Your Prostate Cancer Patient with Bone Metastases: New Understanding, Treatment, and Care

At a symposium held in conjunction with the Twenty-Seventh Annual Congress of the Oncology Nursing Society, three specialists in oncology provided an overview of issues affecting men with prostate cancer and bone metastases. Topics included the pathophysiology of bone metastases, management of skeletal complications, and changes and challenges of advanced prostate cancer.

This program was supported by an unrestricted educational grant from Novartis Oncology.

Speakers

Pathophysiology of Prostate Cancer Bone Metastases  

Prostate cancer, when metastasized, preferentially spreads to the bone, resulting in morbidity and mortality from skeletal complications such as pain, fracture, anemia, and spinal cord compromise. “The pathophysiology of bone metastases is such that prostate cancer cells, osteoclasts, and osteoblasts signal each other via cytokines and growth factors. Through this cell signaling, a ‘vicious cycle’ develops where the tumor and the bone are both stimulated and this ultimately leads to progression of disease,” according to Catherine Van Poznak, MD, Assistant Clinical Physician, Memorial Sloan-Kettering Cancer Center, New York, New York. For this reason, treatment strategies for prostate cancer patients can involve targeting both the prostate cancer cells for an anti-tumor effect as well as the bone to maintain skeletal integrity.

Bone is the organ that provides the structural framework for the body, and helps to maintain both mineral and hematopoietic homeostasis. Normal bone metabolism is characterized by two opposite activities: the formation of new bone by the osteoblast and resorption of old bone by the osteoclast. In healthy adult bone, these processes are continually ongoing, with constant remodeling of the bone matrix and maintenance of the quantity and integrity of bone. Hormones, nutrition, and mechanical stress may influence this remodeling. According to Dr. Van Poznak, in patients with cancer, the remodeling process may be disturbed, resulting in effects such as osteoporosis from the disease or treatment, hypercalcemia of malignancy, or bone lesions from metastases.

Osteoporosis, Bone Metastases, Hypercalcemia of Malignancy
Osteoporosis, which occurs in 28 million Americans, results when bone resorption occurs at a rate greater than bone formation. Osteoporosis is a leading cause of bone fracture, resulting in $10 to $15 billion in healthcare costs annually. In addition, this disease reduces quality of life due to disfigurement, reduction/ loss of mobility, and decreased independence (Marwick 2000). Although osteoporosis is common in postmenopausal women, more than five million men also have this disease. For men with prostate cancer, osteoporosis may have existed before the diagnosis of cancer or they may acquire the disease as a result of the cancer or its treatment. Standard treatments for osteoporosis include diet (calcium and vitamin D) and exercise, hormone therapy, and bisphosphonate therapy (Marwick 2000).

“It appears that prostate cancer cells preferentially seek out bone cells, with 65% to 75% of advanced prostate cancer cases being associated with bone metastases [Coleman 1997],” Dr. Van Poznak pointed out. For the development of distant metastases, the prostate tumor cells need to have the ability to leave the primary site (prostate) and travel via blood or lymphatics, then relocate and grow in the distant organ. When that distant organ is bone, the cell signaling between the cancer cells and bone cells apparently promotes the progression of disease and bone abnormalities. In a vicious cycle of malignancy, the tumor can stimulate the bone microenvironment, the bone itself can release growth factors and cytokines, which in turn can react with tumor cells and further stimulate cancer growth. Bone lesions may be blastic, lytic, or mixed. Lytic metastases are the result of increased bone resorption, while blastic metastases are caused by increased bone deposition. Indeed, prostate cancer is the solid tumor most commonly associated with blastic bone lesions. Osteoblastic metastases most frequently occur in the vertebral column, ribs, skull, and proximal ends of the long bones. Persons with advanced prostate cancer are at risk for skeletal complications of malignancy such as pain, fracture, and spinal cord compression, the need for bone irradiation or surgery, and hypercalcemia.

Hypercalcemia of malignancy, though uncommon with prostate cancer, begins with increased malignancy-related bone destruction and an associated increase in renal tubular resorption of calcium, decrease in urinary calcium excretion, and decrease in bone formation. This leads to abnormally high serum levels of calcium and symptoms of hypercalcemia: nausea, vomiting, dehydration, and altered mental status.

Bone Metastases: Treatment Strategies
In addition to anti-tumor treatments in managing bone metastases, potential targets for maintaining bone integrity may include: 1) interruption of the signaling between the metastatic prostate cells and the bone microenvironment, and 2) targeting the osteoclast itself. Oral bisphosphonates are used for the treatment of osteoporosis and are associated with increased spine, hip, and total-body bone mineral density and with prevention of fractures (Orwoll et al 2000). Intravenous bisphosphonates have also demonstrated efficacy in preventing bone loss in men undergoing hormone manipulation for prostate cancer (Smith et al 2001). Intravenous bisphosphonates have been shown to decrease skeletal complications and their use has resulted in a decrease in morbidity from osseous metastases. “In men with prostate cancer, it is important to ensure the continued development and use of effective therapies not only for targeting the cancer cells but also for helping to maintain bone integrity and enhance quality of life,” Dr. Van Poznak concluded.

Management of Skeletal Complications in Prostate Cancer

“Bone metastases are a major cause of morbidity in men with prostate cancer, causing pain, fractures, and in rare cases hypercalcemia,” said Melissa Goode, RN, BSN, Genitourinary Oncology Clinical Research Nurse Coordinator, Massachusetts General Hospital Cancer Center, Boston. In addition, a mainstay of treatment for metastatic prostate cancer, androgen deprivation therapy (ADT), appears to contribute to these skeletal complications, causing osteoporosis and associated fractures with long-term use. According to Ms. Goode, “Bisphosphonate therapies may play an important role in treating the skeletal complications of prostate cancer, and thus optimizing quality of life for men with this disease.”

Bisphosphonates for Bone Metastases
Although bone metastases from prostate cancer appear osteoblastic on plain radiograph, osteoclast activity also plays a major role in the pathophysiology of prostate cancer-related bone metastases. Bisphosphonate agents work by inducing apoptosis of osteoclasts, and thus can be an important part of the treatment of patients with bone metastases (Figure 1). One bisphosphonate, pamidronate disodium for injection, has been proven effective for the treatment of early bone loss in prostate cancer, but not beneficial for the treatment of bone metastases in prostate cancer. In the past, this agent was the standard of care for patients with multiple myeloma and breast cancer bone metastases. More recently, the U.S. Food and Drug Administration (FDA) approved a new and more potent bisphosphonate, zoledronic acid, for use in the treatment of all bone metastases, including those from prostate cancer. In addition, this agent is infused over a period of 15 minutes, as opposed to the 2 hours needed with pamidronate.

Evaluating the Data
The FDA approval of zoledronic acid for bone metastases associated with prostate cancer was based on the pivotal 039 trial. In this randomized, double-blind, controlled study, men with prostate cancer-related bone metastases and progressive disease after receiving ADT, received either: 1) standard care plus zoledronic acid 4 mg; 2) standard care plus zoledronic acid 8 mg; or 3) standard care plus placebo. Patients received one of these regimens every 3 weeks for 15 months; however, those receiving zoledronic acid 8 mg were switched to zoledronic 4 mg due to renal safety concerns. The primary endpoint was reduction in the number of skeletal-related events, including radiation for bone pain or for the prevention/treatment of pathologic fractures or spinal cord compression; pathologic fracture; change of antineoplastic therapy for bone pain; spinal cord compression; and surgery to the bone. The results showed a significant benefit with the bisphosphonate. Of 643 evaluable patients, 33% of men receiving zoledronic acid 4 mg, 38% receiving 8/4 mg, and 44% receiving placebo experienced one or more skeletal-related events. “In addition, in patients receiving zoledronic acid 4 mg, the improvement remained significant even with the exclusion of pathologic fractures as an event, implying that bisphosphonate therapy may actually prevent the progression of bony metastases,” Ms. Goode explained.

In terms of safety data, zoledronic acid was associated with the transient acute-phase reaction, anemia, and mineral/electrolyte changes that are characteristic of all bisphosphonate therapies. There was also a small excess risk of serum creatinine increase with this agent. “These data indicate that zoledronic acid is well tolerated, and thus far, the only treatment shown to decrease skeletal complications in men with prostate cancer and bone metastases,” Ms. Goode stated.

Future Directions
The positive results of the 039 trial raise an important question for future research: Could earlier bisphosphonate treatment prevent bone metastases? As part of the 704 trial, men who have rising prostate-specific antigen (PSA) levels without radiographically evident bone metastases after ADT (for prostate cancer) will be treated with standard care plus zoledronic acid or standard care plus placebo. The endpoint for this study will be metastases-free survival, and accrual is presently ongoing.

Another important area of future research and treatment is addressing the potential side effects of ADT. Since the advent of PSA screening for prostate cancer, this disease is being detected earlier and ADT administered earlier and for a longer duration. With increased use of ADT comes the increased risk of associated side effects, including osteoporosis and associated fracture. Indeed, Daniell and colleagues (1997) have shown an increased risk for fracture in men with prostate cancer who underwent prolonged ADT, with a cumulative fracture risk of almost 50% (compared with 4% in those not receiving ADT) after 9 years. Other researchers have also documented a decrease in bone mineral density with various ADT agents in the prostate cancer population. Smith and colleagues (2001) have studied the use of pamidronate in men with rising PSA levels and no detectable bone metastases after primary therapy for prostate cancer patients who are being treated with a GnRH agonist. They found that, while GnRH agonist treatment significantly decreases bone mineral density, concurrent treatment with pamidronate prevented bone loss in the hip and spine. A study in the same patient population involved treatment with ADT and zoledronic acid or ADT and placebo. Preliminary results indicate that zoledronic acid may not only prevent bone loss but also increase bone mineral density in this patient population.

In closing, Ms. Goode emphasized that skeletal complications are common in men with prostate cancer, and effective treatments for bone metastases and skeletal side effects of long-term ADT use are essential to achieving decreased morbidity and increased quality of life for men with prostate cancer. Further study of bisphosphonates for their potential to help prevent bone metastases and to increase bone mineral density is needed.

Living with Advanced Prostate Cancer: Changes & Challenges

“A recurrence or progression of prostate cancer often brings more uncertainty and distress for the patient and family than even the initial diagnosis,” said Carol P. Curtiss, RN, MSN, Clinical Nurse Specialist Consultant, Curtiss Consulting, Greenfield, Massachusetts. With the treatment options now available, prostate cancer, even advanced prostate cancer, is a chronic condition. According to Ms. Curtiss, oncology nurses play an important role in helping the patient to face the changes and challenges that arise in living with advanced prostate cancer.

Addressing Psychosocial and Spiritual Issues
Some of the many challenges men with advanced prostate cancer and their families face are coping with a variety of losses and finding hope in their situation. For example, losses may include loss of health, function, or independence. Hope is different for each person and may change from day to day. Patients and families may hope for a long remission, comfort, a good day, or an easy death. Oncology nurses can facilitate this process by asking questions of the patient, to determine what is most important to him right now and in the future.

Assessing and Managing Symptoms
Patients with advanced prostate cancer potentially face many physical changes including pain, fatigue, incontinence, and erectile dysfunction. Using pain as a model, Ms. Curtiss outlined the important issues to address in assessing and managing these and other symptoms. A first step is to discuss the goals of care with the patient and family. This discussion should include information concerning individual preferences and wishes, goals for pain and symptom management, sources of support for the person and family, psychological interventions, and spiritual needs and beliefs. “It is important to ask the patient what goals, values, and hopes he has, and what is important to him now and for the future,” Ms. Curtiss said. In assessing a patient’s pain, oncology nurses should ask the patient whether he has pain and, if so, what he would rate the pain on a 0 to 10 scale. Pain relief, the effects of pain on the person, and the presence of any side effects should also be assessed. In managing pain, oncology nurses should anticipate and prevent pain, manage it aggressively when it occurs, and evaluate pain relief at appropriate intervals. “We need to be persistent in assessing and reassessing, because pain and other symptoms change frequently,” the speaker explained.

In managing pain from bone metastases in men with prostate cancer, several treatment options are available. These include treating the underlying disease with radiation therapy for solitary lesions, radiopharmaceutical agents, hormone therapy, or chemotherapy. In addition, the U.S. Food and Drug Administration has recently approved a bisphosphonate, zoledronic acid, for use in patients with bone metastases. “Once bone metastases are identified, this agent may be given monthly, and may result in strengthening of the bone and reduction in the amount of opioid agents needed for pain,” Ms. Curtiss explained. Studies evaluating whether zoledronic acid might prevent bone metastases are ongoing.

Opioids are the mainstay of management of moderately-severe to severe cancer-related pain. When administering an opioid, physicians and nurses need to consider which agent will best work for the individual. The agent must then be titrated to comfort, administered with a bowel regimen to prevent constipation, and side effects must be aggressively managed. Non-opioids may be added and include non-steroidal anti-inflammatory drugs, acetaminophen, and in some cases, corticosteroids. Examples of nondrug interventions include behavioral interventions, cutaneous stimulation, or assistive devices. The final component of effective pain management is reassessment of pain and pain relief at regular intervals, to verify relief or change the care plan as needed.

Comprehensive assessment and re-assessment is also vital for other symptoms like fatigue, incontinence, and erectile dysfunction. Patients may be reluctant to discuss incontinence or erectile dysfunction. Nurses can assist by asking patients about these issues during routine assessments, and by normalizing these difficulties for the patient. According to Ms. Curtiss, the P-LI-SS-IT model is helpful in assessing the sexual effects of prostate cancer and its treatment. Steps to this model include: Permission (eg, assessment; giving patient permission to discuss sexual issues), Limited Information (eg, education; providing information on what to expect from treatment and side effects), Specific Suggestions (eg, counseling; encouraging communication, symptom management, methods of alternate physical expression), and Intensive Therapy (requires referral for most). “Finally, in assessing these and other physical changes associated with prostate cancer, oncology nurses need to ensure that the emotional, psychosocial, and spiritual needs are also met, with regard to living with advanced disease and, for some, planning for end of life,” said Ms. Curtiss.

In closing, Ms. Curtiss emphasized the importance of patient education for patients and families. Helping patients to navigate the healthcare system, to identify needed knowledge and support, and to make the most of their physician visits can be invaluable in ensuring that symptoms are managed effectively and quality of life is optimal in men living with advanced prostate cancer.