Recurrent Prostate Cancer
Overview
When prostate cancer has been detected or has returned following initial treatment with surgery, radiation therapy and/or hormonal therapy, it is said to be recurrent or relapsed. Prostate cancer that is resistant (does not respond ) to hormonal therapy is also referred to as stage D3.
The course of treatment for relapsed prostate cancer depends on what treatment a patient has previously received and the extent of the cancer. Some patients have only a rise in PSA level as evidence of recurrent cancer. Other patients will have evidence of recurrent cancer on x-rays or scans. Patients who have prostate cancer that continues to grow despite hormone therapy are referred to as having hormone-refractory prostate cancer.
A variety of factors ultimately influence a patient’s decision to receive treatment of cancer. The purpose of receiving cancer treatment may be to improve symptoms through local control of the cancer, increase a patient’s chance of cure, or prolong a patient’s survival. The potential benefits of receiving cancer treatment must be carefully balanced with the potential risks of receiving cancer treatment.
The following is a general overview of the treatment of recurrent prostate cancer. Circumstances unique to your situation and prognostic factors of your cancer may ultimately influence how these general treatment principles are applied. The information on this Web site is intended to help educate you about your treatment options and to facilitate a mutual or shared decision-making process with your treating cancer physician.
Most new treatments are developed in clinical trials. Clinical trials are studies that evaluate the effectiveness of new drugs or treatment strategies. The development of more effective cancer treatments requires that new and innovative therapies be evaluated with cancer patients. Participation in a clinical trial may offer access to better treatments and advance the existing knowledge about treatment of this cancer. Clinical trials are available for most stages of cancer. Patients who are interested in participating in a clinical trial should discuss the risks and benefits of clinical trials with their physician. To ensure that you are receiving the optimal treatment of your cancer, it is important to stay informed and follow the cancer news in order to learn about new treatments and the results of clinical trials.
Treatment of recurrent prostate cancer depends on many factors, including previous therapies and the overall condition of the patient. If the patient had surgery to remove the prostate and the cancer comes back only in a small area near the operation, radiation therapy may be given. If the patient already received radiation therapy to the prostate or to the area of the operation after a radical prostatectomy, radiation therapy typically cannot be administered again to the same part of the body. Systemic therapy using hormonal or chemotherapy treatment is typically given if tests show that the prostate cancer has spread to other parts of the body. Radiation therapy may be given to relieve symptoms, such as bone pain. When prostate cancer continues to grow despite hormone therapy, this condition is known as hormone-refractory prostate cancer. Patients with hormone-refractory prostate cancer have historically had few treatment options.
Recurrent Prostate Cancer After Surgery
Radiation therapy may be recommended to patients following surgical prostatectomy if they are found to have cancer involving the margins of the surgical specimen, the PSA remains persistently elevated or the PSA returns to normal and then begins rising again, assuming there is no evidence of cancer elsewhere in the body.
Patients with cancer involving the surgical margins and a persistently elevated or a rising PSA all have evidence that some cancer was not removed by surgery. For some patients, the remaining cancer will be confined to an area near the prostate gland. For many patients, the cancer will have spread to more distant locations in the body. The difficult question faced by the patients is: What is the chance persistent cancer can be eliminated with additional radiation therapy?
In general, 75% of patients treated with radiation after prostatectomy will still experience recurrence of cancer as evidenced by a rising PSA level within 5 years of radiation therapy. Patients with high Gleason scores, more advanced stages, and higher PSA levels are more likely to have cancer recurrence following radiation than those with lower Gleason scores and lower PSA levels. The high rate of failure following radiation therapy occurs because the radiation could not kill all of the cancer cells or because many undetectable cancer cells had already spread beyond the limited reach of the radiation therapy. Patients must decide whether receiving additional radiation therapy (along with its inconvenience and toxicity) is likely to be beneficial, or whether participation in clinical studies directed at treating cancer that has already spread away from the radiation field are more appealing in offering potential benefit from additional treatment.
Recurrent Prostate Cancer After Radiation Therapy
Depending on the features of the prostate cancer, some patients will experience a rise in the PSA level after radiation therapy. This occurs because cancer cells may have survived despite radiation therapy, or patients may already have small amounts of cancer that have spread outside the prostate and were not treated by the radiation. These cancer cells cannot be detected with any of the currently available tests. Undetectable areas of cancer outside the prostate gland are referred to as micrometastases. The presence of these microscopic areas of cancer or surviving cancer cells can cause the relapses that follow treatment with radiation therapy.
Once a patient has received radiation therapy to the prostate gland, more radiation therapy typically cannot be given to the same area safely. Rarely, surgeons have removed the prostate gland for persistent cancer after radiation therapy. Other surgeons have used cryosurgery, which is a local treatment where the prostate gland is frozen with a probe. Because the complications of surgery or cryosurgery tend to be more frequent in patients previously treated with radiation therapy, most doctors do not advise further local treatments.
Patients with recurrent prostate cancer after radiation therapy are usually treated with hormone therapy. Hormone therapy deprives a man’s body of male hormones necessary for prostate cancer to grow. Hormone therapy can affect the growth of prostate cancer everywhere in the body, whether the cancer cells are in the prostate itself or elsewhere in the body. Recurrent prostate cancer usually can be controlled with hormone therapy for a period of time, often several years. Eventually, however, most prostate cancers continue growing despite the hormone therapy.
Hormone therapy may be administered surgically (orchiectomy) or with drugs. To learn more, go to Hormone Treatment of Prostate Cancer. While hormonal therapy can prevent prostate cancer growth and improve symptoms, it is not curative. Many patients may want to consider participation in clinical studies evaluating new treatment approaches for recurrent prostate cancer.
Hormone-Refractory Prostate Cancer
Prostate cancer cells need male hormones in order to grow. Hormone therapy decreases the level of male hormones in the blood, which causes prostate cancer cells to die. Prostate cancer usually can be controlled with hormone therapy for a period of time, often several years. Eventually, however, most prostate cancers are able to grow and spread despite the hormone therapy, and these cancers are called hormone-refractory. Hormone-refractory metastatic prostate cancer is incurable, with patients surviving an average of 6-9 months after developing resistance to hormone therapy. Treatment options for hormone-refractory prostate cancer include chemotherapy or local radiation therapy for the purpose of alleviating symptoms from progressive cancer or participation in clinical studies evaluating new treatments.
Chemotherapy
Chemotherapy has been shown to reduce the severity and duration of pain and improve overall well-being of patients with hormone-refractory prostate cancer. When treatment with chemotherapy was directly compared to no chemotherapy, the men treated with chemotherapy experienced less severe pain and this improvement lasted 43 weeks, or just over twice as long as patients who did not receive the chemotherapy treatment. Unfortunately, patients who received chemotherapy did not live any longer than those who did not receive chemotherapy.
Taxotere® (docetaxel): A newer chemotherapy drug, Taxotere, has been shown to further improve outcomes over Novantrone chemotherapy. In a direct comparison of treatment with Taxotere/prednisone to the historical standard treatment of mitoxantrone/prednisone, patients treated with Taxotere lived longer. On average, the patients treated with Taxotere survived more than a year and a half (19 months) compared to 16.5 months for patients treated with mitoxantrone. More than a third (35%) of the patients treated with Taxotere experienced reduced pain compared to less than one quarter (22%) of patients treated with mitoxantrone.[1]
There also appears to be a similar improvement in survival when Taxotere is combined with the chemotherapy drug estramustine. Patients treated with the Taxotere combination survived a year and a half (18 months), compared to 15 months for patients treated with standard mitoxantrone/prednisone.[2]
Treatment of Bone Complications
Patients with advanced prostate cancer can have cancer cells that have spread to their bones, called bone metastases. Bone metastases commonly cause pain, increase the risk of fractures, and lead to a life-threatening condition characterized by an increased amount of calcium in the blood called hypercalcemia. Treatments for bone complications may include bisphosphonate drugs or radiation therapy.
Bisphosphonate drugs: Bisphosphonate drugs can effectively prevent loss of bone that occurs from metastatic lesions, reduce the risk of fractures, and decrease pain. Bisphosphonate drugs work by inhibiting bone resorption, or breakdown. Bone is constantly being “remodeled” by two types of cells: osteoclasts, which break down bone; and osteoblasts, which rebuild bone. Although the exact process by which bisphosphonates work is not completely understood, it is thought that bisphosphonates inhibit osteoclasts and induce apoptosis (cell death) in these cells, thereby reducing bone loss. There is also evidence that these drugs bind to bone, thereby blocking osteoclasts from breaking down bone.Cancer cells release various factors that stimulate osteoclastic activity, causing increased breakdown of bone. By inhibiting osteoclasts, bisphosphonate drugs effectively reduce the detrimental impact that cancer cells have on bone density.
Bisphosphonate drugs that are FDA-approved for the treatment of cancer-related skeletal complications include Zometa® (zoledronic acid) and Aredia® (pamidronate). Of these two drugs, Zometa® appears to demonstrate the strongest activity. An added benefit of Zometa® is that it is administered in a dose ten times lower than Aredia®, which considerably reduces the administration time from several hours to 15 minutes, resulting in a more convenient regimen for patients.
Zometa® has been shown to be a safe and effective treatment in prostate cancer patients with bone metastases. Zometa® significantly reduces the proportion of patients who experience skeletal complications, extends the time to first skeletal complication, and reduces the risk of skeletal complications.[3]
Zometa® also appears to benefit patients with prostate cancer undergoing androgen deprivation therapy, or “hormonal therapy”. Hormonal therapy in the treatment of prostate cancer has been shown to cause bone loss.[4]
Researchers from Massachusetts General Hospital and 5 other medical institutions conducted a clinical trial evaluating Zometa® in patients with localized prostate cancer being treated with androgen deprivation therapy. This study included 106 men who were randomly selected to receive either Zometa® or a placebo for one year. Bone mineral density in the spine, hips, and legs increased among patients who were treated with Zometa® and decreased in patients who received placebo.[5]
To learn more about prostate cancer and bone health, go the the Bone Information Center
Radiation therapy: Pain from bone metastases may also be relieved with radiation therapy directed to the affected bones. The side effects of radiation therapy for relief of bone pain depends on the area of the body being treated. Another method for treatment of bone pain is the use of radioisotopes, such as strontium-89. Strontium-89 is given intravenously and accumulates in the bones where it kills prostate cancer cells by delivering small amounts of radiation. Clinical studies have shown that bone pain and the need for pain medications can be reduced in the majority of patients treated with strontium-89. Since strontium-89 is given by vein, it can affect all bones in the body, whereas external radiation therapy is limited to only small areas of the body. The major side effect of strontium-89 is a reduction in blood cell counts.
Strategies to Improve Treatment
The development of more effective cancer treatments requires that new and innovative therapies be evaluated with cancer patients. Clinical trials are studies that evaluate the effectiveness of new drugs or treatment strategies. Future progress in the treatment of recurrent prostate cancer will result from the continued evaluation of new treatments in clinical trials. Participation in a clinical trial may offer patients access to better treatments and advance the existing knowledge about treatment of this cancer. Patients who are interested in participating in a clinical trial should discuss the risks and benefits of clinical trials with their physician. Areas of active investigation aimed at improving the treatment of recurrent prostate cancer include the following:
New chemotherapy regimens: Because hormone therapy is not curative and only controls prostate cancer for a certain amount of time, efforts are underway to discover more effective systemic chemotherapies. Recently, several chemotherapeutic drugs have demonstrated the ability to kill prostate cancer cells in patients with recurrent cancer. Developing and exploring single or multi-agent chemotherapy agents as a treatment approach for patients with recurrent prostate cancer is an area of active investigation. Taxotere®, Novantrone®, paclitaxel, estramustine and other chemotherapy drugs are being evaluated.
Researchers from Columbia University conducted a trial involving 96 men with rising PSA levels following a radical prostatectomy. Patients received either exisulind chemotherapy or placebo (inactive substance) for one year. Overall, exisulind-treated patients had a significantly greater drop in PSA levels during the study period than patients in the placebo group. Compared with placebo, exisulind significantly suppressed the increase in PSA in all patients. In addition, the rate at which PSA levels in the blood increased was delayed in patients on exisulind by 5.5 months compared with those on placebo. Exisulind was well tolerated.
The results from three clinical studies indicate that the novel agent ABT-627 may help delay the progression of prostate cancer and improve quality of life for patients with hormone-refractory disease. One clinical trial evaluating ABT-627 involved 244 patients with hormone-refractory prostate cancer whose disease was progressing. One group of patients received ABT-627 and the other group received a placebo (inactive substitute). Those taking ABT-627 had the progression of their disease delayed by nearly 70 days compared to those taking a placebo. In addition, the group of patients who received ABT-627 took twice as long for a rise in their prostate specific antigen (PSA) levels (a protein secreted by prostate cancer cells used as an indicator for cancer progression). Few patients experienced mild side effects.
A second clinical trial evaluated ABT-627 and its effects on cancer progression, specifically to the bone in hormone-refractory prostate cancer patients. During this trial, patients who received ABT-627 maintained stable levels of blood “markers”, which are used as an indicator of cancer spread to the bones. Conversely, patients receiving a placebo demonstrated a continued elevation in these markers, indicating a continual progression of cancer spread to the bones.
A third study involving ABT-627 evaluated the effects of this agent on a patient’s quality of life. Patients receiving ABT-627 reported a 30% improvement in quality of life issues over patients who received a placebo.
Combination therapy: The growth of prostate cancers can be slowed, but not eliminated, by using drugs that block the effect of hormones on prostate cancer cells. Combining hormonal therapy with chemotherapy treatment appears promising.
Cryosurgery: Cryosurgery is a new treatment procedure that is still in investigative stages for prostate cancer. Cryosurgery is a technique that kills cancer cells by freezing them with sub-zero temperatures. During this procedure, hollow steel probes, guided by ultrasound, are placed inside and surrounding the cancer. Liquid nitrogen is then circulated through the probes, freezing the cancer cells and creating a ball of ice that surrounds the cancer. Once an adequate ice ball is formed, heated nitrogen is circulated through the probes. This process is then repeated. A heated probe is placed near the urethra throughout the freezing process so that the urethra is protected during the entire procedure. It is believed that cryosurgery creates cancer- killing effects through 3 distinct processes. First, ice crystals formed within cells are known to be lethal to nearly all cells. Second, when the ice forms around the cell, it draws water out of the cell which collapses many of the walls or membranes within the cell. Third, when the ice surrounding the cells melts through the heating process, the water rushes back into the shrunken cell and causes it to burst.
Researchers from Canada recently conducted a clinical trial evaluating cryosurgery in 118 patients with prostate cancer who had a local recurrence of their cancer following radiation therapy. Approximately 1.5 years following cryosurgery, 87% of patients were free of cancer according to biopsy results, and 68% of patients had a PSA level of 4 or less. Variables attributing to an unfavorable outcome following cryosurgery included a Gleason score (aggressiveness of cancer) of 8 or greater prior to radiation and cancer that extended outside of the prostate upon diagnosis. Approximately 10% of patients experienced complications from the surgery, including rectourethral fistulas (a passage between the rectum and urethra) and severe incontinence.
Phase I clinical trials: New chemotherapy drugs continue to be developed and evaluated in patients with recurrent cancers in phase I clinical trials. The purpose of phase I trials is to evaluate new drugs in order to determine the safety and tolerability of a drug and the best way of administering the drug to patients. Vitamin D analogues, monoterpenes, flavopirodol, and anti-angiogenesis drugs are currently in development.
Gene therapy: Gene therapy is defined as the transfer of new genetic material into a cell for therapeutic benefit. This can be accomplished by replacing or inactivating a dysfunctional gene or replacing or adding a functional gene into a cell to make it function normally. Gene therapy has been directed towards the control of rapid growth of cancer cells, control of cancer death or efforts to make the immune system kill cancer cells. While there are currently no gene therapies approved for the treatment of prostate cancer, this therapeutic technique offers the hope of changing the way cells function and is beginning evaluation in prostate cancer patients.
References
[1] Tannock I, de Wit R, Berry W, et al.Docetaxel plus Prednisone or Mitoxantrone plus Prednisone for Advanced Prostate Cancer. New England Journal of Medicine. 2004; 351:1502-1512.
[2] Petrylak D, Tangen C, Hussain M, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. New England Journal of Medicine. 2004; 351:1513-1520.
[3] Saad F, Gleason D, Murray R, et al. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. Journal of the National Cancer Institute 2002; 94:1458-1468.
[4] Higano C, Shields A, Wood N, et al. Bone mineral density in patients with prostate cancer without bone metastases treated with intermittent androgen suppression. Urology 2004;64(6):1182-6.
[5] Smith MR, Eastham J, Gleason DM, et al. Randomized controlled trial of zoledronic acid to prevent bone loss in men receiving androgen deprivation therapy for nonmetastatic prostate cancer. Journal of Urology 2003; 169:2008-2012.
[6] Nelson J, Banato A, Battistini B, Nisen P. The endothelin axis: emerging role in cancer. Nat Rev Cancer 2003;3(2):110-116.
[7] Carducci M, Nelson JB, Saad F, et al. Effects of atrasentan on disease progression and biological markers in men with metastatic hormone-refractory prostate cancer: Phase 3 study. Journal of Clinical Oncology, 2004 Annual Meeting Proceedings (Post-meeting edition);22(14S), Abstract #4508.
[8] Lipton A, Sleep DJ, Hulting SM, et al. Benefit of Atrasentan in Men with Hormone Refractory Prostate Cancer Metastatic to Bone. Journal of Clinical Oncology, 2004 ASCO Annual Meeting Proceedings (Post-Meeting Edition);22(14S), Abstract #4687.
[9] Yount S, Cella D, Mulani P, et al. Impact of atrasentan on prostate-specific outcomes with hormone refractory prostate cancer patients. Journal of Clinical Oncology, 2004 ASCO Annual Meeting Proceedings (Post-Meeting Edition);22(14S), Abstract #4582.