Anatomy and Function of the prostate

(Compiled July 2018)

What is it?
The prostate is a small gland about the size and shape of a walnut. It is part of a man’s internal sex organs. All the sex organs play a role in reproduction. The prostate generally increases in size as men age.

Where is it?
It is situated under the bladder and surrounds the urethra which is the tube that transports urine from the bladder to the penis where the urine is released through the ureter. This why problems with the prostate often affect the ability to urinate, causing what doctors call (urinary symptoms).
The rectum sits directly behind the prostate. This means that a part of the prostate can be felt if a finger is inserted up the rectum. (digital rectal examination) or the “finger” test. The tube that carries the semen from the testicles feeds into the ejaculatory ducts which then connect to the seminal vesicles which are just above the prostate. When prostate cancer spreads it often spreads first into these structures that surround the prostate. The prostate has gland tissue and smooth muscles fibres which help it to contract when a man ejaculates. The prostate is surrounded by a loose capsule which is connected to sheaths of pelvic muscles. Before 1981 surgeons were not aware of the nerve bundles towards the back and sides of the prostate that play an important role in erections. The identification of these nerves led to the first “nerve sparing” prostatectomy in 1982. Knowing where these nerves are situated has made a big difference to minimising erectile dysfunction in men who have had a prostatectomy.

Until a few years ago, doctors described the different parts or areas of the prostate as lobes (see illustration below). One method of staging prostate cancer was to determine which lobes had been affected by cancer cells.

A more up-to-date way of describing the different areas of the prostate is the Zonal System.   (See illustration below). 80 to 85% of prostate cancers start in the peripheral zone.

What does it do?
The prostate gland produces prostatic fluid which makes up about 15 to 30% of the semen or ejaculate. The average amount of semen ejaculated is 3.4ml which is less than a teaspoon full. Sperm make-up only 1 to 5% of the total volume of the ejaculate.  The secretions from the seminal vesicles make-up the majority of the ejaculate. The secretions from the various glands that help to produce semen all assist with nourishing and protecting the sperm so that they can survive and impregnate an egg in the process of reproduction.

How common is Prostate Cancer in South Africa?

(Compiled February 2019)

According to Globcan, prostate cancer is the most frequently diagnosed cancer among men in over one‐half the countries of the world including the Americas, Northern and Western Europe, Australia/New Zealand, and much of Sub‐Saharan Africa. It is the leading cause of cancer death among men in 46 countries, particularly in Sub‐Saharan Africa and the Caribbean^{. (1a)}

Although there are no reliable statistics on the incidence of prostate cancer amongst South African men, it is possible to get an idea of how common prostate cancer is in South African men by looking at the data from countries where men have reasonable access to screening for prostate cancer and where there is a significant population of black men with African ancestry. (Race is a proven risk factor for prostate cancer with black American and Jamaican men of African descent having the highest recorded rates of prostate cancer worldwide). ^(2a)

In the USA approximately 11.2 percent of all men will be diagnosed with prostate cancer at some point during their lifetime according to The SEER data from the National Cancer institute. ⁽³⁾ However if we compare the rates of prostate cancer in white vs black African American men there is a significant difference. It is estimated that 1 in 6 black African American men will be diagnosed with prostate cancer in their lifetime compared with 1 in 8 white American men. ^(2b) If we look at the data from 2008 to 2012 it showed that Black African American men had a 70% greater chance of being diagnosed with prostate cancer than white American men. ^(2c) They were also more than twice as likely to die from prostate cancer as their white counterparts, although this has improved in recent years.^(2d)

One major advantage that black American men have over black South African men is that they are more likely to be diagnosed when the cancer is at a local or regional stage.^(2e) (In other words, before it has spread to other parts of the body). This means that after 5 years most of these men will still be alive.  In South Africa, the majority of black men will only be diagnosed when the cancer has spread, this is called metastatic prostate cancer and it is incurable.⁴ This means that after 5 years only about 30% of these men will still be alive. ⁽⁵⁾ Black African men from Southern Africa appear to have an additional disadvantage in that they present with significantly more aggressive prostate cancer than African Americans. ^(1b)  

According to Prostate Cancer UK, 1 in 8 men will be diagnosed with prostate cancer at some point in their lives^(6a) and for black British men of African descent 1 in 4 men can expect to be affected. ^(6b)

We recommend that black South African men consider screening from the age of 40 and that other ethnic groups start screening from 45.

Prostate cancer is more common in men with a family history of prostate cancer. If you have a family history of prostate cancer you are twice more likely to get prostate cancer. Having a brother with prostate cancer appears to put you at a higher risk than if you have a father with prostate cancer. The more family members affected by prostate cancer the more likely you are to get it. ⁽⁷⁾

There is some evidence showing that prostate cancer is also more common in men who have a first degree relative who has been diagnosed with breast cancer, particularly when the breast cancer was diagnosed before the age of 50. ⁽⁸⁾ Men who have a daughter who has been diagnosed with breast cancer have a higher risk for aggressive prostate cancer.

We recommend that men with a family history of prostate or breast cancer in a first degree relative consider screening from the age of 40.

Conclusion

• Based on current USA and UK data and various clinical studies:
• About 1 in 8 to 1 in 9 white South African men are likely to be affected by prostate cancer.
• As life expectancy amongst black South African men increases, between 1 in 4 and 1 in 6 men are likely to be affected by prostate cancer. Black men are more likely to get prostate cancer at a younger age and a more aggressive type of prostate cancer.
• Prostate cancer is more common in men with a family history of breast and prostate cancer.
• Men who are at increased risk for prostate cancer because of their race or family history should consider screening for prostate cancer from the age of 40
• All other men should consider screening from the age of 45

Ref 1 Bray F et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. Ca: A journal for Clinicians. Vol 68 no. 10 Nov/Dec 2018 Available at:  https://onlinelibrary.wiley.com/doi/full/10.3322/caac.21492
Ref 2 Ref DeSantis CE, Siegel RL et al. Cancer Statistics for African Americans,2016: Progress and Opportunities in Reducing Racial Disparities. 2016: CA cancer J Clin 2016;66:290–308
Ref 3 National Cancer Institute. Surveillance, Epidemiology, and End Results Program. Available at: https://seer.cancer.gov/statfacts/html/prost.html
Ref 4 Le Roux HA et al. Prostate Cancer at a regional hospital in South Africa: we are only seeing the tip of the iceberg. S Afr J Surg Vol. 53 no. 3&4. Dec 2015
Ref 5 Kirby RS, Patel M. Fast Facts: Prostate Cancer. Eight Edition 2014.  Health Press Limited
Ref 6 Prostate Cancer UK. Are you at risk? Available at:  https://prostatecanceruk.org/prostate-information/are-you-at-risk
Ref 7 Kicin´ski1 M, Vangronsveld J. An Epidemiological Reappraisal of the Familial Aggregation of Prostate Cancer: Available at: www.plosone.org  Plos One. October 2011 | Volume 6 | Issue 10 | e27130
Ref 8 Lamy P. Trétarre B et al. Family history of breast cancer increases the risk of prostate cancer: results from the EPICAP study. Oncotarget, 2018, Vol. 9, (No. 34), pp: 23661-23669

 

Risk Factors for Prostate Cancer

(Compiled July 2018) (Revised January 2019) 

The best known and proven risk factors for prostate cancer are advancing age, race and a positive family history of prostate cancer. There are other risk factors but there is less evidence for these.

Age
As men get older they are more likely to get prostate cancer. The risk for prostate cancer begins to rise sharply after age 55 years and peaks at age 70–74. Global statistics show that three quarters of prostate cancer occur in men over the age of 65 and that prostate cancer is rare in men below the age of 50. However it is important to note that black African men tend to get prostate cancer at a younger age. (See section on race and prostate cancer)

Race
In the USA the risk of prostate cancer is 60% higher in black American men compared to white males.  The risk of dying of prostate cancer amongst Black African American men is also twice as high as that of white American men. The current statistics in South Africa are unreliable for a number of reasons but based on the studies from the USA and the UK we believe that black African men are at a much higher risk of getting prostate cancer than other race groups. The type of prostate cancer that they get is also is also likely to be more aggressive and to be passed on genetically.

Family history
There is strong evidence to show that a family history of prostate cancer increases a man’s risk of prostate cancer. Men who have a father or brother with prostate cancer are 2 to 3 times more likely to get prostate cancer themselves. The number of relatives with prostate cancer and their age at diagnosis is also important in terms of the likelihood of being affected at a younger age. Some studies show that having a mother or daughter who has had breast cancer also increases a man’s risk for prostate cancer.

References: Gann PH., Reviews in Urology. Vol 4, suppl. 5 2002

Other Modifiable Risk Factors for Prostate Cancer 

Sexual Activity
There is strong evidence to suggest that men who have more frequent ejaculations (more than 21 a month), throughout their adult life are about 20% less likely to get prostate cancer. The ejaculations can be from sex, masturbation or nocturnal emissions.

Ref: Rider, Jennifer R. et al. Ejaculation Frequency and Risk of Prostate Cancer: Updated Results with an Additional Decade of Follow-up. European Urology , Volume 70 , Issue 6 , 974 – 982

Smoking
It is unclear whether smoking increases the risk for prostate cancer. However, there is data that shows that smokers have a 17% greater risk of dying from prostate cancer than non-smokers. Smoking greatly increases the risk of many other cancers so it’s worthwhile for men who smoke to quit.

Ref: Huncharek, Michael et al. Smoking as a Risk Factor for Prostate Cancer: A Meta-Analysis of 24 Prospective Cohort Studies. American Journal of Public Health 100.4 (2010): 693–701. PMC. Web. 20 June 2018.

Obesity
The relationship between obesity and prostate cancer is a complicated one. It is more difficult to detect prostate cancer in obese men for a number of reasons:

• They tend to have lower PSA scores
• They have larger prostates which mean that more cancers are likely to be missed when doctors perform a biopsy
• It is more difficult to perform a digital rectal examination on an obese man

All this means that prostate cancer is less likely to be detected in the early stages in obese men. Obesity is also associated with an increased risk for aggressive prostate cancer and a poorer outcome in men who are treated for prostate cancer. There is strong evidence linking obesity to a number of other serious diseases and for this reason we recommend that obese men get medical assistance to help them get there weight under control.

Ref: Allott, Emma H. et al. Obesity and Prostate Cancer: Weighing the Evidence. European Urology, Volume 63 , Issue 5 , 800 – 809

Dietary factors and prostate cancer
It is important to note that the evidence linking certain foods and vitamins to prostate cancer is not conclusive. We recommend that men follow a diet that has been proven to be good for overall health. Men should also be cautioned about the use of supplements to prevent prostate cancer as there is a possibility that some supplements could increase the risk. The following are some findings that will require additional research before the results can be considered conclusive and recommendations can be made. Please note that the evidence is not currently strong enough for these so we cannot make recommendations.

Saturated Fats
There is some evidence to show that the regular intake of saturated fats can increase the risk of prostate cancer. Saturated fats are animal fats found mostly mainly in dairy products and red meat.

Meat cooked at high temperatures
There is some evidence to show that eating meat that is well-done or meat that is cooked at a high temperature (e.g. grilled, fried, and barbecued meats) increases the risk for advanced prostate cancer. The more of this type of meat that is eaten the greater the risk.

Calcium
There is some evidence to show that a diet that is high in calcium increases the risk for prostate cancer.

Vegetables
A diet that includes plenty of fresh fruit and vegetables has strong health benefits and some of the components found in vegetables have antioxidant properties which may help to reduce the risk for cancer.

Lycopene
There is some evidence to show that lycopene can reduce the risk for prostate cancer through its antioxidant effect.  Lycopene is a substance that is found in various foods. Foods containing high amounts of lycopene include cooked tomatoes and tomato based products like tomato sauce and tomato paste, guavas, watermelon, grapefruit, papaya, sweet red peppers, asparagus red cabbage and mangoes. However, to obtain significant levels of lycopene from tomatoes products like tomato paste are required as raw tomatoes have very low levels. To illustrate this, one slice of raw tomato contains 515 micrograms of lycopene whilst 2 tablespoons of tomato paste contains 13 800 micrograms. Cooking also alters the lycopene’s molecular structure so that it is more easily absorbed by the body.

Vitamin E
There is some evidence that taking a vitamin E supplement may increase the risk for prostate cancer.

References for Dietary Factors and Prostate Cancer

(1)  Gathirua-Mwangi et al. Dietary factors and risk for advanced prostate cancer. European Journal of Cancer Prevention. 23(2):96–109, MAR 2014
(2) Ref: Ford N., Livestrong.com. Accessed on 30/06/2018. Available at: https://www.livestrong.com/article/344493-tomato-cooked-or-raw-lycopene/
(3) Ref: Gann PH. Risk factors for prostate cancer. Reviews in Urology. Vol 4, suppl. 5 2002.
(4) Klein EA et al. Vitamin E and the risk of prostate cancer: Updated results of the selenium and vitamin E cancer prevention trial (SELECT). JAMA. 2011 October 12; 306(14): 1549–1556. doi:10.1001/jama.2011.1437.

 

Alcohol and Prostate Cancer
There is strong evidence showing that alcohol increases the risk for mouth, throat, oesophageal, liver and colorectal cancer. ⁽¹⁾  However the link between alcohol consumption and prostate cancer is less clear and studies have shown conflicting results. We cannot therefore make recommendations based on the current research.
Some evidence shows that men who are heavy regular drinkers and binge drinkers are at increased risk for prostate cancer whilst non-drinkers may be at increased of dying from prostate cancer compared to those who are light users of alcohol. ⁽²⁾
Other studies show that alcohol consumption is not associated with overall prostate cancer risk or risk for low-grade prostate cancer but that the risk for high-grade prostate cancer is increased in men who consumed a minimum of seven drinks per week when aged 15 to 19 years compared with men who did not drink during that period of their lives. The same study showed that men with a higher cumulative alcohol intake throughout their lives were more likely to be diagnosed with high-grade prostate cancer. ⁽³⁾

References for Alcohol and Prostate Cancer:
Ref (1) Testino G, Maedica. A Journal of Clinical Medicine, Volume 6 No.4 2011.
Ref (2) Dickerman A et al. Alcohol intake, drinking patterns, and prostate cancer risk and mortality: A 30-year prospective cohort study of Finnish twins. Cancer Causes Control. 2016 September ; 27(9): 1049–1058. doi:10.1007/s10552-016-0778-6.
Ref (3) Michael J, et. Cancer Prev Res. 2018; Early-Life Alcohol Intake and High-Grade Prostate Cancer: Results from an Equal-Access, Racially Diverse Biopsy Cohort. Available at http://cancerpreventionresearch.aacrjournals.org/content/early/2018/08/16/1940-6207.CAPR-18-0057

 

Symptoms of prostate cancer

(compiled June 2019)

There are generally no symptoms of prostate cancer in the early stages of the disease which is why screening is so important. Some of the symptoms of prostate cancer are the same as the symptoms for an enlarged prostate (benign prostatic hyperplasia or BPH). This condition is also common in older men.

Symptoms in Early (localised) Prostate Cancer
Localised prostate cancer is when the cancer is contained within the prostate. There are generally no symptoms at this stage which is why screening is so important.

Symptoms for locally Advanced Prostate Cancer
At this stage the cancer tumour may have spread to areas surrounding the prostate such as the bladder, the pelvic nerves, the urethra and the seminal vesicles. The tubes carrying the urine (ureters) can be blocked. The following symptoms can occur:

• A need to urinate frequently, especially at night
• An urgent need to urinate
• Difficulty starting urination or holding it in
• Weak or interrupted flow of urine
• Painful urination
• Blood in the urine or semen
• Erectile dysfunction
• Loin pain
• Very little or no urine
• When the tumour enlarges it can push against the rectum which sits behind the prostate causing constipation, cramping and rectal bleeding.

Symptoms for Advanced Prostate Cancer (Metastatic Prostate Cancer)

When prostate cancer spreads to other body parts it may cause:

• Bone pain particularly in the pelvis and lower spine due to bone metastases (cancer tumours that develop in the bones)
• Bone fractures
• Spinal cord compression causing a loss of feeling in the limbs
• Lymph node enlargements
• Loin pain due to a blockage in the tubes carrying urine from the kidneys to the bladder

Other symptoms that occur when the cancer is spread widely throughout the body can include:

• Lack of energy from iron loss (anaemia)
• Weight loss with muscle wasting and loss of appetite

References 1 –  Kirby RS, Patel M. Fast Facts: Prostate Cancer. Eight Edition 2014. Health Press Limited

 

A prostate cancer diagnosis – what now?

Updated 25 June 2024

Being diagnosed with prostate cancer inevitably comes with a sense of shock and even fear. It can be an overwhelming and confusing time with the overriding question often being “What now?”.  First off, take a deep breath or two to assist with keeping the panic at bay.  Remember that most prostate cancers are slow growing, meaning that you likely don’t have to make all of your decisions immediately. Take time to consider the following suggestions:

Educate yourself

If possible read up on prostate cancer or speak to other prostate cancer patients in order to improve your understanding of the disease as this can be helpful in separating fact from fiction. It is important that you deal with fact. Be aware of “Dr Google” as reading up on medical facts without the requisite medical knowledge can be alarming and confusing.

Prepare for your next doctor’s appointment

Your doctor will likely cover the specifics of the cancer that you have and will undoubtedly tell you about treatment options which could include active surveillance (‘watching and waiting’), surgery, radiation therapy, hormone therapy, chemotherapy or even a combination of these . This can be a lot of information to take in at once so, if possible, have a notepad and pen with you so that you can jot down notes that you can look over later.

If possible take a friend or family member along with you.  Not only does this provide you with some support but having another listening ear can also be helpful when there is a lot of information to absorb.

Have a list of questions written down that you would like to ask your doctor. These could include:

• Is the cancer localised or has it spread to other parts of the body (metastatic prostate cancer)?
• Is the type of cancer that I have curable?
• Will further tests be needed? If so, which tests? And who will be available to explain to me what the results mean?
• What are all my treatment options?
• What factors should I consider when choosing a treatment?
• What is your experience with these treatments?
• When can the treatment begin and for how long will it last?
• What are the possible side effects of and/or risks associated with the various treatment options? Could these include incontinence, erectile dysfunction, loss of sex drive, pain? If so, how do I best manage these?
• How will the treatment affect my quality of life?
• If surgery is an option what all does the surgery involve and what would the hospital stay entail?
• Is active surveillance an option for me? If so what does it involve and how often will I need to be checked? What should I be looking out for?
• What if the cancer spreads?
• What other health professionals will be involved in my treatment and care – oncologists, nuclear medicine physicians, psychologists, physiotherapists, anesthaesiologists?
• What outcomes can I realistically expect from a specific treatment option?

Request a copy of all your lab results and any other tests that are done and keep these in a safe place. They are useful to have if you want another opinion and if you do any of your own research.  However always speak to your specialist before you reach any conclusions on your own.

Find the right doctor

If you have a private medical aid you should try to find specialists that you are comfortable with and that you feel you can trust. You’re going to see him/her frequently over an extended period of time, you may as well like him and feel a ‘right fit’ with him.

Initially you will probably be referred to a urologist who will make the diagnosis. Depending on how the cancer is going to be treated you may also be referred to an oncologist, a radiation oncologist or even a nuclear medicine physician. Other healthcare professionals like physiotherapists and sexologists might also assist you at different stages of your treatment.

If you have a family doctor/GP they can help you find a specialist.

Seek a second opinion if necessary

Your health and your treatment are your responsibility. If you are not happy with the advice you are receiving from your doctor seek a second opinion. Do not be concerned about possibly offending your doctor, it is your right to seek out the help you feel you need.

Don’t try and do it alone

This can be a scary time and it is important to draw on all the resources and support structures available to you. Talk to someone – whether it be your partner, a friend, a family member or a professional such as a nurse or a counsellor or a psychologist. Share what you are thinking and feeling. You may well be feeling anxious about the future and about the impact of your illness on the relationships with the people close to you. Talking about these things is not a cure but it will definitely help you feel less burdened and will assist you in processing the confusing thoughts and feelings.

You may well find that your loved ones are as confused and anxious as you are. Their personal discomfort and fear might mean that they find it too difficult to even acknowledge your illness, let alone talk about it. They will not necessarily know how to support you. Be direct and honest about what you need from them and how they can help you. Don’t expect them to be able to read your mind.

Join a support group or talk to a prostate cancer survivor

Becoming part of a group of men who are going through a similar experience to you can be tremendously helpful. It provides you with an opportunity to ask questions and express concerns to people who understand exactly what you are going through. The Prostate Cancer Foundation of South Africa runs an email support group.

Take care of yourself

Do whatever you can to maintain your health. Explore stress management and relaxation techniques. Eat well, remain as active as possible, and get sufficient sleep. Set your own pace. Yes, you have cancer but try not to allow the diagnosis to define you.  Pursue your hobbies and interests and maintain your friendships. Talk about things other than your disease. Set yourself achievable goals, schedule things that you can look forward to.

Seek emotional help if you need it

If you continue to feel overwhelmed and are simply not able to shake anxious and  depressive thoughts and feelings, seek help from a professional. Getting help is a sign of  strength. It is important to take control of the things that you can take control of.

Treatment options for localised prostate cancer

Updated 28 June 2024

If you have been diagnosed with localised prostate cancer there may be various treatment options available to you. Prostate cancer that is diagnosed when it is still localised can be cured. Before deciding on what treatment will be best suited to you, your doctor should assess your life expectancy, health status, frailty and co-morbidities. If your life expectancy is less than 10 years you will be unlikely to benefit from active treatments.

The decision on what treatment will be best for you should be made jointly by you and your doctor. You should be fully informed of all treatment options available to you for your stage of prostate cancer, even if these are not provided by the specialist that you are consulting. You need to ensure that you fully understand the  advantages and disadvantages of all the treatment options and their potential impact on your quality of life, in order to make an informed decision. Prostate cancer is usually a slow growing type of cancer, so you should take your time to understand the side effects of the different treatment options before you make your decision. It’s a good idea to speak to other men who have been in your position before you make your decision. You can do this by joining the Prostate Cancer Foundation’s email support group which is made up of men who have had various treatments.

Treatments options include monitoring the cancer or active treatments

Monitoring the cancer 

• Active surveillance
• watchful waiting

Surgical treatments 

• Open radical prostatectomy
• Laparoscopic prostatectomy
• Robotic assisted Laparoscopic prostatectomy

Radiation Treatments

• Radiotherapy options include
  • External beam radiotherapy (EBRT)
  • Brachytherapy (BT)
  • A combination of EBRT, BT and androgen deprivation treatment

References:

1 Mutambirwa S, Coetzee L, Adam A et al. Prostate Cancer Foundation screening guidelines. Available at: https://prostate-ca.co.za/for-healthcare-professionals/.

ACTIVE SURVEILLANCE FOR LOCALISED PROSTATE CANCER

Updated 28 June 2024

Active surveillance aims to avoid unnecessary treatment and spare men from the side effects of these. Men are closely monitored with the objective of intervening timeously if there is disease progression to ensure that active treatments are still potentially curative.

Patient selection for active surveillance

Not all types of localised prostate cancer are suitable for active surveillance. Only men with low risk disease or favourable intermediate risk disease with no adverse risk features are suitable candidates.

Factors that may exclude men as candidates for AS include:

• extensive disease on MRI
• high PSA density

The following features found on the biopsy also mean that these men are not suitable candidates:

• predominant ductal carcinoma (including pure intraductal carcinoma)
• cibriform histology
• sarcomatoid carcinoma
• small cell carcinoma
• extra capsular extension
• lymph node vesicle invasion in needle biopsy
• Perinural invasion
• High risk disease

For men with very low risk disease, the 2024 NCCN guidelines now recommend that active surveillance should be the treatment of choice. The NCCN define very low risk disease as; PSA level <10 ng/mL, 3 prostate biopsy fragments/cores positive, <51% cancer in each fragment/core, and a PSA density of 0.15 ng/mL/g.)

If you do choose active surveillance, you will need to be regularly monitored to ensure that any disease progression is picked up so that an active treatment can be given before the cancer spreads.

The NICE protocol is one way of monitoring patients on active surveillance

Timing	Test
When starting active surveillance	Multiparametric MRI if not previously performeda
Throughout active surveillance	Monitor changes to the PSAb
Year 1 of active surveillance	Every 3–4 months: measure PSA Every 6–12 months: perform a digital rectal examination (DRE)c At 12 months: do a prostate biopsy
Years 2–4 of active surveillance	Every 3–6 months: measure PSA Every 6–12 months: perform DRE
Year 5 and every year thereafter until active surveillance ends	Every 6 months: measure PSA Every 12 months: perform DRE

^aIf there is concern about clinical or PSA changes at any time during active surveillance, reassess with multiparametric MRI and/or rebiopsy.
^bMay include PSA doubling time and velocity.
^cShould be performed by a healthcare professional with expertise and confidence in performing DRE.

Advantages of active surveillance

• You avoid the side effects of active treatments  which can significantly affect your quality of life
• Active surveillance won’t affect your everyday life as much as active treatment might
• If tests show that your cancer might be growing, you can still have active treatments  that aim to cure your cancer
• In a clinical trial called the ProtecT trial, the number of men with very low risk prostate cancer who died after 10 years following active surveillance compared to men who had a prostatectomy or radiation therapy was very similar

Disadvantages of active surveillance

• You will need to have more prostate biopsies
• Your general health could change, which might make some treatments unsuitable for you if you did need them
• Some men struggle with the anxiety of knowing that they have untreated cancer in their body
• In a small percentage of men who choose active surveillance the cancer spreads spreads , which means that it may no longer be curable
• In a trial comparing men who had low risk prostate cancer after 15 years,  more men in the active surveillance group developed distant or regional node metastases compared to men who had a radical prostatectomy or radiation therapy:
  9.4%   compared with 4.7% in the radical prostatectomy group and 5.0% in the radiation therapy group

References:
1 Mutambirwa S, Coetzee L, Adam A et al. Prostate Cancer Foundation screening guidelines. Available at: https://prostate-ca.co.za/for-healthcare-professionals/.
2 Schaeffer EM, Srinivas S, Adra N, et al. Natl Compr Canc Netw 2024;22(3):140–150. Prostate Cancer, Version 3.2024 Featured Updates to the NCCN Guidelines.

Surgical Treatment for Localised Prostate cancer

Compiled July 2020

Surgery to remove the prostate is called a radical prostatectomy. The entire prostate gland, the seminal vesicles and some adjacent tissue are removed during surgery. In patients with intermediate or high risk localised prostate cancer, some of the lymph nodes may also be removed.
One of the advantages of surgery is that the entire prostate, the seminal vesicles and some of the surrounding tissues are sent to a pathology laboratory and analysed. This provides an opportunity for the prostate cancer to be restaged (pathologic staging). This type of staging is more accurate than clinical staging and you may be given a new Gleason score and tumour stage. If the pathologic staging and the surgeon’s observations show that the cancer is more aggressive than the original biopsy results showed, then your cancer may be reclassified as locally advanced and your urologist may recommend additional treatments.

Prostate cancer surgery is a major operation and, as with all surgery, there are risks that men need to be aware of. These include complications from a general anaesthetic, blood loss and the need for a blood transfusion (this is more common with open surgery), pulmonary embolism and wound infection.

The challenge with prostate cancer surgery is to remove all of the cancer whilst minimising damage to the nerves that enable men to have erections and also preserving the structures and nerve supply that are involved in bladder control (continence). Part of the procedure involves cutting the urethra just below the bladder in order to remove the prostate gland. This results in the removal of one of the sphincters (the internal urethral sphincter) that assists with bladder control (continence).  The urethra is reattached to the bladder after the prostate has been removed and a catheter is kept inserted to allow the join to heal without forming scar tissue (which can result in narrowing of the tube).  The catheter is a tube that drains urine from the bladder through the penis and into a bag. The catheter may be kept in place for a few days or weeks depending on the type of surgery. The two tubes carrying sperm from the testes (vas deferens) are also cut so men will be infertile after the procedure.

Nerve-sparing surgery

There are two main nerve bundles running along the sides of the prostate. These are the nerves that enable a man to have erections and they also play a role in bladder control (urinary continence). Urologists will try to preserve the nerves (a nerve-sparing prostatectomy) but this is not always possible. If the cancer has invaded the nerves they have to be removed. Even if the nerves are not removed there is a chance that they may be damaged during the surgery.

This is why erectile dysfunction is a common side effect of surgery. Full recovery of erectile function is more likely in younger men who had good erectile function before surgery and where the nerves on both sides of the prostate have been preserved. Recovery of continence is also significantly better in men who have had a nerve sparing procedure.

Types of radical prostatectomies available

Irrespective of the type of surgery you undergo, research has consistently shown that the best outcomes are achieved by surgeons who are doing high numbers of prostatectomies.

Open radical prostatectomy (ORP)

This is the traditional way that a radical prostatectomy is done. It is still the most common type of surgery performed in the public sector. Access to the prostate is either through the abdomen (retropubic approach) or the perineum (the area between the scrotum and anus). This type of a prostatectomy is the most invasive as the surgeon opens up the body and operates directly. It can result in blood loss that may require a blood transfusion. This surgery results in a longer hospital stay and recovery period than that with laparoscopic surgery and a robotic-assisted prostatectomy.

Laparoscopic radical prostatectomy (LRP)

With this type of surgery the surgeon makes small incisions across the stomach through which the surgical tools and a camera are inserted. This is why it is commonly known as “keyhole” surgery. The surgeon views the procedure on a video monitor and uses special long-shafted instruments to perform the surgery.

This is far less invasive than open surgery resulting in less blood loss, fewer blood transfusions, a shorter hospital stay and a quicker recovery. The hand movements of the surgeon is restricted because of the way that laparoscopic instruments are fixed at skin level. This type of surgery requires a long learning period for surgeons and the precision, articulation and vision required to perform it means that it is limited to a few surgeons.

Robotic-assisted radical prostatectomy (RARP)

To read more about what expect after you have had a robotic prostatectomy click on the link below:

https://www.woscan.scot.nhs.uk/wp-content/uploads/291393-Robotic-Discharge.pdf

As with normal laparoscopic surgery described above, small incisions are made in the stomach through which cameras and instruments are inserted. However, there are a number of differences with robotic surgery compared with traditional laparoscopic surgery. RARP expands the surgeon’s capabilities as outlined below:

The surgeon’s operating position

With traditional laparoscopic surgery and open surgery, the surgeon physically stands over the patient and operates through the incisions using long-shafted instruments.

With robotic surgery the surgeon sits comfortably at a console away from the patient. The instruments are situated above the patient and are inserted through the incisions. This results in less fatigue for the surgeon.

Manoeuvrability of the surgical instruments

With traditional laparoscopic surgery the instruments used are long shafted instruments which provide less flexibility, dexterity and range of motion than with robotic surgery. With robotic surgery the surgeon controls the robotic instruments using natural hand and wrist movements.  The instruments can rotate through 540 ° and are more mobile than the human hand. The system even filters out unpredictable movements and tremors.

Visualisation

With robotic surgery the surgeon is provided with a magnified high-definition three-dimensional view of the tissue planes, target anatomy and the neurovascular bundles.

For these reasons robotic prostatectomies have become the standard procedure in many developed countries.

Removal of lymph nodes – pelvic lymph node dissection (PLND)

If you have intermediate or high-risk localised prostate cancer then your urologist might remove some of the lymph nodes. In some cases they may only remove lymph nodes in the close proximity to the prostate. Where there is a higher risk of the cancer having spread they may remove lymph nodes further afield, this is called an extended pelvic lymph node dissection. The removed lymph nodes are sent to a laboratory to be checked for prostate cancer. Knowing if the cancer has spread to the lymph nodes is important as this can assist with planning additional treatments. If the laboratory results show that the cancer has spread extensively to the lymph nodes, you may require additional treatment after the surgery in the form of androgen deprivation therapy.

Side Effects of pelvic lymph node dissection

The lymph nodes drain tissue fluid, so removing them can result in a build up of tissue fluids (oedema) in areas where drainage no longer takes place. This is more likely if an extended pelvic lymph node dissection has been performed. Patients may suffer from leg oedema and in some cases oedema of the scrotum and penis.

Monitoring treatment outcomes

Your cancer will be restaged after the surgery based on the laboratory results (see article on prostate cancer staging). This will provide a better indication of how aggressive the cancer is. The laboratory will also report on the surgical margins ie. the presence of (positive surgical margin) or absence (negative surgical margin) of cancer cells in the edge of the tissue surrounding the removed tumour. A negative margin is an indicator that all the cancer was removed.  A report of positive surgical margins is not a 100% accurate predictor that the cancer has spread, as several factors can cause “spillage” of cancer cells into the adjacent tissue that is examined buy the laboratory.

After having a radical prostatectomy the PSA levels should drop to undetectable levels (< 0.01 ng/mL) within 6 weeks as there should no longer be any prostate cells still in the body to produce PSA. This is called the PSA nadir. Failure to reach a PSA level of 0.01 or a rising PSA could mean that there are still some prostate cancer cells in the prostatic bed (the area where the prostate was) and/or there are microscopic deposits of prostate cancer cells (micro metastases) in the body. This is called biochemical recurrence. In this case your urologist may recommend additional treatment with external beam radiation therapy to target prostate cancer cells remaining in the prostatic bed or hormone therapy to stop any other cancer cells in the body from growing.Side effects from a radical prostatectomy

Side Effects

Urinary Incontinence

Many men will experience problems with bladder control (continence) after a prostatectomy. The leaking of urine is called urinary incontinence. It is one of the most irritating and embarrassing side effects that men have to deal with. Most men eventually regain control of their bladder but it can it can take up to a year.

There are two types of incontinence that men can experience after a prostatectomy:

• Stress incontinence is leaking of urine after exertion. Activities or exertion that cause leaking can be as mild as coughing , sneezing or just shifting position. This is the most common type of incontinence after a prostatectomy.
• Urge incontinence occurs when you feel a sudden urge to urinate but you can’t “hold it in” until you get to a toilet.

Click on the link below to read one man’s experience with incontinence:

https://www.pcf.org/c/long-wet-road-back-normal/

Why does urinary incontinence occur after a prostatectomy?

With all the different types of surgery, one of the sphincters (the internal urethral sphincter situated in the bladder neck) is removed. The prostate also plays a role in continence and is also removed. Bladder control is then dependant on one sphincter (the external sphincter) which is situated just below the prostate. This is the strongest and most important of the three continence mechanisms. With two of the mechanisms that normally help with continence having been removed, continence is now reliant on one sphincter.

There are several factors which can affect how quickly and how well you recover bladder control (continence):

Damage to the external sphincter

The external sphincter sits just below the prostate and is the muscle that you use to control your flow of urine. The supporting structures such as nerves, blood supply and the muscle surrounding the sphincter can be damaged during surgery and can take up to a year to fully recover. Men who have problems with urinary continence before the procedure are also more likely to experience problems after the surgery.

Nerve-sparing vs non-nerve-sparing prostatectomy

There are 2 nerve bundles around the prostate that play a role in controlling the flow of urine and erectile function. Urologists will try to do a nerve-sparing procedure in order to try and keep these intact but this is not always possible. Men who have a nerve-sparing prostatectomy are likely to regain bladder control in half the time of men who had a non-nerve-sparing prostatectomy. (5.3 months compared to 10.9 months).

The type of surgery

There is evidence to show that continence rates are better after a robotic prostatectomy than with other types of surgery. Surgeons are better able to see the nerves due to the magnification provided by the robotic cameras and they have more manoeuvrability due to the degree of movement provided by the robotic instrumentation.  This allows for greater precision and preservation of the nerves that supply the external sphincter. In terms of recovery time, some studies have shown that men are continent 44 days after robotic surgery compared to 160 days after traditional open surgery.

The length of the urethra after surgery

The urethra is cut and reattached to the bladder. If the remaining length of the urethra is less than 12mm after surgery this can affect continence.

Age

As men get older the muscles around the sphincter get weaker which means that they are at increased risk for incontinence after surgery.

Obesity

Patients with a body mass index (BMI) over 30kg/m² are three times more likely to have problems with incontinence after surgery.

Sexual side effects

(See section on managing sexual side effects after active treatments)

Ejaculation problems

Men who have undergone a radical prostatectomy will no longer be able to ejaculate. This is because the prostate and seminal vesicles make up most of the ejaculate (seminal fluid) and they are removed. The tube that carries semen from the testes is also tied off, although semen only makes up about 2% of the ejaculate. Men who want to still father children should consider having their semen frozen and stored in a sperm bank before the procedure.

Orgasmic function

Although men will be unable to ejaculate after a prostatectomy they will still be able to experience the sensation of orgasm. The quality of orgasm, however, may be affected. Some men will experience painful orgasms although this tends to improve over time. Men who have a robotic prostatectomy are less likely to experience this problem.

Erectile dysfunction

This is a common side effect that can occur after all active treatments for prostate cancer. The nerves and blood vessels responsible for erections can be damaged by the surgery and can take months to heal. Men who have erection problems before a prostatectomy are more likely to have problems after the surgery. Men who have had a nerve-sparing prostatectomy are more likely to recover erectile function. For men who want to recover erectile function, it is essential that that they begin penile rehabilitation as soon as possible after surgery (see section on managing sexual side effects after active treatments).

Climacturia

This is the loss of bladder control (continence) whilst having an orgasm and it occurs in about 30% of men who have had a prostatectomy. The problem normally improves over time and patients who have had a robotic prostatectomy recover more quickly from this condition. Emptying your bladder before you have sex and using condoms can help. Physiotherapists who work with pelvic dysfunctions can also assist with pelvic floor exercises.

Long term complications

Urinary incontinence and erectile dysfunction are the most common long term complications after a radical prostatectomy. Some men experience penile shortening although this usually corrects as healing progresses and scar tissue softens.

Advantages of Surgery

• If the cancer is contained in the prostate, men will have the reassurance that it has been removed from the body
• Because the prostate and seminal vesicles are removed from the body and sent for laboratory analysis, surgery provides the best way to assess how aggressive the cancer is and the cancer can be more accurately restaged (pathologic staging)
• Men who have an enlarged prostate (benign prostatic hyperplasia) will no longer have symptoms for this condition as the prostate is removed
• Assessing treatment success is quick, as PSA levels should drop to undetectable levels soon after treatment, whereas this can take up to 2 years with radiotherapy
• It is easy to monitor patients to check if the cancer has returned by using PSA tests
• If the treatment has failed, radiotherapy can be used as a backup treatment (salvage therapy)

Disadvantages of Surgery

• A prostatectomy is a major operation and there is a risk of blood loss and the need for a blood transfusion. However, this is less likely to occur with laparoscopic and robotic surgery which also have the benefit of a shorter hospital stay and quicker recovery time
• Patients will be discharged with a urinary catheter which will have to be removed 1 to 2 weeks after being discharged
• Many patients experience urinary incontinence after the catheter is removed. This can take weeks or months to completely clear up, although many patients have acceptable control within the first 3 months

References

(1) Cao L et al. Robot-assisted and laparoscopic vs open radical prostatectomy in clinically localized    prostate cancer: perioperative, functional, and oncological outcomes. A Systematic review and meta-analysis. Medicine (2019) 98:22.
(2) Kirby RS, Patel M. Fast Facts: Prostate Cancer. Eight Edition 2014.  Health Press Limited
(3) Leow, Jeffrey J. et al. Systematic Review of the Volume–Outcome Relationship for Radical Prostatectomy. European Urology Focus, Volume 4, Issue 6, 775 – 789.
(4) Hoyland K et al. Post–Radical Prostatectomy Incontinence: Etiology and Prevention. Reviews in Urology. 2014;16(4):181-188
(5) Jaffe WI et al. Urinary Incontinence After Prostate Cancer Surgery & Radiation. Available at:
www.oncolink.org/cancers/prostate/support-and-survivorship/side-effects/urinary-incontinence-after-prostate-cancer-surgery-radiation-therapy
(6) Mottrie et al. Balancing continence function and oncological outcomes during robot-assisted radical prostatectomy (RARP)
(7) Singla N et al. Post-prostatectomy incontinence: Etiology, evaluation, and management. Turkish Journal of Urology; 40(1): 1-8
(8) For Healthcare professionals: Prostate cancer essentials: Localised prostate cancer. Prostate Cancer UK.
(9) McLeod DG. The Effective Management of Biochemical Recurrence in Patients With Prostate Cancer. Reviews in Urology. vol. 7 suppl. 5 2005
(10) Skove SL et al. Timing of PSA nadir after radical prostatectomy and risk of biochemical recurrence. Urology. 2017 October ; 108: 129–134

Radiotherapy for Treating Localised and Locally Advanced Prostate Cancer

Radiotherapy

Radiotherapy or radiation therapy refers to the use of high energy X- rays used to treat cancer. These high energy X- rays are different from diagnostic X rays such as a CT scan where the X- rays are of a lower energy. Radiation therapy works by destroying a cancer cell’s DNA which prevents the cells from reproducing and causes cell death. The aim is always to deliver a high enough dose to the cancer tumour to maximise disease control, whilst keeping the dose that reaches normal healthy tissues as low as possible to minimise side effects and complications.

Radiotherapy treatments are managed by medical specialists called radiation or clinical oncologists. They are assisted by medical physicists who help with the planning of the treatment and by radiation therapists who set-up the patient for the treatment and operate the machinery required to administer the treatment.

The two types of radiotherapy available in South Africa to treat localised and locally advanced prostate cancer are external beam radiation and brachytherapy.

Cyberknife which uses stereostatic body radiation therapy (SBRT) and computer-assisted image guidance to deliver very high doses of radiation to the tumour, is not yet available in South Africa.

External beam radiation therapy (EBRT)

This treatment option is completely non-invasive. There is no surgery involved, so it is a suitable option for men who do not want any surgery or who are not suitable for surgery because of other health issues.

The treatment is done at a special facility using a machine called a linear accelerator. The machine delivers high energy X-rays to the targeted area.

The challenge with radiotherapy is to deliver a high enough dose to the prostate whilst avoiding damage to the bladder and the rectum. The beam is moved in an arc around the prostate so it will pass through structures like the bowels at some point during the treatment session.

For localised prostate cancer

For low risk localised prostate cancer the whole of the prostate gland is treated but not the seminal vesicles.

For locally advanced prostate cancer

For T3 disease where the cancer has spread outside of the prostate, the seminal vesicles will also be treated. In some patients, the seminal vesicles are close to the rectum which means that it will fall in the treatment area. This will increase the likelihood of gastro-intestinal side effects (bowel side effects).

For intermediate or high risk prostate cancer

Hormone therapy will be given before and/or together with the EBRT. This helps to reduce the tumour size and make the cancer cells more sensitive to the radiation.

Treating the pelvic lymph nodes

Some oncologists may also treat the pelvic lymph nodes if they suspect that the cancer has spread to them. This means that the treatment area will be bigger and that there will be an increased likelihood of gastro-intestinal side effects (bowel side effects).

Types of external beam radiation therapies

With both types, a planning session will be done before the treatment sessions starts. Scans are taken to map the size, shape and location of the prostate so that the exact treatment area will be targeted by the radiation beam. This will help to   avoid damaging healthy tissue.

At some centres, where thelinear accelerator does not have a CT scanner attached, patients may have to have a few  radio-opaque seeds implanted into the prostate so that a normal X-Ray machine can be used for set-up to ensure that the beam is targeted at the prostate.

Three small tattoos will be marked out on your abdomen. These are used to get you in the correct position for each treatment.

3D conformal radiotherapy (3D-CRT)

This system allows the beam to be adjusted to the shape and size of the prostate in all three dimensions. However, the strength of the beam cannot be controlled so all areas of the prostate are treated with the same dose.

Intensity-modulated radiotherapy (IMRT)

This is a newer system than (3D-CRT). The advantage is that the strength of the beam can be adjusted. For example, a lower intensity can be used when the beam passes through the rectum which helps to reduce side effects. Treatment sessions can take longer depending on the machine.

How long does the treatment take?

With the traditional method, small doses of radiation (1.8-2Gy) are delivered daily, Monday to Friday over a period of 7 to 8 weeks until the prescribed dose of 74GY is reached. Each treatment takes about 15 minutes.

Hypo-fractionation treatment

This is a newer EBRT technique that involves delivering a higher daily dose (3Gy) over 4 to 5 weeks until the prescribed dose of 60Gy has been reached. The convenience of a shorter period is making this a popular treatment option.

Treatment set-up

One of the challenges with EBRT is that the beam has to be aimed as accurately as possible at the prostate to insure that the radiation is directed at the targeted area. The problem is that the prostate can move from day-to-day due to pressure from the bladder or the rectum, depending on filling and emptying, so patients may be instructed to try and keep this as consistent as possible.

Patients will also be immobilised for the duration of the treatment and adjustments will be made daily using the machines built-in CT scanner or other imaging methods. This is called Image Guided-Intensity Modulated Radiotherapy (IG-IMRT).

Precision is a key factor with external beam radiation and is even more critical when using higher -dose treatments.

Monitoring treatment outcomes

After the treatment is complete you will be monitored by your oncologist to check if the cancer returns or not. The PSA blood test will be used but it can take up to 2 years to drop to its lowest level. Some patients who have EBRT get a sudden temporary rise in their PSA levels and then it drops down again. This is called PSA bounce and it doesn’t mean that the cancer is growing again.

Once the PSA has reached its lowest level, (nadir) an increase of 2ng/ml is regarded as disease recurrence. eg going from 0.75 to 2.75. This is referred to as biochemical recurrence and it is a sign that the cancer is growing.

Another definition of biochemical recurrence is if there are 3 consecutive rises in the PSA when it is measured at least 3 months apart.

Side Effects of External Beam Radiation

Oncologists have to try and achieve a balance between providing a strong enough dose to destroy the cancer cells whilst minimising the radiation to the surrounding organs. Side effects occur when healthy tissue is damaged by the radiation. Oncologists refer to this as toxicity. The healthy tissue may heal but this can take time.

Short term side effects may begin 2-4 weeks after starting treatment and can last up to 4-8 weeks after treatment. The radiation can cause irritation and inflammation of the bladder (cystitis) and the rectum (proctitis). This can cause urinary and gastro-intestinal side effects. Some patients experience late side effects that only occur after the treatment is completed.

Urinary side effects include:

• the need to urinate frequently
• having to get up at night to urinate
• a sudden urgent need to urinate
• difficulty urinating or slow urination (obstruction)

Gastro-intestinal side effects (bowel side effects) include:

• loose stools (diarrhoea)
• bloody stools
• bleeding from the anus
• needing to defecate frequently
• cramps
• an urgent need to defecate

Sexual side effects

(See section on sexual side effects after active treatments)

All active treatments are likely to affect your sex life. Some studies show that the sexual side effects from EBRT get worse over time.

Ejaculation problems

The majority of men who have external beam radiation therapy will eventually not be able to ejaculate after treatment (anejaculation) and this gets worse over time. In one study 16% of men experienced the problem after 1 year, 69% after 3 years and 89% after 5 years.

Erectile dysfunction

This is a side effect that can occur after all active treatments for prostate cancer. Erectile function before treatment is an important factor.  The dose of radiation that is delivered to structures that play a role in erections such as the penile bulb and the blood vessels appears to have an important effect on erectile function after treatment. Some oncologists have developed techniques to preserve these structures.

Long term complications

The most common long term complication of EBRT is bowel function. In one study, 5 years after treatment 33% of men reported that they are still bothered by an urgent need to defecate. 24% of the men also reported being bothered by slow or difficult urination. Some men will have erectile dysfunction but this can also be related to ageing and other comorbid conditions.

Advantages of External beam radiation therapy (EBRT)

• The treatment is completely non-invasive so it can be given to men who are not fit for surgery or don’t want surgery
• There are none of the problems  or complications that can occur with major surgery
• Most men can continue working whilst having the treatment so there is no need to take time off work (although some men will experience fatigue)
• There is no hospitalisation
• The treatment itself is pain free

Disadvantages of External beam radiation therapy (EBRT)

• This is a time consuming treatment that involves daily visits during the week to a specialised facility for 4 to 8 weeks depending on the treatment regime
• The prostate is not removed as with surgery so restaging the cancer is not possible as it is with surgery
• Using the PSA levels to determine if the treatment has been successful can be difficult, as it can take up to 2 years to drop to its lowest level. Some men get aPSA bounce (temporary rise in PSA levels) which further confuses the issue. If men have hormone therapy together with the EBRT, this will also affect the PSA score.
• If the cancer recurs, further radiation is generally not possible
• If the cancer recurs, salvage surgery is possible, but it is far more difficult than in men who have had no radiation treatment and it has a higher rate of complications
• The gastrointestinal side effects (bowel problems) are higher than with other active treatments
• As with other active treatments, there are urinary and sexual side effects that can have a significant impact on a man’s quality of life
• The beam has to travel through healthy tissue which exposes it to some radiation leading to possible side effects

References

1 Kirby RS, Patel M. Fast Facts: Prostate Cancer. Eight Edition 2014.  Health Press Limited

2 External beam radiation. Prostate Cancer UK. Availble at:  https://prostatecanceruk.org/prostate-information/treatments/external-beam-radiotherapy

3 Dang et al. Image-guided radiotherapy for prostate cancer. Transl Androl Urol 2018;7(3):308-320

4 Prostate cancer essentials: Localised prostate cancer. Prostate Cancer UK

5 Potosky AL et al. Five-Year Outcomes After Prostatectomy or Radiotherapy for Prostate Cancer: The Prostate Cancer Outcomes Study. Journal of the National Cancer Institute, Vol. 96, No. 18, September 15, 2004

6 Samlali H et al. Prospective evaluation of a specific technique of sexual function preservation in external beam radiotherapy for prostate cancer. Br J Radiol 2017; 90: 20160877.

Low Dose Seed Brachytherapy

(High dose rate temporary brachytherapy is not commonly available in South Africa and is therefore not discussed as a treatment option).

Low dose seed brachytherapy involves the permanent insertion of tiny radioactive seeds which are about the size of a rice grain into the prostate gland. These emit low doses of radiation within the prostate over about 3 months, although the seeds remainbiologically active for about 9 months.

The advantage of low dose radioactive seeds is that the radiation decreases in strength as it moves away from the source. This means that the structures surrounding the prostate such as the bladder and rectum are less affected by the radiation.

Assessing patients suitable for brachytherapy

A urologist will have performed the biopsy. This will have enabled the urologist to determine the size and position of the prostate and the stage of the prostate cancer.

If the patient has a very large prostate, then some urologists may use androgen deprivation therapy for 2 to 5 months to shrink the prostate.

Patients who have had a transurethral resection of the prostate (TURP) as a treatment for an enlarged prostate will have to be carefully assessed as performing brachytherapy on these patients is more complicated and technically difficult. If the TURP procedure has damaged the urethra then brachytherapy might not be possible.

Some patients have pelvic anatomy that can make the procedure more difficult.

Patients who have had previous radiation treatments to the pelvic area will have to be carefully assessed as this can result in increased side effects brought about by the additional radiation introduced by brachytherapy.

A simple self-report questionnaire called the International Prostate Symptom Score (IPSS) should be given to all patients to determine if there are urinary symptoms that could be made worse by undergoing treatment with brachytherapy. Men who have existing urinary problems or who score greater than 12 on the IPSS are at increased risk of urinary incontinence and other urinary problems if they have brachytherapy.

For low risk localised prostate cancer

(From American Brachytherapy Society consensus guidelines)

If your Gleason score ≤ 6

PSA<10 ng/mL Tumour stage T1 or T2a Brachytherapy can be used as a single treatment

For intermediate risk localised prostate cancer

(From American Brachytherapy Society consensus guidelines)

If your Gleason score ≤ 7

PSA<20 ng/mL Tumour stage T2b or T2c Brachytherapy can be used as a single treatment but some specialists may combine the treatment with external beam radiation therapy and/or androgen deprivation therapy

For High Risk localised prostate cancer

(From American Brachytherapy Society consensus guidelines)

If your Gleason score is 8 to 10

PSA > 20 ng/mL

Tumour stage T3a

Brachytherapy cannot be used as a single treatment

The treatment will need to be combined with external beam radiation therapy

The inclusion of androgen deprivation therapy is optional but there is limited data on whether it improves the treatment outcomes

The Procedure

A multidisciplinary team of healthcare professionals are involved in planning and administering the treatment. A radiation or clinical oncologist will decide on the number of brachytherapy seeds required and will plan the treatment together with a medical physicist.

Brachytherapy is done in theatre under general anaesthetic either as a day procedure or an overnight admission. The radiation/clinical oncologist and medical physicist will both be in the theatre for the procedure. They will ensure that the seeds are placed in the correct position according to the treatment plan and that surrounding organs are protected from high doses of radiation in order to limit side effects. The urologist may be involved with the insertion of the needles and, in some cases, placement of the seeds.

For the procedure a trans-rectal ultrasound probe is inserted up the rectum which provides an image of the prostate. A Foleys catheter is inserted through the penis to the bladder so that it can be clearly seen. A reference grid is placed above the ultrasound probe and the needles are inserted through the perineum (the area between the anus and scrotum) to the different parts of the prostate as per the treatment plan via the grid. The seeds are deposited through the needles into the prostate. The number of seeds used will depend on the size of the prostate.

 After Treatment

Radioactivity

The brachy seeds that are implanted in your prostate release low doses of radiation and a very low amount of the radiation may be present outside of your body. Although this amount of radiation is small and not considered dangerous, as a precaution after the treatment, men are advised to not spend extended periods of time close to pregnant women or young children for the first two months. Very rarely men may pass a seed when urinating.

Returning to work

There is no prescribed rest period, so theoretically you can return to work the day after the procedure.

Exercising

There is no time restriction on when you can start exercising except for cycling. The perineum will need time to recover so no cycling for at least 6 to 8 weeks.

Sex

There is no time restriction on sexual activity so you can have sex as soon as you want to. There is a very small chance of a radioactive seed being ejaculated so for the first few times that you have sex you should wear a condom. Some men report pain with erections and ejaculation after the procedure. If you want to remain sexually active you should stimulate yourself a few times a day to get erections as this helps to restore circulation and nerve function.

Monitoring treatment outcomes

It can take up to 5 years for the PSA to reach its lowest point after brachytherapy so it won’t be possible to determine if you are cancer-free until the PSA reaches its lowest point. This is called PSA Nadir and ideally it should be below 0.5 ng/mL. 30 % to 40% of men get a sudden temporary rise in their PSA levels and then it drops down again. This is called PSA bounce and it doesn’t mean that the cancer is growing again but it can be confusing. Failure to reach a PSA level of 0.5 ng/mL is associated with an increased risk of recurrence.

Once the PSA has reached its lowest level, an increase of 2ng/ml is regarded as disease recurrence. For example, going from 0.75 to 2.75. This is referred to as biochemical recurrence. Another definition of biochemical recurrence is if there are 3 consecutive rises in the PSA when it is measured at least 3 months apart. If this happens, it may be necessary to have a biopsy and other tests to check if the cancer has spread. After brachytherapy only a transperineal biopsy can only be done.

Side Effects of brachytherapy

Side effects occur when healthy tissue is damaged by the radiation. Oncologists refer to this as toxicity. The healthy tissue may heal but this can take time.

Short term side effects may begin 2-4 weeks after receiving treatment and can last up to 4-8 weeks after treatment. The radiation can cause irritation and inflammation of the bladder (cystitis) and the rectum (proctitis). This can cause urinary and gastro-intestinal side effects. Some patients experience late side effects that only occur after the treatment is completed.

Urinary side effects are often delayed until 1 to 4 months after treatment and are most commonly obstructive or irritative in nature. Most symptoms will resolve within one year.

         Obstructive urinary symptoms

• a percentage of patients (5 to 28%) get complete urinary obstruction (unable to urinate). It is essential to get immediate medical help for this. The problem is easily treated by insertion of a catheter
• straining to urinate
• taking long to urinate
• a feeling of incomplete emptying of the bladder after urinating
• dribbling or a weak stream

Irritative urinary symptoms

About 50% of men experience symptoms as a result of irritation of the urethra. These usually resolve within one year. Irritative symptoms include:

• having to urinate frequently
• having to get up at night to urinate
• a sudden urgent need to urinate
• a burning sensation when urinating
• a weak stream

Gastro-intestinal side effects (bowel side effects) are less common from brachytherapy compared to external beam radiation and may include:

• loose stools (diarrhoea)
• bloody stools
• bleeding from the anus
• needing to frequently defecate
• cramps
• an urgent need to defecate
• pain when passing a stool

Sexual side effects

(See section on sexual side effects after active treatments)

All active treatments are likely to affect your sex life.

Ejaculation problems

There may be blood in the ejaculate in the first few weeks after the procedure. Most men who have ejaculations before treatment will continue to have them after treatment, however there is likely to be a reduced volume of ejaculate and, in some cases, no ejaculate. Some men may experience painful ejaculations. Many men will have delayed or weaker orgasms.

Erectile dysfunction

This is a side effect that can occur after all active treatments for prostate cancer. Erectile function before treatment is an important factor.  With brachytherapy the dose of radiation that is delivered to structures that play a role in erections, such as the penile bulb, appears to have an important effect on erectile function after treatment so the oncologist will generally lower the dose in the seeds near to these areas.

Long term complications

Damage to the urethra from the radiation can cause it to narrow in some men. This is called a

Stricture and it makes it difficult to pass urine. This can be treated with surgery.

Men who had urinary problems before having brachytherapy or who have a large prostate are more likely to have long term urinary symptoms after brachytherapy.

Advantages of Brachytherapy

• This is usually a day procedure so you avoid hospitalisation
• Recovery from brachytherapy is quick, so you can be back at work and exercising the day after the procedure

• You do not have to have a catheter after the surgery
• There is an advantage over EBRT in that the dose is delivered at the source which minimises radiation exposure to surrounding healthy tissue.

Disadvantages of brachytherapy

• It can take 2 years for the PSA to be reliable. So you won’t know if the treatment has been successful until then
• If the treatment has not been successful, surgery can be difficult to perform and the side effects may be worse
• The prostate is not removed as with surgery so restaging the cancer is not possible as it is with surgery
• The procedure is done under general anaesthetic which always has some risk

References:

1 Davis BJ et al. American Brachytherapy Society consensus guidelines for transrectal ultrasound-guided permanent prostate brachytherapy. Brachytherapy 11 (2012) 6-19.
2 Bradley JS et al. Low dose rate prostate brachytherapy. Transl Androl Urol 2018;7(3):341-356.
3 Rukstalis et al. Treatment Options After Failure of Radiation Therapy—A Review. vol. 4 suppl. 2 2002 Reviews in Urology.
4 Steggerda MJ et al. Predicting Urinary Morbidity after Brachytherapy of Localized Prostate Cancer. European Urology Supplements 7 ( 2 0 0 8 ) 723–731.
5 Logghe P et al. Long term outcome and side effects in patients receiving low-dose I125 brachytherapy: a retrospective analysis. Outcome and side effects in brachytherapy. Vol. 42 (5): 906-917, September – October, 2016.
6 Njomnang Soh et al. Erectile function after permanent 125I prostate brachytherapy for localized prostate cancer.  Basic and Clinical Andrology 2013, 23:2
7 Huyghe E et al. Ejaculatory Function After Permanent 125I Prostate Brachytherapy for Localized Prostate Cancer. Int J Radiat Oncol Biol Phys. 2009 May 1;74(1):126-32.
8 For Healthcare professionals: Prostate cancer essentials: Localised prostate cancer. Prostate Cancer UK.
9 Permanent seed brachytherapy. Prostate Cancer UL. Availble at: https://prostatecanceruk.org/prostate-information/treatments/permanent-seed-brachytherapy

10. Kirby RS, Patel M. Fast Facts: Prostate Cancer. Eight Edition 2014. Health Press Limited

Metastatic (Advanced Stage) and Recurrent Prostate Cancer

When prostate cancer spreads (metastasizes) beyond the area of the prostate and starts to grow in other parts of body it is called metastatic or advanced prostate cancer. The new growths are called metastases. Doctors may also refer to the new growths as mets or secondaries. The new growths are still made up of prostate cancer cells, irrespective of where they grow in the body. At this advanced stage the cancer is unfortunately no longer curable but can be contained for a period on appropriate therapies, with the 5 year cancer specific survival for men diagnosed with metastatic prostate cancer hovering between 30 – 40%.

How Does this happen?

There are a few possible reasons as to how men end up with recurrent or metastatic prostate cancer.

1. Recurrence after initial treatment for localised or locally advanced prostate cancer

Some men who have been treated with radiotherapy or a radical prostatectomy for localised or locally advance prostate cancer experience a rise in their PSA score at some point after the treatment. This is referred to as biochemical recurrence and it is usually an indication that the cancer is growing again.

Biochemical recurrence after surgery for localised prostate cancer
In patients who have had a prostatectomy the PSA levels should fall to below 0.1 ng/ml and recurrence is defined as a rise above 0.2 ng/ml

Biochemical recurrence after radiation treatment for localised prostate cancer
In patients who have had radiation therapy a PSA rise of 2 ng/ml above nadir (The lowest PSA level reached after therapy) is considered recurrence.

The average time for metastases to develop in patients who have a rising PSA after treatment is about 8 years. In some men prostate cancer may progress without the development of metastases.

2. Men whose first diagnoses is metastatic prostate cancer

There are usually no symptoms of prostate cancer in the early stages, so if men are not being screened regularly, prostate cancer may progress to an advanced level before symptoms cause a man to seek help. Various studies have shown that men who present with prostate cancer symptoms at South African public hospitals often have advanced metastatic prostate cancer. This may be due to a lack of awareness about age appropriate screening for prostate cancer, a lack of access to screening or a lack of awareness of prostate cancer itself. This is important as early stage prostate cancer is usually only diagnosed as a result of screening and it is potentially curable.

When prostate cancer is diagnosed at the stage when it has already metastasized it called de novo metastatic prostate cancer or synchronous metastatic disease.

Understanding how prostate cancer spreads

If prostate cancer spreads outside of the prostate, the cancer cells may invade the lymph and blood vessels. These can carry cancer cells to other parts of the body resulting in the formation of prostate cancer tumours (metastases) on bone, in lymph nodes and in organs (visceral metastases).

Oligometastatic prostate cancer

This is a relatively new concept and it refers to a sub-group of patients who have relapsed after having local therapy. These patients have less metastatic sites confined to bone or lymph nodes and are therefore not considered to have full blown metastatic disease. It is thought that by using treatments that target the metastases, it may be possible to avoid or delay hormone therapy (androgen deprivation) which is required to treat patients who have metastatic prostate cancer.

How metastatic prostate cancer is staged

The staging of cancer is a way of recording how far the cancer has progressed and what structures in the body it has spread to. The TNM staging system is used:

T describes the primary tumour and how far it has spread

N describes whether or not the cancer has spread to regional lymph nodes

M describes evidence of metastatic prostate cancer

When prostate cancer spreads to lymph nodes

The lymphatic system consists of lymph vessels, lymph nodes and two collecting ducts and is part of the body’s immune system. The lymph vessels carry lymph fluid, which contains nutrients and other substances, which are returned via drainage into the blood stream to circulate back to the rest of the body. Lymph vessels also remove and transport damaged cells, cancer cells, bacteria and viruses that drain from tissues. These are then filtered out when the lymph fluid travels through the lymph nodes.

Prostate cancer tends to spread to regional lymph nodes in the pelvic area near to the prostate first. For staging purposes this is recorded as N1 and it is not classified as metastatic disease. In patients undergoing a prostatectomy the regional lymph nodes may be removed to check if prostate cancer has spread to them (pelvic lymph node dissection). If regional lymph nodes are detected using imaging tests then they may be treated with a combination of radiation and androgen deprivation therapy

If prostate cancer spreads to lymph nodes outside the pelvic area (distant lymph nodes) then this is classified as one of the sites for distant metastases and for staging purposes this is recorded as M1a. The involvement of regional lymph nodes means that a diagnoses of metastatic prostate cancer will be made and treatment for metastatic disease will be initiated.

When prostate cancer spreads to bone (bone metastases)

Prostate cancer cells have a strong affinity to spread to bone which is the most common metastatic site. Prostate cancer cells tend to spread first to the lower spine and pelvic bones and pain in this region is often a symptom of metastatic prostate cancer.

The cancer cells interact with the different types of bone cells. Most commonly the interaction is with the bone’s “builder cells” (osteoblasts) resulting in an abnormal build-up of bone. Less commonly the interaction is with the bone’s “demolisher cells” (osteoclasts) resulting in soft sections of damaged bone. Sometimes a mi

Both types of interaction cause bone weakness and increase the risk of fractures.

The presence of bone metastases is recorded as M1b for staging purposes.

When prostate cancer spreads to organs (visceral metastases)

When prostate cancer spreads to soft tissue organs other than the lymph nodes these growths are called visceral metastases. For staging purposes visceral metastases are indicated as M1c.

Men with visceral metastases generally have a worse outcome than men who only have bone metastases. Typical visceral metastatic sites are the lungs and liver which are generally affected in the late stages of prostate cancer. Most men (76%) that develop lung and liver metastases already have bone metastases.

Less common visceral metastatic sites include the brain/meninges, the thyroid gland, adrenal glands, peritoneum, gastrointestinal tract (stomach and intestine), urinary tract, ureters, urethra and kidneys, spleen or pancreas. Men with liver metastases tend to have the worst survival outcome compared to men with bone metastases or other sites of visceral metastases.

Castrate resistant metastatic prostate cancer

Unfortunately, most advanced prostate cancers treated with hormone /androgen-deprivation therapy begin to progress again within 12 to 33 months. It is thought that cancer cells that are not dependant on testosterone begin to develop, so hormone therapy that deprives the body of testosterone is no longer effective. At this point the prostate cancer is referred to as castrate- resistant prostate cancer (CRPC).

Non-metastatic (M0) castrate-resistant prostate cancer – nmCRPC

If the only sign that the cancer has become resistant to hormone therapy is a rising PSA, then the cancer is referred to as non-metastatic castrate-resistant prostate cancer and this is indicated by M0

Metastatic (M01) castrate-resistant prostate cancer -mCRPC

If imaging tests show metastases and there is a rise in PSA levels then the cancer is referred to as metastatic castrate-resistant prostate cancer and this is indicated by M1

Symptoms of metastatic prostate cancer

Pain in the pelvis and lumbar spine from bony metastases is the most common presenting symptom in men with metastatic prostate cancer.

The bone is weakened from the formation of metastases so these patients are more at risk for fractures of the spine, the hip and the neck of the femur (the long leg bone that attached to the hip joint)

In about 12% of men, tumours that form on the vertebra can cause spinal cord compression resulting in neurological symptoms such as sciatica (pain down the back of the leg) and even paraplegia.

Metastases to the lymph nodes can cause lymph node enlargement and this can result in:

• obstruction of the ureters (the tubes that carry urine from the kidney’s to the bladder
• loin pain
• swellings that can be felt
• failure of the kidney’s to produce urine (anuria)
• (swelling) of the lower limbs due to the build- up of lymph fluid ( lymphedema)

Systemic metastases can cause non-specific symptoms such as fatigue due to loss of red blood cells (anaemia) or the build-up of urea in the blood (uraemia), weight loss and muscle wasting.

Prognosis

Although metastatic prostate cancer in not curable, there are numerous treatment options that can slow the progression of the cancer and prolong life. These are discussed in the section on treatments for metastatic prostate cancer.

General health measures such as exercise and not smoking also contribute to prolongation of survival. Bone, heart and mental health also need to be addressed and should be a part of both patient and treating team’s goals.

In addition, other first degree family members may have an increased risk of developing cancers, particularly breast and prostate cancer and so should be advised about age appropriate screening for higher risk groups.

References

1. Coetzee L. Metastatic Prostate Cancer. Health Press Limited 2017.
2. Gandaglia G et al. Distribution of Metastatic Sites in Patients with Prostate Cancer: A Population-Based Analysis. Prostate 74:210–216, 2014.
3. Barbosa FG et al. Revisiting prostate cancer recurrence with PSMA PET: Atlas of typical and atypical patterns of spread. Radiographics 2019; 39:186-212
4. AJCC Cancer Staging Handbook. Seventh Edition. Springer 2010
5. Douketis JD. Overview of the Lymphatic System. Merck Manual. Consumer Version. Available at: https://www.merckmanuals.com/home/SearchResults?query=lymphatic+system. (Accessed on 5th July 2016).
6. Wong SK et al. Prostate Cancer and Bone Metastases: The Underlying Mechanisms. Int. J. Mol. Sci. 2019, 20(10), 2587
7. Klaassen Z., The Impact of Visceral Metastasis in Prostate Cancer Patients. Available at: https://www.urotoday.com/library-resources/mcrpc-treatment/111525-the-impact-of-visceral-metastasis-in-prostate-cancer-patients.html
8. Kirby RS, Patel I. Fast Facts: Prostate Cancer. Eighth edition. Health Press Limited. Jan 2014.

Treatments for Advanced Prostate Cancer

Many men will be diagnosed and treated for prostate cancer in the earlier stages. In about 30% of these men treated for localised or locally advanced prostate cancer, the cancer will eventually recur. This is usually diagnosed by a consistent rise in PSA levels.
Some men will only be diagnosed when the cancer is already at an advanced stage when the cancer has spread to other parts of the body This is called de novo or metachronous disease.
Androgens are male sex hormones. The main one that we are all familiar with is testosterone, but testosterone is broken down or converted into other hormones which work on different parts of the body. In the prostate it’s dihydrotestosterone that affects the functioning of the prostate. To keep things simple we’ll refer to the various androgens as testosterone.
Testosterone is produced mainly in the testes, although a small amount is also produced by the adrenal glands. Unfortunately testosterone is what fuels the growth of prostate cancer cells, so once prostate cancer spreads, the only way to slow the growth of the cancer cells, is to deprive them of testosterone. This is called androgen deprivation therapy (ADT). ADT is sometimes also referred to as hormone therapy. ADT is the mainstay for treating metastatic prostate cancer and it is used alone or in combination with other treatments.
Unfortunately, ADT means that all the good things that testosterone normally does in the adult male body are affected. In order to understand the impact of removing most of the body’s testosterone it is important to have a basic understanding of its role and function in the body.

The role of testosterone and the effects of low testosterone levels

Function of testosterone in adult men	Result of low testosterone
Gives a man his sex drive	Low sex drive
Causes spontaneous night time  and waking erections	Loss of spontaneous night time and waking erections
Provides men with energy and drive	Loss of energy and drive
Provides men with a general sense of wellbeing and helps with mental functioning	Depression and lack of mental sharpness
Regulates the functioning of the internal sex organs responsible for sperm production, orgasm and  ejaculation	Low fertility and reduced orgasmic and ejaculatory function
Maintains lean muscle mass	Loss of lean muscle mass and Increased abdominal obesity Obesity leads to an increased risk for high cholesterol , cardiovascular disease and type 2 diabetes
Maintains muscle strength	Loss of muscle strength and reduced athletic performance
Promotes bone density	Increased risk for osteoporosis and pathological fractures

Androgen deprivation therapy (ADT)

Once advanced prostate cancer is diagnosed, androgen deprivation therapy (ADT) is usually initiated to stop testosterone production by the testes.  Advanced prostate cancer that has never been treated with (ADT) is referred to as hormone sensitive metastatic prostate cancer (mHSPC) or castrate sensitive prostate cancer. The objective of ADT is to reduce testosterone levels to below 1.73nmol/l. This is referred to as castrate levels of testosterone.

Normal testosterone levels	12 to 40 nmol/l
Intermediate testosterone levels	8 to 12 nmol/l
Low testosterone levels	<8 nmol/l
Castrate testosterone levels	<1. 7 nmol/l

There are two ways to reduce testosterone to castrate levels:

Surgical Castration (orchidectomy)

The removal of the testicles is still commonly used as a form of androgen-deprivation therapy (ADT) within public sector hospitals in South Africa, as it is cost effective and does not require patients having to take medications on an ongoing basis. The main disadvantage is that the procedure is irreversible. It is a simple procedure that can be performed under local anaesthetic.

Chemical castration

This involves the use of medication (injections or tablets) to block the production of testosterone.

In men with symptoms caused by metastatic prostate cancer, treatment is usually started immediately. In men who have a rising PSA but no symptoms from the cancer spreading and no signs showing on imaging tests (biochemical recurrence), there are different approaches. Beginning hormone therapy immediately can help to reduce or delay some of the debilitating symptoms of metastatic prostate cancer like spinal cord compression, pathological fractures and urethral obstruction. However this decision has to be weighed up against the impact of ADT on a man’s quality of life, so some men may prefer to delay treatment until they begin to experience symptoms (see section on side-effects of hormone therapy/androgen- deprivation therapy). Men will need to make an informed decision based on their particular circumstances and preferences.

In addition to ADT, other treatments may be administered as part of the first line treatment strategy. This is now recognised as the standard of care and includes ADT combined with chemotherapy or one of the new second generation antiandrogens. In some cases, ADT may be combined with both of these (triplet therapy). These options are discussed in more detail further on.

Androgen deprivation therapy (ADT) medications

Luteinising hormone-releasing hormone agonists (LHRH agonists)

Administration – by depot injections or a small implant injected under the skin

LHRH agonists available in South Africa: goserelin, triptorelin and leuprorelin acetate
Given 1, 3 or 6 months depending on which medication is prescribed
This medication works by blocking the release of luteinising hormone (LH) which leads to a reduction of testosterone that is equivalent to surgical castration. However, at the start of treatment they can cause an initial surge in testosterone production. This can result in tumour flare which can cause a temporary worsening of symptoms, particularly in patients with spinal metastases who are at risk of spinal cord compression and in patients with bladder neck obstruction. This can be avoided by using an antiandrogen medication together with the LHRH agonist during the first 4 to 6 weeks of treatment.

Gonadotropic –releasing hormone antagonists (GnRH).

Administration – by depot injections

GnRH medications: Degarelix
These medications inhibit LHRH release without causing an initial surge in testosterone which can lead to tumour flare. Testosterone levels drop within a day after having the injections.
Some studies suggest that GnRH medications may cause less cardiovascular side effects than LHRH agonists. They also allow for the rapid return of testosterone to normal levels, which is particularly useful if men are undergoing intermittent hormonal therapy.

Continuous versus Intermittent androgen deprivation therapy
This treatment involves intermittent periods of active treatment with ADT followed by periods of no treatment to allow testosterone levels to return to normal. This minimises the side effects caused by continuous ADT and improves quality of life during the “non-treatment” periods. There is also some evidence that this form of treatment may delay the onset of castrate resistant prostate cancer. This is when the prostate cancer becomes resistant to ADT.
Treatment is given for 6 to 9 months, if there are no clinical signs of the cancer progressing and a PSA <4ng/ml is reached in men with confirmed metastatic prostate cancer, or a level of 0.5ng/ml in men who have relapsed after treatment for localised or locally advanced prostate cancer. Treatment is then stopped to allow testosterone levels to return. The PSA is strictly monitored and treatment is resumed if it rises. 10-20ng/ml is used as the threshold for men with confirmed metastatic prostate cancer and a level of 4 to 10ng/ml for men who have relapsed after treatment for localised or locally advanced prostate cancer or if there are clinical signs that he cancer has progressed. This cycle is repeated until the first signs of castration resistance appear. A GnRH medication may be preferable for this type of treatment as it does not cause tumour flare and it potentially allows testosterone to return to normal levels more quickly than with a LHRH agonist.

Combinations of ADT and other treatments

ADT in combination with first generation antiandrogens

These medications don’t stop testosterone production but instead block the uptake of testosterone by the androgen receptors. They are not as effective as LHRH agonists when used alone. They are most commonly used when initiating treatment with LHRH agonists to prevent tumour flare.

There are 2 types of antiandrogens:

Steroidal antiandrogens (cyproterone acetate)
This drug has a central testosterone lowering effect and can be taken alone, although they are not as effective as LHRH agonists.

Non-steroidal antiandrogens (bicalutamide)
These drugs block the uptake of testosterone at the receptor sites and should not be used alone.

ADT in combination with chemotherapy
For men with high volume metastatic prostate cancer, ADT alone is no longer considered to the standard of care. It is recommended that it be combined with chemotherapy or one of the new second generation antiandrogens.
Docetaxel is a form of chemotherapy, and it has been shown to be more effective at delaying cancer progression and prolonging life than just ADT alone in men with hormone sensitive prostate cancer. The benefit appears to be the greatest in men who have high volume metastatic prostate cancer. A man is considered to have high volume prostate cancer if he has a visceral metastasis (cancer that has spread to soft tissue organs such as the lungs, liver etc) or if he has 4 or more bone lesions, one of which is beyond the vertebrae or pelvis.
Chemotherapy may not be an option in men who are frail as it can cause a variety of toxic side effects. Patients must have frequent blood count tests to monitor for neutropenia which can compromise the body’s ability to fight infections.

ADT in combination with second generation antiandrogens

ADT alone is no longer considered to be standard of care and the latest international guidelines now recommend that ADT should be combined with chemotherapy for patients with high volume prostate cancer or with one of the new second generation antiandrogens. This combination treatment prolongs life for a longer period than ADT alone. It also helps to delay symptoms and the progression of the disease to a castrate resistant state.

ADT in combination with Abiraterone acetate

Abiraterone acetate  was the first 2^nd generation antiandrogen. It blocks an enzyme which stops testosterone production in the testes, adrenal glands and cancer cells. It still needs to be taken together with ADT, and is given with low-dose corticosteroids, because it affects certain functions of the adrenal glands. Patients need to be closely monitored for changes to liver function, blood pressure, potassium levels and for fluid retention.

ADT in combination with Androgen Receptor Pathway Inhibitors

The first of the new androgen receptor pathway inhibitors (ARTA’s) to be launched was enzalutamide, followed by apalutamide and darolutamide. For prostate cancer cells to grow, androgens have to attach themselves to a protein called an androgen receptor inside the prostate cancer cell and then move to the nucleus of the cell in order to produce more cancer cells. These new 2^nd generation antiandrogens block this pathway, hence their name. They are still used with ADT. The benefits of combining ADT with ARTA’s, is that they increase life expectancy and delay the progression to castrate resistant prostate cancer. For the best outcomes, they should be given when ADT is started. Because of the improved outcomes of the combination of ADT and the new 2^nd generation ARTA’s, ADT alone, is no longer considered standard of care in many developed countries. Recommendations are that they should be combined with one of the 2^nd generation antiandrogens for optimal outcomes. However, due to the cost of these new medications this is not always possible within the South African context.

Castrate resistant metastatic prostate cancer and treatment options

Unfortunately most advanced prostate cancers treated with androgen deprivation therapy (ADT) begin to progress again within 12 to 33 months. It is thought that some cancer cells that are not dependant on testosterone begin to develop and so the cancer becomes resistant to androgen deprivation treatment. When prostate cancer becomes resistant to androgen deprivation therapy it is called castrate resistant metastatic prostate cancer (CRPCA).

Most men are diagnosed with castrate- resistant prostate cancer when PSA levels begin to rise despite having castrate levels of testosterone. However men with CRPC can be at very different stages of the disease process. Various tests will help to establish at what stage of the disease process a man is at. Knowing this will help doctors with treatment planning and it will also give an indication as to how long a man might expect to live for. This is referred to as a survival rate.

Further Tests for men with CRPCA

Various tests are used to determine where the cancer has spread to and the extent. Tests may include:

Regular PSA testing

For men with no radiographic signs of the cancer spreading (non- metastatic castrate-resistant prostate cancer) but with a rising PSA level the time that it takes for the PSA to double is highly significant.

Traditional diagnostic imaging tests

Bone scans – These are used to detect cancer that has spread (metastasised) to bone

A CT of the chest, abdomen and pelvis

An MRI in men who can’t have a CT scan.

However these generally only show signs of the cancer spreading in men if the PSA is ≥10 ng/mL.

 Next generation diagnostic imaging

Newer imaging tests such as (PMSA) PET CT or PET/MRI scans can detect cancer cells that have  spread but are not visible with the older imaging tests.

Measuring circulating tumour cells (CTC’s)

An increasing number of CTC’s at baseline results in shorter overall survival rates.

Changes in CTC’s can also be a response to treatment and associated with longer overall survival.

Genetic testing

Genetic testing can help to identify specific genetic mutations in cells. There are targeted treatments available depending on the type of mutation. The types of genetic tests that are recommended are:

A germline genetic test

Germline mutations occur in a sperm cell or an egg cell and are passed directly from a parent to a child at the time of conception. They are copied into every cell in the body and can be passed from generation to generation. The recommended panel of genes that should be tested are:

mutL homolog 1 (MLH1), mutS homolog 2 (MSH2), mutS homolog 6 (MSH6), and postmeiotic segregation increased 2 (PMS2; for Lynch syndrome); breast cancer susceptibility gene (BRCA) 1; BRCA2; ataxia telangiectasia mutated (ATM); partner and localizer of BRCA2 (PALB2); and checkpoint kinase 2 (CHEK2).

About 5 to 10 percent of patients have germline mutations in DNA mismatch repair genes. These patients can be treated with poly (ADP-ribose) polymerase (PARP) inhibitors.

Next generation sequencing of prostate tumour tissue to identify somatic mutations

These mutations occur from damage to genes in an individual cell during a person’s life. Somatic or acquired mutations are the most common cause of cancer. This type of genetic testing can identify potentially targetable abnormalities for which various drug treatments are available.

 

Mutation	Treatment
homologous recombination repair [HRR] deficiency	poly[ADP-ribose] polymerase inhibitor
deficient mismatch repair [dMMR] or high levels of microsatellite instability [MSI-H]	pembrolizumab
rare neurotrophic tyrosine receptor kinase [NTRK] fusions	tropomyosin receptor kinase [TRK] inhibitor

Treatments for castrate resistant prostate cancer

Continuation of androgen deprivation therapy

In most cases ADT can be continued whilst other treatments are added. Some of the newer treatments are not available at public sector hospitals due to cost. Medical aids may also not provide full reimbursement for these.

Treatments for men with non-metastatic castrate resistant prostate cancer

This is classified as: (M0 CRPC)

These are men who have a rising PSA but no signs of metastases.

Drugs that work by interfering with androgenic stimulation of prostate cancer cells in conjunction with ADT have been shown to delay disease progression and prolong survival. These include:  enzalutamide and apalutamide.

Treatments for men with metastatic castrate resistant prostate cancer

This is classified as: (M1 CRPC)

These are men who have metastases. Various treatments given in conjunction with ADT can prolong life. These include:

Drugs that interfere with androgenic stimulation of prostate cancer cells

These include enzalutamide and apalutamide

Drugs that Inhibit androgen biosynthesis

Abiraterone

Chemotherapy

Chemotherapy is usually reserved for men with prostate cancer that is causing symptoms and where there are signs that the cancer is progressing at a rapid rate

First line chemotherapy with docetaxel

Docetaxel is the first chemotherapy treatment option for men who have metastases and castrate resistant prostate cancer and who are well enough to tolerate treatment. (Various assessment screening questionnaires can be used to determine if a man is likely to be fit enough for this treatment option). It is given every 3 weeks for up to 10 cycles. Treatment is continued, provided men are able to tolerate it and there is no evidence from imaging tests that the disease is progressing.

Second-line chemotherapy with cabazitaxel

Once patients become resistant to treatment with docetaxel, the next option is to use a drug called cabazitaxel.

Alternative chemotherapy treatment

Another option is available for those men who are unable or unwilling to have docetaxel or cabazitaxel. This treatment consists of mitoxantrone plus prednisone and although it doesn’t prolong life, it can help with relieving the symptoms of advanced prostate cancer.

Treatments for bone metastases

In most men who have metastatic prostate cancer, the cancer will spread to bone. The cancer cells interact with the different types of bone cells. Most commonly the interaction is with the bones “builder cells” (osteoblasts) resulting in an abnormal build-up of bone. Less commonly the interaction is with the bones “demolisher cells” (osteoclasts) resulting in soft sections of damaged bone. Some men will have a combination of these interactions. The result is bone pain and an increased risk of fractures (pathological fractures).

Treatment is aimed at:

• slowing the spread of the cancer to bones
• relieving bone pain
• strengthening bones to prevent fractures

Pain medication for bone metastases

Bone pain often starts in the lower back, pelvis and/or hips. It is likely to get worst as the cancer progresses and eventually it usually becomes constant. Everyone has a different ability to tolerate pain, so it’s important to get help when you need it. Different pain medications are available depending on how you are managing.

Initially mild pain killers will help. As pain increases, mild opioids are usually prescribed. For severe pain, strong opioids are generally used. Other medications that are not pain killers can also be helpful. These include antidepressants, sedatives, anti-seizure meds, muscle relaxants and anxiolytics.

Radiotherapy for bone metastases

Focal External beam radiation can help if there only a few sites (See section on external beam radiation). 80% of men report a rapid reduction in pain. Treatment may be for one session only or over 2 to 3 weeks. There are minimal side effects from this type of radiation treatment.

When there are multiple metastases wide-field radiation may be given. This involves the administration of radiation to a large section of the body (from the jaw to the pelvis, from the chest to the pelvis or from the pelvis to the ankles). This treatment can both, slow the progression of existing metastases and the development of new ones. Side effects can include inflammation of the lungs, cataracts, nausea, vomiting and diarrhoea. More rarely, blood cells can be adversely affected.

Bisphosphonates and denosumab for bone metastases

These medications help to slow down the bone damage caused by osteoclasts. These are the bodies bone “demolisher cells” (osteoclasts) which react with prostate cancer cells resulting in soft sections of damaged bone.

Treatment with these medications can help with the symptoms caused by bone metastases as well as helping to delay bone-related events in men with castrate resistant prostate cancer.

Radiopharmaceuticals for bone metastases

This is a rapidly evolving field. Currently in South Africa Radium -223 is available. It is used to treat low-volume bone metastases. It helps by reducing bone pain and delaying fractures.

Treating spinal cord compression

Spinal cord compression caused by bone metastases usually results in low back pain with numbness and weakness in the legs, although any area of the spine may be affected. This may be followed by the loss of bowel and bladder control. A spinal MRI can be used to confirm the diagnosis. Urgent surgery is required to prevent or reduce neurological impairment, gait disturbance and the impact on quality of life. This involves decompressing the vertebra and in some cases stabilization.

External beam radiation and steroids may be used as follow-up treatment.

References

1. Kirby RS, Patel M. Fast Facts: Prostate Cancer. Eight Edition 2014. Health Press Limited
2. Coetzee L. Fast Facts: Metastatic Prostate Cancer. Health Press Limited 2017
3. For Healthcare professionals: Prostate cancer essentials: Hormone therapy. Prostate Cancer UK. Available at: https://prostatecanceruk.org/for-health-professionals.
4. Dawson NA et al. Overview of the treatment of castration-resistant prostate cancer (CRPC). In: UpToDate, Post, N V (Ed). UpToDate, Waltham, MA, 2021.

5 Mutambiwa S. Understanding recucrrent and metastatic prostate cancer