Hormonal therapy is used to shut down the body’s production of testosterone. Also called androgen deprivation therapy (ADT), it has been the mainstay of treatment for patients with advanced prostate cancer for over 50 years. In men with locally advanced cancer (that has spread outside the prostate gland into nearby tissue) or metastatic disease (more distant spread to the lymph nodes, bones or other organs), ADT has been shown to improve both overall and disease-free survival rates.
ADT is now also being used earlier, for example in cases where rises in PSA point to relapse even before any symptoms or metastases show up. Despite the benefits, longer use of ADT (e.g. in younger men with longer life expectancies) is not without side effects, including bone loss (osteoporosis), sexual dysfunction, anemia, weight gain, muscle loss, hot flashes and mood swings. In light of these risks, ongoing studies on the optimal timing of ADT and the impact on quality of life are of the utmost importance.
This article looks at how ADT works, how it’s used today and men’s options when its effectiveness wears off.
The male hormonal system
Male hormones, or androgens, are produced by the testicles (and in smaller amounts by the adrenal glands located above the kidneys). Androgens stimulate growth in the prostate gland and can also fuel cancer cells. Here’s how the male hormonal system works:
- The hypothalamus gland (located in the brain) produces luteinizing hormone-releasing
- hormone (LHRH)
- LHRH stimulates the pituitary gland (attached to the hypothalamus) to release luteinizing hormone (LH)
- LH travels down to the testes and signals them to make testosterone (the most important male sex hormone)
- By activating the androgen receptor, testosterone and other androgen-like molecules stimulate growth in the prostate gland, regulating its size and secretions
Hormonal therapy blocks the production and/or action of androgens; it can take various surgical or medical forms, including:
- Orchiectomy: removal of the testicles, which cuts off testosterone at the source
- LHRH analogues: drugs that reduce LH secretion by the pituitary gland, in turn shutting off testosterone production
- Antiandrogens (sometimes used in combination with LHRH analogues): medications that prevent testosterone from reaching the androgen receptors on prostate cells, thus blocking their effect
When’s the best time to start ADT?
Indications for considering immediate ADT include when cancer has already spread to other organs at the time of diagnosis, and for patients with high-risk cancers who are undergoing radiation therapy. In patients with lymph node metastases who have had a radical prostatectomy, there’s evidence that immediate ADT is much better than waiting for symptoms or other metastases to occur; however, even then it may be possible to wait to start ADT until the PSA goes up.
If cancer recurs after a radical prostatectomy or radiation therapy (as detected by rises in PSA), the timing of ADT remains controversial. It’s clear that introducing ADT before metastases appear will significantly improve a man’s life expectancy, but we’re still not sure just how early to start the hormones. Obviously, patients most at risk of having a clinical progression of their disease need to be treated as soon as possible. One of the best predictors of how things will evolve is the rate at which PSA rises (PSA doubling time or PSA velocity). Combined with other parameters, for example Gleason score and the interval between initial treatment and recurrence, this information can help estimate the risk for individual patients. In weighing the risks and benefits of early ADT, physicians will also consider other important factors such as a man’s age, health and personal preferences.
When cancer resists
In many men with advanced disease, prostate cancer will remain in remission until it eventually stops responding to hormonal treatment. Hormone-resistant, or -refractory, prostate cancer (HRPC) may result in serious illness and eventual death. Treating symptoms and pain associated with metastatic HRPC presents complex challenges; fortunately, new options are available that may also improve survival.
Bone loss and related complications — both due to the disease itself and to ADT — may lead to serious consequences for men with prostate cancer. Also, approximately 70% of men with advanced prostate cancer will develop bone metastases. As bones become more fragile, the risk of fractures, debilitating bone pain and spinal cord compression can have a serious effect on quality of life. Controlling these symptoms is a primary goal of management.
Chemotherapy
In 1996, mitoxantrone combined with prednisone was shown to significantly reduce pain and improve quality of life for patients with HRPC, compared with prednisone alone. Although it didn’t improve overall survival, this regimen was approved for HRPC based on its palliative benefits (i.e. for relieving symptoms). In 2004, a large trial comparing two groups of patients — one taking docetaxel plus prednisone and the other, mitoxantrone plus prednisone — demonstrated a significant survival advantage for the men in the docetaxel group. The docetaxel/ prednisone combination also improved pain and PSA rates compared with mitoxantrone/prednisone. Although docetaxel was generally well tolerated, common side effects included hair loss, fatigue, nausea as well as low white blood cell counts (but these were rarely severe enough to require hospitalization or treatment). Docetaxel is now the standard chemotherapy for men with HRPC.
Bone-targeted therapy
For patients whose cancer has spread to the bones, external radiation or radioisotope (injection of a radioactive substance) therapy can provide tremendous pain relief and may also prevent fractures. But it can only focus on one area at a time, so patients at high risk of developing bone complications may need other preventive treatments.
Bisphosphonates (commonly used to treat osteoporosis in women and men) can slow down or stop bone loss in prostate cancer patients on ADT. One of them, zoledronic acid, also builds up bone mineral density. Zoledronic acid has shown significant benefits in men with bone metastases, including the delay and prevention of skeletal complications and lasting pain relief. Clinical trials have tested zoledronic acid along with a variety of cancer chemotherapies, with no reports of a marked increase in side effects. Experiments with docetaxel and zoledronic acid suggest that this drug combination could have additive antitumor activity in patients with HRPC.
Second-line hormonal strategies (i.e. introduction or change of antiandrogen; use of ketoconozole) may lower PSA levels temporarily, but haven’t been shown to improve survival. Stopping antiandrogens is now a matter of course if a patient’s cancer progresses while he’s on hormone therapy (indicating it’s no longer working), but we’re not sure if there’s any
benefit to changing antiandrogens or increasing the dose of a given antiandrogen.
In the pipeline
Researchers are investigating several novel treatment options:
- A RANK ligand inhibitor (denosumab), shown to protect men on ADT against bone loss, is being studied in bone metastatic HRPC.
- Targeted agents such as endothelin receptor antagonists (which block excess endothelin in the blood vessels) appear to be effective in slowing down progression in HRPC. Phase III studies in preventing cancer spread and treating patients with metastatic HRPC will help define their role in clinical practice.
- Vaccines and antisense oligonucleotides (RNA or DNA strands that target genes which make cancer cells resist chemotherapy) show promising results in Phase II clinical trials.
- In men who respond to initial chemotherapy with docetaxel, the same agent can be tried again. Clinical trials are exploring promising agents targeting androgen production and others targeting vascular growth. Antisense clusterin oligonucleotides are also being studied as second-line options to see if they will enhance the effect of chemotherapy.
The challenge ahead
Advanced prostate cancer is a multifaceted problem requiring an interdisciplinary approach. New avenues of research are leading to more and different treatment approaches, including new drugs and drug combinations. Urologists, medical oncologists and radiation oncologists and allied health professionals will have to work together more closely than they have in the past. Physicians and patients should be aware of the possible risks associated with hormone therapy, especially to bone health. On the upside, they can be optimistic about the survival benefit provided by chemotherapy with docetaxel, and the potential of drugs such as zoledronic acid to reduce bone complications. Hopefully, the results will lead to improved quality of life for men with advanced hormone-resistant prostate cancer.
Dr. Fred Saad is Director of Urologic Oncology at the Centre hospitalier de l’Université de Montréal (CHUM), Hôpital Notre-Dame, and Professor in the Department of Surgery/Urology at the Université de Montréal in Québec.
