PSA Prostate Cancer Support Association

Providing support and information for all those affected by prostate cancer

Radical Prostatectomy

- Keyhole Surgery

Radical Radio Therapy  

- Brachytherapy

Active Surveillance

Watchful Waiting

Hormone Manipulation

Orchidectomy

Cryo-ablation Therapy

Vaccine

Bone Integrity

Treatments

This is one of the two main radical treatments for Prostate Cancer offered in the UK at the present time for patients mainly under 70 years old. In the USA it is the main form of treatment. It is regarded as too risky for most patients over 70, and as prostate cancer is usually slow growing, other treatments are considered more suitable.

To remove the whole prostate is a major operation, you will expect to be in hospital for about a week and you will have a catheter in place for 3 - 4 weeks.

Very occasionally at the start of the operation the surgeon will find the cancer has spread beyond the prostate and in these cases he may not remove it.

Most men will suffer some urinary incontinence after the operation but this will improve. A very few men will have permanent incontinence problems. Most men will suffer some degree of impotence after the operation, but this may be short lived.

There is a risk of high blood loss during the operation, and like any major surgery there is a one per cent chance that you may not survive it.

However if all goes well you probably have the best chance of a cure with this treatment.

                    
By courtesy of the Covent Garden Cancer Research Trust (illustrations by Diane Mercer).

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Laparoscopic (Keyhole) Surgery

There have been several recent advances in the UK in laparoscopic (keyhole) surgery.

This technique requires 5 small ½ inch incisions in the abdomen, Carbon dioxide is pumped in and this lifts the abdomen wall so that the surgeon gets a better view of what is happening, instruments are then inserted through narrow hollow tubes placed in the incisions. The surgeon is then guided by the laparoscope (camera) which is inserted through the remaining tube.

The advantages of laparoscopy are fairly well known,

· It can shorten your stay in hospital, 50% of men are discharged after one day.

· There is significantly less bleeding.

· You are less likely to need pain killers when you leave hospital.

· Usually the catheter is removed one week after the operation.

· Approx. 90% of men can return to work two to three weeks after the operation.

The main disadvantage is that the laparoscpic operation may well take twice as long on the operating table as the traditional open surgery method.

Studies from Europe and the US suggest that the rates of prostate cancer recurrence are the same for both techniques as is the incidence of impotence and incontinence.

One interesting index which is used to assess the effectiveness of a Radical Prostetectomy, either traditional open surgery or laparoscopic is the 'positive surgical margin.' This measures the presence of cancer cells at the cut margin of the removed prostate. The best result worldwide is around 20%. The reason one cannot get much lower than this is because 2/3rds of cancers occur in the periphery of the prostate. In the UK both traditional open and laparoscopic surgery averages out at about 30%, the reason for the higher figure is that in the UK prostate cancer is operated on at a later stage than in the US and Europe, presumably due to a lack awareness and screening.

There are two variations of the Keyhole technique the first is where the surgeon operates by hand using the laparoscope. This is conducted at the North Hampshire Hospital Basingstoke (over 100 operations) and also at Kings College Hospital and Southmead Hospital Bristol (smaller numbers). The second variation is where the surgeon uses a robot to carry out the operation which he can operate from another room or in theory even another town. This is conducted at St Mary's Hospital Paddington.

For further information see the websites available in the links section.

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Radical Radiotherapy

This is an alternative to a Radical Prostatectomy and is the other main form of treatment for prostate cancer in the UK at the present time. The treatment is administered daily over a 4 - 6 week period as an outpatient at a hospital. Each session lasts only minutes but on each occasion you will need to be positioned on the equipment very carefully. The effect of the treatment is cumulative and some patients will have difficulty lasting the full course.

                    
By courtesy of the Covent Garden Cancer Research Trust (illustrations by Diane Mercer).

Side Effects

The main side effect is irritation or pain to the bladder and/or rectum. This will usually subside within 4 - 6 weeks after the treatment but in many cases it will need medication.

Very occasionally there will be long term damage to the bladder or rectum resulting in incontinence.

Some men will suffer from impotence after the treatment and lose their sex drive.

Associated Treatments

1. Hormone Treatment

It is fairly common to be given Hormone treatment before commencing radiotherapy as this will shrink the prostate and make it more easy for the radiation to work.

In addition a course of hormone injections is some times given after the treatment for 6 - 18 months. This will help to starve any remaining cancer cells and keep the PSA count low.

2. Conformal Radiotherapy

This is an alternative to the standard treatment mentioned above it is only practised at a few hospitals and requires special equipment. The equipment focuses the beams more precisely so that they can be aimed directly at the cancer. This enables a higher dose of radiation to be given and provided it hits the spot it can be more effective and have fewer side effects.

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Brachytherapy

Further information on Brachytherapy is available on the Prostate Brachytherapy Advisory Group website: www.prostatebrachytherapyinfo.net

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Active Surveillance

As the name implies this is a holding position. It involves regular check ups to monitor the cancer. You will need to see the specialist every 6 to 12 months for a PSA test and a rectal examination. No treatment is involved unless the cancer develops. Watchful waiting is usually appropriate for older patients of 70 years or more.

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Hormone Treatment

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Orchidectomy

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Cryoablation

What is vaccination and immunity?

Since Jenner's first successful vaccine against smallpox many successful vaccines have been produced. A vaccine is usually made from a "weakened" form of a known germ (pathogen). The weakened form of a germ does not cause illness. but the vaccine teaches the body what the germ looks like and protects the person from ever becoming severely infected by the contagious form of the germ in the future.

Can we have vaccines for cancer? Cancers are not contagious like the diseases which spread through proximity to other infected people and through contaminated water, but vaccines represent important new therapeutic treatments for cancers. Scientists have been trying to find ways of triggering an immune response to cancerous cells for many years, but since the cancer cells are part of the patient's own tissue and not "foreign", the immune system may be "tolerant" and ignore them. This is explained in the article: "Smallpox, polio and now a cancer vaccine?" Donald W. Kufe, Nature Medicine Vol. 6 No. 3 March 2000. He says that - "Advances in our understanding of anti-tumour immunity and the genetic alterations that accumulate in the progression to malignancy have recently provided unforeseen opportunities for the development of more selective and safer approaches." More information can be found at the web site provided by CancerHelp UK, http://medweb.bham.ac.uk/cancerhelp/public/

How are cancer vaccines developed? Although, in the future, vaccines may be produced to prevent cancer, research studies are concentrating on developing vaccines as a therapeutic treatment for those who already have cancer. The approach sometimes adopted is to use the patient's own cancer cells to make the vaccine. This is called an "autologous" vaccine, and the process requires laboratory cultivation of the cells. This painstaking laboratory work can be conducted for a few patients only. For this reason, it is necessary to develop "allogeneic" vaccines. These are not made using the patient's own cells, but from related cancer cells, and would allow a larger number of patients to be treated.

Trials for prostate cancer. The development of vaccines for prostate cancer is possible because of our improved theoretical understanding and laboratory techniques. Treatment with vaccines is usually a course of several injections is given under the skin, which may have to be repeated to reactivate the immune response.

Clinical trials are in progress at many hospitals. For example, those conducted at Johns Hopkins University School of Medicine on prostate cancer patients showed encouraging results, and further trials are planned. Dr Jonathan Simons has published a report of this work in Cancer Research 59, 5160-5168, October 15 1999, and refers to the web site: http://www.cellgenesys.com

In addition trials have recently started at St George's Hospital Medical School in south London with Onyvax TMP. This is a therapeutic vaccine designed to provoke the immune system to attack prostate cancer cells. At this stage the trial will enrol patients who are in the early stages of the disease, those who have tried Hormone therapy but where the PSA has again started to rise. For further information phone 020 8682 9131 or use website www.onyvax.com

How could genetic engineering enhance the immune response? Many techniques are being developed, using genetic technology. A piece of DNA may be added to a cancer vaccine to help make a marker visible to the immune system, or dendritic cells may be used, taken from a patient, grown in an incubator and treated with some patient tumour cells to teach an immune response before returning these to the patient. Another technique is to inject cancer cells combined with either foreign bacteria cells such as BCG, or a protein, to trigger an immune response. Refer to the Cancer Research Campaign and Everyman at: http://www.crc.org.uk/science/therapy3.html and http://www.icr.ac.uk/everyman/

What are the side effects of vaccine treatment? Established treatments for cancers, such as chemotherapy, radiotherapy and hormone therapy may have serious side effects, and in many instances are only palliative. In contrast cancer vaccines have so far caused only mild side effects, like a mild influenza. Vaccines represent a more hopeful methodology for producing effective treatments, and are less physically taxing for the patient than the multiplicity of drug therapies applied using a pragmatic approach.

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Bone Integrity

Bone Integrity and Prostate Cancer - Beginning The Debate.

A review by Roy Nixon

Unfortunately for men with prostate cancer, cancer cells are often attracted to bone. As if this was not bad enough, androgen deprivation can also result in bone problems by causing a reduction in bone mineral density. This can result in osteoporosis, causing bone pain and an increased risk of fracture. From time to time I hear from men whose first realisation that this is a possibility is when they have to attend the Accident and Emergency Department of their hospital following a fracture. It seems likely to me that as men may live for many years requiring hormone therapy, the number of men developing fractures as a result of androgen depletion is likely to increase over the coming years. It seems relevant, therefore to try to prevent this problem occurring, rather than dealing with osteoporosis and fractures. In order to do this we, and our doctors need to become proactive in this area.

There are tests that can measure levels of bone density, and apart from placing an additional burden on NHS resources (and this is a very relevant factor that must be brought into the debate) I can see no reason for not performing a bone-mineral density test to give a baseline, before men start on hormone therapy. This could be followed by periodic follow up tests.

Oseoclasts and osteoblasts

It is difficult to discuss bone integrity without giving some basic information about the processes that are relevant to the structure of bone. However, I will try not to be too technical about it.

Bone is essentially a latticework of collagen fibrils that are mineralised. Osteclasts are cells that attach themselves to the bone and excrete acids and digestive enzymes, which erode the bone. This process is called resorption. Androgens and oestrogens inhibit osteoclasts and also stimulate bone-forming cells, known as osteoblasts. A reduction in androgens (essentially male hormones) and oestrogens (essentially female hormones) causes an increase in the population of osteoclasts, resulting in an increase in bone resorption

The purpose of osteblasts is to migrate to areas of bone that have been eroded by osteoclasts, and lay down minerals and collagen in the cavities that have been left. This process of osteoclast and osteoblast activity is essential for remodelling our skeleton as changes become necessary. The problem occurs when osteoclastic and osteoblastic activity becomes excessive, either from cancer activity, Paget's disease, or hormone alteration such as that which occurs with hormone therapy resulting in androgen deprivation. We then get into a vicious circle.

Cancer cells survive by producing products that stimulate self-growth. (For those who wish to know this is referred to as autocrine loops) or by producing proteins or enzymes that affect nearby cells (paracrine loops) such as osteoblasts. Osteoblastic growth requires calcium and causes a reduction in serum calcium. This reduction stimulates osteoclastic resorption in order to maintain serum calcium. The process of attempting to re-establish the balance of serum calcium also requires an increase in a hormone called parathormone (PTH) and vitamin D levels.

Osteoclastic activity releases certain growth factors such as Insulin growth factor-1 (IGF-1) and transforming growth factor-beta (TGF-beta). These stimulate the growth of the cancer cell population, which in turn release more insulin growth factors and proteins, as well as interluken-1 (IL-1). Together these stimulate the osteoblasts to produce interluken-6 (IL-). IL-6 stimulates more osteoclasts and osteoclast precursors.

Overproduction of osteoclasts results in resorption of bone, which in turn causes an increase in osteoblastic activity. Thus, we get an increase in bone formation, but also an increase in bone resorption. Significantly, new bone resorption and formation can take place at different sites. The bone formation therefore does nothing to contribute to bone strength.

How can we interrupt this process?

An exciting contributor in the interruption of this process is likely to be a class of drugs called bisphosphenate. (Remember that name - you will hear a lot about it over the next few months and years). Bisphosphenates are not new. They have been around for 30 years. They work by inhibiting osteoclastic activity and are often used to treat osteoporosis and

Paget's Disease. I believe that in the not too distant future they will have an increasing role to play in metatstic prostate cancer (cancer that has spread beyond the prostate gland) and for treating cancer-induced hypocalcaemia. Bisphosphenates have been shown to work at the tissue, cellular and molecular level. By that I mean they decrease bone turnover, by reducing bone resorption. They inhibit osteoclastic activity to the bone surface, thus shortening the life span of osteoclasts. At the molecular level, bisphosphenates inhibit essential components such as squalene synthatase and protein tyrosine phosphatase.

Put simply, bisphosphenates appear to:

· Cause cell death (apoptosis) of osteoclasts
· Interferes with osteoclastic precursor cells
· Interferes with the adhesion of osteoclasts to the bone matrix
· Interferes with the adhesion of cancer cells to the bone matrix - but only amino bisphosphenates do this.


Zoledronic acid (Zoledronate)

Since bisphosphonates were first introduced 30 years ago, there have been 3 generations of the drug. Clodronate is classed as first generation. Pamidronate (Aredia) and Alendronate (Fosamax) are second generation. Now enters the third, and possibly most exciting generation. These include Ibandrinate and Zoledronate. Like second-generation bisphosphonates, they are amino- bisphosphonates, but are many times more potent. Zoledronate, for example, has a relative potency (RP) of 1000 compared to Clodronate, which has an RP of 1. Fosamax has an RP of 100, and Ibandronate has an RP of 500.

Zoledronate is made by a Swiss pharmaceutical company called Novartis, and is sold under the name of Zometa. It is given by intravenous injection and is being 'fast-tracked' by the USA Food and Drug Administration (FDA). This indicates recognition by the FDA that Zometa may provide a significant improvement over existing drugs. A similar submission was made to the EMEA in the European Union on the 30th July 2001.

The fact that Zometa is given by intravenous injection may also be an important factor to consider. Oral administration has proved

difficult with gastrointestinal absorption, which is said to be about 2%. An interesting suggestion by Alfredo Berruti et al is that for a successful response, high doses of a potent bisphosphenate should be given intravenously, initially, followed by intravenous or oral administration at levels sufficient to maintain suppressed bone resorption.

Is there a down side?

Like all treatments for prostate cancer, there are potential difficulties connected with the administration of bisphosphonates that also need to be considered. It has been suggested that bisphosphonates do not affect osteoblastic activity, and that a persistently high rate of bone formation may result in hypocalcaemia and the chronic stimulation of parathyroid hormone secretion. If high levels of parathyroid persist for a long time, it could impair the mineralisation of newly formed bone. Some researchers have suggested, however, that patients with prostate cancer who are being treated with bisposphenates should also be given a supplement of calcium during treatment to prevent this response.

A further possibility is that of an acute phase response, which is often associated with fever within 28-36 hours of the initial injection. A doctor I know in the USA, Dr Steven Strum, who uses Aredia counters this by giving the first dose of 30 milligrammes over a period of one and a half hours. He then increases the dose to between 60 -90 milligrammes every 2 weeks thereafter. He has seen 2 cases of kidney damage after an initial high dose, and says that this is another good reason for giving a lower initial dose.

Trials in the UK

The Prostate Cancer Working Party, that is part of the Medical Research Council are engaged in 4 separate trials using oral clodronate and zoledronic acid.

300 participants will be involved in a multi-centre double blind randomised trial to see whether oral sodium clodronate prolongs the time for relapse in patients on hormone therapy for established bone metastasis.

In the second trial sponsored by Novartis, zoledronic acid is being compared to a placebo in more than 600 men with prostate cancer and a history of bone metastasis and increasing PSA levels, despite hormone therapy. The

object is to assess zoledronic acid for preventing fractures, spinal chord compression, surgery to bone and radiation. It will also assess tumour and bone response on bone scan, disease progression, tolerability and safety.

The third trial involves 500 men without bone metastasis and compares the use of oral clodronate plus hormone therapy, with men who are using hormone therapy only.

Additionally 520 men who are apparently free from bone involvement, but have a rising PSA during hormone therapy, are being randomised to intravenous zoledronate compared to men using a placebo.

At the moment published data is insufficient to make a definitive statement about the efficacy of bisphosphonates. Pre-clinical data, however, strongly suggests that bone disease that is related to prostate cancer can benefit from drugs that inhibit osteoclastic activity. Bisphosphonates appear to be the most effective drug for doing just that.

Vitamin D3

In 1993 Dr Charles 'Snuffy' Myers reviewed vitamin D3 in the area of bone integrity. He found that research suggests that synthetic vitamin D3 (Rocaltrol, or Calcitriol) can enhance calcium absorption from the gastrointestinal tract. He also reports that Rocaltrol has anti-proliferative and anti-angiogenisis effects on prostate cancer growth, and is able to slow the rate of PSA rise in men with early recurrent prostate cancer. (Anti-angiogenesis means that it makes it more difficult for the cancer cells to form healthy blood vessels. Cancer cells need a good supply of blood in order to develop.) He suggests that it may cause an increase in urinary excretion of calcium, but that calcium supplements taken at night, as well as a bisphosphonate would drive the calcium into the bone and decrease the amount excreted. He suggests that synthetic vitamin D3 should also be taken at bedtime, to decrease urinary calcium excretion.

Gren Oades is also carrying out research into the effects of vitamin D at St George's Hospital, London. He makes the point, as did Gary Schwartz in 1990, that death from prostate cancer is higher in North America, where there is less sunlight, than in the south.

As we age we are likely to have lower circulating levels of vitamin D. Gren Oades also hypothesises that this may offer a partial explanation for the increased risk of African- American men developing prostate cancer, as a result of their darker skin pigmentation impairing vitamin D synthesis. If this is true, it is highly likely that synthetic vitamin D may offer some protection to African-Caribbean men living in the UK.

It seems that the treatment of men who have prostate cancer could be enhanced by careful and regular thought to the integrity of bone, particularly those men who have metastatic spread to the bone, or are on androgen deprivation. It would appear appropriate, therefore that a debate about this area of treatment begins in earnest immediately.

* I would like to thank my friends in the USA, Dr Charles 'Snuffy' Myers, Dr Steven Strum and Roy Bradbrooke for providing much help and information for this article.

References:
Steven Strum. PCRI Insights (Prostate Cancer Research Institute) January 1999. volume 2:1

DE. Hughes et al 'Bisphosphonates promote apoptosis in murine osteoclasts in vitro and vivo'. Journal of Bone Mineral Res. 10. 1478-1487. 1995

Berruti et al. 'Metabolic bone disease induced by prostate cancer: Rationale for the use of bisphosphonates'. Journal of Urology, 166; 2023-2031. December 2001

Charles Myers. 'The Prostate Forum' January 1999

Gren Oades. Update (Prostate Research Campaign UK) October 2001

Roy Nixon
January 2002


Please note that the late Roy Nixon wrote as a prostate cancer patient, not as a health professional. This article is intended to stimulate debate between patients and doctors and also between health professionals, rather than provide medical advice .All information has been checked as thoroughly as possible, but discussion with health professionals should always take place before taking or stopping any medication.

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