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Hormone therapy for treating prostate cancer

Richard Gledhill
RGN
Prostate Cancer Charity Nurse Specialist
Queen Elizabeth Hospital
Birmingham

Prostate cancer is the most common male cancer in the UK with over 31,000 new cases diagnosed annually. Although treated with curative intent in its early stages, around 40% of men initially present with metastatic disease, which is incurable. Despite 10,000 men dying from prostate cancer annually, the public profile of it is lower than female malignancies such as breast and cervical cancer.

Hormone therapy is commonly used in the treatment of prostate cancer and has a role to play in localised, locally advanced and advanced stages of the disease. Despite the similarities in name, hormone therapy for prostate cancer should not be confused with hormone replacement therapy for treating women during the menopause, which strives to maintain hormonal balance. The reverse is the desired response in hormonal therapy for prostate cancer. Hormonal imbalance is sought by reducing or blocking testosterone, which is the fuel that prostate cancer cells need to survive.

History
The use of hormones in treating advanced prostate cancer is not a new concept. It dates back to the 1940s when patients were either deprived of testosterone by surgical castration (orchidectomy) or given oestrogens. As a result of this treatment a reduction in pain was noted and survival increased. In poorer, underdeveloped countries, orchidectomy remains the primary method of testosterone deprivation. It provides a simple and cost-effective treatment. However, it is not without its problems, namely irreversibility and altered body image. Advancements in pharmacological hormone treatments in recent decades have been shown to be as effective as surgical castration, but without the irreversibility. The advent of pharmacological hormone manipulation enables hormone therapy to be used in not just advanced prostate cancer but also the treatment of localised prostate cancer. Treatment is given by tablet or injection (monotherapy) or both (maximum androgen blockade).
 
Drug administration
There are various brands of the injection available in the form of pellet implants (Zoladex) or liquids (Prostap). These should be administered either four- or 12-weekly. As studies have shown them to have similar efficacy, the decision regarding what frequency to administer them is between the patient and the general practitioner.(1) The four-weekly injection (12 visits yearly) has a shorter side-effect duration and allows regular contact between patient and practitioner, which may be appropriate and welcome, whereas the 12-weekly injection (four visits yearly) maintains patient independence and enables normality of life. Injections of the pellet-type drug should be injected subcutaneously into the abdomen. Local anaesthetic is not necessary, although some patients and practitioners prefer its use. The liquid-type drug need not be injected into the abdomen, and a suitable area of the upper arm should be identified. The biological action of luteinising hormone-releasing hormone (LHRH) injections stops testosterone being released from the testes. However, this causes an initial temporary increase in testosterone levels, known as the flare phenomena. To minimise the effect of the testosterone rise potentially provoking disease progression, the injections should be scheduled two weeks into a four-week course of antiandrogen tablets, which can then be stopped.

Pharmacological effects
Regardless of the manner in which hormone therapy is administered, the treatment aim is to minimise the amount of available testosterone that the prostate cancer needs to grow. Antiandrogens are tablets that block or inhibit the circulating testosterone in the bloodstream, and LHRH agonists are injections that inhibit the release of testosterone from the testes. As expected when depriving the body of the male sex hormone, there is a loss of libido and impotency is more common. There are also other unwanted side-effects that include tiredness, weight gain, mood swings, gynaecomastia and hot flushes.(2)

Shared care
Hormone therapy is a convenient and effective method of treating prostate cancer without the need for hospital visits. After treatment is initiated in hospital, administration of injections can safely be continued in primary care. This is convenient as in today's climate it avoids unnecessary visits to hospital, which may involve lengthy waits in overcrowded clinics and expensive car parking charges. This principle is known as shared care and benefits not only patients by being in their local community but also the hospital by maximising clinic time for more appropriate appointments.(3)

Treatments

Localised disease
Prostate cancer that is localised within the prostate gland (T1-T2) (see Figure 1) is curable and is currently treated by one of three methods. These treatment options include radical prostatectomy (total removal of the prostate gland) and two types of radiotherapy. Patients with a high PSA or high-grade cancer are managed by one of these methods. There is a further option, active monitoring, for low-grade cancers where there is no immediate treatment. The activity of the cancer is monitored regularly by measuring the prostate-specific antigen (PSA) circulating in the bloodstream and with regular digital rectal examinations (DREs). Careful and thorough counselling by urologists, oncologists and nurse specialists assist the patient in deciding which treatment to undergo while discussing the advantages and potential disadvantages of all treatments.(4)

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Radiotherapy to the prostate gland is by either an external source of high-energy X-rays aimed at the prostate (external beam radiotherapy - EBRT) or by implanting radioactive seeds into the prostate gland (brachytherapy). Combining hormone therapy with radiotherapy has a dual role. First, neoadjuvant hormones given before radiotherapy can reduce the size of the prostate, allowing for a more accurate delivery of the radiation. This in turn reduces unwanted toxicity effects, such as diarrhoea and dysuria. Secondly, patients with a high-grade cancer are noted to have a reduced risk of disease progression if given hormones prior to their radiotherapy.(5)

Locally advanced disease
Hormones are also widely used in treatment of locally advanced prostate cancer (T3/4). This is extension of cancer through the prostatic capsule in the absence of measurable metastases. Radiotherapy is often recommended by the multidisciplinary team to increase the likelihood of cure. A larger radiotherapy field can be aimed at the prostate and surrounding affected tissue. Halting the cancer's growth and reducing the prostate size are of obvious benefit, and there is up to a 79% chance of patients being disease-free at five years. Furthermore, adjuvant hormones have been shown to improve survival for patients with locally advanced cancer or high Gleason grade/ high PSA when given for a period of three years following radiotherapy.(6)

Advanced disease
The greatest use of hormones is in advanced prostate cancer (TxNxM1/TxN1-2Mx) where there is evidence of metastases, commonly in bones. In this instance hormones are used to control the progression of the disease as opposed to curing it. Hormones will slow the growth of prostate cancer deposits globally throughout the body and will frequently cause regression. However, their effectiveness at controlling the metastatic disease is limited (approximately 18 months).
 
Prostate cancer cells will eventually mutate and develop a phenotype that will thrive despite the absence of testosterone. This is known as hormone-refractory prostate cancer (HRPC). It is identifiable by sequential rises in the PSA level, an indicator of prostate cancer activity. At this point in the evolution of the disease possible second-line hormone manipulation can be explored by the removal of antiandrogens or addition of oestrogens. However, the PSA fall is usually only short-lived, and referral to a community palliative care team for support and management of symptoms ought to be discussed with the patient and family. Additional pharmacological treatments could be employed at this stage of the disease. Chemotherapy may be considered, as recent advances with docetaxel show an effective palliative response.(7) Disease that has spread to the bones not only can cause pain but can weaken them also. The British Association of Urological Surgeons (BAUS) recommends the use of bisphosphonates. These drugs have been shown to strengthen bones and reduce pain, the likelihood of fracture to the affected bones and the need for palliative radiotherapy.(8) Further studies into the antimetastatic properties of bisphosphonates are underway to determine whether early administration can prevent bony metastases.
 
Clinical trials
Painful bony metastases can also be effectively treated with radioisotopes, such as strontium and samarium. Clinical trials examining combinations of hormone therapy with individual and combined effects of chemotherapy, bisphosphonates and radioisotopes are currently underway (TRAPEZE).(9) Active management of HRPC through these therapies can give an overall survival of 24-36 months.
 
Although there is little conclusive evidence that they prolong survival, LHRH injections are commonly continued in patients that develop HRPC.(10) However, withdrawal of treatment without an alternative has potential psychological issues. Furthermore, there are cost implications for continuing an ineffective treatment. Local management at this stage of the disease will determine its suitability to continue. Robust referral pathways between hospitals, primary care teams and hospices will promote effective palliation for these patients and support for their families.

Conclusion
Men diagnosed with localised prostate cancer are now in a position to select the most appropriate treatment for their age and personal circumstances. Many opt for treatments with curative intent, and a minority opt for active surveillance. However, a significant number of men still present with incurable prostate cancer. Locally advanced and advanced prostate cancer can be managed in partnership between hospital and primary care for many years with hormone therapy with acceptable side-effects that balance a good quality of life with effective cancer control.

References

  1. Tunn U, Bargelloni U, Cosciani S, Fiaccavento G, Guazzieri S, Pagano F. Comparison of LH-RH analogue one-month depot and three-month depot by their hormone levels and pharmacokinetic profile in patients with advanced prostate cancer. Urol Int 1998;60(S1):9-16.
  2. O'Connor K, Fitzpatrick J. Side-effects of treatments for locally advanced prostate cancer. BJU Int 2005;97:22-8.
  3. Kirby R, Fitzpatrick J, Kirby M, Fitzpatrick A. Shared care for prostatic diseases. Oxford: Isis Medical Media; 1995.
  4. National Institute for Clinical Excellence. NICE guidance on cancer services: improving outcomes in urological cancers. London: NICE; 2002.
  5. D'Amico A, Schultz D, Loffredo M, Dugal R, et al. Biochemical outcome following external beam radiation therapy with or without androgen suppression therapy for clinically localized prostate cancer. JAMA 2000;284:1280-3.
  6. Bolla M, Collette L, Blank L, Warde P, Dubois J, Mirimanoff R, et al. Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial. Lancet 2002;360:103-8.
  7. Tannock I, De Wit R, Berry W, Horti J, Pluzanska A, et al. Docetaxel plus prednisone for advanced prostate cancer. N Engl J Med 2004;351:1502-12.
  8. Saad F, Gleason D, Murray R, Tchekmedyian S, Venner P, et al. Long-term efficacy of zoledronic acid for the prevention of skeletal-related events in patients with metastatic hormone-resistant prostate cancer. J Natl Cancer Inst 2004;96(11):879-82.
  9. TRAPEZE. Phase II efficacy and safety clinical trial in hormone refractory prostate cancer. Available from URL: http://www.trapeze.bham.ac.uk/Trapeze-Protocoll.pdf
  10. Hussain M, Wolf W, Marshall E, Crawford E, Eisenberger M. Effects of continued androgen-deprivation therapy and other prognostic factors on response and survival in phase II chemotherapy trials for hormone-refractory prostate cancer: a Southwest Oncology Group report. J Clin Oncol 1994;12:1868-75.

Resources
Prostate Cancer Charity
W:www.prostate-cancer.org.uk

CancerHelp UK
W:www.cancer help.org.uk