Patient X was diagnosed with prostate cancer 10 years ago and had a radical prostatectomy. He started hormone therapy a few years later and has been on and off it ever since. Apart from a few side effects, he’s been feeling relatively well. But at his last appointment, his doctor said he was concerned about his rising PSA.
What is castration-resistant prostate cancer, and what happens if I have it?
Castration-resistant prostate cancer (CRPC) is disease that has progressed despite the use of therapy aimed at depleting the body’s supply of testosterone, which fuels the growth of prostate cancer. In spite of very good initial response rates to androgen deprivation therapy (ADT; also called hormonal therapy), prostate cancer will eventually progress in nearly all men.
CRPC doesn’t behave the same way in all men. For some men, the only sign that hormone therapy has stopped working is a rising prostate-specific antigen (PSA) level. In some cases the prostate cancer recurs locally, in the same area as the treated prostate. In others it may spread, or metastasize, to other parts of the body. Among men with CRPC, 90% will develop metastases to the bones, which can lead to severe pain. Treatment for CRPC will also vary for different men, depending on characteristics of their disease as well as their age, overall health and personal preferences. Not all men who have CRPC will have the same outcomes.
Being diagnosed with advanced cancer means you might need different types of treatment than you had when you were first diagnosed. Understanding more about your cancer, the available options, and what you can expect from these treatments can help prepare you to make informed decisions about your care. The Canadian Urologic Oncology Group of the Canadian Urological Association (CUA) recently put out new guidelines outlining current evidence-based strategies for managing CRPC (Saad F. Hotte SJ. Can Urol Assoc J 2010;4:380-4). The foremost aim is to ensure that patients maintain the best possible quality of life for as long as possible.
This article summarizes some of the CUA’s key recommendations.
A second round of hormones
Since in most patients with CRPC, the androgen receptor (responsible for “switching on” signals that initiate cancer cell growth) remains active, the current thinking is that ADT should be continued. A change in hormonal therapy may be an option for men with few symptoms. The new strategy might entail adding an antiandrogen (medication taken orally) for people on luteinizing hormone-releasing hormone (LHRH) analogues (given by injection) or men who had an orchidectomy (surgical removal of the testicles). This is called total androgen blockade (TAB), and the idea is to completely rid the body of testosterone.
For patients who’ve undergone TAB, doctors might try stopping the antiandrogen. Some patients experience PSA reductions due to something called antiandrogen withdrawal response. Introducing an antiandrogen, switching to a different antiandrogen, or trying ketoconazole (an antifungal drug that also lowers testosterone) have been shown to reduce PSA in about 30% of patients.
If there are no signs of cancer having spread to distant parts of the body, the CUA recommends bone scans to screen for bone metastases and monitoring with abdominal computed tomography (CT) scans and chest x-rays. Doctors will look at the PSA doubling times (how fast the PSA level doubles) to guide them on when these imaging tests should be done. At this point, they still aren’t clear about the role of other tests such as magnetic resonance imaging (MRI) and positron emission tomography (PET).
Steroids
Low-dose prednisone or dexamethasone may improve PSA values and/or relieve men’s symptoms. They may also have some anticancer effects on prostate cancer.
When is it time for chemotherapy?
Men with CRPC should be referred early for possible chemotherapy if they have detectable metastases. Otherwise, they may be eligible for chemotherapy within a clinical study (see box, page 6). Treatment for advanced prostate cancer is still palliative (meaning it can’t provide a cure), and patients are encouraged to join clinical trials to give them the best possible chances of survival and quality of life.
Based on the results of two large randomized controlled trials, docetaxel chemotherapy given along with prednisone is now standard of care for men with CRPC who have detectable metastases. The studies compared this combination to the previously established standard of mitoxantrone and prednisone. A regimen consisting of docetaxel once every three weeks (given by injection) and prednisone taken twice daily (in pill form) improved overall survival, disease control, symptom relief and quality of life. The CUA recommends that treatment last as long as benefits outweigh side effects. Assessment of response to therapy or disease progression shouldn’t only be based on the PSA results, but should also take into account clinical and radiographic data.
Other regimens or therapies improve disease control, symptoms and quality of life (e.g. weekly docetaxel plus prednisone and mitoxantrone plus prednisone), but they haven’t demonstrated improvement in overall survival.
With patients who have evidence of metastases but no symptoms yet, doctors should discuss when to start docetaxel chemotherapy, and treatment should be tailored to men’s clinical status and wishes.
If chemo doesn’t work, what’s next?
For patients who progress while they’re on docetaxel-based chemotherapy or soon after, available options include mitoxantrone (but it has limited activity and increased side effects) and possible retreatment with docetaxel.
In addition, we expect two new drugs to be approved soon. Cabazitaxel is a chemotherapeutic drug that may soon be a key player as second-line treatment in CRPC. In a recently reported study, cabazitaxel showed a significant survival advantage in men who had been previously treated with docetaxel. The median survival rate was 15.1 months with cabazitaxel, compared to 12.7 months with mitoxantrone. Another agent that has demonstrated positive results is abiraterone. This oral drug has been shown to significantly improve survival in men who’ve had prior treatment with docetaxel, and should be available in Canada in the future. This area of prostate cancer remains very active in re- search to further improve patient outcomes.
How can radiation help?
Prostate cancer that has spread to the bones can cause significant pain. Most men will get full or partial relief from radiation directed at the sensitive area. Treatment may need to be repeated if pain recurs. If bone pain is not confined to one spot, radioisotopes (such as strontium and samarium) can be injected into the bloodstream to reach other affected areas. These drugs can affect the immune system, so men starting them must have adequate blood counts.
Looking after your bones
Treatment for prostate cancer affects the bones in several ways. ADT is associated with bone loss and increased risk of bone fractures. Also, the bones are the most common site of cancer spread in men with metastatic CRPC. Bone metastases cause local decreases in bone strength and quality, leading to serious risk of complications including fractures, severe bone pain and spinal cord compression. All of these can have a debilitating effect on quality of life.
Zoledronic acid, a bisphosphonate given by injection every three to four weeks, is now recommended to preserve bone health and prevent prostate cancer-related bone complications in men with CRPC and bone metastases. The CUA advises continuing the drug as long as it shows benefits. Clinical trials have also shown that zoledronic acid can be safely used with different types of chemotherapy.
Some cautions need to be taken with bisphosphonates. Dosages must be adjusted (reduced) for men with kidney problems. Bisphosphonates are also associated with a risk of osteonecrosis of the jaw (ONJ), a rare but serious condition involving deterioration of the jawbone. Most cases have been diagnosed in people who’ve had previous dental work, such as tooth extractions, dental implants or treatment for a mouth infection. Good oral hygiene and dental evaluation before starting bisphosphonate treatment are recommended. To reduce the risk of ONJ, men may also be advised to avoid invasive dental surgery while they are taking bisphosphonates for advanced prostate cancer.
A new agent called denosumab prevents bone loss and new vertebral fractures due to ADT, and has also been shown to be very effective in reducing bone complications related to metastases. Denosumab should also become available for patients with metastatic CRPC.
Work in progress
Men with advanced CRPC have complex and varied physical, psychological and spiritual needs that benefit from a multidisciplinary approach. The priority is to maintain quality of life and provide support for patients and their families. Various new therapies have been introduced in recent years, such as docetaxel-based chemotherapy to improve survival and quality of life, and zoledronic acid to reduce the risk of bone complications. Researchers continue to investigate new treatments that they hope will become available soon to further improve the outlook.
Dr. Fred Saad is Professor and Chief of Urology at the Centre hospitalier de l’université de Montréal.
