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Management of Metastatic Bone Disease Algorithms for Diagnostics and Treatment ANTICANCER RESEARCH 36: 2631-2638 (2016) Review Management of Metastatic Bone Disease Algorithms for Diagnostics and Treatment CHRISTIAN F. JEHN1, INGO J. DIEL2, FRIEDRICH OVERKAMP3, ANDREAS KURTH4, REINHOLD SCHAEFER5, KURT MILLER6 and DIANA LÜFTNER1 1Department of Hematology, Oncology and Tumor Immunology, University Hospital Charité, Berlin, Germany; 2Practice for Medical Oncology and Gynaecology am Rosengarten, Mannheim, Germany; 3Practice for Medical Oncology, Recklinghausen, Germany; 4THEMISTOCLES GLUCK Hospital Ratingen, Ratingen, Germany; 5Practice for Urology Bonn-Rhein-Sieg, Bonn, Germany; 6Department of Urology, University Hospital Charité, Berlin, Germany Abstract. Background: Bone is a frequent site of metastases Structural integrity of the bone is meticulously regulated in advanced cancer and is associated with significant skeletal through the actions of osteoclasts and osteoblasts. The morbidity. Current treatment options are aimed at preserving dynamics of bone resorption and formation in this context and improving functional independence and quality of life. are determined by the stress and force bone is subjected to Materials and Methods: A review of current literature and orchestrated by cytokines and other factors. The healthy focusing on diagnostic tools and treatment approaches of skeletal structure is lost if this balance is disturbed by the bone metastasis in advanced cancer was performed and detrimental effects of either bone metastasis or cancer conclusions were incorporated into diagnostic and treatment treatment (1). In cancer patients, the skeletal morbidity is algorithms. Results: Radiologic imaging has added valuable conferred upon by the burden of bone metastasis and by tools for screening and diagnostics of bone metastasis. cancer treatment-induced bone loss (CTIBL). Cessation of Clinical management of skeletal metastasis includes improved hormonal support, necessary for maintenance of healthy pain management, introduction of bone modifying agents and bone structure, is a common problem for aging men and advancements in surgical and radiation therapy. We propose women. In this context of treatment, adjuvant use of three algorithms enhancing the sensitivity of diagnostics and aromatase inhibitors (AI) in breast cancer and androgen improving multidisciplinary management of vertebral and deprivation therapy (ADT) in prostate cancer are associated non-vertebral bone metastasis. Conclusion: Bone metastases with an additional significant bone loss and an increased are an expression of a systemic disease. Treatment options fracture rate (2-4). In fact, the Fracture Intervention Trial include highly specialized modalities yet need to be tailored (FIT) showed a significant increase in mortality risk in to individual needs. Algorithms help standardize treatment postmenopausal women with osteoporosis-induced fractures procedures and can improve treatment outcome in a (5). The lifetime risk of fracturing either the hip or spine multidisciplinary setting. averages almost 40% in women and 12% in men over 50, reflecting the need for early detection and treatment of these endocrine disturbances and the resulting osteoporosis (6, 7). This article is freely accessible online. This increase in fracture rate and its consequences associated with use of an AI or ADT has not been adequately Correspondence to: Dr. med. Christian Jehn, Medizinische Klinik und addressed in the oncology setting in the past. Increased Poliklinik m. S. Onkologie & Hämatologie, Charite Campus Virchow, awareness and approval of the osteoprotective agent Augustenburgerplatz 1, 13353 Berlin, Germany. Tel: +49 30450653653, denosumab, in this non-metastatic setting, has led to a Fax: +49 30450513924, e-mail: [email protected] significant reduction in bone fractures in postmenopausal Key Words: Metastatic bone disease, algorithm for diagnostic and breast cancer patients treated in the adjuvant setting with an treatment, bone-targeted agents, skeletal morbidity, multidisciplinary AI and non-metastatic prostate cancer patients treated with management, vertebral bone metastasis, non-vertebral bone ADT (8, 9). In addition to anti-hormonal treatment, prolonged metastasis, review. chemotherapy can also affect the endocrine output of 0250-7005/2016 $2.00+.40 2631 ANTICANCER RESEARCH 36: 2631-2638 (2016) reproductive hormones critically necessary for maintaining prevention of SREs has the best chance to succeed. We, healthy bone metabolism (10, 11). therefore, propose a clinical algorithm for diagnostics and Metastasis to the bone occurs in 70% of advanced breast, treatment of bone metastasis and integrate the current lung, kidney, thyroid and prostate cancer, whereas patients management and research into it. with gastrointestinal cancers suffer from this form of metastasis in only 20% of cases. Metastasis to the bone can Algorithm I: Presentation and Diagnostics present itself as either lytic, blastic or as mixed lesions (12). In osteolytic bone lesions, bone resorption exceeds the rate Metastases of the bone can be asymptomatic and detected of bone formation, whereas in osteoblastic lesions the incidentally during initial staging, at follow-up examination opposite is true. In both cases, a fragile bone structure is in the adjuvant setting or at treatment re-evaluation restaging. produced. Bone metastases form breast cancer have been However, in 75% of patients, metastatic bone disease described as prototypic osteolytic lesions, whereas bone presents with pain, warranting further examination (21). We metastases from prostate cancer as osteoblastic metastases. propose a diagnostic algorithm in Figure 1. Histologically, however, accelerated osteolytic and Bones, which must endure constant static force, such as osteoblastic pathological processes can coexist in the same the hips, femurs and vertebral column, become symptomatic lesion, irrespective of the radiological appearance (13). early on, whereas other non-weight bearing bones, such as Various biological factors endorse the bone as a common ribs or skull, may only become symptomatic late in disease site of cancer metastasis. Besides a favorable high blood flow due to pathologic fractures. Common sites of bone metastasis to the red bone marrow, adhesive factors in the bone marrow are the proximal femurs, pelvis, spine, ribs and skull. Rarely, stroma and the special environment within the hematopoetic acral metastasis to the hands and feet occur, mostly stem cell niche allow tumor cells to take up residency and associated with lung cancer (22, 23). dormancy, thereby evading possible effects of systemic Besides pain and pathological fractures, hypercalcaemia is therapy (14). a hallmark of advanced cancer, occurring in only about 10% About half the patients with these lesions suffer skeletal of the patients with bone metastasis. However, hypercalcaemia complications like pathological fractions, spinal cord is often of paraneoplastic origin through parathyroid hormone- compression and eminent pain requiring radiation therapy or related protein without signs of metastasis to the bone (24). surgery. These four complications are referred to as skeletal- Spinal cord compression, through infiltrating vertebral related events (SRE) and confer morbidity and major loss of metastases or fractured osteolytic lesions, can cause quality of life upon patients with metastasis of the bone. debilitating pain and major neurological deficits. Several studies have even shown a reduction in overall Presentation of localized pain in the context of cancer survival (15-17). Pathological fractures and the necessity of usually warrants radiological imaging. Due to cost restraints, a radiation therapy are the most common SREs, emphasizing plain radiograph is usually the initial diagnostic step to the extent of bone damage and pain associated with evaluate bone pain. However, for bone metastasis to be metastasis to the bone. Such pain-inducing complications recognized by this method, osteolytic lesions must be at least further lead to immobility and loss of functional 1 cm in diameter with a loss of bone mineral of 25-50% (25). independence (18). Under-treatment of bone pain occurs in Higher resolution and additional three-dimensional anatomic up to 60% of patients with advanced cancer and constitutes information is achieved through computed tomography (CT) a major cause of psychological distress, manifesting itself in scans and magnetic resonance imaging (MRI) imaging. CT depression and anxiety (19, 20). shows its strength in visualizing the cortical integrity and helps Current management of bone metastases entails a evaluate the extent of structural destruction, outperforming multidisciplinary approach since cancer is an expression of a MRI in this aspect. With its high contrast resolution, CT easily systemic disease. Therefore, integrating various disciplines differentiates between osteolytic lesions, sclerotic lesions and like orthopedic surgery, radiation oncology and medical soft tissue. This virtue is particularly useful, when localizing oncology into the big picture of an individual case can cause lesions for biopsy (26). some friction. The best course of action is not always straight With MRI very small skeletal metastasis can be detected. forward since each specialty might look at the problem at MRI is favored for detection of vertebral metastasis and hand from a different angle. The best way to unite these evaluating their association with the spinal cord. These different angles and views is often through
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