial systemic hormone therapy are considered to have castration-resistant prostate cancer (CRPC).
A PSA relapse after treatment is defined differently depending on the treatment modality. After radical prostatectomy, biochemical recurrence is defined as two blood tests with serum PSA ≥0.2 ng/mL (6).
After radiation therapy, defining biochemical failure can be difficult as some normal prostatic glandular tissue remains and serum PSA levels are unlikely to fall to undetectable levels. It may take 1-2 years after treatment for serum PSA to reach its nadir. The Phoenix criteria of biochemical relapse is a PSA rise of 2 ng/mL or more above the nadir PSA (2).
In cases of PSA relapse, several clinical factors should be evaluated to determine whether or not treatment is indicated. Evaluating the clinical features at original presentation and pathologic findings for men undergoing prostatectomy is important. In addition, other features such as PSA doubling time, Gleason score and PSA response to androgen deprivation therapy can differentiate men who are likely to develop clinically significant disease compared to indolent disease (3). The main treatment modalities for biochemically-recurrent prostate cancer include salvage radiation therapy and hormone therapy.
The following table presents treatment modalities for metastatic prostate cancer, as well as their advantages and disadvantages (2, 9). It is important to note that often, treatment modalities may be provided in combination with one another, rather than individually.
Systemic Therapy Options
Castration-resistant prostate cancer (CRPC) is defined by disease progression after surgical or medical castration. Recommendations for treatment include continuing androgen-deprivation therapy while adding additional systemic therapy. The following table lists the noted chemotherapy and hormone therapy drugs used for systemic therapy, their individual mechanisms of action, and common side effects from use (7-13).
Palliative Treatment
Palliative treatment plans include a combination of radiotherapy, hormone therapy, analgesics and TURP as needed for symptomatic relief.
In men with advanced prostate cancer, most bone metastases are osteoblastic lesions, which frequently cause pain and can cause complications such as pathological fractures. Treatment may include analgesics, hormone therapy, radiotherapy, radiopharmaceuticals and chemotherapy for pain relief. Men should also be taking an osteoclast inhibitor (e.g. denosumab, zoledronic acid) to reduce the risk of skeletal complications of bone metastases.
Summary
The first-line treatment for metastatic prostate cancer is androgen deprivation therapy which can be achieved through medical hormone therapy or bilateral orchiectomy. Additional systemic agents may be indicated in cases of castration-sensitive and castration-resistant prostate cancer that are either high-risk or metastatic. These treatment regimens are made of several combinations of chemotherapy agents as well as steroids such as prednisone. Palliative treatments may include a variety of modalities with the goal of symptomatic relief.
Prognosis of prostate cancer patients can be evaluated by reviewing the Gleason score, PSA levels, and the clinical stage. Patient factors such as specific gene mutations, age and comorbid conditions will also influence prognosis. 5-year survival for Stage I-III or non-metastatic Stage IV prostate cancer is nearly 100% (1). 5-year survival for metastatic Stage IV prostate cancer is 28% (1). Although individual patient factors will determine individual prognoses, in general, the lower the risk, the greater the potential for complete remission. Risk stratification for prostate cancer is discussed earlier in the module.
This case study was designed to supplement your knowledge on the workup of prostate cancer and test what you have learned after going through the module. Use your mouse to click through the slides and answer each question in the text box provided.
Note: This case can be completed on an iPad. To do this download the (free) Articulate Mobile Player for the iPad by clicking here.
Use your mouse to click through the slides and answer each question in the text box provided.
Note: This case can be completed on an iPad. To do this download the (free) Articulate Mobile Player for the iPad by clicking here.
