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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 is part of the male reproductive system. It is located between the bladder & external urinary sphincter and the rectum, and below the pubis. It surrounds the prostatic urethra below the urinary bladder and is palpable on DRE. The cavernous nerves run posterior and laterally to the prostate gland from the pelvic plexus to the corpus cavernosum muscles. Prostate cancer and some treatments can damage these nerves affecting urinary, sexual and bowel functions.1
The prostate gland secretes an alkaline fluid that aids in sperm survival. PSA, prostatic acid phosphatase and other proteolytic enzymes are secreted by the prostate during ejaculation.
The prostate gland is controlled by androgens, specifically, dihydrotestosterone.
The prostate can be divided into 4 zones for pathological classification. The majority of prostate cancers occur in the peripheral zone.
Prostate cancer is now the most common cancer in Canadian men with 25,500 estimated new cases in 2009.(1) In British Columbia, the incidence was rising at a rate of 3% per year through the 70’s to 90’s but levelled out in the mid 90’s.(2) This increase may be due to detection from transurethral resection of the prostate (TURP) being performed more often for benign prostatic hyperplasia (BPH), prostate specific antigen (PSA) screening and DRE testing.(2) There has been a slight reduction in prostate cancer mortality since the 90’s which has been attributed to treatment option availability.(2)
At the age of 50 years, men have a 40% chance of developing prostate cancer and by 80 years, 70% of men will have prostate cancer detectable on biopsy. Over 90% of those diagnosed with prostate cancer are over the age of 60. The median age of diagnosis is 72.
The number one risk factor for prostate cancer is age. One in eight men between the ages of 60 and 80 will have prostate cancer and the risk continues to increase with age.
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 increases the relative risk by 1.5-2 fold and having 2 first degree relatives increases the risk 4-5 fold for prostate cancer.
Some genes that may be involved in prostate cancer development are c-myc (growth regulation), bcl-2 (anti-apoptosis), 5-alpha-reductase, and telomerase. Tumour suppressor genes such as p53, Rb, PTEN and TGF-β may also be involved.(3)
The BRCA-2 gene involved in breast and ovarian cancer also increases the risk of prostate cancer.(3) A dominantly inherited gene, prostate cancer susceptibility gene (PRCA-1) has not been identified but may be involved in prostate cancer.(3)
Prostate cancer is most prevalent in African American men which may be due to higher serum testosterone levels.(4) There is an intermediate risk for prostate cancer in the Caucasian population in comparison. Asian Americans have a relative lower risk of developing prostate cancer.
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, not genetic, causes.(5)
A recent paper analysing studies correlating serum testosterone levels with prostate cancer risk have indicated there is no correlation between the two parameters.(6)
Some studies have indicated that increased serum levels of IGF-1 may increase the risk of prostate cancer. IGF-1 may do this in three ways: acting as a mitotic agent on prostate cancer cells, decreasing SHBG, and increasing androgen synthesis. These studies are inconclusive and measuring IGF-1 levels in prostate cancer patients is not currently recommended.
Diets high in saturated fat are associated with a 1.6-1.9 times greater risk of prostate cancer.(3) This is more specifically associated with red meat and butter intake and other foods with high levels of alpha-linoleic acid. This fatty acid may cause an increase in androgen production.
The soybean isoflavinoid compound genistein may reduce the risk of prostate cancer by inhibiting the 5-alpha-reductase enzyme that converts testosterone to DHT. (3) Vitamins A, E, and β-carotene may also be protective through anti-oxidation mechanisms but there is currently insufficient evidence to support this.(6)
A high body mass index (BMI) has also been correlated with increased prostate cancer recurrence and mortality. (6)
Prostate cancer is the most common cancer in males in Canada. Some of the important risk factors for prostate cancer are: age, ethnicity, family history and diet. Smoking and alcohol are not associated with an increased risk for prostate cancer.
Screening for prostate cancer is generally done using the Prostate Specific Antigen (PSA) serum test which was introduced in 1994. PSA is a prohormone protease that is specific to the prostate gland and produced in prostate acinar glands. After entering the glandular lumen it is cleaved by an enzyme and then enters the blood stream where it has a half life of two days. Its function is to liquefy semen coagulum, aiding in fertility.
The baseline serum PSA values can be increased or decreased in a variety of situations, as outlined below.
Causes for Increase and Decrease in Serum PSA Values:
Normal PSA ranges can be characterized by age:
Age
<50
50-60
60-70
70-80
Value (ng/ml)
<2.5
<3.5
<4.5
<6.5
Further investigations are generally recommended when the PSA values are greater than >4ng/ml. 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%.
Prostate cancer can cause disruption of the acinar gland basement membranes which causes more PSA to enter the bloodstream before it is cleaved in the glandular lumen to become free PSA (unbound state). When it enters the bloodstream uncleaved, it is bound to the protein carrier alpha-1-chymotrypsin. Thus, in prostate cancer the ratio of free to total PSA decreases (unbound PSA/total PSA). This can be quantified by a blood test. (4)
Percent of free total PSA
<25%
<15%
<7%
Percent risk of cancer
Increased risk
50%
90%
The PSA values can also be related to the size of the prostate which is approximated by transrectal ultrasound (TRUS). This may be done to correct for increased PSA values due to BPH. In general, there is a 10x greater increase in PSA levels per gram of tissue with cancer than with BPH. PSAD is a relatively new parameter and is currently being evaluated for its sensitivity and specificity.
PSAD Density (ng/ml per cm3)
<0.1
0.1-0.15
>0.15
Interpretation
BPH
Suspicious
Suggestive of cancer
The PSA velocity measures the increase in PSA values over time. It can 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.(4)
Digital rectal examination is also used to detect prostate enlargement. 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. Up to 50% of nodules found on DRE are malignant.
Screening has been shown to increase detection rate of early stage cancer, but there is insufficient evidence supporting reduced mortality from prostate cancer.(2)
The current recommendations for PSA screening as set out by the BC Cancer Agency are to offer annual DRE and PSA tests to men between the ages of 50-70 years. Patients should be made aware of the risks and benefits before deciding whether they want to partake in screening. Screening should be stopped when the patient’s life expectancy is less than 10 years. PSA should also be evaluated in men presenting with lower urinary tract complaints or with positive findings on DRE.(2)
Prostate cancer is screened by the PSA test and DRE which should be offered to men 50-70 years old and in men with lower urinary tract symptoms. This test has not shown to decrease prostate cancer mortality and false positives and negatives are common. Other parameters such as PSA velocity, density, and free PSA may also aid in screening, diagnosis, and treatment follow-up.
For treatment and classification purposes, adenocarcinoma is divided into 3 subcategories: low risk, intermediate risk, and high risk by the Canadian Consensus Guidelines as outlined below.
The prostate gland is a tubuloalveolar exocrine gland which is part of the male reproductive system. Prostate adenocarcinoma is the most common type of prostate cancer but other more aggressive forms exist. Prostate cancer is classified as low risk, intermediate risk and high risk according to Canadian Consensus Guidelines.
Prostate cancer is most commonly detected by finding nodules or indurations on DRE or by PSA screening. This is because most prostate cancer patients are asymptomatic in early stage disease. However, some patients may present with urinary tract obstruction, bleeding or bone pain and these symptoms warrant further investigation.
Voiding symptoms can occour 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, dribbling, decreased or narrow stream, and incomplete bladder emptying. It is important to note BPH and prostate cancer have different etiologies and BPH is not a pre-cancerous lesion.(1)
The International Prostate Symptom Score (IPSS) is a questionnaire that is often used for assessment of voiding symptoms. The patients can fill out the survey themselves and a score out of 35 is calculated to assess voiding symptom severity and frequency. A copy of the questionnaire can be found here at the Urology Sciences Research Foundation.
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).
Metastatic prostate cancer can spread to the bones and cause bone pain, most commonly in the lumbar spine, pelvis and femur. Bone metastasis can also cause pathological fractures in late stages.
Prostate cancer can rarely present with urinary retention due to epidural metastases causing spinal cord compression. Prostate cancer may also lead to sexual dysfunction and changes in ejaculation.
Prostate cancer can present with urinary obstructive symptoms but most commonly it is asymptomatic in early stages. Prostate cancer may cause a variety of symptoms due to local invasion or metastasis in later stages of the disease.
Information about past investigations such as PSA, DRE, and biopsy should be elicited. Questions about urinary obstructive symptoms, sexual dysfunction, genitourinary bleeding and bone pain should also be asked. A family history of prostate cancer should also be investigated.
A digital rectal examination should be performed to assess for nodules, enlargement, or indurations of the peripheral zone of the prostate. Inguinal nodes and external genitalia should be examined for signs of locally advanced disease.
Examination of the skeleton and abdomen should also be completed to assess for signs of distant metastasis.
The following laboratory tests may be completed as part of the complete prostate cancer workup if there are indications in the history of more advanced disease.
Needle biopsy is the gold standard in prostate cancer diagnosis. The indications for prostate biopsy include: PSA > 4 ng/ml or above age-specific ranges, nodules, symmetry or indurations found on DRE, or evaluation of a T1a or greater tumour detected on TUPR. A transrectal ultrasound (TRUS) is used to guide biopsies and assess the prostate size. On ultrasound, cancer often appears 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. However, these findings are not specific for prostate cancer and biopsy is required. Biopsy cores are taken from the visualized lesions and eight quadrants including the left & right apex, middle, and the base of peripheral zone.(1)
An 8 core biopsy has 90-95% sensitivity and a 10 core biopsy has 99% sensitivity. Sensitivity also depends on the prostate size, a 40 cc gland needs 12 cores for 98% sensitivity while a 60 cc gland needs 17 cores to achieve the same sensitivity. The false positive rate is 0-2%.
The biopsy provides information on location, size, and number of positive cores. The histological type can be assessed and a Gleason grade can be calculated (see pathology section for more information). Vascular, lymphatic, and neuron invasion may also be assessed as well as invasion beyond the prostate capsule.
Imaging is used to assess for local invasion and distant metastasis. Indications for a bone scan include symptomatic bone pain or a PSA greater than 15 ng/ml. The incidence of bone metastasis is related to PSA levels. PSA levels of less than 8 ng/ml rarely have skeletal involvement. False positives may occur with concurrent healing fractures, arthritis or Paget’s disease.(2)
CT scans and MRI of the abdomen and pelvis will be performed as indicated.
A relatively new technique, ProstaScint can be performed using SPECT imaging. An antibody to prostate specific membrane antigen (PSMA) can be used to detect the ratio of prostate antigen to muscle background (P/M) to assess pelvic node involvement for staging purposes. This is not commonly used in Canada.
Diagnosis of prostate cancer involves history taking, physical examination, laboratory tests including PSA, TRUS core biopsy and imaging.
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) Also, the basal cell layer may be lost and there may be signs of anaplasia.(1) These lesions are often located adjacent to areas of proliferative inflammatory atrophy, or (PIA) which consists of undifferentiated prostate epithelial cells.(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 search for cancer in other areas of the prostate. Studies are in progress to determine if finasteride, a 5-α-reductase inhibitor, can be used in patients with PIN to prevent progression to adenocarcinoma.
On gross examination, prostate cancer appears heterogeneous, pale yellow with grey flecks and multifocal.
Prostate cancer histopathology is evaluated using the Gleason Scoring System. 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. Higher scores indicate more aggressive cancers and worse prognosis. 85% of cancers are Gleason Grades 5-7.(1) Transitional zone cancers are usually higher grade and extend outside the prostate.(1)
Primary Grade (/5) + Secondary Grade (/5) = Gleason Score (/10)
It is important to note that a Gleason Score of a 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)
Score
2-6
7
8-10
Risk
Low risk
Intermediate risk
High risk
Prostate cancer is often multifocal with numerous heterogeneous tumours. Local spread is common via areas of thin and weak capsule to the bladder neck, seminal vesicles, ejaculatory duct insertion, and rarely to the bladder. Apex tumours spread earlier in their course as there are more capsule defects at this location.(1)
Prostate cancer can spread systemically to the obturator, hypogastric, presacral and external iliac lymph nodes.(1)
The most common location for distant metastases is the bone. Very rarely, the liver and lungs are involved.(1)
To assess prostate cancer pathology the Gleason score is calculated based on microscopic examination of biopsy cores and assesses degree of glandular atypia. Prostate cancer can spread locally, hematogenously, and via the lymphatic system.
Prostate cancer staging involves classifying the extent and progression of the disease using the TNM system. Staging helps in deciding a patient’s treatment plan, understanding prognosis and allowing research comparison. Staging also allows different health care professionals to communicate and provides international standardization.
History, physical examination, laboratory tests including PSA and TRUS biopsy are used in prostate cancer staging. If radical prostatectomy and lymphadenectomy are performed, this will also provide valuable information. Chest X-ray, CT, MRI and bone scans may also be used to evaluate metastasis.
The DRE and PSA can give an initial indication of the prostate gland size, degree of enlargement and location but neither test is sensitive and specific and further testing must be done. TRUS can indicate which areas of the prostate are hypoechoic, which is a decreased tissue density detected by ultrasound waves. This finding is non-specific and biopsy is needed for diagnosis.
Prostate gland biopsy provides information on the cancer type, degree of atypia, presence of PIN, Gleason score, and rectal, fibrous/adipose tissue, and seminal vesicle involvement.(1)
If radical prostatectomy is indicated for treatment, it provides information on the type, size, percent involvement, Gleason score, extra-prostatic involvement, positive margins, vascular invasion and lymph node involvement.(1) Both biopsy and radical prostatectomy can provide important information for staging and prognosis. Specifically, positive margins and extra-prostatic involvement can predict the success of different treatment options.
In recent years, pelvic lymph node involvement on initial presentation has decreased and not all patients will undergo lymph node dissection.(1) Calculations based on TNM, PSA levels and Gleason scores can provide an estimated risk of metastasis. If the risk is low, lymph node dissection may not be performed. Dissection is now performed by laparoscopic pelvic lymphadenectomy.
A bone scan, or bone scintography, is performed if the patient is symptomatic, has a PSA greater than 10ng/ml, stage T3/4 or a Gleason score of greater than 8 to assess for bone involvement. This is the most common location for prostate cancer metastasis.
MRI and CT scanning are not as useful in staging prostate cancer as they are in other cancers. Research has shown no statistical difference between TRUS and MRI for prostate cancer staging.(1) CT has not been shown to provide more information than DRE as it cannot accurately detect extra-prostatic involvement or differentiate between benign and malignant lesions.(1)
CT is useful, however, to look for intrabdominal lymph node metastases. A CT scan should be strongly considered in patients with high risk disease (see risk groupings).
The greatest challenge in prostate cancer staging is identifying patients with microscopic extra-prostate invasion that may not be apparent on biopsy. Research is currently being conducted to find techniques that can be used to assess for this in the initial work up.(1)
Prostate cancer is staged worldwide using the TNM system which was updated in 2002.
T – Tumour extent
N – Nodal involvement
M – Metastasis
The TMN classification can be grouped into Stages from I through to IV. While the Stages are important, it is the classification of low, intermediate and high risk that is used to make most treatment decisions.
Prostate cancer staging involves assessment of the extent and the progression of prostate cancer. This is done using laboratory testing, biopsy, imaging, and/or surgery. The tests involved in staging depend on the extent of the disease and the risk of metastasis. The TNM system is used for staging and can help guide treatment protocols along with the low, intermediate and high risk classification system.
The treatment for prostate cancer can be divided into three categories, low risk, intermediate, and high risk. This classification, along with the TNM staging and patient performance status, provides guidance for physicians and patients in selecting treatment options. The advantages and disadvantages of treatment options are discussed with the patient and appropriate referrals are made. Active surveillance, watchful waiting, curative, or palliative treatment options may be explored.
Low risk prostate cancer is defined as: stage T2a or lower, Gleason score of less than 7 and a PSA score of less than 10ng/ml according to the Canadian Consensus Guidelines. The treatment intent of localized prostate cancer will often be curative. Prostate cancer cure can be defined in numerous ways, including: death from another cause, no dissemination or local disease, normal DRE, undetectable serum PSA or negative biopsy specimens after treatment.(1)
Curative treatment is usually recommended when life expectancy is greater than 10 years. This is because prostate cancer is initially asymptomatic and may take over 10 years to progress. If the patient’s life expectancy is less than 10 years, the morbidity from treatment may be greater than the expected benefit of cure. The two modalities used for curative treatment of low risk prostate cancer are radical prostatectomy and radiation therapy. Expectant management where treatment is delayed until the disease progresses or symptoms appear is also an option.
This treatment is commonly used if the entire extent of the cancer can be surgically excised.(2) Indications for radical prostatectomy include: stage T1/T2, 10 year life expectancy and no contraindications for surgery. Patients are evaluated by laboratory tests including CBC, creatinine, and urinalysis, chest X-ray and electrocardiogram to ensure that they are surgical candidates. The goals of surgery are to completely excise the malignant tissues while maintaining as much urinary function and sexual function as possible.(3) Perineal or retropubic surgeries are the two options for prostate removal.
Perineal prostatectomy was the first surgical method used and involves an incision between the rectum and scrotum.(2) There may be fewer complications such as blood loss with this approach, however, pelvic lymph nodes cannot be dissected and there is less tissue access.(1)
Retropubic prostate removal is performed through an excision from the umbilicus to the pubic symphysis and allows for more tissue to be removed. This is important if there is extra-capsular extension. Pelvic lymphadenectomy can also be performed at the same time. Nerve sparing surgery can also be performed to preserve erectile function but may not be possible depending on the age, tumour stage and pre-operative sexual function. If both pelvic plexus are spared, there is 50-70% success. If only one plexus is spared there is 0-20% chance of conserved function.(2)
In both surgeries, the seminal vesicles, prostatic urethra and prostate gland are removed from the membranous urethra to the bladder neck and the urethra is re-connected. The procedure takes 2-3 hours and most patients will leave the hospital in 3-5 days. A urinary catheter is kept in for two weeks and continence usually returns a few days following removal.(1)
The advantages and disadvantages are outlined in the table below.
Patients receiving radical prostatectomy now have a better outcome than in the past. More patients are presenting with earlier stage cancer and there is a better ability to stage the cancer pre-operatively (ie: bone scintography) allowing for better selection of surgical candidates with localized disease. Neoadjuvant therapy using LHRH analogues or anti-androgenic treatment before surgery to decrease the prostate and tumour size and lower PSA levels is being investigated to assess its effect on survival and recurrence.
Patients are followed up with assessment of PSA serum levels as PSA should become undetectable in the blood within 2 days after surgery.(1) Adjuvant radiotherapy may be used if patients are at risk for relapse and may increase survival rates.(1) The reappearance of PSA in the blood stream indicates biochemical relapse but not necessarily clinical relapse. Patient follow up is then performed by re-assessing the pathology reports and performing bone scintography to assess for distant metastasis. The faster the PSA doubling time, the greater the risk for clinical relapse, which is defined by signs and symptoms of recurring cancer.(1)
Approximately 81% of patients with localized prostate cancer receiving radical prostatectomy will have not progressed by 5 years. As there are few recurrences after 7 years, this approximates the percent of patients that will remain disease free.(3)
Radiation therapy is the other modality commonly used for curative treatment of low risk, localized prostate cancer. The indications for radiation therapy are localized T1/T2 disease (may be considered in T3/T4), life expectancy greater than 10 years, absence of lower gastrointestinal and urinary tract disease and no recent TURP procedure.
The advantages and disadvantages are outlined in the table below.
There have been very few reliable randomized controlled trials comparing radical prostatectomy and radiation therapy for low risk disease.(1) Comparison studies have, however, shown similar 5, 10, and 15 year survival rates between surgery and radiation.(1) Hormone therapy is not commonly used with low-risk disease except in cases where it is necessary to shrink the prostate gland prior to treatment.
The outcome of radiation therapy is assessed by PSA levels. Unlike radical prostatectomy, it may take years before PSA reaches nadir, the lowest post-treatment level. The nadir level varies between individuals and depends on pre treatment PSA levels.
Brachytherapy can also be used to treat prostate cancer alone or in combination with external beam radiotherapy. Brachytherapy involves implanting radio-active Iodine125 or Palladium103 seeds into the prostate under ultrasound guidance. These seeds remain in the prostate gland and kill rapidly dividing tumour cells.(1) Treatment is provided by an interdisciplinary team of radiation oncologists, medical physicists and OR nurses.(1)
The procedure involves minimal discomfort and is done under anaesthetic. Patients are discharged without a catheter the same day.(1) Contraindications for brachytherapy include a moderate-high International Prostate Symptom Score (IPSS), large prostate, unfit for anaesthesia, or recent TUPR.(1)
No randomized controlled studies have compared this to conventional external beam radiotherapy, but retrospective studies have shown similar efficacies to both external beam radiotherapy and radical prostatectomy.(1) Neoadjuvant hormonal therapy may also reduce the prostate size to allow for more effective brachytherapy as large glands can make it more difficult to evenly insert the radioactive seeds.(1) Follow up is done at one month, every 3 months for a year, then every 6 months by physical examination and PSA testing.(1)
Patients may decide to wait before undergoing radical prostatectomy or radiotherapy. This option is offered according to the Epstein criteria or a life expectancy of less than 10 years. In the US, one in four men is managed expectantly.(3)
Parameter
Prostate gland
PSA density
Gleason Score
Biopsy core
Outcome
Non-palpable
<0.15 ng/ml
<6
<50% positive
Two different forms of expectant management may be explored.
Watchful waiting is used when treatment is not expected to alter life expectancy, or the patient does not want to pursue treatment. Palliative treatment is given when the patient becomes asymptomatic.
Active surveillance involves closer observation and treatment options used when the disease progresses with intention to cure.
In the watchful waiting approach, patients are monitored by following PSA levels and performing DRE examination once or twice yearly. Once patients are symptomatic, palliative treatment is provided. Some treatment options include LHRH analogue treatment, orchidectomy, or TURP.
The Swedish randomized controlled trial compared watchful waiting to radical prostatectomy found a 10 year overall survival rate 5% greater with treatment, 19% less deaths from prostate cancer and decreased metastasis and localized progression. Results were most significant for men less than 65 years.(4) Long term follow up of patients managed by watchful waiting has indicated that a subset of patients are not destined to die from prostate cancer; the challenge is in identifying this subset of patients.(5)
With active surveillance, another biopsy may be performed 3 months after initial assessment to reassess cancer extent. PSA and DRE are performed every 3-6 months and TRUS at 6 months then every 2-3 years. Another biopsy is done 3 years after initial treatment. Follow up is done by urologists or radiation oncologists depending on the future treatment option (surgery or radiotherapy) that is chosen.
Progression to stage T3, Gleason grades of 4-5 on re-biopsy, PSA doubling time faster than 3 years (based on 3 lab results) and patient choice are all indications for beginning treatment. Curative treatment such as radiotherapy and radical prostatectomy are then used.
Low risk prostate cancer is treated curatively by radical prostatectomy and radiotherapy. Expectant management may also be employed where patients are monitored and treatment is initially withheld until the disease progresses. The efficacy of neoadjuvant and adjuvant hormonal therapy in low risk prostate cancer is being investigated.
Prostate cancer is defined as intermediate risk if it is classified by any one of the following: Stage T2c, Gleason score of 7 and PSA between 10-20 ng/ml as outlined by the Canadian Consensus Guidelines. The best treatment for this stage of cancer is not clear as there has not been any long term randomized controlled trials showing clear evidence. Numerous modalities may be employed including: intermittent and continuous hormonal treatment, radical prostatectomy with or without hormones, radiotherapy with or without hormones, and expectant management.
Radiotherapy, when used alone for intermediate risk prostate cancer, may result in a non-suppressible PSA serum level and, frequently, positive post-treatment biopsies.(1) With neoadjuvant hormonal therapy there is a greater chance that irradiation will kill the majority of the tumour cells. Randomized controlled trials have shown a clear benefit with increased survival with the addition of hormonal therapy to radiotherapy for higher risk disease.(1)
Hormones are often used for the “high” intermediate disease and radiation alone for the good intermediate disease (PSA less than 15, T2b, Gleason 3+4).
Surgery alone for intermediate risk cancer may be associated with morbidity and mortality with eventual dissemination.(1) Neoadjuvant therapy which involves giving LHRH analogues and anti-androgens for 3 months prior to surgery has shown to decrease positive margins but the effects on survival are unknown.(1) A combination of surgery and radiotherapy may also be used in certain situations.
Androgens control the proliferation of prostate gland cells by three mechanisms: increasing DNA synthesis and proliferation, preventing apoptosis, and preventing the limitation of the number of cells in the gland.(1) Anti-androgen therapy is used to eliminate circulating androgens so that prostate cells will undergo apoptosis and die, killing malignant cells and preventing further spread.
Hormonal therapy can be used for prostate cancer treatment in three ways. It can be used as neoadjuvant therapy, which is therapy provided before radiation or prostatectomy. Therapy can also be provided as an adjuvant, which is given during or after radiation or surgery. It can also be the primary therapy, which is first line treatment for advanced metastatic cancer.
In the case of intermediate risk prostate cancer, the duration of hormone use is variable. They may be given for 3-6 months prior to radiation and continued for a total duration of 1-2 years.
Treatment is provided by giving anti-androgens and LHRH analogues. LHRH analogues prevent pulsatile LHRH release which prevents LH and FSH release and thus less androgens are released into the bloodstream. When LHRH agonists are first given there is a surge in testosterone. The anti-androgen medications block the androgen receptor on prostate cells competitively and thus prevent binding of the testosterone to the prostate cells during the surge. Once the LHRH agonist has been present for several weeks, the surge settles and the anti-androgens can be stopped.
Watchful waiting is considered if life expectancy is less than 10 years depending on patient preference. Active surveillance may also be done regardless of life expectancy.
Prostate cancer is classified as low, intermediate and high risk in Canada and this system is used for treatment selection.
Intermediate risk prostate cancer can be treated using numerous modalities including prostatectomy and radiotherapy with and without hormonal therapy or hormone therapy alone. Patients may also choose expectant management.
Prostate cancer is defined as high risk if it is classified by any one of the following: Stage T3 or greater, Gleason score of 8-10 and PSA above 20ng/ml, as outlined by the Canadian Consensus Guidelines. If metastasis are not present, radiotherapy or androgen ablation are used alone or combined. Surgery is generally not an option at this stage.
If metastases are present, first line therapy is androgen ablation. 80-90% of patients will initially respond, however, almost all patients progress to a state of androgen-independence characterized by a rise in PSA (an indicator of prostate cell proliferation).(1)
If there are no metastasis present, radiotherapy is often combined with neoadjuvant hormonal therapy and adjuvant hormone therapy. The combination of external beam radiotherapy and hormones improves survival in locally advanced disease. The total duration of hormones is usually 2-3 years.
High risk prostate cancer may be treated with radiotherapy, hormones alone or together, but radical prostatectomy is generally not an option.
LHRH analogues will initially cause an increase in LH and FSH causing a transient rise in testosterone levels. This may cause an increase in symptoms such as bone pain, obstruction, or rarely, spinal cord compression. It is recommended to use an anti-androgen for 4 weeks to prevent this flare-up. By three weeks, the analogues will cause a suppression of gonadotropin release leading to a drop in testosterone levels.(1) The mean survival length for patients with metastasis undergoing LHRH therapy alone is between 18-28 months which is equivalent to patients who undergo bilateral orchidectomy.(1)
Two forms of anti-androgen therapy may be used: continuous and intermittent.
Patients are kept on a constant dose. PSA levels are monitored to assess for prostate gland suppression. There are numerous side effects to treatment which are listed below.
Short term
Impotency
Loss of libido
Anemia
Nausea
Vomiting
CNS/mood changes
Galactorrhea
Long term
Muscle wasting
Osteoporosis
Anemia
Delayed testosterone recovery
Increased AST/LDH
Gynecomastia
Hot flashes
With continuous treatment, all the malignant cells may not be killed and the presence of anti-androgens may select for androgen-insensitive cells. This may cause a quicker progression to an androgen-independent state where malignant prostate cells can divide and replicate even in the absence of androgens.(1)
Intermittent hormonal treatment can be used to prevent some of the side effects from anti-androgen therapy and may have a role in decreasing progression to androgen-independence. If PSA levels are stable at 24-32 weeks after treatment began, therapy can be interrupted at 36 weeks. Therapy is resumed when the PSA levels return to pre-treatment levels.(1) These cycles are continued and in general patients spend 35-50% of their time off of therapy, decreasing with each cycle. Studies comparing continuous and intermittent therapy have shown varying effects on survival.(1)
With orchidectomy and LHRH therapy, the adrenal glands are still able to produce androgens via ACTH stimulation. This generally accounts for 5% of the total androgen production in a healthy male.(1) Maximum androgen blockade (MAB) is done by adding an anti-androgen therapy to the above treatment options to suppress this production. It is theorized that the prostate may depend on the adrenal androgen production and this may cause cancer recurrence.(1) MAB may increase survival rates and time to progression and normalize PSA levels but results from randomized controlled trials are conflicting.(1)
Removal of the testes is done as a day surgery under local or general anaesthetic. There is little associated morbidity but majority of patients prefer hormonal therapy when given the option.(1) Side effects include hematoma and infection at the wound site, decreased libido, impotence and hot flushing. The response rate is over 75% with an immediate decrease in symptoms and a drop in PSA levels.(1)
There are other hormonal agents that may be used such as diethylstilbestrol (DES) which inhibits FSH production. This is not commonly used now. Some trials have shown similar survival rates to LHRH and orchidectomy but levels of about 1 mg/day may cause cardiotoxicity.(1)
If the treatment plan is palliative, patients may choose radiotherapy and hormones alone or combined or may also elect to undergo hormonal therapy and TURP as needed for symptomatic relief.
Most bone metastases are osteoblastic but some may contain osteolytic lesions. Alkaline phosphate serum levels are often elevated and can be followed along with bone scans and plain films. Pathological fractures and bone pain may also occur. Treatment may include analgesics, hormonal therapy, radiotherapy and chemotherapy for pain relief.
Another option is treating with biphosphonates to decrease skeletal complications such as fractures, osteopenia or the need for surgery, chemotherapy or radiation. According to the BC Cancer Agency, biphosphonates do not affect survival rates, pain, or quality of life.(6)
The first line treatment for metastatic prostate cancer is androgen ablation by hormonal therapy or bilateral orchidectomy. Palliative treatment may include a variety of modalities for symptomatic relief depending on location of metastasis.
The prognosis of prostate cancer can be evaluated by the Gleason score, PSA levels, and the clinical stage. Molecular factors such as gene mutations also affect prognosis.
A PSA relapse after treatment is defined differently depending on the treatment modality. After prostatectomy, a PSA value above 0.3 ng/ml on two consecutive blood tests may be defined as a relapse.
After radiation therapy, an increase in PSA value after reaching the lowest level (which may take 1-2 years) may be considered as a PSA relapse. The Phoenix definition for PSA biochemical relapse is the nadir PSA value plus 2 ng/ml which can predict overall survival from prostate cancer.(1)
Biochemical evidence of no disease (BNED) depends on spread beyond the capsule, positive margins, seminal vesicle involvement, and nodal disease. PSA biochemical failures are 2-3 times more common than clinical failures which are defined by signs and symptoms of recurrent cancer. Local failures are greater if there are positive margins after surgery. Redevelopment of nodules on DRE may also indicate relapsing and will require additional treatment.
Prostate cancer biochemical relapse can be assessed by monitoring PSA levels. The definition of PSA relapse varies depending on the treatment modality. Biochemical relapse does not necessarily indicate clinical relapse, characterized by signs and symptoms of recurrent cancer.
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