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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 , 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 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 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 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 . 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 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. 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, , thyroid and prostate cancer, whereas patients management and research into it. with gastrointestinal 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 (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 or related protein without signs of metastasis to the bone (24). . These four complications are referred to as skeletal- , 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 guidelines and advantages and the multi-planar imaging capability make algorithms, which can yield a foundation for decision MRI a helpful imaging tool in preparation for surgical and making but can also be tailored to individual needs, often the radiation procedures (27, 28). case in advanced cancer. For initial staging of cancer disease or in the context of Through implementing evidence-based diagnostics and follow-up examinations in disease-free patients, nuclear bone interventions the striving for improvement in survival and scintigraphic imaging with Technetium-99 (99mTc) is widely

2632 Jehn et al: Management of Metastatic Bone Disease (Review) accepted since it evaluates the whole skeletal system and is been reported to cause less cement extravasation as the most relatively inexpensive. 99mTc bone-scan cannot directly common complication enabling a superior restoration of detect osteolytic metastasis since it is incorporated into sites vertebral body height. Both techniques appear to have a with elevated bone turnover rates and is, hence, a marker of comparable effectiveness in achieving pain relief; however, osteoblastic activity (29). Osteolytic metastasis with minimal differences in functional outcome remain unclear (35). osteoblastic bone formation can, thereby, produce false Besides surgery, radiation therapy is an efficacious negative bone scans. If hotspots are detected, CT or MRI is treatment method for local tumor control and for palliation of needed to clarify further anatomic detail. In disease-free painful bone metastasis. For pain control, high response rates patients and in the absence of other metastasis in the follow- of 85% have been reported with complete pain relief in about up examinations, a biopsy may be necessary to confirm half of the patients. Most responders showed fast symptom metastatic disease. In addition, patients with oligo/singular relief within the first 2 weeks (36). Radiation therapy bone metastasis and in the absence of other/visceral promotes ossification of osteolytic bone metastasis and can metastasis need to be identified with a high sensitivity since numb small nerve endings, thereby relieving pain and potential curative localized treatment options may be increasing stability of the bone (37). For patients already warranted. Novel imaging technologies with projected treated with external-beam irradiation (EBRT), a re-treatment increased sensitivity and specificity have not been adequately approach with stereotactic body radiation therapy (SBRT) can tested in prospective trials if they offer additional value in be considered. SRBT minimizes radiation doses to the spinal terms of impact on skeletal morbidity and survival through cord by precise radiation delivery to vertebral metastases, earlier and more reliable detection of metastasis (30, 31). thereby allowing effective retirement in terms of pain and local tumor control of previously radiated regions with EBRT (38). Algorithm II: Treatment of Vertebral If symptomatic metastasis to the bone is diffuse and of Bone Metastases osteoblastic nature, therapeutic radioisotopes can be a treatment choice. 153Samarium and 89strontium deliver a When cancer metastasizes to the bone, the axial skeleton is therapeutic dose of beta radiation simultaneously to multiple preferred. Within the axial skeleton, the vertebral column is bone sites. 223Radium has a strong affinity towards the bone most often affected. In more than 10% of cancer patients, and emits short-ranged high energy α-particles to cells (39). these metastases are symptomatic (32). In a Phase III Trail (ALSYMPCA) with patients with When treating metastatic lesions to the bone, a castrate-resistant prostate cancer and bone metastasis only, it multidisciplinary approach is necessary to gain local control proved its efficacy, compared to best supportive care, by over the lesions by means of radiation therapy or surgery. We improving overall survival and the quality of life, in addition propose, therefore, algorithm II for treatment of vertebral to reducing skeletal morbidity. However, the patient bone metastasis in Figure 2. population was heterogeneous, including patients who had When tumor masses and pathological fractures of the previously received docetaxel and patients deemed either vertebra cause compression of myeloradicular structures (i.e. unfit or unwilling to receive chemotherapy (40). nerve roots, spinal cord) with neurological deficits or uncontrollable pain, immediate surgical intervention is Algorithm III: Treatment of Non-vertebral warranted. To provide temporary relief of symptoms related Bone Metastasis to pressure and edema secondary to tumor mass a therapy with corticosteroids should be concurrently initiated (33). The treatment goals and caveats of non-vertebral bone Different factors must be considered when choosing the metastasis are similar to the previous said, with palliation of aggressiveness of the surgical intervention. Besides the pain and preservation and restoration of function being the preoperative neurological condition and the performance primary focus. We, therefore, propose algorithm II for status, the aggressiveness of the primary tumor and the life treatment of non-vertebral bone metastasis in Figure 3. expectancy of the patient are the determining factors (34). In Pathological fractures are clearly an indication for surgical advanced cancer diseases, a palliative decompression and intervention with internal fixation even in advanced disease. stabilization, followed by radiation therapy, can improve the An impending fracture of a long bone can warrant in selected quality of life. However, if a prolonged overall survival is patients with advanced disease a prophylactic fixation estimated, due to a very slow growing tumor or a relatively followed by postoperative radiation therapy (41). We good prognosis, more aggressive interventions can be recommend a prophylactic radiation of asymptomatic non- justified. Clearly, a sound interdisciplinary communication vertebral bone metastasis to increase local tumor control. If is necessary in order to select patients appropriately. multiple symptomatic non-vertebral bone metastases are Pain inflicted by vertebral body fractures can also be present, a treatment with therapeutic radioisotopes can be treated by vertebroplasty or kyphoplasty. Kyphoplasty has considered.

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Figure 1. Diagnostic algorithm for bone metastases. *AP, LDH, Hb, leucocytes, thrombocytes, calcium; ** algorithms for vertebral and non-vertebral bone metastases. CT, computed tomography; Hb, haemoglobin; LDH, lactate dehydrogenase; OP, surgical treatment; Ox, osteoprotective therapy; PET, positron emission tomography; Px, pain therapy; Rx, radiotherapy; Tx, cancer treatment; MRI, magnetic resonance imaging.

Besides effective systemic cancer treatments, bone- zoledronic acid in breast cancer and castration-resistant prostate targeted agents like biphosphonates and the receptor activator cancer regarding such clinical end-points as time to first SRE, of nuclear factor-kB ligand (RANKL) denosumab prevention of subsequent SREs and overall risk (49-51). have changed the course of metastatic cancer to the bone by In order to delay time to first SRE and reduce skeletal reducing skeletal morbidity (42, 43). morbidity in patients, it is recommended to initiate treatment Biphosphonates accumulate in the bone where they with bone-targeted agents as soon as metastases of the bone decrease bone resorption and increase mineralisation by are diagnosed, regardless if the metastases are symptomatic inhibiting the osteoclasts and inducing their apoptosis. or not. This incremental gain in time before first SRE Possible anti-tumor and anti-angiogenetic effects are still translates into additional quality of life since the matter of current research (44). Pamidronate and zoledronic consequences of a SRE can alter the course of the disease. acid have been approved in the US and Europe for the The costs of consecutive treatments for early SREs are by far treatment of cancer-related bone complications. Both higher than the costs of bone-targeted agents preventing or biphosphonates have been shown to reduce skeletal delaying first SREs (52, 53). morbidity by 30%, lower the incidence of SREs and delay time to first SRE in patients with metastatic bone disease Conclusion significantly (45). Zoledronic acid has shown a greater risk reduction for development of skeletal complications than There has been major progress in reducing skeletal morbidity pamidronate in breast cancer by multiple event analysis (46). in CTIBL and management of bone metastases in the last years. More than half of the patients reported moderate pain In the advanced cancer setting, treatment of bone metastases improvement, lasting almost 12 weeks. Besides being an aims at palliating pain, maintaining function and preventing additional treatment approach for pain relief, biphosphonates SREs. The development of new bone-targeted agents has are part of the standard therapy for hypercalcaemia (47). significantly reduced skeletal morbidity and increased quality Denosumab is a monoclonal antibody that inhibits of life for patients with metastatic disease involving the bone. osteoclast-mediated bone destruction by binding to RANKL It is recommended to apply these drugs early on at diagnosis of (48). Denosumab has shown superior efficacy compared to bone metastases and not to wait until symptoms arise.

2634 Jehn et al: Management of Metastatic Bone Disease (Review)

Figure 2. Treatment of vertebral bone metastases. OP, Surgical treatment; Ox, osteoprotective therapy; Px, pain therapy; Rx, radiotherapy; Tx, cancer treatment; Rx/RN, radiotherapy and/or radionuclide therapy. Osteoprotective therapy: denosumab or bisphosphonates (as approval), calcium and vitamin D supplementation (as prescribing information).

Figure 3. Treatment of non-vertebral bone metastases. OP, Surgical treatment; Ox, osteoprotective therapy; Px, pain therapy; Rx, radiotherapy; Tx, cancer treatment; Rx/RN, radiotherapy and/or radionuclide therapy. Osteoprotective therapy: denosumab or bisphosphonates (as approval), calcium and vitamin D supplementation (as prescribing information).

Specific local treatment modalities for bone metastasis Conflicts of Interest have to be incorporated into comprehensive treatment approaches reflecting the systemic nature of metastatic Dr. Jehn has received consulting and speaker fees from Amgen and Merck. Prof. Diel has received consulting and speaker fees from disease. Treatment algorithms can promote such integration Amgen, Medtronic, Riemser and Teva. Dr. Overkamp has received of various disciplines like orthopedic surgery, radiation consulting and speaker fees from Amgen. Dr. Schaefer has received oncology and medical oncology, in pursuit of tailoring consulting and speaker fees from Amgen. Prof. Kurth has received optimal treatment strategies to individual patient need. consulting and speaker fees from Amgen, Roche and Implantcast.

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