In the early 1940s, Dr. Charles Huggins (a Canadian-born physician) and colleagues reported their discovery that prostate cells — both benign and cancerous — depend on androgens (male hormones such as testosterone) for their growth. Since then, hormone therapy (or androgen deprivation therapy) has been widely studied and used to treat prostate cancer. Contrary to what people often think, this treatment doesn’t involve injecting hormones into the body. Instead, it refers to methods that block the circulation of androgens and/or binding of androgens to receptors in the prostate — either by surgical removal of the testes or the use of medications.
Regardless of the method, if androgen deprivation therapy is used continuously and for a long time, most patients will develop resistance to it. In other words, prostate cancer cells will continue to grow and divide despite the treatment.
Side effects: still a problem
Hormone therapy is standard treatment for men with metastatic prostate cancer, as well as those whose cancer has come back after radiotherapy. When the disease has spread outside of the prostate gland, several studies have shown positive results with uninterrupted hormone treatment. On the other hand, continuous hormone therapy is associated with a variety of side effects: loss of sex drive (libido), hot flashes, breast tenderness and growth of breast tissue, osteoporosis (loss of bone density and bone strength), anemia, loss of muscle mass, weight gain, fatigue, increased cholesterol, hypertension and higher chance of developing diabetes. The risk of heart attacks might also be higher in men on hormone therapy.
Medication “holidays”
Due to the downside of continuous androgen suppression, some physicians started to use an intermittent — or on/off — schedule. Treatment is stopped once the patient shows an initial response to therapy, and androgen levels are allowed to rise before the next treatment period begins. This method produces clinical outcomes at least as good as continuous therapy. Potential advantages include reducing chronic drug-related side effects as well as decreasing the risk or delaying the onset of hormone resistance.
Several retrospective and phase II studies have shown improved quality of life during the “off-treatment” time. Also, analyses of three ongoing phase III trials reported that intermittent therapy was as good as continuous hormone treatment in terms of:
- biochemical progression (measured by a significant rise in PSA);
- progression-free survival rate (meaning the number of people living with a disease that doesn’t get worse);
- overall survival rate (the percentage of people in a study who are still alive for a certain defined period of time).
Of note, one of these studies showed that intermittent hormonal therapy was significantly better than continuous use with respect to the risk of cancer progression within three years.
What’s the “recipe”?
Different treatment schedules have been used.
- Androgen suppression can be stopped once the PSA drops to a very low level (usually less than 4 ng/mL), then started again when it rises to a predetermined level. But there’s disagreement about when is the right time to resume treatment. Some studies use 10 ng/mL, others 20 ng/mL, as their cut-off point.
- Another way is to give the treatment for fixed periods, e.g. eight to nine months on, then nine months off.
- A third way is to mix the above-mentioned schedules: give the treatment for a certain time, followed by a “time out” lasting until the PSA rises to a set level.
Clinical trials of intermittent hormone therapy are in progress and will help clarify many questions, including: What’s the most effective schedule? Which patients would benefit the most? Are we certain this approach is better than continuous hormone suppression? But just the fact that it allows some men to avoid medication side effects for a time is very important. Another factor to consider is the probable cost-effectiveness of intervals of stopping treatment.
Doctors are generally comfortable prescribing intermittent hormone therapy. The decision must be based on the best medical evidence, and should balance the goals of effective cancer control with maintenance of the patient’s quality of life. It’s important to discuss the available options for your specific case with your doctor.
Dr. Fabio Cury is an Assistant Professor in the Department of Oncology, Division of Radiation Oncology, at McGill University in Montreal, Québec.
Dr. Alan Dal Pra is a Fellow in Urologic Oncology at McGill University.
