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© 2003 The Journal of Bone and Joint Surgery, Inc.
What's New in Musculoskeletal Oncology
Kristy L. Weber, MD The field of orthopaedic oncology encompasses the care of patients with benign and malignant bone and soft-tissue neoplasms, who are usually managed by orthopaedists with special training in this area. However, a much larger group of patients includes those with carcinomas that have metastasized to bone, who are treated not only by orthopaedic oncologists but also by general orthopaedists. The past two updates focused on (1) biological advances in the diagnosis and prognosis of sarcomas and (2) functional outcomes and quality-of-life measures after limb-salvage surgery. This year, the focus will be on current developments in the treatment of metastatic disease, with specific emphasis on staging, surgical treatment, and the interaction of tumor cells with the bone microenvironment. To illustrate the rapidly advancing science in this area, recent biologic findings and their clinical implications will be reviewed. Metastatic Bone Disease The field of musculoskeletal oncology involves the care of patients with primary bone and soft-tissue neoplasms as well as those with metastatic disease from cancers in visceral sites. Primary bone tumors represent a small percentage of the neoplasms in patients with bone cancer. Nearly 1.3 million cases of cancer were diagnosed in 2001, of which about 50% had the potential to spread to the musculoskeletal system. In comparison, 2900 primary bone tumors and 8700 primary soft-tissue tumors were diagnosed during this period 1 . Whereas great strides have been made in the treatment of osteosarcoma, with improvement in overall survival and the development of limb-sparing surgery, the treatment of bone metastases remains primarily palliative. Metastasis to the skeleton can cause substantial morbidity, including pain, pathologic fractures, neurologic deficits, anemia, and hypercalcemia secondary to bone lysis and forced immobilization. Patients lose their ability to walk, to perform necessary activities of daily living, and to use external walking aids. Therefore, the goals of treatment have been pain relief and maximal functional restoration for the remaining life of the patient. Medical treatment with chemotherapy and bisphosphonates, radiation or radioisotope treatment, and surgical intervention have been the primary methods used to achieve these goals. Recent improvements in our understanding of the biological and molecular mechanisms involved in bone metastasis may lead to improved methods of early diagnosis and treatment. Biology of Bone Metastasis Metastasis from a primary site is the main cause of mortality associated with most cancers. Tumor cell movement from the primary organ of involvement to distant sites is not random. Sir James Paget's "seed and soil" hypothesis in 1889 held that different end organs provided optimal environments for specific cancers. The specific mechanisms involved in determining why certain cancers metastasize to bone are largely unknown, but exciting new findings relative to the biology and mechanisms of metastasis may eventually lead to therapeutic interventions that will target the metastatic process. Current treatment efforts are palliative and are focused on the inhibition of bone destruction to minimize the morbidity induced by bone metastasis. There are many steps that a tumor cell takes between its primary site and its eventual growth in the bone microenvironment. Tumor cells must have the capacity to detach from their primary site, to produce or induce proteolytic enzymes that allow them to move through the extracellular matrix and enter the circulation, to migrate to the bone, to attach to the stroma, and to induce osteolysis 2 . Tumor cells produce a wide variety of cytokines, proteases, and growth factors. A recent study showed that breast cancer cells that had been selected for their ability to grow in bone and brain exhibited different biological properties that allowed them to maintain specificity to their particular organ of metastasis 3 . The targets for these tumor cell-produced factors include bone-derived endothelial cells, stromal cells, osteoblasts, osteoclast precursors, and osteoclasts. In a recent laboratory study, osteoblast-like cells were found to produce factors that induce nonmetastatic prostate cancer cells to assume a molecular phenotype found in prostate cancer cells derived from a bone metastasis 4 . Those authors found that genes primarily involved in motility, metabolism, signal transduction, tumorigenesis, and apoptosis were differentially expressed after exposure to these soluble factors. Multiple autocrine or paracrine pathways are likely to be involved in tumor growth within the bone that results in bone destruction. Why do certain tumor cells have a predilection to metastasize to bone? One explanation is that adhesion molecules are involved in cell-cell attachments thought to be important in bone metastasis. By modulating cell adhesion molecules, invasiveness, implantation, and mobility may be affected. Haq et al. 5 used an intracardiac injection model to determine that a metastatic prostate cancer cell line preferentially adhered to bone-derived endothelial cells as opposed to osteoblasts or hepatic endothelial cells. This supports the finding that organ-specific endothelial cells play a role in determining the development of metastasis. Laminin is an important glycoprotein that is involved in the attachment of tumor cells to basement membranes. Studies have shown that metastatic lesions increase in multiple organs in the presence of laminin. A study involving an intracardiac injection model of metastatic melanoma cells revealed that intraperitoneal injection of a laminin antagonist decreased the formation of osteolytic bone metastasis 6 . Once a tumor cell reaches a site of skeletal attachment, it interacts with the extracellular matrix. A vicious cycle occurs in which tumor-produced factors act on the surrounding bone, which, in turn, produces additional factors to stimulate tumor cell growth. The invasive nature of metastatic tumor cells allows them to produce proteolytic enzymes and to degrade collagen and the extracellular matrix. Tumor cells produce various proteases such as metalloproteinases (MMPs), which are involved in bone matrix turnover and stimulate the proliferation of tumor cells 7 . MMP-2 and MMP-9 can degrade type-I collagen in the absence of osteoclasts and are overexpressed in many cancers, including breast and prostate cancer. MMP-3 can activate other MMPs, such as MMP-1 and MMP-9. It has been shown that inhibition of MMP production by tumor cells can decrease osteolysis 8,9 . In a prostate cancer model involving nude mice, inhibition of MMP activity with use of batimastat, a broad-spectrum MMP inhibitor, decreased tumor cell proliferation, recruitment of osteoclasts, and bone matrix degradation 9 . Similar findings were shown in a breast cancer model involving the use of batimastat 8 . The authors proposed that, in a clinical situation, MMP inhibitors should be given prior to the discovery of bone metastasis in order to prevent lytic bone destruction. Overexpression of natural MMP-inhibitors such as the tissue inhibitor of MMP-2 (TIMP-2) has also been shown to be effective in reducing osteolytic lesions in a breast cancer model 10 . The urokinase plasminogen activator (uPA) system is also believed to be an important pathway in the development of metastasis of breast, lung, and prostate carcinomas as well as lymphoma and various soft-tissue sarcomas. One study of paraffin-embedded normal breast tissue and breast cancer tissue showed that increased uPA, its receptor (uPAR), and plasminogen activator inhibitor type-1 (PAI-1) predicted a poor prognosis. Factors within this system have both proteolytic and nonproteolytic actions, which may be associated with interaction of this pathway with matrix proteins in the bone microenvironment 11 .
Tumor cells also produce cytokines such as interleukins (IL-1, IL-6, IL-8) and tumor necrosis factor-alpha (TNF- Two pathways that have recently been further characterized namely, the receptor-activated NF-kappa B ligand (RANKL)/osteoprotegerin (OPG) pathway and the parathyroid hormone-related peptide (PTHrP)/transforming growth factor-beta (TGF-ß) pathway hold promise for treatment. Osteoblasts and marrow stromal cells produce RANKL, a member of the TNF gene family, which binds to the RANK receptor on osteoclast precursors. RANKL, a cytokine that is a critical regulator of osteoclast differentiation and activation, activates intercellular signaling proteins (NFkB and JNK kinase) to induce osteoclast differentiation and activation. Mice that do not express RANKL have osteopetrosis and an absence of osteoclasts, and transgenic mice that overexpress the factor have severe osteoporosis. Samples from human osteolytic bone metastasis immunostained for RANKL showed the presence of the factor in the tumor cells 13 . OPG is a soluble decoy receptor and a member of the TNF receptor superfamily that acts as an antagonist to RANKL 14 . OPG inhibits osteoclast activation, thereby blocking bone destruction. Therefore, RANKL and OPG are both produced by factors in the bone marrow microenvironment, and the ratio of one to the other regulates osteoclast formation and activity. OPG has been shown to decrease tumor-associated osteoclasts and to prevent osteolytic lesions in mouse models of colon and breast cancer metastasis to bone 15 . A randomized, double-blind, placebo-controlled, sequential dose-escalation study of postmenopausal women showed that a single subcutaneous dose of OPG effectively caused a prolonged reduction in bone turnover as monitored by markers of collagen degradation 16 . This work suggested that OPG may be effective for the treatment of bone diseases that are characterized by increased bone resorption such as osteoporosis and may have implications for patients with bone metastasis as well. There has been recent compelling work to support a role for transforming growth factor-beta (TGF-ß) in the metastasis of breast cancer to bone 17,18 . This growth factor is released from bone by the action of osteoclasts and acts directly on the tumor cells. TGF-ß stimulates the breast cancer cells to produce parathyroid hormone-related protein (PTHrP). This protein stimulates osteoclast formation in the presence of marrow stromal cells by inducing the production of RANKL. TGF-ß induces PTHrP through both the Smad and mitogen-activated protein (MAP) kinase pathways 18 . Smads and MAP kinase pathways are downstream intracellular effectors that relay the signal from the cell membrane to the nucleus, where they affect the transcription of target genes 19 . There are multiple possible targets along these pathways that may be promising for therapeutic intervention to decrease bone destruction. An antibody to PTHrP decreased bone destruction, osteoclastic resorption, and tumor growth in a mouse model of breast cancer metastasis to bone 18 . Growth factors and their receptors are frequently produced and overexpressed, respectively, by tumor cells. Similar to the findings in studies of breast cancer, TGF-ß1 and TGF-ß2 are found in prostate cancer cells and have stimulatory effects on osteoblasts 20,21 . The bone morphogenetic proteins (BMPs) are members of the TGF-ß superfamily. Several BMPs are produced by prostate cancer cells and are potent stimulators of bone formation. Some or all of these factors may play an important role in the osteoblastic lesions found in metastatic prostate cancer. Fibroblast growth factor (FGF) is also highly expressed in prostate cancer cells 22 and is known to stimulate osteoblast proliferation and bone formation 23 . Fibroblast growth factor inhibits osteoclastic resorption, leadin to a net increase in bone as is found in osteoblastic metastasis. Many tumor cells produce vascular endothelial growth factor (VEGF), which has a stimulatory effect on host endothelial cells, leading to increased blood vessel formation or angiogenesis. This contributes to tumor growth in the bone as well as in other organ environments. Recently, targeted therapy of signal transduction pathways has been successful in the treatment of several types of cancer. Imatinib mesylate (Gleevec), a small molecule tyrosine kinase inhibitor that selectively targets critical components of cancer cell growth while minimizing host toxicity, has been found to be effective for the treatment of gastrointestinal stromal tumors 24 . Preliminary work has shown that Gleevec also may be effective for inhibiting the platelet-derived growth factor receptor (PDGF-R) found on metastatic prostate cancer cells in bone 20 . The biology of osteoblastic bone metastasis is less well understood. Prostate and breast cancer are the prototypes that cause bone-forming metastasis. Animal models of osteoblastic metastasis of prostate and breast cancer are available. Extracts from certain prostate cancer cell lines have induced mitogenesis in osteoblast-type cells and proliferation in fibroblasts 25 . With further development of animal models to study osteolytic and osteoblastic metastasis, our knowledge of the relevant pathways involved in tumor-induced bone destruction will improve. Better understanding of the biology of metastasis ideally will translate into novel, specific treatments with cytotoxic agents, small molecule inhibitors, anti-angiogenic therapies, vaccines, and gene therapy. Diagnosis There have been improvements in our ability to stage metastatic disease with use of advanced, functional radiographic techniques such as positron emission tomography (PET) scanning. Labeling a radiopharmaceutical that closely mimics an endogenous molecule such as glucose allows for the evaluation of tumor cell metabolism. 2-[18F]-fluoro-2-deoxy-D-glucose (FDG) is metabolized similarly to glucose and is readily taken up by tumor cells. FDG-positron emission tomography scanning has demonstrated increased specificity and accuracy when compared with traditional scintigraphy 26 . In the future, there will likely be a fusion of FDG-positron emission tomography and computerized tomographic or magnetic resonance imaging techniques to allow anatomic images to be combined with imaging of the areas of increased metabolic uptake. When a patient is diagnosed with a bone metastasis and no primary lesion is readily identified, routine histological analysis may be inadequate for determining the origin of the tumor. Immunostaining techniques can help to pinpoint the location of the primary tumor 27 . Thyroid transcription factor 1 (TTF1) is indicative of bronchogenic and thyroid adenocarcinoma 28 , whereas CK20 is more indicative of colon carcinoma 29 . cDNA microarray analysis is a powerful and highly sensitive new technique used to analyze gene expression in a given sample of mRNA derived from a tumor that is compared with a carefully selected control. Currently, sarcomas are starting to be subclassified on the basis of their genetic features and chromosomal abnormalities (e.g., translocations) in addition to their light microscopic appearance and histological profile. Although microarray technology is being applied to metastatic lesions when a primary lesion cannot be determined with conventional techniques, the tissue is often so poorly differentiated that expression profiles may yield little additional information. One important use for microarray studies in the diagnosis of metastatic disease may be to improve our understanding of the pathogenesis of a given tumor's propensity to metastasize to a certain organ system. For example, in a recent study, cDNA microarray analysis was used to compare prostate cancer cell lines derived from bone with those derived from soft tissue from the same patient 30 . Protease-activated receptor 1 (PAR1) had increased expression in the bone-derived cell line that was confirmed to be functional with additional in vitro studies. Currently, there are no reliable markers to predict which primary tumors will spread to bone. Comparisons between matched human primary and metastatic lesions may help to identify factors that will assist in diagnosis or prognosis for these patients. Historically, there have been no reliable urine or serum markers with which to identify the presence of bone metastasis or to follow the progression of disease. New studies evaluating biochemical markers of bone turnover have revealed promising data 31,32 . N-telopeptide (NTX) and C-telopeptide (ICTP) are peptide-bound collagen type-I cross-links that arise from mature collagen degradation and reflect bone breakdown. There have been conflicting results with regard to which of these markers is most predictive in detecting bone metastasis or disease progression. Urine NTX can also be used to assess the inhibitory effect of bisphosphonates on osteoclastic bone resorption 32,33 . Most authors have suggested that these markers should be used in conjunction with serial bone surveys or bone scans. Another possible predictive marker in patients with prostate cancer is plasma TGF-ß. This factor is markedly elevated in patients with metastasis to lymph nodes or bone. Patients with elevated levels of TGF-ß and no known metastasis were found to have a high likelihood of subsequent disease progression 34 . Plasma osteopontin has also been shown to correlate with the extent of disease and the rate of survival in patients with breast and prostate carcinoma 35 . Treatment
Medical The medications that are currently used to treat primary carcinomas may or may not be effective for the prevention or treatment of bone metastasis. Therapies specifically targeting the bone lesions associated with multiple myeloma or metastatic carcinoma have improved markedly with the advent of nitrogen-containing bisphosphonates. These compounds inhibit osteoclastic bone resorption, thereby decreasing the likelihood of pain and pathologic fractures. In general, they do not have a direct effect on tumor growth. In one study, 380 randomized patients with breast cancer that had metastasized to bone were given either a placebo or a two-hour monthly infusion of pamidronate for one year 38 . The pamidronate group had significantly better results with regard to the median time to initial skeletal complications, the number of skeletal complications, bone pain, and performance status (p < 0.05). In a twenty-four-month follow-up study of these same patients, the skeletal morbidity rate (expressed as the number of events per year) was 2.4 in the pamidronate group and 3.7 in the placebo group (p < 0.001) 39 . Skeletal complications occurred in 51% of the patients in the pamidronate group, compared with 64% of those in the placebo group (p < 0.001). Pain and analgesic scores in the placebo group were significantly worse than those in the pamidronate group (p < 0.001). Pamidronate is still commonly used for patients with metastatic breast cancer, but the newest clinically available bisphosphonate, zoledronic acid (Zometa), is being used for patients with multiple myeloma, renal cell carcinoma, and breast cancer. Zoledronic acid has been shown to be 100 to 850 times more potent than pamidronate in both in vitro and in vivo models in which indices of bone resorption were assessed. A phase-I study involving the use of monthly infusions of zoledronic acid showed that it was safe, well tolerated, and resulted in dose-dependent decreases in urine markers of bone resorption 40,41 . For patients with bone metastasis, a combined therapeutic approach involving the use of standard chemotherapy to decrease the spread of tumor cells and bisphosphonates to inhibit osteoclastic bone resorption should be employed. A preclinical study involving the use of the bisphosphonate ibandronate and breast cancer cells transfected with TIMP-2 revealed that the combination of these treatments was most effective for inhibiting osteolytic bone lesions in a mouse model 10 . Bisphosphonates have also been proven to be beneficial in the treatment of patients who have multiple myeloma but, because there have been no direct comparisons between clodronate and pamidronate or zoledronic acid, the superiority of one agent over another is unclear. Currently, intravenous pamidronate or zoledronic acid is recommended for patients with myeloma 40 .
Radiation Another nonoperative option that has been used to decrease pain in patients with bone metastasis is the administration of radioisotopes 45 . This method can address all sites of osteoblastic or mixed metastasis and can decrease the doses of external beam radiation needed at a specific site. It is performed as a single therapy, which can be repeated. The use of these radiopharmaceuticals has been associated with improved mobility, decreased use of narcotic analgesics, improved performance status and quality of life, and, in some reports, improved survival. These compounds target the osseous sites of metastases but have a low concentration in normal bone and other surrounding tissues. The treatments can decrease blood cell counts and must be used with caution in patients receiving cytotoxic chemotherapy. Strontium-89 is an electron (beta particle)-emitting radioisotope with a half-life of fifty days. It is incorporated into remodeling bone by osteoblasts as it is chemically similar to calcium. Tu et al. recently reported improved survival in a group of patients with prostate cancer that was metastatic to bone who received strontium-89 and doxorubicin weekly for six weeks 46 . This therapy was effective when given to patients in whom the disease was stable or responding after induction chemotherapy. Samarium-153 EDTMP has both beta and gamma emission and has a similar half-life to strontium-89. EDTMP is a bisphosphonate complex that is added to the radioisotope and that binds to the remodeling bone. In addition to its use in patients with metastatic disease, high-dose samarium has been shown to be effective in some patients with skeletal metastases from osteosarcoma 45,47 .
Surgical
Minimally Invasive Techniques Innovative techniques such as vertebroplasty and kyphoplasty have been associated with substantial pain relief in patients with vertebral collapse secondary to metastatic disease. Vertebroplasty involves the injection of polymethylmethacrylate cement into the cancellous bone of the vertebra, whereas kyphoplasty involves the percutaneous placement of an inflatable bone tamp into the fractured vertebral body. As the tamp is inflated, vertebral body height is restored and a cavity is created within the vertebral body. This cavity is filled with cement under low pressure, restoring vertebral height. A recent study demonstrated less vascular and transcortical extravasation of injected contrast medium in association with kyphoplasty than in association with vertebroplasty 49 . Dudeney et al. reported on eighteen patients with multiple myeloma who had fifty-five consecutive kyphoplasty procedures for pathologic vertebral compression fractures50. There were no major complications, 34% of lost vertebral height was restored, and there was early clinical pain relief. A more recent application of this technique is percutaneous acetabuloplasty, which may prove beneficial in providing pain relief and avoiding major reconstruction in selected patients with lytic acetabular metastases 51 .
Standard Operative Procedures One of the recent controversies in the surgical management of metastatic bone disease is whether resection of a solitary metastasis in the bone will improve overall survival. Studies of patients with renal cell carcinoma have shown improved survival after the resection of a solitary metastasis in the bone 54-56 . The benefit was most often noted if there had been a long interval between the treatment of the primary renal carcinoma and the development of the metastasis and if the metastasis was in a nonpelvic location. Since renal cell carcinoma tends to be relatively resistant to radiotherapy, there has been a trend toward resection of solitary metastases in patients with renal carcinoma if the morbidity is not deemed to be too severe. Other studies have not supported such an approach 57 , and whether this approach is reasonable for renal cell carcinoma and other carcinomas such as breast carcinoma deserves further study. Other candidates for resection include patients with extensive lesions in whom secure fixation is questionable, those with radioresistant lesions that are likely to progress, and those with failure of previously placed fixation. The recently developed intercalary metal spacer is helpful when a patient has had resection of a large diaphyseal lesion as it allows the adjacent joints to be spared 58 . Additional engineering advances in prosthetic devices have allowed more options and improved fixation in patients with bone metastasis. Increased modularity, improved joint design, extracortical bone-bridging, and a potential for tendon and soft-tissue attachments have all improved the current implants. A relatively new metal used in total joint replacements, tantalum, may allow more secure fixation in selected patients 59 . In the future, the increased ability to surgically stabilize or remove metastatic disease must be weighed against improvements in quality of life. Outcome measurements that are available for use in clinical research have been utilized in the evaluation of patients with sarcoma. Large studies will be necessary to better identify when to operate and how aggressive the surgery should be. With advances in the earlier diagnosis and treatment of cancer, patients will survive longer with their disease. There will be more patients living with bone metastasis in the future. This subset of patients can present with decreased quality of life, pain, fractures, neurologic compromise, and an inability to perform their normal daily activities. Orthopaedic surgeons are an integral part of the multidisciplinary team necessary to treat these patients, especially to provide pain control and to allow improvement in function. Recent advances in understanding the molecular mechanisms involved in osteolytic bone destruction, improved diagnosis and staging of disease, and treatment with a combination of chemotherapy, bisphosphonates, radiation, and surgery have improved our ability to treat patients who have metastatic bone disease.
References
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), which are involved in the stimulation of osteoclastic bone resorption
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