Prostate cancer with metastases: treatment and survival

In the Netherlands, approximately 9,500 men are diagnosed with prostate cancer every year. This is the most common form of cancer in men. The number of cases is expected to increase in the coming years due to population growth and aging. This article focuses specifically on regular life-prolonging and palliative treatments for metastatic prostate cancer. Hormonal treatment is the mainstay of treatment for metastatic prostate cancer.

Metastatic prostate cancer

    • Prostate cancer with metastases
    • Treatment of metastatic prostate cancer
    • Hormonal treatment
  • LHRH agonists
  • Anti-androgen
  • Estrogens
  • Orchidectomy (surgical castration)
  • Maximum androgen blockade
  • Side effects and course
    • Chemotherapy
    • Hormone therapy in combination with chemotherapy
    • Radioactive radium-223
    • External radiation
    • MR-HIFU for painful bone metastases
    • Radioactive isotope treatment
    • Bisphosphonates
    • Corticosteroids
    • Pain relief
    • Life expectancy (survival)

This article is dedicated to ES, who died on October 4, 2011 after slowly declining health as a result of metastatic prostate cancer, which he was diagnosed with in September 2006. In addition to regular medical treatment, he adhered to the Moerman diet. This alternative treatment method against cancer consists of a diet and the administration of extra nutrients through nutritional supplements.

PSA test / Source: Istock.com/jarun011

Prostate cancer with metastases

Patients who reach the point where the prostate cancer cells have spread to other parts of the body and are also growing there may have various disease histories. One person has already undergone three or even four other prostate cancer treatments (for example, an operation to remove the prostate, then – when the cancer turned out to still be growing – radiation therapy with perhaps hormonal treatment), while the other – completely unexpectedly – is immediately diagnosed with prostate cancer even though it has already spread. In the Netherlands, the latter occurs in approximately 1 in 20 prostate cancer patients. Now that prostate cancer is being detected earlier and earlier thanks to PSA measurements, this number will become increasingly smaller. For metastatic prostate cancer, treatment is palliative and mainly aimed at prolonging life and relieving pain.

Treatment of metastatic prostate cancer

Hormonal treatment is the mainstay of treatment for metastatic prostate cancer. Because 80% of prostate cancers grow less quickly without the male sex hormone testosterone, it is a life-prolonging treatment for many patients. Hormonal treatment does not kill cancer cells, but stops the growth of cancer cells by stopping the production of testosterone. The effect is also that the tumors often shrink somewhat. Here in this country, approximately 80% of patients with metastatic prostate cancer choose hormonal treatment as their first therapy. Another option is ‘watchful waiting’ until the patient is bothered by those metastases.

Hormonal treatment

Hormonal treatment is the most effective therapy in patients with metastatic prostate cancer and is therefore the treatment of choice. There are five different hormonal treatments available, which are aimed at inhibiting the growth-promoting effect of testosterone on prostate cancer cells:

Pituitary gland / Source: Tefi/Shutterstock.com

LHRH agonists

The hypothalamus secretes LHRH (Luteinizing Hormone Releasing Hormone), which then flows past the pituitary gland – a hormone-producing gland – causing it to produce luteinizing hormone (LH), which ends up in the blood. LHRH is also called GnRH (gonadotropin releasing hormone). As soon as LH cells enter the testicles, testosterone is produced there. This testosterone is released into the blood. LHRH agonists mimic the action of natural LHRH, causing the pituitary gland to release LH, which causes the testicles to produce testosterone. LHRH agonists therefore stimulate testosterone production. This sounds contradictory, since they are intended to slow down testosterone production. But after a week the pituitary gland becomes exhausted and stops producing LH. This causes testosterone production in the testicles to collapse and chemical castration is a fact. The disadvantage is that a testosterone peak occurs in the first week, which sometimes results in bone pain due to flare-ups of metastases.[1] The main side effects are impotence, loss of libido and ‘hot flashes’.

Anti-androgen

This group of medications also causes chemical castration. Antiandrogens mimic testosterone to some extent. They bind to prostate (cancer) cells just like testosterone, but they just do not send the signal that they need to grow, like testosterone. Because anti-androgens bind to the same cells and are located in exactly the same place as testosterone, testosterone can no longer reach them. This group of medications therefore prevents testosterone from stimulating prostate (cancer) cells to grow.

Estrogens

The third way of chemical castration is the administration of female sex hormones, estrogens (or synthetic substances with the same effect).

Orchidectomy (surgical castration)

The surgeon makes an incision in the scrotum and removes the tissue that produces testosterone from both testicles. In fact, there is no better method than surgical castration. The testicles produce 95% of the testosterone in a male body. The adrenal cortex makes up the other 5%.

Maximum androgen blockade

This is the combination of orchiectomy with anti-androgens, which also blocks the 5% testosterone that the adrenal cortex produces.

Side effects and course

The side effects of the aforementioned hormonal treatments are very similar. Common side effects include impotence (the inability to get an erection), loss of libido (loss of sex drive) and ‘hot flashes’.

It is decided on an individual basis when to start hormonal therapy. Delay means that the patient is stronger, more vital and able to have sex for longer. On the other hand, the patient is more likely to experience pain if metastases start to grow in the bone.

Orchidectomy, an LHRH agonist and maximal androgen blockade all work equally well. If hormonal therapy is successful, the PSA level will drop. In most patients with metastatic prostate cancer, the tumor no longer responds to the testosterone deficiency after one and a half to two years and the cancer starts to grow again. This is called castration-resistant prostate cancer. In the case of metastatic prostate cancer that is no longer hormone sensitive, hormonal treatment is nevertheless continued.

Chemotherapy

For castration-resistant prostate cancer, cell-killing chemotherapy is the only therapy that extends life. It can add an average of 2.5 months to life.[2] The drug docetaxel (known under the brand name Taxotere®) can extend life. The side effects are not too bad: 1 in 14 patients suffers significantly from them. On the other hand, 1 in 3 patients have less pain and 1 in 5 patients feel better, in the sense that they believe that their quality of life has improved significantly due to chemotherapy. The docetaxel treatment, which the patient receives once every three weeks, is combined with prednisone in order to suppress a possible immune response against the drug. If a patient does not wish to receive chemotherapy, the treating physician will wait until the patient develops complaints and then alleviate them.

In 2011, the European Registration Authority (EMA) approved the registration of cabazitaxel (known under the brand name Jevtana®) for the treatment of patients with metastatic prostate cancer who have previously been treated with docetaxel-based chemotherapy. Cabazitaxel achieves a clinically relevant survival benefit while maintaining the patient’s overall condition.[3]

Hormone therapy in combination with chemotherapy

Men with prostate cancer with metastases should also receive chemotherapy with the drug docetaxel in addition to hormone therapy. This significantly increases the chance of survival. This is evident from two studies published in the journals The Lancet and The Lancet Oncology . The researchers do not make any statements about the effect of the combination therapy in patients with prostate cancer that has not yet spread. They don’t have enough data for that, but research is already underway. (Source: National Healthcare Guide, 28-12-2015)

Radioactive radium-223

Terminal prostate cancer patients with metastases in their bones and who no longer respond to chemotherapy, who no longer want to undergo chemotherapy or who are too weak for it, can be treated with radioactive radium-223 since the beginning of 2014. The treatment extends their life by four to six months and it also reduces pain and ensures a better quality of life. The treatment basically consists of one monthly injection for six months. No serious side effects are reported.

External radiation

In addition to pain, metastases in the bones can also cause other complaints such as muscle weakness and sensory disturbances due to pressure on nerve pathways. A patient can receive radiation to improve pain complaints. The first days to two weeks after radiation, the patient may temporarily experience more pain in response to the radiation. In that case, the pain medication is temporarily increased. Then the pain decreases. This effect is often long lasting.

MRI scanner / Source: Dept. radiology, UMC Utrecht.” onclick=”openImage(this);”> MRI scanner / Source: Radiology Department, UMC Utrecht.

MR-HIFU for painful bone metastases

MR-HIFU (Magnetic Resonance Imaging-guided High Intensity Focused Ultrasound) is a relatively new treatment method for painful bone metastases. This is a treatment that aims to reduce pain and maintain or, where possible, improve quality of life. The treatment is only applied to patients in the palliative phase, which means that they can no longer be cured with regular treatments.

Radioactive isotope treatment

If there are metastases in the bone in several places in the body, treatment with a radioactive isotope (for example Strontium or Samarium) can provide a solution. These drugs are distributed throughout the body by means of an infusion, after which the radioactive agent accumulates in the metastases in the bone. This reduces or disappears. The first week or two weeks after treatment, a so-called ‘flare up’ may occur, a temporary revival of the pain. Afterwards, treatment often reduces the pain for a number of weeks to months. The disadvantage of this treatment is that it can disrupt the production of blood cells, which can lead to anemia or infections. A blood transfusion can provide a solution in that case. The patient then receives a quantity of donor blood. For this he is admitted for a day and sometimes also a night. After a blood transfusion, the patient often feels better. The effect of a blood transfusion is temporary, until the number of red blood cells drops again after a few weeks.

Bisphosphonates

These substances prevent weakening of the skeleton and combat pain caused by metastases in the bones. Research has shown that bisphosphonates reduce the risk of bone fractures and spinal cord injury, for example.

Corticosteroids

These anti-inflammatories can lead to a reduction in complaints, such as the threat of spinal cord injury, pain, fatigue, lack of appetite, nausea and tumor fever. In practice, corticosteroids are often given in combination with radiation or chemotherapy.

Paracetamol has an analgesic and fever-reducing effect / Source: Martin Sulman

Pain relief

Pain relief for prostate cancer with metastases initially consists of paracetamol or NSAIDs (ibuprofen, diclofenac, naproxen or the newer types such as valdecoxib or etoricoxib). Later this can be combined with weakly acting opioids, such as codeine or tramadol. At a later stage – in moderate to severe pain complaints – pain complaints are treated with a strong opioid, for example morphine, usually in combination with paracetamol or NSAIDs.

Life expectancy (survival)

Men with non-metastatic prostate cancer have an 80% chance of living longer than 10 years. The prospects for metastatic prostate cancer are less favorable. Despite this, about half of patients live longer than 3 to 4 years and 10 years after diagnosis, 20 to 25% are still alive. These figures apply to the Dutch situation.[4] Half of men with metastatic prostate cancer die as a result of this disease. Many patients die of something else, as many are already elderly when they are diagnosed with prostate cancer. Many of them reach a normal age.

Notes:

    1. It would be beneficial if there were a drug that blocks the LHRH receptors in the pituitary gland, but does not stimulate the pituitary gland to produce LH. Such a substance would then be an LHRH antagonist, a so-called ‘counteracter’. This prevents a testosterone peak in the beginning. Degarelix, a GnRH antagonist, can achieve similar reductions in testosterone levels as with GnRH agonists. However, unlike GnRH agonists, data on long-term safety and effect on survival are lacking for degarelix. Experience with degarelix is limited, which means that a good assessment of the occurrence of side effects in the longer term is not yet possible (source: http://www.fk.cvz.nl).
    2. Wim Köhler: The prostate cancer logbook , Uitgeverij Thoeris, Amsterdam, 2009, p.131.
    3. New medicine registered for prostate cancer patients who have completed treatment, at: http://www.prostaat.nl (last consulted on October 8, 2011)
    4. Wim Köhler, p.117.

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