This review of Prostate cancer drugs and prostate cancer chemotherapy was published in our magazine icon, about 4 years ago. As such it is a little dated, but we felt it could still be useful to people wanting to find out more details, so we have left it up on our web site for the time being. Anyone wishing to find out the very latest information about any cancer drug need only click here.
Prostate Cancer Drugs
Report by Melanie Hart
If you, or someone close to you, has been diagnosed with prostate cancer, the next stage can be very confusing. Your oncologist may start you on hormone therapy, either before or after surgery or radiotherapy - or as your sole treatment. There are several kinds of hormonal therapy, as well as other drugs that you will hear mentioned in the course of treatment. There are also clinical trials underway here, and in the States, on several new ones - and on new uses for existing drugs.
So read on to find out the uses, proven benefits and risks of the main prostate cancer drugs used in the UK today, with expert commentary from Dr Robert Huddart, senior lecturer and honorary consultant in radiotherapy and oncology at The Institute of Cancer Research and the Royal Marsden. Dr Huddart works in a unit which specialises in the research and management of prostate cancer and is part of the South of England Prostate Cancer Collaborative.
Hormone Therapy LHRH-Agonists
These stop the testes making testosterone. They will only make testosterone if switched on by leuteinising hormone (LH), which is released by the pituitary gland. LHRH-agonists reduce the production of leuteinising hormone, causing the levels of testosterone to fall. This can result in shrinkage or slowing down of the growth of the cancer. There may be a brief increase in testosterone levels and other symptoms, (flare), in the first few days or weeks of starting treatment.
Zoladex (goserelin) made by AstraZeneca
A pellet given by injection, in a relatively big needle, once a month, or once every three months.
Side effects may include: hot flushes, mood swings, impotence, breast tenderness, fatigue, weight gain, pain in muscles and joints, nausea, vomiting and mild diarrhoea.
Long-term risk: osteoporosis.
Dr Robert Huddart: "The acceleration of bone loss tends to be less of a problem in men, than in the women who take Zoladex for breast cancer, because men normally have a higher base line level. Zoladex would be my first choice treatment, because the majority of men have minimal side effects, enjoy a good quality of life and their cancer is controlled extremely well. Over 90% of men with prostate cancer would expect to see a major fall in their PSA. It is used as the sole treatment for men with advanced prostate cancer, or in some older men who have more localised disease where you may not want to treat with radiotherapy or surgery.
Prostap (Leuprorelin) made by Wyeth Pharmaceuticals
This is a liquid that needs to be made up by the doctor and given by injection. Men on Warfarin may be given this, rather than Zoladex, which may make them bleed more with a bigger needle.
Possible side effects: as with Zoladex. Also peripheral oedema, swelling, fluid retention and occasional breathless sensation.
Dr Huddart: "Prostap is identical to Zoladex - it’s just a different preparation."
Triptorelin (De-capeptyl SR) made by Ipsen
Possible side effects: as with previous two.
Dr Huddart: "I’ve not actually used it, because it hasn’t been widely available until recently and would have exactly the same side effects as the other drugs. I’m not aware of any benefits over the other two, but I’ve no reason to think it would be less successful."
Anti-Androgens
These work by attaching themselves to proteins (receptors) on the surface of the cancer cells to stop the testosterone from entering. Men given hormone therapy injections will usually be given anti-androgens to avoid the effects of "tumour flare", connected with the first dose of treatment. The tablets are given three days to a week before injections, and for about two weeks afterwards.
Steroidal Anti-Androgens
Cyprostat (Cyproterone Acetate) made by Schering Health Care
Possible side effects may include: fatigue, low mood, breast tenderness and fullness, osteoporosis, shortness of breath, liver disorders, risk of thromboembolism, nausea, diarrhoea, reduced volume of ejaculation and decreased sperm count.
Liver dysfunction is one to worry about with long-term treatment
Dr Huddart: "The volume of ejaculation and decreased sperm count are what you expect from any hormone treatment. Liver dysfunction is one to worry about with long-term treatment, and you probably shouldn’t give it to someone with a history of heart disease or blood clots. This is the oldest and cheapest anti-androgen and, despite having the most side effects, it would be my first choice as a short-term treatment to reduce flare. I would use the two drugs below for long-term treatment.
Non-Steroidal Anti-Androgens
These drugs can be used as a combination treatment with one of the LHRH-agonists in a treatment called complete (combined), or maximal androgen blockade, CAB or MAB. It blocks the testosterone produced from the testicles, and the 5% or so that’s produced by the adrenal glands and other parts of the body. You would use slightly lower doses in CAB.
Another way of using these drugs is to use an LHRH-agonist, and if that treatment starts failing, then do the combined treatment.
Flutamide (Chimax, Drogenil) made by Schering Health Care
This is a tablet, taken three times a day with the other hormone therapy injection, as above.
Possible side effects: decreased sperm count and volume of ejaculation, diarrhoea, nausea, tiredness, risk of liver dysfunction and occasionally blurred vision.
Dr Huddart: "If somone has liver or bowel problems I would give them Bicalutamide instead. Some people advocate using the combined treatment, CAB or MAB, as the primary treatment. There’s a lot of debate on whether starting off using both together has an advantage over just using an LHRH-agonist on its own. There have been lots of trials on this and if there is a difference, it’s very small. I prefer to do the treatments sequentially, starting with the anti-androgens. That way you don’t have all the extra side effects of the two sets of drugs to deal with, and the treatment is not as expensive."
Bicalutamide (Casodex) made by AstraZeneca
It is no longer recommended for early prostate cancer
This tablet is taken just once a day, with a hormone therapy injection, or it can be used on its own to treat prostate cancer that has begun to spread into the tissues outside the prostate gland (locally advanced). It is no longer recommended for early prostate cancer (contained within the prostate gland) after a trial suggested a possible increased risk of heart attacks.
Possible side effects: decreased sperm count etc as above, breast tenderness and enlargement, hot flushes, mild itching and dryness of skin, nausea, vomiting and mild diarrhoea, drowsiness and occasionally blood in the urine.
Dr Huddart: "I think people tend to use this drug because it’s a simple once-a-day tablet and probably has fewer side effects.
Bicalutamide can be used as a sole treatment, using a tablet with three times the dose of the one in CAB. It is usually used with advanced, but non-metastatic cancer, as there is some evidence that it is not as effective once the cancer has spread to the bone. This has the advantage over a LHRH-agonist of causing less of the hot flushes, fatigue, and probably less bone loss. About 30-50% of men will retain sexual activity on this drug, so it is particularly favoured by those who feel that is an important part of their lives. This is actually a surprisingly small number because the disadvantage of Bicalutamide is that it tends to cause breast enlargement in 80% of men using it as a single treatment. This can be painful and needs additional treatment, using a low dose of Tamoxifen or a short course of radiotherapy to the breast. So when given the choice, a lot of men would rather lose sexual activity than get bigger breasts."
Oestrogens
Stilboestrol (DES, Diethylstilbestrol)
A synthetic oestrogen, given in tablet form, for the treatment of advanced prostate cancer. By increasing the level of the female hormone, oestrogen, the production of testosterone is "switched off". This reduced level of testosterone can help slow down the growth of the cancer cells and may cause the cancer to shrink in size.
Possible side effects may include: blood clotting (thrombosis), fluid retention, breast tenderness or enlargement, lowering of libido and impotence, tiredness, nausea, mood swings and weight gain.
Dr Huddart: "This drug was used as a first choice treatment because it had great success, but there were two main problems: the 5-10% risk of blood clots and breast enlargement. It went out of favour, but a lot of people are using it again because they realise it has activity you don’t see with other treatments - even men resistant to other standard hormone treatments (ie, the cancer has started growing again) will often respond to Stilboestrol. It will at least halve the PSA for the four weeks of treatment in 30-50% of men.
It will at least halve the PSA for the four weeks of treatment in 30-50% of men
It is given in much lower doses now, 1-3mgs, as opposed to the 5-10mgs given in the 60s. There is still a risk of blood clots, and it is contraindicated with menwith a history of those, heart disease or stroke - unless they’re on full-dose anti-coagulation with Warfarin. The breast enlargement can be problematic, as with the Bicalutamide, but you can’t use Tamoxifen. Breast irradiation is used instead to try to stop that."
Oestrogen patches
Oestrogen patches are also being tried with prostate cancer.
Dr Huddart: "There are people saying it has less of the thromboembolic effect. We did try it at the Marsden and were less impressed with the activity than we were with Stilboestrol. Our results are very anecdotal, though. The use of oestrogen patches is still being explored, but we don’t feel we got as many responses as we expected."
PC Spes
This was one of the most popular herbal treatments, a combination of eight herbs. It was withdrawn after the National Cancer Institute of the USA found it was contaminated with synthetic drugs, including Stilboestrol and Warfarin. Unknowingly taking extra doses of this drug could be dangerous for people already on them.
Dr Huddart: "It was contaminated with oestrogens, which is actually why it was effective." Another form of this herbal treatment, called PC-HOPE is available on the web. It contains 10 herbs, but its effect on prostate cancer has not been tested.
Steroids
Prednisolone made by Chauvin
Steroids switch off the extra bit of testosterone produced elsewhere in the body to decrease swelling and pain
A type of medicine known as a corticosteroid, which is similar to a natural hormone produced by the adrenal glands which controls the inflammatory response. Prednisolone is given orally in a dose of 7.5-10mgs in the morning. It is used in prostate cancer as a treatment for men with hormone refractory disease, and also as an alternative to the anti-androgens. Steroids switch off the extra bit of testosterone produced elsewhere in the body to decrease swelling and pain.
Possible side effects may include: insomnia, depression, thinning of the skin, adrenal suppression, weight gain, acne, ulceration of the stomach or intestine, increased risk of fractures of the bones, high blood pressure.
Dr Huddart: "This is often used alongside chemotherapy, but it is an active agent in its own right. There are side effects but both these drugs are designed to mimic the steroids in your body, so if you take them at the same sort of level that your body produces them - a very low dose - they don’t tend to be major side effects. As well as the reasons for using it given above, it’s possible there might be a direct action on prostate cancer cells as well."
Dexamethasone made by Organon
Also a tablet, but given in a dose of .5mgs.
Possible side effects: stomach irritation, vomiting, insomnia, headache, dizziness, depression, acne and easy bruising.
Dr Huddart: "In the past year, we have switched over to use this at the Marsden as there is some suggestion that it might be more effective than Prednisolone."
Trials: Some newer types of hormonal therapy have been developed, including Abarelix, Degarelix, Ganirelix and Cetrorelix, which are all in trials.
Chemotherapy Drugs
Chemotherapy may occasionally be given if hormonal therapy is no longer effective. Although the chemotherapy cannot get rid of all the cancer cells, it can shrink the tumour and reduce symptoms.
Adriamycin (doxorubicin) made by Pharmacia
Adriamycin is used to treat other cancers, but is not used much to treat prostate cancer in the UK at the moment. It is administered intravenously.
Side effects may include: decreased white blood cell and platelet counts, increased risk of infection, loss of appetite, darkening of nail beds and skin creases of hands, hair loss, nausea and vomiting, mouth sores and, at higher doses, it may be toxic to the heart.
Patients with pre-existing heart problems may need to have a cardiac evaluation before use.
Epirubicin (pharmorubicin) made by Pharmacia
Epirubicin has similar activity to Adriamycin.
Side effects: similar to adriamycin, but it is less toxic on the heart.
Dr Huddart: "Both of these drugs were used quite frequently about 10 or 15 years ago, and are possibly still being used in some areas of the UK, but we tend to use drugs with much less cardiotoxicity now like Mitoxantrone (below)."
Mitoxantrone (Novantrone) made by Lederle Laboratories
An outpatient treatment given once every three weeks in a short intravenous injection, over 15 to 30 minutes.
Side effects may include: as with Adriamycin, but less hair loss and nausea, and possibly less bone marrow suppression.
Dr Huddart: "This was my first choice chemotherapy drug up until a year ago. It became the standard chemotherapy in prostate cancer after it was shown in randomised trials to improve the quality of life, when given with Prednisolone. It was better than Prednisolone on its own. About a third of people get a major benefit in terms of symptom relief and PSA falls, a third find their cancer stabilises for a period of time and a third see no benefit at all."
Taxotere (Docetaxel) made by Aventis
It is usually given intravenously once every three weeks
Taxotere resembles taxol in chemical structure (Taxol is called a mitotic inhibitor because it interferes with cells during mitosis, cell division). It is usually given intravenously once every three weeks. Because the side effects can be bothersome, additional drugs can be prescribed to help counter them. For example, Dexamethasone is commonly used to prevent fluid retention while on Taxotere.
Possible side effects include: decrease in white blood cells, fever (often a warning sign of infection), fluid retention, mouth ulceration, hair loss, nail and skin changes and diarrhoea.
Dr Huddart: "Taxotere is used in breast cancer, and about a year ago two major trials showed that it improved survival in prostate cancer better than Mitoxantrone. The problem with Taxotere at the moment is getting funding within the NHS. I think that most men being treated privately will get it, if they are fit enough. Men have to be fitter to have it because it is more toxic than Mitoxantrone."
Cyclophosphamide (cytoxan) made by Asta Medica
Like Adriamycin, Cyclophosphamide is toxic to cancer cells. It is taken orally, in tablet form, or intravenously over 30-60 minutes.
Side effects may include: decreased white blood cell count, with increased risk of infection, hair loss, nausea and vomiting, loss of appetite, mouth or lip sores, diarrhoea.
Dr Huddart: "This is not one I use regularly. It’s difficult to know how it stacks up against the others, as it’s not been particularly well studied. Some people have reported getting good responses with it, but I’m not sure it’s as active as Mitoxantrone and Taxotere."
Estramustine (Emcyt, Estracyte) made by Pfizer
In tablet form, this is a combination of a chemotherapy agent, nornitogen mustard, and an oestrogen, so it has the advantages and disadvantages of both.
It is not known exactly how it works
It is not known exactly how it works. It does not directly damage DNA like other alkylating agents. It seems to act on structures in cells called microtubules in a similar way as Taxotere.
Possible side effects include: all the side effects of Stilboestrol (above), particularly nausea, plus bone marrow suppression, drop in white and red blood cell count, increased risk of blood clots (thrombosis). Tell your doctor if you have diabetes, kidney or other health problems.
Dr Huddart: "I never use this drug. I’ve not been convinced that it is any more active than Stilboestrol. It is more commonly used in the United States because Stilboestrol isn’t licensed there."
Chemotherapy combinations
Dr Huddart: "By and large, in prostate cancer, you tend to be using single agent chemotherapy because the majority of men are elderly and often have bone disease, so are quite fragile in terms of their blood count. There hasn’t been a lot of good evidence on combination, although recently there was a combination reported as having quite impressive results: Epirubicin, Carboplatin and 5-FU (Fluorouacil). This hasn’t been compared with other treatments to see if there is an advantage in using combination, say over Taxotere. "
Radioactive Isotopes
These are used to reduce bone pain in men with prostate cancer. The radioactive isotope is given as an intravenous injection and goes into activity in the bone. Strontium (Protelos) made by Servier Laboratories
Side effects may include: suppression of the bone marrow, permanently in some men.
Dr Huddart: "There is pretty good evidence that it reduces bone pain with prostate cancer and may reduce the development of further bone pain. In trials, men who had Strontium as their treatment, compared to just having a bit of radiotherapy or having radiotherapy and Strontium, had better pain relief. We tend to be a bit reluctant to do chemotherapy after Strontium partly because a lot of our men are in trials which don’t allow you to give a radioactive isotope beforehand. We would use hormone treatment, chemotherapy and, only when that doesn’t work, think about Strontium. By then the bone marrow is a bit weak, and it’s very difficult to give, so we don’t tend to use a lot of it. It doesn’t affect survival, but symptomatically can be very effective."
Bisphosphonates
Using bisphosphonates is a controversial area
These may be able to control bone pain, and slow down the damage caused to the bone in men whose prostate cancer has spread there.
Dr Huddart: "Using bisphosphonates is a controversial area. There is a reasonable amount of evidence that they can reduce bone pain in a proportion of people with advanced bone disease, and that is probably the commonest place to use these drugs. There is one published trial which suggests that using a bisphosphonate quite early on, after receiving some treatment for metastatic disease, reduces skeletal-related events like bone fractures and bone pain compared to not having the drug.
But there is some debate about the size of the benefit and whether it is large enough to make the trouble of receiving it and side effects worth it.
There are a number of different drugs, including Pamidronate - the standard NHS bisphosphonate at the Marsden - and Clodronate which is not used much now, but Zometa is probably the most potent and has the best evidence from trial. There are trials going on on another new drug, Ibandronate.
Zometa (zoledronic acid or Zoledronate) made by Novartis
NHS access to this drug can vary. Data from three clinical trials, involving more than 3,000 patients, have shown that Zometa is more effective at preventing or delaying complications such as bone fractures, compression of the spinal cord, and severe bone pain than Pamidronate. In the US, patients who were given Zometa also experienced longer periods before relapse than those who received Pamidronate (30 days for Zometa versus 17 days for pamidronate). Zometa can be given during a 15-minute infusion time, versus an infusion time of two to 24 hours necessary with the other.
Zometa can be given during a 15-minute infusion time
Side effects may include: fever, chills, bone pain, muscle or joint pain, nausea or vomiting.
Pamidronate (aredia) made by Novartis
Pamidronate is a nitrogen-containing bisphosphonate.
Side effects may include: fever, fatigue, nausea and vomiting, initial bone pain, lack of appetite and anaemia (decrease in red blood cells).
Endothelin Blockers
These may block the growth of cancer cells by attaching themselves to growth receptors (endothelin receptors) on the surface of the prostate cancer cells. The drugs are given as tablets and may be called endothelin receptor agonists.
Early trials are currently under way with Atrasentan and another drug called YM598. Early results from some trials show that endothelin blockers may be able to slow down the growth of cancer in the bone and delay the symptoms of secondary bone cancer, when given to men with advanced prostate cancer. It will be some years before it is known how useful these drugs may be.
Dr Huddart: "Results to date have been promising, but we will have to wait and see if they become licensed in the United States and Europe."
For more information about a particular drug use your favourite internet search engine and type in the drug you’re researching, or log onto www.cancerbacup.org.uk. This site provides useful tips on lessening side effects."
Questions To Dr Huddart From Chris Woollams
CW:
"What is your view on the Thomson US research from Texas (MD Anderson 2003), supported by Australia and Singapore studies, that prostate cancer can be caused by localised oestrogen (oestradiol) converting ’safe’ testosterone to the highly active and dangerous hormone DHT? How then, do doctors justify giving oestrogen injections?"
Dr H:
"All testosterone is converted to DHT, that is how it works. This is blocked by drugs like Finsteride. But using this drug has minimal impact on cancer. I’m not really familiar with the data you quote. We use oestrogen because it works, both as a primary treatment (although it is too toxic to use routinely) and as a second-line/third-line treatment. That it does work suggests that the above theory is wrong."
CW:
"Why not try to cut oestrogen out (as with women and aromatase inhibitors)?"
Dr H:
"We have tried and it doesn’t work. The AROI are inactive."
CW:
"If you give men oestrogen, surely after about three years the body will just fight back and overcome the testosterone deficiency by making more so the cancer is bound to reapppear."
Dr H:
"How? The signal to produce testosterone is cut off and, if you measure testosterone, you can show levels remain low."
CW:
"What is your view on Ablatherm? (High Intensity Focused Ultrasound - HIFU) To date 7,000 patients have been successfully treated using this therapy in 61 centres in France, Germany, Italy, Belgium, Russia and Switzerland. They had an 87 per cent success rate, without relapse at five years in Munich (Dr Stefan Thuroff of the Krankenhaus Munchen Harlaching)."
Dr H:
"It’s a promising alternative to surgery or radiotherapy for organ-confined local disease, or for relapse after radiotherapy. We plan a trial of this starting this year at the Royal Marsden. It is being used at the Institute of Urology, in London".
CW:
"Why is it not already used instead of drugs in the UK?"
Dr H:
"It is not an alternative to drugs. Drugs are for advanced disease largely (outside of the prostate) and HIFU is for localised disease, to treat disease in the prostate.
CW:
"We understand that the UK trial only started a year ago in Stockport, why have we been so slow with it when its success is way better than the 53.8% UK 5-year average?"
You are comparing chalk and cheese here
Dr H:
"You are comparing chalk and cheese here. The localised disease results, in the UK with radical prostatectomy or radiotherapy are much better than 58.3%. Standard treatments are at least as good as HIFU. The machines cost 500,000, which is a lot for a machine that only treats prostate cancer. For the same cash you can buy a radiotherapy machine which treats lots of different cancers."
CW:
"Can you explain why we seem to be lagging behind our peer countries in Europe (European average 65.4%)?"
Dr H:
"Difficult to answer. There are many reasons, apart from issues of whether treatment is better or worse here or in Europe. These include: the different ways data is collected (UK may be more accurate while other countries miss bad prognosis patients, making us look worse); less PSA testing to detect prostate cancer. PSA testing finds a lot of early asymptomatic cancers with good prognosis. The more you find of these the better the overall results look (the ’Will Rogers effect’).
Other articles of interest:
A complete review of prostate cancer - click here
Ben Pfeifer’s non-drug protocol - click here
Building an Integrated Therapy Programme -click here
Beware of taking toomany drugs -Polypharmacy -click here