ABSTRACT: With recent advances in the management of cancer, the clinical course of patients with metastatic bone disease is more likely to be prolonged and accompanied by morbidity, including severe pain, hypercalcemia, pathologic fracture, and spinal cord and/or nerve root compression. The early identification of patients at higher risk for developing bone metastases enables practitioners to be proactive in their diagnosis and treatment. A multidisciplinary approach that integrates the diagnosis and treatment of the cancer, symptom management, and rehabilitation ensures optimal care. Bisphosphonates can reduce the number of skeletal-related complications, delay the onset of progressive disease in bone, and relieve metastatic bone pain caused by a variety of solid tumors with a resulting enhanced quality of life. The complexity of the clinical problem and the need to involve an array of health-care providers present a logistical and clinical challenge. A strong argument is made for a thematically integrated bone metastases program as part of the primary care of patients with cancer.
Bone metastases are most commonly associated with tumors of the breast, prostate, lung, and kidney, and with multiple myeloma. Bone metastases can also occur in association with other solid tumors. The spread of any cancer to bone can cause significant morbidity, including severe pain, hypercalcemia, pathologic fracture, and spinal cord and/or nerve root compression. Randomized trials have determined that major skeletal events occur in patients with advanced breast cancer, on average, every 3 to 4 months, with 45% to 75% of patients developing pain and functional disability. Hypercalcemia occurs in 10% to 15% of patients, and fracture occurs in 10% to 20% of those with long bone metastases.[2,3]
Interdisciplinary assessments and interventions can result in improvement in quality of life and a decrease in the incidence of additional bone complications. However, the logistics and practicality of interdisciplinary assessments and interventions in this patient population are challenging. Physicians caring for patients with bone metastases should have ready access to all practitioners who can contribute to appropriate management. In addition to medical management, patients with bone metastases should be managed in the context of "whole/total" care, with the emphasis on psychosocial adaptation and quality of life.
Clinical pathways should be developed with early assessment and intervention for patients at higher risk for bone metastases (Figure 1), or with evident metastases, ensuring access, evaluation, and treatment by the full range of health-care providers. Such a team may include primary care physicians, medical/radiation/surgical oncology specialists, orthopedic surgeons, physiatrists, advanced practice nurses, social workers, and physical therapists.
That said, few health-care systems have formalized clinical pathways for the management of bone metastases. The object of this paper is to review the evidence for multidisciplinary care of patients with bone metastases.
Pathophysiology of Bone Metastases
Roodman reviewed the biology of the osteoclast and the pathophysiology of bone metastases and provided a foundation for clinical management.[ 4] The fundamental hypothesis of the development of bone metastases is that an interaction between tumor and bone cells leads to an increase in bone destruction and proliferation of tumor cells within the bony compartment. Local production of osteolytic factors by cancer cells in bone stimulates osteoclast-mediated bone resorption, which induces the produc tion of numerous growth factors and stimulates secretion of osteolytic cytokines, resulting in local foci of osteolysis.
The tumor and cancer cytokines have both a local and systemic impact. Locally, the tumor can stimulate osteoclasts in the microenvironment to produce interleukin (IL)-6, IL-1, tumor necrosis factor (TNF)-alpha, and macrophage inflammatory protein- 1-alpha. Systemically, the tumor can produce parathyroid hormonerelated protein, the mediator of the humoral hypercalcemia of malignancy. The combination of these effects can induce further stimulation of cancer cell growth, initiating a vicious cycle. Bone resorption may also play a role in formation of the osteoblastic lesions in patients with prostate cancer and occasionally in patients with other cancers.
Bone metastases in women with breast cancer are a major clinical issue. Of the 200,000 women who are diagnosed with breast cancer annually in the United States, approximately 30% will develop bone metastases. Body's review of bone metastasis statistics in women with breast cancer provides the rationale for early assessment and intervention. The bones are the most common site of metastatic disease, both at initial presentation of metastases and as a site of first recurrence. The common sites of bone metastases in decreasing order of probability are the thoracolumbar spine, pelvis, lower extremities, upper extremities, and skull.
Body and others estimate that among women with bone metastases as their first site of recurrence, approximately one-third can expect to develop major complications. The probability of bone complications is greatest in patients with bone-only disease compared to patients with extraosseous first recurrences, 81% vs 21%. The incidence of fractures is more common in women with breast cancer than in men with prostate cancer, because fractures are more common in lytic than in blastic bone metastases.
A rationale for proactive management in women with breast cancer and bone-dominant metastases is provided by the observation that these women have a better prognosis than those without bone metastases, can expect a major skeletal event on average every 3 to 4 months, and usually live beyond 2 years. Indeed, approximately 10% live 5 to 10 years from the diagnosis of bone metastases. In other words, women with initial presentations involving bone metastases as opposed to other sites show increased survival times, with a median survival of 48 months compared to 17 months. Women who have bone-only disease are more likely to be older, to have axillary node involvement, and to have lobular carcinoma.
The International Breast Cancer Study Group (IBCSG) has formulated risk assessment guidelines for breast cancer patients. Their study evaluated patterns of recurrence among 6,792 patients included in IBCSG trials of adjuvant treatment and found that the highest cumulative incidence of bone metastases occurred among patients presenting with four or more positive axillary nodes at the time of diagnosis (15% at 2 years and 41% at 10 years) and among those who had a locoregional recurrence or a recurrence in soft tissue as their first event, without other evident metastases (22% at 2 years from first recurrence and 37% at 10 years). The authors proposed that this higher-risk subset of patients could benefit most from early assessments and interventions for bone metastases.
Bone metastases from prostate cancer differ significantly from those of other primary cancer sites, in light of the usual occurrence of both osteoblastic and osteolytic lesions. Predictors of skeletal morbidity are generally thought to be the extent of bone involvement, the severity of pain, the patient's overall performance status, the serum alkaline phosphatase level, the urinary deoxypyridinoline level (which maintained its significance in a multivariate analysis), and androgen deprivation.
Dawson and others have provided statistics demonstrating the profound impact of bone metastases on men with prostate cancer. For example, 80% of men who die of prostate cancer have bone metastases at autopsy, and bone pain is a clinical problem in 88% of such patients. In a prospective study of 112 men with hormone-refractory prostate cancer and bone metastases, 30% had documented skeletal complications at death or last follow-up (at an annual incidence of 12%). In 18%, the complication involved vertebral collapse or deformity, 9% had pathologic fractures, and 6% had spinal cord compression. The median time to initial skeletal complication was 9.5 months.
With the availability of prospective clinical trials in men with bone metastases from prostate cancer, we now have data to predict skeletally related events. In a 15-month prospective study period of observation alone in prostate cancer patients with bone metastases, 44% had at least one skeletal event, 22% had a fracture, and the time to first occurrence of any skeletal event was 321 days. These statistics put into perspective the importance of reducing skeletally related events and morbidity in this high-risk population.
Multiple myeloma, which is newly diagnosed in approximately 14,000 people per year in the United States, is another cancer in which skeletal complications are clinically important. The mechanisms of bone destruction are related to cytokines produced by the myeloma cell and normal bone marrow stromal cells. The important bone resorbing factors are thought to be IL-1, IL-6, TNF, and the receptor for activation of nuclear factor kappa- B ligand.[13-15] The increased osteoclastic activity in the bone marrow causes loss of bone structure and pathologic fractures, hypercalcemia, and pain. The radiographic appearance is almost always purely lytic with little or no osteoblastic component and is more likely to fracture, resulting in significant morbidity. These fractures are most troublesome when associated with collapse in the vertebral spine.
Other Tumor Types
Bone-related complications occur in other solid tumors as well. Approximately 30% to 60% of patients with advanced lung cancer develop bone metastases. Among patients with invasive bladder cancer, 22% develop bone metastases, and of patients with locally advanced or metastatic renal cancer, 35% have bone metastases at their initial diagnosis.[ 18] Aggressive solid tumors are often refractory to current therapies, and treatment of the primary cancer rarely achieves responses in bone. Furthermore, bisphosphonates have not been extensively studied in these patient populations.
Bone Metastasis Markers
Markers of bone metastases could potentially be used to establish the diagnosis and/or to predict which patients are at higher risk. In general, the ability to associate specific biomarkers with the presence of or increased likelihood of developing bone metastases has value. These bone biomarkers could either be elevated in patients with bone metastases or related to tumor-specific markers. Bone markers would be of value for early detection and follow-up to assess the clinical course of metastatic bone disease. These markers could also provide targets for novel therapeutic approaches that interfere with growth and enhance apoptosis in bone stromal compartments.
Immunohistochemical methods may offer useful predictors of patients at higher risk for bone relapse. Although not validated in large numbers of patients, elevated serum levels of bone sialoprotein and parathyroid hormone- related protein appear to correlate with an increased incidence of bone metastases in breast cancer patients. More recent studies have supported this hypothesis by demonstrating that serum bone sialoprotein level is the most important independent prognostic marker for subsequent development of bone metastasis in patients with breast cancer.
Other studies have shown that transforming growth factor (TGF)- beta-1 levels are increased in prostate cancer patients with metastases to regional lymph nodes and bone. In men without clinical or pathologic evidence of metastases, an elevated preoperative plasma TGF-beta 1 level is an independent predictor of progression and associated with occult metastatic disease. Elevated preoperative levels of IL-6 and soluble IL-6 receptor may also be associated with bone relapse in men with prostate cancer.
Fewer studies exploring markers of bone metastases in primary lung cancers have been published. Izumi et al demonstrated that urinary pyridinoline cross-linked N-telopeptides of type I collagen may be the most useful biomarker in the assessment of bone metastases in patients with lung carcinoma.
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