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Secondary Bone Cancer (bone metastasis)

Secondary bone cancer is where malignant cells have spread to the bones from other parts of the body. This is different to cancer that actually started in the bones (primary bone cancer). Virtually all types of cancer can spread to bone. Bone metastases are particularly common in people with breast, lung or prostate cancer. Bone metastases are usually multiple, they cause pain and can can lead to other symptoms such as hypercalcemia (abnormally high levels of calcium in the blood).

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Bone Cancer

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    MeSH term: Bone Neoplasms
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Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Tahara T, Fujii S, Ogawa T, et al.
Fluorodeoxyglucose Uptake on Positron Emission Tomography Is a Useful Predictor of Long-Term Pain Control After Palliative Radiation Therapy in Patients With Painful Bone Metastases: Results of a Single-Institute Prospective Study.
Int J Radiat Oncol Biol Phys. 2016; 94(2):322-8 [PubMed] Related Publications
PURPOSE: To determine whether fluorodeoxyglucose positron emission tomography (FDG-PET) before and after palliative radiation therapy (RT) can predict long-term pain control in patients with painful bone metastases.
METHODS AND MATERIALS: Thirty-one patients with bone metastases who received RT were prospectively included. Forty painful metastatic treatment fields were evaluated. All patients had undergone pre-RT and post-RT PET/CT scanning. We evaluated the relationships between the pre-RT, post-RT, and changes in maximum standardized uptake value (SUVmax) and the pain response, and between SUVmax and pain relapse of the bone metastases in the treatment field. In addition, we compared the SUVmax according to the length of time from the completion of RT to pain relapse of the bone metastases.
RESULTS: Regarding the pain response at 4 weeks after the completion of RT, there were 36 lesions of 27 patients in the responder group and 4 lesions of 4 patients in the nonresponder group. Changes in the SUVmax differed significantly between the responder and nonresponder groups in both the early and delayed phases (P=.0292 and P=.0139, respectively), but no relationship was observed between the pre-RT and post-RT SUVmax relative to the pain response. The responder group was evaluated for the rate of relapse. Thirty-five lesions of 26 patients in the responder group were evaluated, because 1 patient died of acute renal failure at 2 months after RT. Twelve lesions (34%) showed pain relapse, and 23 lesions (66%) did not. There were significant differences between the relapse and nonrelapse patients in terms of the pre-RT (early/delayed phases: P<.0001/P<.0001), post-RT (P=.0199/P=.0261), and changes in SUVmax (P=.0004/P=.004).
CONCLUSIONS: FDG-PET may help predict the outcome of pain control in the treatment field after palliative RT for painful bone metastases.

Stevenson JD, McNair M, Cribb GL, Cool WP
Prognostic factors for patients with skeletal metastases from carcinoma of the breast.
Bone Joint J. 2016; 98-B(2):266-70 [PubMed] Related Publications
AIMS: Surgical intervention in patients with bone metastases from breast cancer is dependent on the estimated survival of the patient. The purpose of this paper was to identify factors that would predict survival so that specific decisions could be made in terms of surgical (or non-surgical) management.
METHODS: The records of 113 consecutive patients (112 women) with metastatic breast cancer were analysed for clinical, radiological, serological and surgical outcomes. Their median age was 61 years (interquartile range 29 to 90) and the median duration of follow-up was 1.6 years (standard deviation (sd) 1.9, 95% confidence interval (CI) 0 to 5.9). The cumulative one- and five-year rates of survival were 68% and 16% (95% Cl 60 to 77 and 95% CI 10 to 26, respectively).
RESULTS: Linear discriminant analysis identified a 'quadruple A' predictor of survival by reclassifying the sum of the albumin, adjusted calcium, alkaline phosphatase and age covariates each multiplied by a determined factor. The accuracy of this 'quadruple A' predictor was 90% with a sensitivity of 100% and a specificity of 88%. A receiver operating characteristic (ROC) curve revealed an area under the curve of 79%. Survival analysis for this 'quadruple A' predictor (< = one or > one year survival) was statistically significant using the log rank test (p = 0.0004) and Cox proportional hazard (p = 0.001). Multivariate analysis showed the 'quadruple A' predictor to be the only independent predictor of survival (p = 0.01).
DISCUSSION: The 'quadruple A' predictor, together with other positive predictors of survival, can be used by oncologists, orthopaedic and breast surgeons to estimate survival and therefore guide management.

Prabhu R, Sharma S, Sadhu S, Shenoy R
Hard nodular lesions over the chest wall.
J Fam Pract. 2016; 65(1):53-5 [PubMed] Related Publications
Thirteen years after undergoing a mastectomy for breast cancer, this patient developed lesions near the scar.

Cook GJ, Azad GK, Goh V
Imaging Bone Metastases in Breast Cancer: Staging and Response Assessment.
J Nucl Med. 2016; 57 Suppl 1:27S-33S [PubMed] Related Publications
Bone metastases are common in patients with advanced breast cancer. Given the significant associated morbidity, the introduction of new, effective systemic therapies, and the improvement in survival time, early detection and response assessment of skeletal metastases have become even more important. Although planar bone scanning has recognized limitations, in particular, poor specificity in staging and response assessment, it continues to be the main method in current clinical practice for staging of the skeleton in patients at risk of bone metastases. However, the accuracy of bone scanning can be improved with the addition of SPECT/CT. There have been reported improvements in sensitivity and specificity for staging of the skeleton with either bone-specific PET/CT tracers, such as (18)F-NaF, or tumor-specific tracers, such as (18)F-FDG, although these methods are less widely available and more costly. There is a paucity of data on the use of (18)F-NaF PET/CT for response assessment in breast cancer, but there is increasing evidence that (18)F-FDG PET/CT may improve on current methods in this regard. At the same time, interest and experience in using whole-body morphologic MRI augmented with diffusion-weighted imaging for both staging and response assessment in the skeleton have been increasing. However, data on comparisons of these methods with PET methods to determine the best technique for current clinical practice or for clinical trials are insufficient. There are early data supporting the use (18)F-FDG PET/MRI to assess malignant disease in the skeleton, with the possibility of taking advantage of the synergies offered by combining morphologic, physiologic, and metabolic imaging.

Bhojwani N, Huang J, Gupta A, et al.
Rectal carcinoid tumor metastasis to a skull base meningioma.
Neuroradiol J. 2016; 29(1):49-51 [PubMed] Related Publications
Carcinoid tumors are rare, slow-growing neuroendocrine tumors that most frequently develop in the gastrointestinal tract or lungs and have high potential for metastasis. Metastasis to the brain is rare, but to another intracranial tumor is extremely rare. Of the intracranial tumors, meningiomas are the most common to host metastases, which may be related to its rich vascularity and E-cadherin expression. We describe the case of a 65-year-old female with active chemotherapy-treated neuroendocrine carcinoma who presented with left-sided facial numbness, headaches, and blurry vision. Initial imaging revealed a 1 cm irregular dural-based left petrous apex mass suggestive of a meningioma that was re-imaged four months later as a rapidly enlarging, extra-axial, mass extending into the cavernous sinus, effacing Meckel's cave that resembled a trigeminal schwannoma. Pathology revealed a carcinoid tumor metastatic to meningioma. While the mass displayed characteristic imaging findings of a schwannoma, rapid growth in the setting of known active malignancy should prompt the clinician to consider mixed pathology from metastatic disease or a more aggressive meningioma.

Kang EJ, Lee SY, Kim HJ, et al.
Prognostic Factors and Skeletal-Related Events in Patients with Small Cell Lung Cancer with Bone Metastases at the Time of Diagnosis.
Oncology. 2016; 90(2):103-11 [PubMed] Related Publications
BACKGROUND/OBJECTIVE: The aim of this study was to evaluate the characteristics and prognostic factors of small cell lung cancer (SCLC) with bone metastases. We also investigated the characteristics and predictive factors of skeletal-related events (SREs) in these patients.
MATERIALS AND METHODS: Sixty-one patients who were first diagnosed with SCLC with bone metastases at our institution were included in this retrospective analysis.
RESULTS: The overall survival (OS) of patients with bone metastases was shorter than that of patients without bone metastases (4.13 vs. 6.17 months, p = 0.015). Poor Eastern Cooperative Oncology Group (ECOG) performance status (PS; ≥2) and higher serum alkaline phosphatase (ALP; above upper normal limit × 2) were independent poor prognostic factors (p = 0.027 for ECOG PS, p = 0.002 for ALP). More than 1 SRE occurred in 21 patients (34.4%). Cervical spine metastasis, thoracic spine metastasis, pelvic bone metastasis, more than 5 bone metastatic regions and higher serum lactate dehydrogenase were correlated with the occurrence of SREs. Thoracic spinal metastasis was a strong predictive factor for the occurrence of SREs (odds ratio = 5.475; 95% CI: 1.080-27.755).
CONCLUSION: Our study demonstrates the poor prognosis of SCLC patients with bone metastases. Physicians should treat SCLC patients with bone metastases with caution.

Kotecki N, Hiret S, Etienne PL, et al.
First-Line Chemotherapy for Metastatic Esophageal Squamous Cell Carcinoma: Clinico-Biological Predictors of Disease Control.
Oncology. 2016; 90(2):88-96 [PubMed] Related Publications
OBJECTIVE: This study aimed to identify predictors of tumor control (TC) in metastatic esophageal squamous cell carcinoma patients receiving first-line chemotherapy.
METHODS: A development cohort of 68 patients from a prospective multicenter trial (NCT01248299) was used to identify predictors of TC at first radiological tumor assessment and to generate a predictive score for TC. That score was applied in an independent retrospective single-center validation cohort of 60 consecutive patients.
RESULTS: Multivariate analysis identified three predictors of TC: body mass index ≥18.5 (OR 4.5, 95% CI 0.91-22.5), absence of bone metastasis (OR 4.6, 95% CI 0.91-23.2) and albumin ≥35 g/l (OR 3.5, 95% CI 1.0-12.1). Based on the presence or absence of these three independent prognosticators, we built a predictive model using a score from 0 to 3. In the development cohort, the TC rates were 14.3 and 78.0% and in the validation cohort 12.5 and 44.2%, for scores of 0-1 and 2-3, respectively. With negative predictive values of 85 and 88% in the development and validation cohorts, respectively, we were able to identify patients with a very low probability of TC.
CONCLUSION: We have developed and validated a score that can be easily determined at the bedside to predict TC in metastatic esophageal squamous cell carcinoma patients.

Zhao J, Zhang X, Chen Z, Wu JH
Case Report: Bazex Syndrome Associated With Pulmonary Adenocarcinoma.
Medicine (Baltimore). 2016; 95(2):e2415 [PubMed] Free Access to Full Article Related Publications
Bazex syndrome, a rare paraneoplastic syndrome characterized by psoriasiform eruptions, palmoplantar keratosis, and symmetric onychodystrophy, is most prevalent with squamous cell carcinomas of the upper aerodigestive tract.Here, we reported an uncommon case of Bazex syndrome about an 83-year-old man with pulmonary adenocarcinoma and osseous metastasis, Physical examination found psoriasiform eruptions on the nose, cheeks, ears, knees, and the dorsa of interphalangeal joints, along with plantar keratosis and symmetric onychodystrophy involving hands and feet. Imaging analyses pulmonary adenocarcinoma with both local metastatic nodules and osseous metastasis.Symptomatic treatment with topical corticosteroids and oral retinoids showed no improvement. A 4-month follow-up showed that Gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, successfully reduced primary tumor size and alleviated cutaneous lesions.Our report here highlighted a potential correlation between pulmonary adenocarcinoma and Bazex syndrome, which is characterized by hallmark nail destruction and preferential involvement of body extremities. Moreover, etiological therapy against underlying malignancy is essential for treating paraneoplastic Bazex syndrome.

Lindholm PF, Hwang YS
LPA Increases Tumor Growth and Bone Destruction Through Enhancement of Osteoclastogenic Cytokines.
Anticancer Res. 2016; 36(1):61-70 [PubMed] Related Publications
BACKGROUND: Lysophosphatidic acid (LPA) production in osteoblasts has multiple effects on osteoclast formation and function and raises the possibility that LPA may serve as a signaling molecule for the reciprocal conversation of both osteoblasts and osteoclasts within the tumor-bone microenvironment for bone resorption. However, little is known on the effect of LPA in regulating the function of both cancer cells and osteoclasts in the bone microenvironment.
MATERIALS AND METHODS: PC-3 tumor growth and bone destruction upon LPA administration were observed in a mouse calvarium xenograft. The osteoclastogenic cytokines produced by LPA-stimulated prostate cancer cells were also defined.
RESULTS: LPA administration was found to increase PC-3 tumor growth and bone destruction in a mouse calvarium xenograft. Using a cytokine antibody array, LPA highly stimulated the expression and release of osteoclastogenic cytokines from PC-3 cells. Conditioned medium from LPA-stimulated PC-3 cells containing enhanced levels of osteoclastogenic cytokines facilitated osteoclast formation. Histopathologically, LPA administration supports the erosive type of bone destruction by PC-3 prostate cancer cells.
CONCLUSION: LPA is a critical regulator in the tumor-bone microenvironment and may be a therapeutic target for patients with prostate cancer. In addition, LPA-enhanced osteoclastogenic cytokines are critical to therapeutic strategies targeting osteolytic prostate cancer.

Li H, Hu H, Wang R, et al.
When Should ⁹⁹mTc Bone Scintigraphy Be Performed in cT1N0 Non-Small Cell Lung Cancer Patients?
Medicine (Baltimore). 2015; 94(51):e2309 [PubMed] Free Access to Full Article Related Publications
The aim of this retrospective study was to investigate the risk factors for bone metastases (BM) in clinical T1N0 non-small cell lung cancer (NSCLC) patients.From January 2010 to June 2012, 739 patients with primary diagnosed cT1N0 NSCLC were eligible for this study. Clinical variables, including sex, smoking history, age at diagnosis, tumor size, pathologic subtype, preoperative serum Carcino embryonie antigen (CEA) level, lesion imaging performance, and skeletal system symptom, were collected.BM were found in 7 patients (0.95%), in whom 6 patients had skeletal system symptom and 1 had silent metastasis. The frequency of BM was significantly high in younger patients (P = 0.007) and in patients with higher preoperative serum CEA level (P = 0.05). In multivariate analysis, age less than 50 years old (OR = 2.23, 95% CI: 1.56-4.21, P = 0.02), presence of clinical symptom (OR = 3.15, 95% CI: 1.98-6.42, P = 0.008), and CEA level over 5 μg/mL (OR = 2.14, 95% CI: 1.37-3.53, P = 0.03) were independently associated with BM in cT1N0 NSCLC patients.Presence of skeletal system symptom is not the unique criteria for performing BS. Younger age at diagnosis and higher preoperative serum CEA level are also risk factors for BM in cT1N0 NSCLC patients. Therefore, the selection of early-stage NSCLC patients being performed BS should be more precise in the future.

Thibault I, Chang EL, Sheehan J, et al.
Response assessment after stereotactic body radiotherapy for spinal metastasis: a report from the SPIne response assessment in Neuro-Oncology (SPINO) group.
Lancet Oncol. 2015; 16(16):e595-603 [PubMed] Related Publications
The SPine response assessment In Neuro-Oncology (SPINO) group is a committee of the Response Assessment in Neuro-Oncology working group and comprises a panel of international experts in spine stereotactic body radiotherapy (SBRT). Here, we present the group's first report on the challenges in standardising imaging-based assessment of local control and pain for spinal metastases. We review current imaging modalities used in SBRT treatment planning and tumour assessment and review the criteria for pain and local control in registered clinical trials specific to spine SBRT. We summarise the results of an international survey of the panel to establish the range of current practices in assessing tumour response to spine SBRT. The ultimate goal of the SPINO group is to report consensus criteria for tumour imaging, clinical assessment, and symptom-based response criteria to help standardise future clinical trials.

Magnusson LU, Hagberg Thulin M, Plas P, et al.
Tasquinimod inhibits prostate cancer growth in bone through alterations in the bone microenvironment.
Prostate. 2016; 76(4):383-93 [PubMed] Related Publications
BACKGROUND: Tasquinimod (ABR-215050) is an orally active quinoline-3-carboxamide analog that inhibits occurrence of experimental metastasis and delays disease progression of castration resistant prostate cancer in humans. Its mechanism of action is not fully elucidated, but previous studies show immunomodulatory and anti-angiogenic effects. The aim of the present study was to investigate the tumor inhibiting effect of tasquinimod in bone of castrated mice as well as to elucidate its working mechanism related to bone microenvironment.
METHODS: Effects of tasquinimod on prostate cancer metastasis to bone was studied in an intratibial xenograft model. Animals were treated with tasquinimod and tumor establishment and growth, immunological status, as well as markers for bone remodeling were analyzed. Direct effects of tasquinimod on osteoblasts were studied in vitro.
RESULTS: Establishment and growth of tumors in the bone after intratibial implantation in castrated mice was suppressed by tasquinimod treatment. The treatment effect was linked to decreased potential for immunosuppression in the pre-metastatic niche in bone (lower levels of CD206 and Arg1 expression in combination with increased iNOS expression) as well as in the tumor microenvironment (less Gr1 and CD206 staining). The shift to a pro-inflammatory, anti-tumorigenic milieu was also reflected in serum by increased levels of IFN-γ, CCL4, IL-5, LIX, IP-10, and MCP-1 as well as decreased TGF-β. Tasquinimod treatment also affected expression of factors involved in the pre-metastatic niche in the bone microenvironment (Lox, Cdh2, Cdh11, and Cxcl12). In addition, tasquinimod treatment caused a decreased osteogenic response indicated by decreased expression of Ocn, Runx2, and Col1a2 and increased expression of osteoclast stimulating CSF2. In vitro studies on mouse osteoblasts showed impaired osteoblast mineralization upon tasquinimod treatment.
CONCLUSIONS: The present study shows that tasquinimod reduces establishment and progression of tumor growth in bone likely through a combination of effects on the pre-metastatic niche, homing, immunological status, and osteogenesis. It was concluded that tasquinimod interferes with the metastatic process, presumably by inhibition of tumor establishment. Hence, our data suggest that tasquinimod might be most effective in inhibiting the occurrence of new metastatic lesions.

Spick C, Polanec SH, Mitterhauser M, et al.
Detection of Bone Metastases Using 11C-Acetate PET in Patients with Prostate Cancer with Biochemical Recurrence.
Anticancer Res. 2015; 35(12):6787-91 [PubMed] Related Publications
AIM: To evaluate the diagnostic accuracy of (11)C-acetate positron-emission tomography (PET) in the detection of bone metastasis in patients with prostate cancer with biochemical recurrence.
PATIENTS AND METHODS: Ninety patients (100%) with rising prostate-specific antigen (PSA) levels (>0.2 ng/ml) after radical prostatectomy, who had both (11)C-acetate PET and bone scan performed and who had clinical follow-up/imaging follow-up for bone metastasis, considered a gold standard, were included. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for (11)C-acetate PET were calculated on a per-patient basis.
RESULTS: (11)C-Acetate PET and (99m)Tc-dicarboxypropane-diphosphonate findings were concordant in 84 (93.3%) patients [35 (38.9%) true-positive, 49 (54.4%) true-negative]. Discordant findings were observed in six patients (6.7%). (11)C-Acetate PET presented two (2.2%) false-positive and four (4.4%) false-negative findings. The sensitivity, specificity, PPV, and NPV for (11)C-acetate PET were 89.7%, 96.1%, 94.6%, and 92.2%, respectively. The median PSA of patients with multiple skeletal metastases (median=23.64 ng/ml, range=3.16-551.1 ng/ml) differed significantly (p=0.018) from that of patients with focal metastases (median=6.7 ng/ml, range=0.31-12.8 ng/ml).
CONCLUSION: (11)C-Acetate PET is a useful tool for patients with prostate cancer with biochemical recurrence, as it can depict multiple sites of recurrence and in particularly shows a high diagnostic value equivalent to that of bone scan for the detection of bone metastases.

Faltermeier CM, Drake JM, Clark PM, et al.
Functional screen identifies kinases driving prostate cancer visceral and bone metastasis.
Proc Natl Acad Sci U S A. 2016; 113(2):E172-81 [PubMed] Free Access to Full Article Related Publications
Mutationally activated kinases play an important role in the progression and metastasis of many cancers. Despite numerous oncogenic alterations implicated in metastatic prostate cancer, mutations of kinases are rare. Several lines of evidence suggest that nonmutated kinases and their pathways are involved in prostate cancer progression, but few kinases have been mechanistically linked to metastasis. Using a mass spectrometry-based phosphoproteomics dataset in concert with gene expression analysis, we selected over 100 kinases potentially implicated in human metastatic prostate cancer for functional evaluation. A primary in vivo screen based on overexpression of candidate kinases in murine prostate cells identified 20 wild-type kinases that promote metastasis. We queried these 20 kinases in a secondary in vivo screen using human prostate cells. Strikingly, all three RAF family members, MERTK, and NTRK2 drove the formation of bone and visceral metastasis confirmed by positron-emission tomography combined with computed tomography imaging and histology. Immunohistochemistry of tissue microarrays indicated that these kinases are highly expressed in human metastatic castration-resistant prostate cancer tissues. Our functional studies reveal the strong capability of select wild-type protein kinases to drive critical steps of the metastatic cascade, and implicate these kinases in possible therapeutic intervention.

Greenwood TJ, Wallace A, Friedman MV, et al.
Combined Ablation and Radiation Therapy of Spinal Metastases: A Novel Multimodality Treatment Approach.
Pain Physician. 2015; 18(6):573-81 [PubMed] Related Publications
BACKGROUND: Radiation therapy (RT) is the current gold standard for palliation of painful vertebral metastases. However, other percutaneous modalities such as radiofrequency ablation (RFA), cryoablation, and vertebral augmentation have also been shown to be effective in alleviating symptoms. Combined RT and ablation may be more effective than either therapy alone in palliating painful metastatic disease to the spine.
OBJECTIVE: To evaluate the safety and efficacy of combined ablation, either RFA or cryoablation, and RT in the treatment of spinal metastases.
STUDY DESIGN: Retrospective study.
SETTING: This is a retrospective study at a single institution.
METHODS: Medical records of all patients who underwent ablation of spine lesions at a single institution between March 2012 and June 2014 were reviewed; patients treated with both RT and either RFA or cryoablation concurrently were identified. Pain scores before and after RFA were measured with the numerical rating scale (NRS) (0-10 point scale) and compared. Procedural complications, changes in general activity level, and pain medication usage after ablation were also recorded. When available, follow-up imaging was evaluated for evidence of residual or recurrent disease.
RESULTS: Twenty-one patients with 36 spine metastases were treated with RT and percutaneous ablation concurrently; either RFA (21/22) or cryoablation (1/22). One patient received 2 separate RFA treatments. Overall, mean worst pain score (8.0, SD = 2.3) significantly decreased at both one week (4.3, SD = 3.1; P < .02) and 4 weeks (2.9, SD = 3.3; P < .0003). Temporary post-procedural radicular pain occurred after one RFA treatment (4.5%; 1/22). Seven patients had radiation resistant tumors (renal cell, melanoma, or sarcoma). Post-procedural imaging (median 6 months; range 2-27 months) showed stable treated disease in 12/13 treatments at 3 months and 10/10 at 6 months.
LIMITATIONS: The therapeutic effect of vertebral augmentation versus percutaneous ablation cannot be separated in this retrospective study. Radiation treatment protocols were variable and included both stereotactic body and conventional RT which may have different safety and efficacy profiles.
CONCLUSION: Percutaneous ablation and concurrent RT is safe and effective in palliating painful spinal metastases and can be effective in those who have radiation resistant tumor histology.

Wang C, Shen Y, Zhu S
Distribution Features of Skeletal Metastases: A Comparative Study between Pulmonary and Prostate Cancers.
PLoS One. 2015; 10(11):e0143437 [PubMed] Free Access to Full Article Related Publications
Bone scintigraphies are widely applied for detecting bone metastases. The aim of this study was to investigate distribution features of bone metastases in pulmonary and prostate cancers. Bone scintigraphies were performed in 460 patients with pulmonary cancer and 144 patients with prostate cancer. Patients were divided into three groups according to the total number of bone metastases: few bone metastases, moderate bone metastases, and extensive bone metastases. We compared the distribution of bone metastases in the two cancers, and analyzed the relationship between the distribution of metastatic lesions and their metastatic patterns. A total of 2279 and 2000 lesions of bone metastases were detected in 258 patients with pulmonary cancer and 102 patients with prostate cancer, respectively. In patients with few bone metastases, the distributions of metastatic lesions in the vertebrae (χ2 = 16.0, P = 0.000) and thoracic bones (χ2 = 20.7, P = 0.002) were significantly different between pulmonary and prostate cancers. In cases with moderate bone metastases, the distributions in the vertebrae (χ2 = 6.6, P = 0.010), pelvis (χ2 = 15.1 P = 0.000), and thoracic bones (χ2 = 38.8, P = 0.000) were also significantly different between the two cancers. However, in patients with extensive bone metastases, the distributions were very similar. As the total number of bone metastases increased, their distribution in pulmonary cancer did not noticeably change, but the distribution in the vertebrae and thoracic bones of prostate cancer patients significantly changed. Accordingly, the distribution characteristics of bone metastases differed in pulmonary and prostate cancers, mainly in the early stages of metastasis.

Fehlings MG, Nater A, Tetreault L, et al.
Survival and Clinical Outcomes in Surgically Treated Patients With Metastatic Epidural Spinal Cord Compression: Results of the Prospective Multicenter AOSpine Study.
J Clin Oncol. 2016; 34(3):268-76 [PubMed] Related Publications
PURPOSE: Although surgery is used increasingly as a strategy to complement treatment with radiation and chemotherapy in patients with metastatic epidural spinal cord compression (MESCC), the impact of surgery on health-related quality of life (HRQoL) is not well established. We aimed to prospectively evaluate survival, neurologic, functional, and HRQoL outcomes in patients with MESCC who underwent surgical management.
PATIENTS AND METHODS: One hundred forty-two patients with a single symptomatic MESCC lesion who were treated surgically were enrolled onto a prospective North American multicenter study and were observed at least up to 12 months. Clinical data, including Brief Pain Inventory, ASIA (American Spinal Injury Association) impairment scale, SF-36 Short Form Health Survey, Oswestry Disability Index, and EuroQol 5 dimensions (EQ-5D) scores, were obtained preoperatively, and at 6 weeks and 3, 6, 9, and 12 months postoperatively.
RESULTS: Median survival time was 7.7 months. The 30-day and 12-month mortality rates were 9% and 62%, respectively. There was improvement at 6 months postoperatively for ambulatory status (McNemar test, P < .001), lower extremity and total motor scores (Wilcoxon signed rank test, P < .001), and at 6 weeks and 3, 6, and 12 months for Oswestry Disability Index, EQ-5D, and pain interference (paired t test, P < .013). Moreover, at 3 months after surgery, the ASIA impairment scale grade was improved (Stuart-Maxwell test P = .004). SF-36 scores improved postoperatively in six of eight scales. The incidence of wound complications was 10% and 2 patients required a second surgery (screw malposition and epidural hematoma).
CONCLUSION: Surgical intervention, as an adjunct to radiation and chemotherapy, provides immediate and sustained improvement in pain, neurologic, functional, and HRQoL outcomes, with acceptable risks in patients with a focal symptomatic MESCC lesion who have at least a 3 month survival prognosis.

Yaegashi H, Izumi K, Konaka H, et al.
Long-term survival following multidisciplinary treatment of metastatic sarcomatoid renal cell carcinoma: a case report.
J Med Case Rep. 2015; 9:261 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: We report the case of a 62-year-old woman diagnosed with sarcomatoid renal cell carcinoma.
CASE PRESENTATION: A 62-year-old Asian woman presented with macroscopic hematuria. A histological and immunohistochemical study of a tumor biopsy specimen led to a suspected diagnosis of sarcomatoid renal cell carcinoma. She underwent surgical tumor resection that included her left kidney. A histological and immunohistochemical study of the resected tumor confirmed the diagnosis of sarcomatoid renal cell carcinoma. The pathological stage was pT3bpN2, and multiple lung metastases were detected (pT3bpN2cM1; stage IV). Our patient was classified as "poor risk" according to the Memorial Sloan Kettering Cancer Center risk criteria. Interferon-α was administered as adjuvant therapy, and her lung metastases remained stable. However, a computed tomography scan and bone scintigraphy 2 years later revealed multiple bone metastases. External beam radiotherapy was performed for the bone metastases. Despite continuing interferon-α during radiotherapy, multiple skull and liver metastases appeared. Oral administration of the tyrosine kinase inhibitor axitinib was initiated as a second-line therapy, and our patient achieved a stable state for 11 months. As the liver metastases progressed and meningeal dissemination newly appeared, oral administration of the mammalian target of rapamycin inhibitor everolimus was initiated as a third-line therapy. Our patient remains alive 71 months after diagnosis and has maintained a comparatively good quality of life.
CONCLUSION: A literature review revealed that metastatic sarcomatoid renal cell carcinoma has very poor prognosis, with a survival of <1 year despite systemic therapy. Our patient in this present case achieved long-term survival, a rare incidence worthy of report.

Liu J, Huang W, Zhou R, et al.
Bisphosphonates in the Treatment of Patients With Metastatic Breast, Lung, and Prostate Cancer: A Meta-Analysis.
Medicine (Baltimore). 2015; 94(46):e2014 [PubMed] Free Access to Full Article Related Publications
The purpose of this meta-analysis was to investigate whether bisphosphonates are a key therapy for bone metastases in lung cancer, breast cancer, and prostate cancer by comparing all randomized controlled trials that appraised the effects of bisphosphonates on risk of skeletal-related events (SREs).PubMed, Embase, and Medline databases (up to December 2014) were used to search all related articles. Using the data from 19 available publications, the authors examined the efficacy in treating or reducing the risk of SREs in lung cancer, breast cancer, and prostate cancer by meta-analysis.Bisphosphonates have demonstrated efficacy in treating or reducing the risk of SREs in lung cancer [odds ratio (OR) = 0.81, 95% confidence interval (CI) = 0.69-0.95, P = 0.008], breast cancer (OR = 0.62, 95% CI = 0.54-0.71, P = 0.000), and prostate cancer (OR = 0.62, 95% CI = 0.45-0.86, P = 0.004).This meta-analysis suggests that bisphosphonates have demonstrated efficacy in treating or reducing the risk of SREs in lung cancer, breast cancer, and prostate cancer.

Hiraga T, Ito S, Nakamura H
EpCAM expression in breast cancer cells is associated with enhanced bone metastasis formation.
Int J Cancer. 2016; 138(7):1698-708 [PubMed] Related Publications
Epithelial cell adhesion molecule (EpCAM) has been implicated in multiple cellular functions including cell adhesion. EpCAM has also recently been identified as a marker for cancer stem cells (CSCs). Here, we examined the roles of EpCAM in the development of bone metastasis of breast cancer by using well-characterized animal models. Morphological and real-time reverse transcriptase-polymerase chain reaction data showed that the EpCAM-negative and -positive (EpCAM(neg) and EpCAM(pos) ) cell populations isolated from breast cancer cell lines exhibited mesenchymal and epithelial phenotypes, respectively. Flow cytometric analysis revealed that EpCAM(pos) , but not EpCAM(neg) , cells possessed self-renewal and differentiation potentials. Tumorsphere formation in suspension cultures and tumorigenicity in the orthotopic mammary fat pad of mice were significantly greater in EpCAM(pos) cells than in EpCAM(neg) cells. The development of bone metastases induced by an intracardiac injection was markedly increased in mice inoculated with EpCAM(pos) cells. Furthermore, intracardiac inoculations of parental cells demonstrated that the EpCAM(pos) population in cancer cells that colonized in bone was significantly higher than that in parental cells. However, stable transduction of EpCAM into EpCAM(neg) cells failed to reproduce the phenotypes of EpCAM(pos) cells. These results suggest that the expression of EpCAM in breast cancer cells is associated with CSC-like phenotypes, which contribute to the promotion of bone metastases by enhancing tumorigenicity. Our results also support the possibility that the epithelial phenotypes of EpCAM-expressing cells confer advantageous properties for the development of bone metastases, at least after entering the circulation, while EpCAM is likely not solely responsible for the phenotypes of EpCAM(pos) cells.

Gurzu S, Jung I, Kadar Z
Aberrant metastatic behavior and particular features of early gastric cancer.
APMIS. 2015; 123(12):999-1006 [PubMed] Related Publications
In this paper, we have focused on the metastatic behavior of EGC and its particularities. The main factors that are currently considered as predictors of the metastatic behavior and that are used in the therapeutic decision (endoscopic resection vs surgical removal) are the tumor size (upper or bellow 2 cm), depth of infiltration, angiolymphatic invasion, the presence or absence of ulceration, and histologic type (undifferentiated vs differentiated carcinomas). However, most of the metastatic cases were published as case reports or case series. This is the reason why a proper estimation of metastatic risk in EGC is not well known. To date, 79 cases presenting bone metastases, three reports of brain metastases, and one EGC that was associated with skin metastasis were published. However, occult metastasis, lymph node micrometastasis, and skip metastasis can also occur and should be identified. Making a synthesis of the literature data that is correlated with our experience, we finally proposed the inclusion of the six Japanese subgrouping system, tumor size, angiolymphatic invasion, and micrometastasis as components of the pTNM staging system, which should be particularly adapted for EGC.

McDonald R, Probyn L, Poon I, et al.
Tumor Response After Stereotactic Body Radiation Therapy to Nonspine Bone Metastases: An Evaluation of Response Criteria.
Int J Radiat Oncol Biol Phys. 2015; 93(4):879-81 [PubMed] Related Publications
PURPOSE: To evaluate the applicability of the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) and University of Texas MD Anderson (MDA) Cancer Center criteria in the setting of stereotactic body radiation therapy (SBRT) to nonspine bone metastases.
METHODS: Patients who were treated with SBRT to nonspine bone metastases were identified by retrospective chart review. An independent musculoskeletal radiologist evaluated response to treatment using computed tomography (CT) scans.
RESULTS: Thirty-three patients were treated to 42 nonspine bone metastases. The most common primary cancer cites were renal cell carcinoma (RCC) (33.3%), lung (24.2%), and prostate (18.2%). Bone metastases were either mainly lytic (57.1%), mainly sclerotic (28.6%), or mixed (14.3%). When lytic and sclerotic lesions were evaluated according to RECIST 1.1, local control (LC) was 83%, 85%, 88%, and 80% for those with CT imaging between months 1 to 3, 4 to 6, 7 to 9, and 10 to 12, respectively. When evaluated by the MDA criteria by density, LC within each time period was slightly greater. Overall LC decreased considerably when evaluated by MDA in terms of size.
CONCLUSIONS: Consensus definitions of response are required as they have implications on clinical trials and disease management. Without consistent response criteria, outcomes from clinical trials cannot be compared and treatment efficacy remains undetermined.

Manickavasagar T, Gilson C, Chowdhury S, Kirby R
New developments in metastatic prostate cancer therapy.
Practitioner. 2015; 259(1781):21-4, 2-3 [PubMed] Related Publications
Metastatic prostate cancer is still commonly a lethal condition. The concept that 'men with prostate cancer die with rather than of their cancer' has been shown to be false. It is estimated that 10-20% of men in the UK present with locally advanced disease. Median overall survival remains only 3.5 years for men presenting with metastatic disease. The use of LHRH analogues to achieve medical castration has become the gold standard for both locally advanced prostate cancer, combined with radiotherapy, and metastatic disease. Androgen deprivation therapy (ADT) is the standard first-line treatment for advanced disease resulting in improvements in symptoms, radiological findings and PSA levels. Ultimately the majority of men with advanced prostate cancer will develop resistance to ADT Docetaxel is the standard first-line therapy recommended by international guidelines for patients with symptomatic metastatic castrate refractory prostate cancer who are suitable candidates for chemotherapy. More than 90% of patients with castrate refractory prostate cancer have bone metastases. Radium-223 dichloride is a novel alpha-emitting radiopharmaceutical agent, which mimics calcium and therefore targets bone metastases. It is indicated in patients with metastatic castrate refractory prostate cancer who have symptomatic bone metastases without visceral metastases.

Maier GS, Horas K, Kurth AA, et al.
Prevalence of Vitamin D Deficiency in Patients with Bone Metastases and Multiple Myeloma.
Anticancer Res. 2015; 35(11):6281-5 [PubMed] Related Publications
BACKGROUND/AIM: Breast and prostate cancer are amongst the most prevalent malignancies globally and up to 40% of patients will develop metastatic disease, particularly to the skeleton. Multiple myeloma is the most common cancer to affect bone with up to 90% of patients developing bone lesions. Although several studies demonstrated that endocrine changes such as vitamin D deficiency promote secondary cancer growth in bone, relatively few have reported its prevalence. For this reason, the purpose of the present study was to evaluate the prevalence of hypovitaminosis D in patients with bone metastases and multiple myeloma.
PATIENTS AND METHODS: Serum 25-OH-D levels of patients with metastatic bone disease were measured on admission. Statistical analyses was performed to evaluate for possible confounders of hypo-vitaminosis D.
RESULTS: We found a widespread and alarming rate of vitamin D deficiency in patients with metastatic bone disease and multiple myeloma. Of note, patients with bone metastases due to breast cancer, prostate cancer and multiple myeloma rarely reached sufficient serum 25-OH-D levels.
CONCLUSION: It is of utmost clinical importance to assess vitamin D levels in cancer patients, especially in those with, or at high risk of developing metastatic bone disease.

Yang L, Du S
Efficacy and Safety of Zoledronic Acid and Pamidronate Disodium in the Treatment of Malignant Skeletal Metastasis: A Meta-Analysis.
Medicine (Baltimore). 2015; 94(42):e1822 [PubMed] Free Access to Full Article Related Publications
Solid tumors frequently metastasize to bone. Two bisphosphonates have been investigated for bone metastases including pamidronate disodium and zoledronic acid.By searching the PubMed, Embase, Wanfang, and China National Knowledge Infrastructure (CNKI) databases, we conducted a meta-analysis to determine the efficacy and safety of zoledronic acid compared with pamidronate disodium in reducing pain in patients with bone metastases.Studies were pooled, and the relative risk (RR) and its corresponding 95 % confidence interval (CI) were calculated. Version 12.0 STATA software was used for statistical analysis. Twenty relevant articles were included for this meta-analysis study.The complete response rate in cancer patients treatment with zoledronic acid was significantly higher than that with pamidronate disodium (relative risk [RR] = 1.32 [95% confidence interval (CI), 1.00-1.75]; P = 0.987, I = 0%). However, there was no significant difference in the rate of partial response rate (RR = 1.04, 95% CI: 0.90-1.20; P = 0.942, I = 0%) and in the total effective rate (RR = 1.06, 95% CI: 1.00-1.12; P = 0.998, I = 0%). For adverse events (AE), the incidence of headache in cancer patients with zoledronic acid was significantly lower than that with pamidronate disodium (RR = 0.82, 95% CI: 0.70-0.96; P = 0.793, I = 0%). There was no significant difference in nausea or vomiting (RR = 1.00, 95% CI: 0.92-1.09; P = 0.494, I = 0%), fever (RR = 0.98, 95% CI: 0.85-1.14; P =0.633, I = 0%), fatigue (RR = 1.01, 95% CI: 0.91-1.11; P = 0.914, I = 0%) and anorexia (RR = 1.31, 95% CI: 0.91-1.87; P = 0.024, I = 64.4%).In conclusion, this meta-analysis indicates that treatment with zoledronic acid was more effective than pamidronate disodium in the complete response assessments and the incidence of headache, an AE, was significantly lower in cancer patients with zoledronic acid.

Chow E, Meyer RM, Ding K, et al.
Dexamethasone in the prophylaxis of radiation-induced pain flare after palliative radiotherapy for bone metastases: a double-blind, randomised placebo-controlled, phase 3 trial.
Lancet Oncol. 2015; 16(15):1463-72 [PubMed] Related Publications
BACKGROUND: Pain flare occurs after palliative radiotherapy, and dexamethasone has shown potential for prevention of such flare. We aimed to compare the efficacy of dexamethasone with that of placebo in terms of reduction of incidence of pain flare.
METHODS: In this double-blind, randomised, placebo-controlled phase 3 trial, patients from 23 Canadian centres were randomly allocated (1:1) with a web-based system and minimisation algorithm to receive either two 4 mg dexamethasone tablets or two placebo tablets taken orally at least 1 h before the start of radiation treatment (a single 8 Gy dose to bone metastases; day 0) and then every day for 4 days after radiotherapy (days 1-4). Patients were eligible if they had a non-haematological malignancy and bone metastasis (or metastases) corresponding to the clinically painful area or areas. Patients reported their worst pain scores and opioid analgesic intake before treatment and daily for 10 days after radiation treatment. They completed the European Organisation for Research and Treatment of Cancer (EORTC) quality of life QLQ-C15-PAL, the bone metastases module (EORTC QLQ-BM22), and the Dexamethasone Symptom Questionnaire at baseline, and at days 10 and 42 after radiation treatment. Pain flare was defined as at least a two-point increase on a scale of 0-10 in the worst pain score with no decrease in analgesic intake, or a 25% or greater increase in analgesic intake with no decrease in the worst pain score from days 0-10, followed by a return to baseline levels or below. Primary analysis of incidence of pain flare was by intention-to-treat (patients with missing primary data were classified as having pain flare). This study is registered with ClinicalTrials.gov, number NCT01248585, and is completed.
FINDINGS: Between May 30, 2011, and Dec 11, 2014, 298 patients were enrolled. 39 (26%) of 148 patients randomly allocated to the dexamethasone group and 53 (35%) of 150 patients in the placebo group had a pain flare (difference 8·9%, lower 95% confidence bound 0·0, one-sided p=0·05). Two grade 3 and one grade 4 biochemical hyperglycaemic events occurred in the dexamethasone group (without known clinical effects) compared with none in the placebo group. The most common adverse events were bone pain (61 [41%] of 147 vs 68 [48%] of 143), fatigue (58 [39%] of 147 vs 49 [34%] of 143), constipation (47 [32%] of 147 vs 37 [26%] of 143), and nausea (34 [23%] of 147 vs 34 [24%] of 143), most of which were mild grade 1 or 2.
INTERPRETATION: Dexamethasone reduces radiation-induced pain flare in the treatment of painful bone metastases.
FUNDING: The NCIC CTG's programmatic grant from the Canadian Cancer Society Research Institute.

Rief H, Förster R, Rieken S, et al.
The influence of orthopedic corsets on the incidence of pathological fractures in patients with spinal bone metastases after radiotherapy.
BMC Cancer. 2015; 15:745 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Clinical care of unstable spinal bone metastases in many centers often includes patient immobilization by means of an orthopedic corset in order to prevent pathological fractures. The aim of this retrospective analysis was to evaluate the incidence of pathological fractures after radiotherapy (RT) in patients with and without orthopedic corsets and to assess prognostic factors for pathological fractures in patients with spinal bone metastases.
METHODS: The incidence of pathological fractures in 915 patients with 2.195 osteolytic metastases in the thoracic and lumbar spine was evaluated retrospectively on the basis of computed tomography (CT) scans between January 2000 and January 2012 depending on prescription and wearing of patient-customized orthopedic corsets.
RESULTS: In the corset group, 6.8 and 8.0 % in no-corset group showed pathological fractures prior to RT, no significant difference between groups was detected (p = 0.473). After 6 months, patients in the corset group showed pathological fractures in 8.6 % and in no-corset group in 9.3 % (p = 0.709). The univariate and bivariate analyses demonstrated no significant prognostic factor for incidence of pathological fractures in both groups.
CONCLUSIONS: In this analysis, we could show for the first time in more than 900 patients, that abandoning a general corset supply in patients with spinal metastases does not significantly cause increased rates of pathological fractures. Importantly, the incidence of pathological fracture after RT was small.

Hanyok BT, Howard LE, Amling CL, et al.
Is computed tomography a necessary part of a metastatic evaluation for castration-resistant prostate cancer? Results from the Shared Equal Access Regional Cancer Hospital Database.
Cancer. 2016; 122(2):222-9 [PubMed] Related Publications
BACKGROUND: Metastatic lesions in prostate cancer beyond the bone have prognostic importance and affect clinical therapeutic decisions. Few data exist regarding the prevalence of soft-tissue metastases at the initial diagnosis of metastatic castration-resistant prostate cancer (mCRPC).
METHODS: This study analyzed 232 men with nonmetastatic (M0) castration-resistant prostate cancer (CRPC) who developed metastases detected by a bone scan or computed tomography (CT). All bone scans and CT scans within the 30 days before or after the mCRPC diagnosis were reviewed. The rate of soft-tissue metastases among those undergoing CT was determined. Then, predictors of soft-tissue metastases and visceral and lymph node metastases were identified.
RESULTS: Compared with men undergoing CT (n = 118), men undergoing only bone scans (n = 114) were more likely to have received primary treatment (P = .048), were older (P = .013), and less recently developed metastases (P = .018). Among those undergoing CT, 52 (44%) had soft-tissue metastases, including 20 visceral metastases (17%) and 41 lymph node metastases (35%), whereas 30% had no bone involvement. In a univariable analysis, only prostate-specific antigen (PSA) predicted soft-tissue metastases (odds ratio [OR], 1.27; P = .047), and no statistically significant predictors of visceral metastases were found. A higher PSA level was associated with an increased risk of lymph node metastases (OR, 1.38; P = .014), whereas receiving primary treatment was associated with decreased risk (OR, 0.36; P = .015).
CONCLUSIONS: The data suggest that there is a relatively high rate of soft-tissue metastasis (44%) among CRPC patients undergoing CT at the initial diagnosis of metastases, including some men with no bone involvement. Therefore, forgoing CT during a metastatic evaluation may lead to an underdiagnosis of soft-tissue metastases and an underdiagnosis of metastases in general. Cancer 2015. © 2015 American Cancer Society. Cancer 2016;122:222-229. © 2015 American Cancer Society.

Leporini C, Ammendola M, Marech I, et al.
Targeting mast cells in gastric cancer with special reference to bone metastases.
World J Gastroenterol. 2015; 21(37):10493-501 [PubMed] Free Access to Full Article Related Publications
Bone metastases from gastric cancer (GC) are considered a relatively uncommon finding; however, they are related to poorer prognosis. Both primary GC and its metastatic progression rely on angiogenesis. Several lines of evidence from GC patients strongly support the involvement of mast cells (MCs) positive to tryptase (MCPT) in primary gastric tumor angiogenesis. Recently, we analyzed infiltrating MCs and neovascularization in bone tissue metastases from primary GC patients, and observed a significant correlation between infiltrating MCPT and angiogenesis. Such a finding suggested the involvement of peritumoral MCPT by infiltrating surrounding tumor cells, and in bone metastasis angiogenesis from primary GC. Thus, an MCPT-stimulated angiogenic process could support the development of metastases in bone tissue. From this perspective, we aim to review the hypothetical involvement of tumor-infiltrating, peritumoral MCPT in angiogenesis-mediated GC cell growth in the bone microenvironment and in tumor-induced osteoclastic bone resorption. We also focus on the potential use of MCPT targeting agents, such as MCs tryptase inhibitors (gabexate mesylate, nafamostat mesylate) or c-KitR tyrosine kinase inhibitors (imatinib, masitinib), as possible new anti-angiogenic and anti-resorptive strategies for the treatment of GC patients affected by bone metastases.

Ashworth A, Kong W, Chow E, Mackillop WJ
Fractionation of Palliative Radiation Therapy for Bone Metastases in Ontario: Do Practice Guidelines Guide Practice?
Int J Radiat Oncol Biol Phys. 2016; 94(1):31-9 [PubMed] Related Publications
PURPOSE: To evaluate the effect of a provincial practice guideline on the fractionation of palliative radiation therapy for bone metastases (PRT.B) in Ontario.
METHODS AND MATERIALS: The present retrospective study used electronic treatment records linked to Ontario's population-based cancer registry. Hierarchical multivariable regression analysis was used to evaluate temporal trends in the use of single fractions (SFs), controlling for patient-related factors associated with the use of SFs.
RESULTS: From 1984 to 2012, 43.9% of 161,835 courses of PRT.B were administered as SFs. The percentage of SF courses was greater for older patients (age <50 years, 39.8% vs age >80 years, 52.5%), those with a shorter life expectancy (survival >12 months, 36.9% vs < 1 month, 53.6%), and those who lived farther from a radiation therapy center (<10 km, 42.1% vs > 50 km, 47.3%). The percentage of SFs to spinal fields was lower than that to other skeletal sites (31.5% vs 57.1%). The percentage of SFs varied among the cancer centers (range, 26.0%-67.8%). These differences were all highly significant in the multivariable analysis (P<.0001). In 2004, Cancer Care Ontario released a practice guideline endorsing the use of SFs for uncomplicated bone metastases. The rate of use of SFs increased from 42.3% in the pre-guideline period (1999-2003) to 52.6% in the immediate post-guideline period (2004-2007). However, it subsequently decreased again to 44.0% (2009-2012). These temporal trends were significant after controlling for patient-related factors in the multivariable analysis (P<.0001). Large intercenter variations in the use of SFs persisted after publication of the guideline.
CONCLUSIONS: The publication of an Ontario practice guideline endorsing the use of SF PRT.B was associated with only a transient increase in the use of SFs in Ontario and did little to reduce intercenter variations in fractionation.

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