Prostate Cancer

History

Local, curable disease is frequently asymptomatic.

Advanced disease can lead to:

• weight loss
• fatigue
• urinary obstruction
• bone pain from metastasis

Physical Exam

Physical exam should routinely include digital rectal exam (DRE) in men over 50, or with symptoms. A DRE can detect tumours in the posterior and lateral areas of the prostate. Nodules indicative of cancer may be firm, asymmetric or have induration involving one or both lobes. Symmetrical firmness or enlargement usually indicate Benign Prostatic Hypertrophy (BPH).

Screening

The goal of screening is to identify presence of disease when curable treatment is available. Ideally, the test is both sensitive and specific, and detects clinically relevant disease. Screening to reduce mortality remains unproven. Screening for prostate cancer is controversial. The best tools for screening are the digital rectal exam and prostate specific antigen (PSA) blood test.

Screening should be offered to men in high risk populations:

• men 50-70, if at least 10 year life-expectancy
• black men (start at age 40)
• people with family history (start at age 40)

Digital Rectal Examination

Digital rectal examination (DRE) is a useful test for detecting abnormalities in the posterior and lateral aspects of the prostate. However, only 85% of cancers arise from these areas, so the DRE is likely to miss some. In addition, stage 1 cancers are not palpable by DRE. As a result, many abnormalities felt on DRE represent more advanced cancers. There is also the chance of having a false positive. Reasons for this include: stones, scarring from previous infection, or surgery.

PSA

PSA is a serine protease secreted by prostate epithelial cells. Prostate cancer increases the PSA and it is possible to see a rise in PSA 5-10 years before the onset of clinical symptoms. While PSA is specific for the prostate, there are many benign factors that cause an increased PSA. These include age, race, BPH, infection and manipulation by catheter, biopsy or DRE. Therefore, an elevated PSA does not always mean the patient has prostate cancer. The accuracy of PSA can be improved by looking at different variables:

Age adjusted PSA: PSA naturally rises with age The approximate levels one would expect to detect in a man based on his age are:

• 40-49: <2.5 (ng/mL)
• 50-59: <3.5 (ng/mL)
• 60-69: <4.5 (ng/mL)
• 70-79: <6.5 (ng/mL)

PSA Density: absolute PSA level divided by prostate volume in mL. In some studies, it is suggested that a cut-off of 0.15 be used as an indication for prostate biopsy.

PSA Velocity: Change in PSA level over time. Best determined using 3 measurements over a 2 year period. A cut-off of 0.35ng/mL/year for PSA <4ng/mL and 0.75 ng/mL/year for a PSA of >4ng/mL may be used as a guideline for when to get a biopsy done.

Free-Complexed PSA: In prostate cancer, there is a higher percentage of complexed PSA. This test may be used as an adjunct to PSA values in the grey zone. The cut-off for this test is controversial, however, a value >25% usually indicates the absence of a clinically significant prostate cancer.

The cut off between abnormal and normal levels and when to refer for biopsy is controversial and ranges from 2.5 to 4.0ng/mL. The grey zone refers to PSA values between 4-10 ng/mL. There are many risks and benefits associated with screening for prostate cancer. Benefits include finding cancers that are clinically localized and easy to treat. However, there is the risk that screening will detect cancers that would have never become clinically significant. The detection of these cancers results in patients being put through risky and invasive biopsies and potential treatment that may do more harm than good. Therefore, it is important make sure the patient is informed about the advantages and disadvantages to screening for prostate cancer.

Current recommendations for screening include:

- A discussion about prostate cancer and screening, starting at age 40-45 in black men, men with a positive family history and men who are known or suspected to have the BRCA1 mutation, and age 50 in most other men. These men should also have a life expectancy of least 10 years.
- for men that decide to undergo screening, a PSA should be done every 2-4 years up until age 75 or when the life expectancy is less than 10 years.
- Men with PSA between 4-10ng/mL should be considered for trans-rectal ultrasound-guided biopsy; however, the current recommendations indicate that the decision to biopsy the prostate should be made based on DRE in combination with other variables. These include other PSA variables (velocity, density, free and total levels) and the clinical information of the patient (age, ethnicity, comorbidities and prior history).

The best approach is to discuss pros and cons of screening with patient so that they can make an informed decision.

1410 men would need to be screened, and 48 additional cases of cancer would need to be treated, to prevent one death - (Schroeder et al, 2009).

Factors altering PSA include age, race, manipulation (catheter, DRE), BPH, infection, cancer

Lab Investigations

PSA

As discussed above, PSA is useful for screening. It is also useful to use as a baseline to monitor effectiveness of treatment.

Diagnostic Imaging

A palpable nodule on DRE, or an elevated serum PSA, should be investigated by trans-rectal ultrasound (TRUS) biopsy. While a TRUS is useful in evaluating the size of the prostate, it is not usually done without also doing a biopsy. A definitive diagnosis of prostate cancer is made based on the biopsy results.

CT/MRI/Bone scan: Used for staging and planning treatment.

Early stage Cancer

For early stage cancers, treatment options include:

• active surveillance
• radical prostatectomy
• external beam radiotherapy
• brachytherapy (radioactive seeds)
  

Active Surveillance
Reserved for very low grade cancers (Gleason score 4 or lower) or low volume (less than 3 of the core biopsies involved). In these cases, there is a low risk of tumour progression. Therefore, patients can avoid the side effects of treatment. They are monitored closely for disease progression so that appropriate treatment can be initiated as soon as possible. Active surveillance is also used for some patients with a life expectancy <10 years (from age or another medical condition), where it is estimated that they will likely die of something other than prostate cancer.

Definitive treatment in the form of Radical prostatectomy or radiation is recommended for men with intermediate-high risk T1/T2 prostate cancer. The decision to choose one over the other is controversial and should be made on an individual basis.

Radical prostatectomy
Surgical removal of entire prostate. This procedure is offered to men with a life expectancy >10 years and there is a greater chance of cure if the cancer is still confined to the prostate gland. This procedure can be performed using an Open or laparoscopic/robotic approach. Complications include incontinence and erectile dysfunction.

Radiation

External beam- treats the prostate gland and surrounding healthy tissue. Side effects include radiation cystitis or proctitis, and erectile dysfunction (40% of patients).

Brachytherapy- radioactive source is implanted into the prostate with the goal of targeting the prostate without damaging surrounding tissue. It can be done in a single session. It is well tolerated with the major side effects being urinary frequency and urgency that can last for months. Incontinence and proctitis are two other side effects, but are less common.

The above treatments may all be effective in treating early prostate cancer, and varies between patients. Therefore, it is important to consider many factors such as the patient's age, co-morbid conditions, stage and grade of the tumour.

Advanced Cancer

Because the growth of most prostate cancers relies on testosterone, androgen deprivation therapy can be used to help impair tumour growth. This can be achieved by medical or surgical means and is considered palliative, not curative.

GnRH agonists are the most widely used. They work by providing continuous stimulation to the pituitary gland, down-regulating receptors and suppressing testosterone production. Examples include Leuprolide, Goserelin and Buserelin. One of the drawbacks is that the agonists cause an initial surge in LH before being supressed, which can cause a transient rise in testosterone and tumour growth. GnRH antagonists can also be used to decrease testosterone production. They work by binding to GnRH receptors in the pituitary gland, therefore decreasing the signal to the gonads to produce testosterone. Side effects from these treatments include impotence, hot flashes, decreased libido and osteopenia.

Anti-androgens work by competitively inhibiting androgen binding to receptors. They do not cause a decrease in testosterone, and may in fact increase testosterone levels. This decreases the degree of impaired libido, hot flashes and osteopenia. However, using anti-androgen therapy alone is less effective than GnRH agonists. Most patients receive a combination of GnRH agonists and anti-androgens in the first 2-4 weeks of treatment. The anti-androgen protects against the initial flare in testosterone production from GnRH agonists by competing with testosterone to bind to cells. Side effects of anti-androgens include nausea, diarrhea, breast growth or tenderness, skin rashes and liver problems (rare). Examples of anti-androgens include Flutamide, Bicalutamide and Nilutamide.

Testosterone depletion is achieved by a bilateral orchiectomy. Surgical treatment is less common than medical management, however, bilateral orchiectomy may be the treatment of choice in men who need an immediate decrease in testosterone or in those who cannot afford or will not adhere to medical treatment. In some parts of the world, this is the primary method of hormonal therapy for metastatic prostate cancer. Depleting the body of androgens can cause impotence, hot flashes, osteoporosis, change in body composition (increased fat, decreased muscle), gynocomastia, thinning body hair, decreased size of penis, fatigue and cognitive changes.

Hormonal therapy is only considered palliative because eventually the cancer will become hormone refractory and grow despite the absence of testosterone. In these patients, there are a few strategies that can be used to prolong the effectiveness of hormonal therapy. High dose ketoconazole inhibits androgen production by the adrenals and has direct cytotoxic effects on the prostate tumour. Its side effects include nausea and vomiting in up to half of patients, as well as weakness and fatigue. Glucocorticoids may also be effective in some men, by decreasing the production of ACTH, resulting in decreased production of adrenal androgens. When hormonal therapy is no longer effective, chemotherapeutic agents can be used as palliative treatment to decrease pain. Docetaxel (Taxotere) is the recommended initial chemotherapeutic drug. It is also recommended that it be used in conjunction with glucocorticoids.

Pain becomes a significant component of advanced metastatic prostate cancer. For bony metastasis, external beam radiation may help to decrease pain. Bisphosphonates may also help to decrease bony metastasis progression and pain. Analgesics, both opioid and non-opioid can also be used to manage pain. NSAIDs can be especially helpful for bony pain.