PSA Levels in Metastatic Prostate Cancer

Prostate cancer  

Prostate is a small gland in men that produces seminal fluid which helps in nourishment and movement of sperms. It is a part of the male reproductive system including the penis, seminal vesicles, and testicles. The prostate is located in front of the rectus muscle and beneath the bladder. It encircles the urethra which is the tube that empties urine from the bladder and is about the size of a walnut. 

Causes

The main cause of prostate cancer is still unknown; however, there are factors that increase the risk of getting prostate cancer(increased risk does not mean that you are definitely going to get prostate cancer if you fall in the category).³

• Age: prostate cancer is more common in older men (most common being between the age of 75-79). This is because it is usually slow growing and requires DNA damage over a long period of time. Most cases are diagnosed in men over 50. 

• Ethnicity: Black men have the highest lifetime risk of being diagnosed with prostate cancer (1 in 4), then white (1 in 8) and Asian men (1 in 12). It is important to note that studies which calculated this risk used “major” ethnicities. Therefore, the specific ethnicities can again have various lifetime risks.^3,4

• Genetics: certain genes increase the risk of lifetime risk of prostate cancer, for example, people with mutated BRCA genes have a slightly increased risk compared to the general population. 

• Family history: Having a brother or a father who developed prostate cancer before age of 60 is a risk factor alongside having a female family member who developed breast cancer. 

• Obesity: Overweight and obese men tend to have a higher risk of getting aggressive prostate cancer.^3,5 

Symptoms

Symptoms of prostate cancer are very similar to benign prostatic hyperplasia, a common condition where the prostate is enlarged over time. This is not cancer and does not affect the risk of prostate cancer. 

Symptoms of prostate cancer appear when the prostate has grown large enough to put pressure on the urethra (the tube that allows urine to be passed out of the body). The symptoms may include (not everyone with prostate cancer experiences symptoms): 

• Urge to pee more often
• Not being able to fully empty the bladder
• Getting up at night to pass urine 
• Blood in urine or in semen 

If cancer spread to other parts of the body (from the prostate), symptoms such as weight loss, bone pain, and testicle pain can be experienced.^6,7 

Stages

Prostate cancer is staged using 3 different factors, 

• Size of the tumour (T), 
• If it has spread to lymph nodes (N), and 
• Metastasis which is the extent that cancer has spread to other parts of the body (M). 

Size of tumour (T)

There are 4 main stages that describe the size of prostate cancer. Simply known as the T1- T4 stages. 

• T1: Where cancer is extremely small and undetectable via scans or examination of the prostate. 

• T2: Where cancer is only in the prostate gland. At this stage, cancer can be either in the left, right, or both sides of the prostate. 

• T3: At this stage cancer has spread to the covering capsule that covers the prostate or to the semen-carrying tubes (seminal vesicles). 

• T4: When cancer has spread to the surrounding organs near the prostate such as the bladder and the pelvic wall with the most common places being the surrounding bones and the lymph nodes.^8,9 

Node (N)

Prostate cancer can spread to the lymph nodes in the groin which causes swelling and pain as the cancer cells prevent lymph nodes to drain as they should. Knowing if cancer has spread to the lymph nodes can highly affect the prognosis of cancer.^8,9

Metastasis(M):

Metastasis is the spread of cancerous cells to other parts of the body for example distant lymph nodes away from the pelvis, bones, lungs and other parts of the party.⁸ 

Diagnosis

There is no single test that can definitely diagnose prostate cancer. The diagnosis is reached by using a combination of symptoms experienced by the patient and various tests.^8,10 

Test carried out in GP surgeries: 

Digital rectal examination (DRE):

This test involves the patient lying on their side with their knees bent towards their chest, while the doctor or the nurse slides their finger in the back passage. If the prostate feels lumpy or hard, it could suggest prostate cancer. 

Prostate-specific test (PSA):

A blood test measures the amount of a protein called PSA in the blood (this is explained further below). 

Hospital tests: 

If referred to the hospital, a specialist nurse or urologist will normally discuss the various tests, they might repeat the DRE and PSA tests. However, they can request further tests including⁸:

• Magnetic resonance imaging(MRI) scan:

It uses a magnetic field and computerised radio waves to create a picture of the prostate and the surrounding tissues. This scan helps doctors decide to carry on with a biopsy (explained below) or which part of the prostate they should take the biopsy from.

• Computerised tomography(CT) scan:

CT scan uses X-rays to take pictures from various angles to produce a 3- dimensional (3D) picture. Prior to the scan, a contrast medium which is a dye that helps organs and tissues be more visible when scanning is injected or sometimes given in the form of a drink. This detects whether cancer has spread to surrounding areas like lymph nodes and bones or not. 

• Biopsy:

A biopsy is essentially surgically removing the tiniest amount of prostate tissue and examining to look for cancer cells. This is a confirmatory test for cancerous cells.  

• PET scans: 

Positron emission tomography (PET) scans use radiotracers to scan changes in the physiological activities of the body such as oxygen usage, blood flow and glucose uptake. This scan is usually used with CT scans to produce more detailed pictures.^8,10

Treatments 

Not everyone with prostate cancer would require treatment. Depending upon various factors, doctors might suggest monitoring cancer. There are two ways that prostate cancer is monitored:

-Active surveillance: In this, there will be regular hospital appointments with tests such as MRI scans, PSA tests, and DRE to monitor the development of cancer.^11,12 

-Watchful waiting: This is where regular appointments take place at the GP surgery, where regular PSA tests are carried out and any new symptoms would be monitored. 

The treatment of prostate cancer highly depends on how far the cancer spreads to other parts of the body or if it's still contained in the same area. Furthermore general well-being of the patient is also considered as a lot of treatments have side effects.^11,12 

The various treatment options are outlined below:

Hormone deprivation therapy: 

The growth of prostate cancer highly depends on testosterone levels and reducing its circulating amount around the body can halt or slow the growth of cancer. If used alongside other treatments it reduces the risk of prostate cancer coming back. 

There are 3 different types of hormone therapy:

1. Injections: 

Luteinising hormone-releasing hormone agonists (LHRH agonists): 

These medications work on the pituitary gland in the brain that signals the testicles to produce testosterone. After initially using this injection there will be a sudden increase in the testosterone levels where there could be worsening of symptoms due to tumour flare-up and then over time the amount of testosterone is reduced by up to 95% of the baseline testosterone levels.¹² 

Leuprorelin, Goserelin, Buserelin, and Triptorelin are part of this group of medications. Leuprorelin and goserelin are injected every 4 weeks or 12 weeks, and Triptorelin is used either once a month, 3 months or 6 months. Buserelin comes in the form of nasal spray and injection that are used daily.¹¹ 

Degarelix is another drug used as a hormone deprivation therapy specifically for spinal metastasis.¹¹

Anti-androgen tablets: 

These are effective because they stop testosterone from having its effect by blocking the receptors that it normally binds to. These can be used alongside LHRH agonists or on their own, as they are less likely to cause erectile dysfunction than LHRH agonists.

Examples of anti-androgen tablets include: 

• Cyproterone is used in 2-3 divided daily doses 
• Bicalutamide, used either as 50 mg or 150mg once daily 
• Flutamide, taken 3 times a day 

1. Surgically removing testicles (orchidectomy):

Testicles are the main production site for testosterone although small amounts are produced by adrenal glands and removing them reduces the amount of testosterone around the body significantly. 

This is not a first line for reducing the amount of testosterone; however, it reduces the amount of testosterone rapidly and is used when the amount of testosterone needs to be lowered urgently. For example if cancer has spread to the spine. 

Surgically removing some parts or entire prostate gland:

There are different types of surgeries to remove parts of the prostate or the entire gland. These surgeries can be open surgery (abdominal incision is made), keyhole surgery (smaller incision is made) to remove the prostate with less disruption to the surrounding tissue, and robotic surgery where a keyhole is formed and a special robot is used to do the operation.

1. Radiotherapy: 

External beam therapy is when the source of ionizing radiation is from outside the body. This type of radiotherapy is done in sessions usually over 4 to 8 weeks. 

Internal radiotherapy (brachytherapy): 

A type of radiotherapy in which the radioactive source is placed inside the body. Permanent seed brachytherapy is when a small radioactive metal seed is placed in the prostate and slowly releases radiation. Temporary brachytherapy is when pellets of radioactive materials are placed in the prostate gland and release radiation to destroy cancer cells.

Chemotherapy:

In this, the anti-cancer (cytotoxic) drugs circulate in the body to destroy cancerous cells. Although effective it destroys healthy cells as well. As cancer cells tend to grow faster than healthy cells more cancer cells are destroyed by cytotoxic drugs. 

Taxanes are the most common group of cytotoxic drugs used in prostate cancer. They work by disrupting microtubules which are essential for cell division and therefore interrupting the replication of cancer cells. Drugs such as paclitaxel, and docetaxel are part of this group.¹¹ 

What is Metastatic Prostate Cancer?

Metastatic prostate cancer also known as advanced prostate cancer. It occurs when cancer has spread from the prostate to other parts of the body such as the bones in the pelvic or lymph nodes. It can also spread to more distant organs like the liver, lung, bladder.¹³ 

What is a PSA test?

Introduction

Prostate-specific antigen (PSA) is a protein that is normally produced to help liquefy ejaculation to allow semen to swim freely. PSA testing is a way to screen for prostate cancer and is used as a diagnostic tool. PSA levels are measured as nanograms of PSA per milliliter of blood (ng/ml). PSA levels above 3 ng/ml could suggest prostate cancer or other prostate-related disorders such as benign prostatic hyperplasia (BPH) and prostatitis.¹⁴ 

There are various factors that can either reduce or increase PSA levels. 

Factors increasing PSA levels:¹⁵

• Age: as men tend to grow older the amount of PSA in their blood increases. 

• Ethnicity: there is a small variation between PSA levels among different ethnicities

• Prostate size: some men can have a larger prostate than usual and they produce a higher amount of PSA, therefore their PSA test would suggest a higher level.

• Benign prostatic hyperplasia(BPH): it a condition where the prostate has increased in size significantly and puts pressure on the urethra. Men with this condition tend to have higher levels of PSA.

• Ejaculation: It can increase PSA levels and if the PSA test is carried out within 48 hours of ejaculation, a higher level of PSA is read. 

Factors reducing PSA levels:¹⁵

• Weight: men who are obese or overweight tend to have lower PSA levels .

• Smoking: smokers tend to have a lower PSA levels than those who don’t smoke. 

• Medications: 5 alpha-reductase inhibitors are used to treat BPH and male pattern baldness. For example, finasteride can reduce PSA levels by up to 50% even in patients with prostate cancer.¹⁶

Who should have a PSA test?

There is no national screening programme for prostate cancer. Men above 50 years of age can request a PSA test from their GP as a part of an informed national programme where men can consider the pros and cons of the PSA test.¹⁷

Are they accurate?

The PSA tests are not accurate. About 15% of people with normal PSA levels end up with prostate cancer (2% advanced prostate cancer) and two third of men who undergo biopsy because of their elevated PSA have no prostate cancer.¹⁸

Reading PSA test results (what is a healthy level vs sign of cancer)

A rise to 3ng/ml is considered normal between the ages of 50 and 69 and should not be cause for alarm. However false negatives can still occur. Levels of 4-10 ng/ml can suggest a 1 in 4 chance of cancer and levels of 10ng/ml can suggest a chance of over 50% of having prostate cancer.¹⁸ 

How else can prostate cancer be diagnosed?

The only absolute way diagnosing prostate cancer is by biopsy, as it takes some tissue from the prostate gland and examines them for cancerous cells. 

A combination of MRI, CT, bone scan and PET scans are often used to assess the extent of the spread of cancer. 

Use of Gleason scoring:

After biopsy, if cancerous cells are found, they are compared to non-cancerous cells and are given a score. If cancer looks like normal prostate cells, its grade 1. If cancerous cells look abnormal it is graded between 2-10 depending on the extent of abnormality. Scores below 6 tend to be low grade that means they grow slowly and less likely to spread than a higher grade cancer. 7 is medium grade and score 8-10 tend to be high-grade cancer.^10,13 

Treating advanced prostate cancer

Advanced prostate cancer is when cancer has spread to other parts of the body. At this stage, it is not curable and treatment is only given to control the symptoms and further growth of the tumours around the body.19 

When prostate cancer has spread locally, it penetrats the prostate's outer capsule and reached the lymph nodes, the bladder, or the rectum. In this case radiotherapy and hormone therapy can help shrink the prostrate cancer that has spread.

Prostate cancer that has progressed to distant organs, such as the liver, lung, or spine, is referred to as advanced (metastatic) prostate cancer. In this case hormone therapy can be used to keep cancer under control and it can be life long treatment. If the initial hormone deprivation therapy fails, a different type of hormone therapy is offered that is called Abiraterone. Radiotherapy is also used to control symptoms.19 

Summary

Briefly, prostate cancer mostly occur in older men which varies with etnicities. Prostate cancer could be either due to genetic changes, family history or obesity. Most of the times, symptoms appear only when cancer size increased. Treatment options vary based on the extent of cancer. For an appropriate diagnosis one should visit GP and undergo different medical examinations. The level of Prostate-specific antigen (PSA) which is protein, used as a screening and diagnostic tool for prostate cancer and other prostate-related disorders. It is alarming when its level is above 3ng/ml. However, PSA levels changes with age, size of prostate, weight, smoking medication and etc. Therefore, it is advised to men above 50 years undergo PSA test from their GP and do accordingly.