Stage IV (D) Prostate Cancer
A stage IV prostate cancer is said to exist if the final evaluation shows that the cancer has spread to distant locations in the body, which usually includes bones. Stage IV disease may be further classified as the following depending on the extent of the cancer (tumor):
- The tumor has spread to pelvic lymph nodes or is obstructing the ureters (the tubes from the kidneys to the bladder), or both.
- Cancer spread (metastasis) to lymph nodes outside the pelvic area, bone involvement, or spread to other distant parts of the body.
Prostate cancer diagnosed in this stage is often difficult to cure, although patients may live for several years with effective treatment.
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Patients diagnosed with stage IV prostate cancer can be broadly divided into two groups. Patients with cancer locally confined to the pelvis, but involving adjacent organs or lymph nodes have localized stage IV or D1 prostate cancer. Patients with disease that has spread to distant organs, most commonly the spine, ribs, pelvis and other bones have metastatic stage IV or D2 prostate cancer.
Prostate cancer may not be diagnosed until it has invaded adjacent organs, such as the rectum or bladder, or spread to lymph nodes in the pelvis. When this occurs, surgery (radical prostatectomy) is seldom an effective treatment. Current treatment involves a combination of external beam radiation therapy (EBRT) and hormone therapy. Hormone therapy deprives a man’s body of male hormones necessary for prostate cancer to grow. In localized stage IV prostate cancer, hormone therapy and radiation therapy are often given together; however, new treatment strategies that offer patients a chance of cure are needed.
Combined Modality Therapy
Patients with prostate cancer documented to involve the pelvic lymph nodes have an average time to cancer progression of approximately 18 months and this is reduced to less than 12 months in patients with high-grade cancer. Historically, standard treatment of these patients has involved hormonal therapy, surgery or radiation therapy. Treatment with either hormonal therapy or radiation therapy is associated with an approximate 55% chance of patients surviving 5 years without evidence of cancer progression, compared to approximately 20-40% for patients treated with surgery.
It has been demonstrated in several other cancers that multi-modality treatments that use combinations of chemotherapy, surgery, radiation and hormonal therapy improve cure or survival rates compared to treatment with a single therapy. In order to evaluate whether combination therapy could be beneficial in the treatment of prostate cancer that involves pelvic lymph nodes, a clinical study compared radiation therapy followed by immediate hormonal therapy to radiation therapy followed by delayed hormonal therapy, which was initiated only at the time of cancer progression.
Patients treated with radiation therapy and immediate hormonal therapy were more likely to be alive 5 years from initiation of treatment without evidence of cancer progression or development of distant metastatic disease than patients treated with radiation and delayed hormonal therapy. Both treatments, however, produced a similar chance of survival 5 years following treatment. The results of this clinical study suggest that the combination of radiation therapy and hormonal therapy reduces the time to cancer recurrence and development of metastatic disease, and may improve a patient’s quality of life. The combination of radiation and immediate hormonal therapy increased the survival of some patients.
Clinical studies are ongoing comparing hormonal treatment to radiation treatment alone to determine whether radiation is necessary. Perhaps of greater interest, however, is whether the addition of other anti-cancer treatments directed at controlling cancer that has spread away from the prostate could improve the outcome of patients when combined with hormonal therapy, radiation therapy, or both. In other cancers, delivery of systemic treatment (hormonal therapy or chemotherapy) prior to radiation therapy has been demonstrated to improve both local control of the cancer and long-term cancer-free survival. Delivery of hormonal therapy or chemotherapy prior to radiation treatment (neoadjuvant therapy) may also be a more promising way to combine these treatment approaches.
Prostate cancer that has spread to distant organs and bones is treatable, but not curable with current standard therapies. Hormonal therapy has been the standard treatment of metastatic prostate cancer for many years. Metastatic 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 despite the hormone therapy. To learn more, go to Hormonal Treatment of Prostate Cancer.
Some patients with metastatic prostate cancer may not have any symptoms from their cancer. Previously, many of these patients were “observed” and only treated when problems did eventually develop. The results from a clinical study conducted by doctors in England comparing immediate hormone treatment to hormone treatment at the time of worsening cancer has shown improved survival for men treated immediately compared to those receiving treatment at the time of cancer progression. Complications from metastatic prostate cancer were also less frequent in men receiving immediate treatment. Patients with metastatic prostate cancer are currently being treated with hormone therapy using medications or orchiectomy soon after diagnosis.
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.
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.
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.
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.
 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.
 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.
 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.