Prostate Cancer

Oncology Modules
Last Updated
December 20, 2021

Objectives
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:

1. Understand the incidence of prostate cancer in Canada.

2. Know the general prevalence of the different types of prostate cancer.
3. List some of the important risk factors for prostate cancer.
4. Recognize the various screening tests that are used for prostate cancer.
5. Understand the indications for prostate cancer screening.
6. Know the benefits and risks of prostate cancer screening.
7. Describe the basic anatomy and location of the prostate gland.
8. Understand the classification of prostate adenocarcinoma.
9. Recognize the signs & symptoms of prostate cancer and understand that
localized prostate cancer is usually asymptomatic.
10. Demonstrate understanding of DRE and prostate specific antigen in the
diagnosis and follow-up of prostate cancer patients.
11. Describe an approach to diagnose prostate cancer.
12. Understand the Gleason score.
13. List the patterns of prostate cancer spread.
14. Understand the purpose of prostate cancer staging.
15. Understand the tests used in prostate cancer staging.
16. Know how the TNM stages apply to prostate cancer and be able to describe
the prostate risk groupings (low, intermediate and high).
17. Demonstrate a basic understanding of the treatment options available for
localized, metastatic (castrate-sensitive, castrate-resistant) prostate cancer.
18. Describe the factors influencing prostate cancer management.
19. Recognize the different health care providers involved in prostate cancer
management.
20. Understand the different modalities used for prostate cancer treatment.
21. Understand which treatment options are available for low, intermediate and
high risk prostate cancer.
22. Know some of the major benefits and risks for each treatment.
23. Demonstrate an understanding that prostate cancer is common and know the
prognosis.
24. Know the difference between watchful waiting and active surveillance.
25. Understand PSA relapse.

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Anatomy Review
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.
‍

Epidemiology
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).

Risk Factors
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.

Prevention and Screening Guidelines

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

 Prostate cancer
 Normal (benign) asymmetry
 Benign prostatic hypertrophy
 Prostatitis
 Cyst
 Prior TURP/biopsy scar
 ‍
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.

Presentation
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::

1. Urinary Tract Obstruction

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).

2. Bleeding

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

1. Bone Pain

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).

2. Less Common Symptoms

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.

Diagnosis
Focused Medical History and Physical Examination
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.

Laboratory Testing
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).

Imaging/Biopsy to confirm pathological diagnosis

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.

Pathology and Grading

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).

Staging
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.
Figure 1: bone scan showing distant metastases
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.

Treatment and Follow-Up/Survivorship

Care
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.
Adapted from NCCN Guidelines Version 3.2020 Prostate Cancer - NCCN Evidence Blocks
‍
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):

 Men with very low-risk prostate cancer

 Men with an estimated life expectancy <10 years regardless of risk group features
 Men with high risk or very high risk prostate cancer who:

 Have an estimated life expectancy <5 years with no symptoms

 Have adverse features with or without lymph node metastases

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:

1. Low dose rate (LDR) brachytherapy involves permanently implanting

radioactive iodine-125 or palladium-103 seeds into the prostate under
ultrasound guidance. These seeds remain in the prostate gland and destroy
rapidly-dividing tumour cells over a long period of time, but the dose of
radiation released is smaller and the duration of release is extended (Figure
3) (1).
2. In comparison, high dose rate (HDR) brachytherapy involves temporary
implantation of radioactive Iridium-192 source through needles inside the
prostate gland, also under ultrasound guidance. The radiation team then
plans the amount and duration of radiation that will be sent to different regions
of the prostate, through each needle. This procedure is typically performed in
the operating room setting, and is a one-time procedure. The needles are
removed at the end of the procedure.
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:

 Impotency
 Loss of libido
 Anemia
 Nausea
 Vomiting
 CNS and neurological function changes
 Galactorrhea
 Muscle atrophy
 Osteoporosis
 Delayed testosterone recovery
 Increased AST/LDH
 Gynecomastia

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.

1. TREATMENT OF BONE PAIN

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
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.
Virtual Patient Case
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.