Secondary Bone Cancer (bone metastasis)
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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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Latest Research Publications

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

Ugras N, Yalcinkaya U, Akesen B, Kanat O
Solitary bone metastases of unknown origin.
Acta Orthop Belg. 2014; 80(1):139-43 [PubMed] Related Publications
Patients with a newly detected solitary bone metastasis and no history of cancer need extensive diagnostic testing. One hundred and twenty biopsy samples of patients with metastatic bone disease were referred to the authors' pathology department between June 2005 and December 2012. Thirty-three (27.5%) of these patients with a solitary metastasis of unknown origin, and without visceral metastases, were studied retrospectively. Most metastases were found in the spine (14/33 or 42.4%), or in the pelvis (7/33 or 21.2%). The lung was the most common primary site, but this is not universal in the literature. A useful flowchart for the clinician, confronted with a bone metastasis from an unknown primary site, is the following, according to the literature: history and physical examination, biochemistry with tumor markers and immunoelectrophoresis, chest radiograph, CT-scan of chest and abdomen, and bone scan.

Related: Lung Cancer Cancer of Unknown Primary

Aoude A, Amiot LP
A comparison of the modified Tokuhashi and Tomita scores in determining prognosis for patients afflicted with spinal metastasis.
Can J Surg. 2014; 57(3):188-93 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The prognosis of patients with spinal metastasis is not very promising and hard to predict. It is for this reason that scoring systems, such as the modified Tokuhashi and Tomita scores, have been created. We sought to determine the effectiveness of these scores in predicting patient survival.
METHODS: We retrospectively reviewed the data of all patients treated for spinal metastasis between March 2003 and March 2012 in our centre. We computed the Tokuhashi and Tomita scores and compared them with documented patient survival. The 2 scores were also compared with one another.
RESULTS: We identified 128 patients with spinal metastasis. The average survival of patients with predicted poor, average and good prognosis was 5, 17 and 25 months, respectively for the modified Tokuhashi score and 3, 16 and 19 months, respectively, for the Tomita score. Poor, average and good prognosis predictions differed significantly from one another for all 3 categories for the Tokuhashi score (all p < 0.05). There was no significant difference in the moderate and good prognoses for the Tomita score (p = 0.15). When comparing both scores, we obtained a weighted κ of 0.4489 (standard deviation 0.0568, 95% confidence interval 0.3376-0.5602), demonstrating moderate agreement between scores.
CONCLUSION: Both scores have merit for use in a clinical setting and can be used as tools to help determine treatment choice. The modified Tokuhashi score had better accuracy in determining actual survival.

Polishchuk AL, Li R, Hill-Kayser C, et al.
Likelihood of bone recurrence in prior sites of metastasis in patients with high-risk neuroblastoma.
Int J Radiat Oncol Biol Phys. 2014; 89(4):839-45 [PubMed] Related Publications
PURPOSE/OBJECTIVES: Despite recent improvements in outcomes, 40% of children with high-risk neuroblastoma will experience relapse, facing a guarded prognosis for long-term cure. Whether recurrences are at new sites or sites of original disease may guide decision making during initial therapy.
METHODS AND MATERIALS: Eligible patients were retrospectively identified from institutional databases at first metastatic relapse of high-risk neuroblastoma. Included patients had disease involving metaiodobenzylguanidine (MIBG)-avid metastatic sites at diagnosis and first relapse, achieved a complete or partial response with no more than one residual MIBG-avid site before first relapse, and received no total body irradiation or therapy with (131)I-MIBG before first relapse. Anatomically defined metastatic sites were tracked from diagnosis through first relapse to determine tendency of disease to recur at previously involved versus uninvolved sites and to assess whether this pattern was influenced by site irradiation.
RESULTS: Of 159 MIBG-avid metastatic sites identified among 43 patients at first relapse, 131 (82.4%) overlapped anatomically with the set of 525 sites present at diagnosis. This distribution was similar for bone sites, but patterns of relapse were more varied for the smaller subset of soft tissue metastases. Among all metastatic sites at diagnosis in our subsequently relapsed patient cohort, only 3 of 19 irradiated sites (15.8%) recurred as compared with 128 of 506 (25.3%) unirradiated sites.
CONCLUSIONS: Metastatic bone relapse in neuroblastoma usually occurs at anatomic sites of previous disease. Metastatic sites identified at diagnosis that did not receive radiation during frontline therapy appeared to have a higher risk of involvement at first relapse relative to previously irradiated metastatic sites. These observations support the current paradigm of irradiating metastases that persist after induction chemotherapy in high-risk patients. Furthermore, they raise the hypothesis that metastatic sites appearing to clear with induction chemotherapy may also benefit from radiotherapeutic treatment modalities (external beam radiation or (131)I-MIBG).

Kosaka T, Yamaki E, Mogi A, Kuwano H
A case of lung adenocarcinoma with postoperative recurrence of multiple bone metastases that showed a gradual complete response to combined administration of erlotinib and zoledronic acid.
Tumori. 2014 Mar-Apr; 100(2):e45-8 [PubMed] Related Publications
We describe a case of lung adenocarcinoma with multiple postoperative bone metastases that showed a gradual but complete response to combined administration of erlotinib and zoledronic acid. A 76-year-old man with moderately differentiated adenocarcinoma underwent a radical left upper lobectomy and mediastinal lymph node dissection. Three and a half years after the operation, serum carcinoembryonic antigen (CEA) was elevated and 18F-fluorodeoxyglucose positron emission tomography (18FDG-PET) revealed multiple bone metastases. Pretreatment evaluation of EGFR mutations in the resected primary adenocarcinoma specimen showed an L858R mutation in exon 21. Gefitinib was started as first-line treatment. However, evaluation 1 month after administration revealed progressive disease. Erlotinib was started as second-line treatment, and evaluation 1 month after administration revealed that the disease was stable. Administration of zoledronic acid was then begun with continuation of erlotinib. After 2 courses of zoledronic acid, the serum CEA level had not changed but the maximum standardized uptake values of each region uniformly decreased. Furthermore, the uptake of 18FDG completely disappeared after 6 courses. Subsequently, the serum CEA level continued to decrease and the disappearance of 18FDG uptake was confirmed after 10 courses (12 months after initiation of erlotinib administration). Our results suggest that the combined administration of both drugs is effective against bone metastases.We experienced a case of lung adenocarcinoma with postoperative recurrence of multiple bone metastases that showed a gradual but complete response to combined administration of erlotinib and zoledronic acid. Our results suggest that the combined treatment of both drugs is an effective therapy against bone metastases.

Related: Non-Small Cell Lung Cancer Bisphosphonates Lung Cancer Zoledronic acid (Zometa) EGFR Erlotinib (Tarceva) Gefitinib (Iressa)

Boyer MJ, Salama JK, Lee WR
Palliative radiotherapy for prostate cancer.
Oncology (Williston Park). 2014; 28(4):306-12 [PubMed] Related Publications
Radiotherapy is an effective tool for the palliation of symptoms commonly caused by prostate cancer. The majority of painful bone metastases respond equally well to single or multiple fractions of external radiotherapy. Retreatment with a second course of radiation induces pain responses in approximately 50% of patients. For more diffuse metastases, either hemibody radiation or systemic radiopharmaceuticals can reduce pain, and radium-223 is associated with improved survival in men with castration-resistant prostate cancer. Hematuria, bladder outlet obstruction, and rectal compression are all improved with palliative radiotherapy. The ability of stereotactic body radiation therapy to reduce pain compared with standard external radiation is being investigated, as is its role in treating those with limited metastatic disease.

Related: Prostate Cancer

Sartor O, Coleman R, Nilsson S, et al.
Effect of radium-223 dichloride on symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases: results from a phase 3, double-blind, randomised trial.
Lancet Oncol. 2014; 15(7):738-46 [PubMed] Related Publications
BACKGROUND: Bone metastases frequently cause skeletal events in patients with metastatic castration-resistant prostate cancer. Radium-223 dichloride (radium-223) selectively targets bone metastases with high-energy, short-range α-particles. We assessed the effect of radium-223 compared with placebo in patients with castration-resistant prostate cancer and bone metastases.
METHODS: In this phase 3, double-blind, randomised ALSYMPCA trial, we enrolled patients who had symptomatic castration-resistant prostate cancer with two or more bone metastases and no known visceral metastases, who were receiving best standard of care, and had previously either received or were unsuitable for docetaxel. Patients were stratified by previous docetaxel use, baseline total alkaline phosphatase level, and current bisphosphonate use, then randomly assigned (2:1) to receive either six intravenous injections of radium-223 (50 kBq/kg) or matching placebo; one injection was given every 4 weeks. Randomisation was done with an interactive voice response system, taking into account trial stratification factors. Participants and investigators were masked to treatment assignment. The primary endpoint was overall survival, which has been reported previously. Here we report on time to first symptomatic skeletal event, defined as the use of external beam radiation to relieve bone pain, or occurrence of a new symptomatic pathological fracture (vertebral or non-verterbal), or occurence of spinal cord compression, or tumour-related orthopeadic surgical intervention. All events were required to be clinically apparent and were not assessed by periodic radiological review. Statistical analyses of symptomatic skeletal events were based on the intention-to-treat population. The study has been completed and is registered with, number NCT00699751.
FINDINGS: Between June 12, 2008, and Feb 1, 2011, 921 patients were enrolled, of whom 614 (67%) were randomly assigned to receive radium-223 and 307 (33%) placebo. Symptomatic skeletal events occurred in 202 (33%) of 614 patients in the radium-223 group and 116 (38%) of 307 patients in the placebo group. Time to first symptomatic skeletal event was longer with radium-223 than with placebo (median 15·6 months [95% CI 13·5-18·0] vs 9·8 months [7·3-23·7]; hazard ratio [HR]=0·66, 95% CI 0·52-0·83; p=0·00037). The risks of external beam radiation therapy for bone pain (HR 0·67, 95% CI 0·53-0·85) and spinal cord compression (HR=0·52, 95% CI 0·29-0·93) were reduced with radium-233 compared with placebo. Radium-223 treatment did not seem to significantly reduce the risk of symptomatic pathological bone fracture (HR 0·62, 95% CI 0·35-1·09), or the need for tumour-related orthopaedic surgical intervention (HR 0·72, 95% CI 0·28-1·82).
INTERPRETATION: Radium-223 should be considered as a treatment option for patients with castration-resistant prostate cancer and symptomatic bone metastases.
FUNDING: Algeta and Bayer HealthCare Pharmaceuticals.

Araujo A, Cook LM, Lynch CC, Basanta D
An integrated computational model of the bone microenvironment in bone-metastatic prostate cancer.
Cancer Res. 2014; 74(9):2391-401 [PubMed] Article available free on PMC after 01/05/2015 Related Publications
Bone metastasis will impact most men with advanced prostate cancer. The vicious cycle of bone degradation and formation driven by metastatic prostate cells in bone yields factors that drive cancer growth. Mechanistic insights into this vicious cycle have suggested new therapeutic opportunities, but complex temporal and cellular interactions in the bone microenvironment make drug development challenging. We have integrated biologic and computational approaches to generate a hybrid cellular automata model of normal bone matrix homeostasis and the prostate cancer-bone microenvironment. The model accurately reproduces the basic multicellular unit bone coupling process, such that introduction of a single prostate cancer cell yields a vicious cycle similar in cellular composition and pathophysiology to models of prostate-to-bone metastasis. Notably, the model revealed distinct phases of osteolytic and osteogenic activity, a critical role for mesenchymal stromal cells in osteogenesis, and temporal changes in cellular composition. To evaluate the robustness of the model, we assessed the effect of established bisphosphonate and anti-RANKL therapies on bone metastases. At approximately 100% efficacy, bisphosphonates inhibited cancer progression while, in contrast with clinical observations in humans, anti-RANKL therapy fully eradicated metastases. Reducing anti-RANKL yielded clinically similar results, suggesting that better targeting or dosing could improve patient survival. Our work establishes a computational model that can be tailored for rapid assessment of experimental therapies and delivery of precision medicine to patients with prostate cancer with bone metastases.

Related: Prostate Cancer

Xie F, Hopkins RB, Burke N, et al.
Time and labor costs associated with administration of intravenous bisphosphonates for breast or prostate cancer patients with metastatic bone disease: a time and motion study.
Hosp Pract (1995). 2014; 42(2):38-45 [PubMed] Related Publications
OBJECTIVES: To estimate, using a time and motion method, the time and labor costs associated with the administration of zoledronic acid and pamidronate in cancer patients with metastatic bone diseases.
METHODS: During clinic visits for participating patients receiving intravenous zoledronic acid or pamidronate, all times and activities associated with the administration of bisphosphonates were recorded by a trained observer using a stopwatch and data recording forms. The total time associated with the administration of bisphosphonates was estimated and converted to labor costs by applying corresponding health care professional hourly wage rates plus the fringe-benefit rate. The costs were presented in 2011 Canadian dollars.
RESULTS: A convenience sample of 37 patients from 2 hospital outpatient oncology clinics in Ontario and Quebec participated in the study. Nineteen patients were diagnosed with breast cancer and 18 with prostate cancer. The average patient age was 66 years, and patients had been diagnosed with cancer and metastatic bone disease for 8 years and 3 years, respectively. The times and costs associated with the administration of bisphosphonates for the 28 patients who did not receive concurrent chemotherapy during the scheduled clinic visits are also reported. The mean infusion time for patients receiving zoledronic acid was 20.6 minutes. With the use of ambulatory infusion devices, the mean infusion time of pamidronate was 23 minutes (limited to observations of patients who were seated during administration). In contrast, the mean infusion time using regular infusion devices was 162 minutes. The mean labor cost for administering zoledronic acid was $20. The mean labor cost for administering pamidronate was $10 using ambulatory infusion devices and $68 using regular infusion devices.
CONCLUSION: The time burden to cancer patients with metastatic bone disease who receive intravenous bisphosphonates and the costs to the health care system are substantial, especially when regular infusion devices are used.

Related: Breast Cancer Canada Bisphosphonates Prostate Cancer Zoledronic acid (Zometa) Pamidronate (Aredia)

Purushotham A, Shamil E, Cariati M, et al.
Age at diagnosis and distant metastasis in breast cancer--a surprising inverse relationship.
Eur J Cancer. 2014; 50(10):1697-705 [PubMed] Related Publications
INTRODUCTION: Predictors for site of distant metastasis and impact on survival in breast cancer are incompletely understood.
METHODS: Clinico-pathological risk factors for site of distant metastasis and survival were analysed in patients with invasive breast cancer treated between 1986 and 2006.
RESULTS: Of 3553 patients, with median follow-up 6.32years, 825 (23%) developed distant metastasis. The site of metastasis was bone in 196/825 (24%), viscera in 540/825 (65%) and unknown in 89 (11%). Larger primary invasive tumour size, higher tumour grade and axillary nodal positivity increased risk of metastasis to all sites. Lobular carcinoma was more likely to first metastasise to bone compared to invasive ductal carcinoma (NST). Oestrogen receptor (ER) negative, progesterone receptor (PgR) negative and/or Human epidermal growth factor (HER2) positive tumours were more likely to metastasise to viscera. A striking relationship between increasing age at diagnosis and a reduction in risk of distant metastasis to bone and viscera was observed. Median time to death from onset of metastatic disease was 1.52 (Interquartile range (IQR) 0.7-2.9)years for patients with bone metastasis and 0.7 (IQR 0.2-1.5)years for visceral metastasis. On multivariate analysis, despite the decrease in risk of distant metastasis with increasing age, there was an elevated hazard for death in patients >50years at diagnosis of metastasis if they developed bone metastasis, with a similar trend observed in the >70years age group if they developed visceral metastasis.
CONCLUSION: These findings indicate that there are biological mechanisms underlying the impact of age on the development of distant metastasis and subsequent death. This may have important implications in the treatment of breast cancer.

Related: Breast Cancer EGFR

Deng X, He G, Liu J, et al.
Recent advances in bone-targeted therapies of metastatic prostate cancer.
Cancer Treat Rev. 2014; 40(6):730-8 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
Prostate cancer is one of the most common malignancies affecting men worldwide, with bone being the most common site of metastasis in patients that progress beyond organ confinement. Bone metastases are virtually incurable and result in significant disease morbidity and mortality. Bone provides a unique microenvironment whose local interactions with tumor cells offer novel targets for therapeutic interventions. Several attractive molecules or pathways have been identified as new potential therapeutic targets for bone metastases caused by metastatic castration-resistant prostate cancer. In this review, we present the recent advances in molecular targeted therapies for prostate cancer bone metastasis focusing on therapies that target the bone cells and the bone microenvironment. The therapies covered in this review include agents that inhibit bone resorption, agents that stimulate bone formation, and agents that target the bone matrix. Suggestions to devise more effective molecular targeted therapies are proposed. Hopefully, with better understanding of the biology of the disease and the development of more robust targeted therapies, the survival and quality of life of the affected individuals could be significantly improved.

Related: Bisphosphonates Prostate Cancer Signal Transduction

Hurwitz MD, Ghanouni P, Kanaev SV, et al.
Magnetic resonance-guided focused ultrasound for patients with painful bone metastases: phase III trial results.
J Natl Cancer Inst. 2014; 106(5) [PubMed] Article available free on PMC after 01/07/2015 Related Publications
BACKGROUND: Pain due to bone metastases is a common cause of cancer-related morbidity, with few options available for patients refractory to medical therapies and who do not respond to radiation therapy. This study assessed the safety and efficacy of magnetic resonance-guided focused ultrasound surgery (MRgFUS), a noninvasive method of thermal tissue ablation for palliation of pain due to bone metastases.
METHODS: Patients with painful bone metastases were randomly assigned 3:1 to receive MRgFUS sonication or placebo. The primary endpoint was improvement in self-reported pain score without increase of pain medication 3 months after treatment and was analyzed by Fisher's exact test. Components of the response composite, Numerical Rating Scale for pain (NRS) and morphine equivalent daily dose intake, were analyzed by t test and Wilcoxon rank-sum test, respectively. Brief Pain Inventory (BPI-QoL), a measure of functional interference of pain on quality of life, was compared between MRgFUS and placebo by t test. Statistical tests were two-sided.
RESULTS: One hundred forty-seven subjects were enrolled, with 112 and 35 randomly assigned to MRgFUS and placebo treatments, respectively. Response rate for the primary endpoint was 64.3% in the MRgFUS arm and 20.0% in the placebo arm (P < .001). MRgFUS was also superior to placebo at 3 months on the secondary endpoints assessing worst score NRS (P < .001) and the BPI-QoL (P < .001). The most common treatment-related adverse event (AE) was sonication pain, which occurred in 32.1% of MRgFUS patients. Two patients had pathological fractures, one patient had third-degree skin burn, and one patient suffered from neuropathy. Overall 60.3% of all AEs resolved on the treatment day.
CONCLUSIONS: This multicenter phase III trial demonstrated that MRgFUS is a safe and effective, noninvasive treatment for alleviating pain resulting from bone metastases in patients that have failed standard treatments.

Related: Cancer Prevention and Risk Reduction

Putz C, Gantz S, Bruckner T, et al.
Preoperative scoring and limits of prognostication: functional outcome after surgical decompression in metastatic spinal cord compression.
Oncology. 2014; 86(3):177-84 [PubMed] Related Publications
OBJECTIVE: To determine whether preoperative parameters correlate with the postoperative functional outcome in para- and tetraplegic patients with lung, kidney, breast and prostate cancer and metastatic spinal cord compression (MSCC).
METHODS: Information on 43 patients undergoing decompressive surgery and rehabilitation for MSCC was reviewed, including primary tumor, age, pre- and postoperative ambulation status, mobility subcategory of the Spinal Cord Injury Measure (mSCIM) and the Tokuhashi score. Differences between groups were analyzed by the nonparametric χ(2) test, and correlation coefficients (Spearman's rho) were computed.
RESULTS: Preoperative ambulation (p < 0.001), the American Spinal Injury Association Impairment Scale (p < 0.001) and the type of operation (p = 0.02) influenced the postoperative functional outcome. Any positive change in the mSCIM was influenced by preoperative ambulation (p < 0.001). Patients with breast carcinoma showed significantly more positive changes in the mSCIM compared with other tumors (p = 0.002). No correlation was found between the treatment categories of the Tokuhashi score and the preoperative ambulatory status (p = 0.13) or the change in ambulation status (p = 0.29).
CONCLUSION: The postoperative functional outcome of MSCC patients shows a linear association between the categories of the Tokuhashi score and the change in ambulation status. We recommend surgical decompression even in a palliative situation (Tokuhashi score 0-8) with the aim of optimizing the short-term rehabilitation outcome.

Kaloostian PE, Zadnik PL, Kim JE, et al.
High incidence of morbidity following resection of metastatic pheochromocytoma in the spine.
J Neurosurg Spine. 2014; 20(6):726-33 [PubMed] Related Publications
Pheochromocytomas of the spine are uncommon and require careful preoperative planning. The authors retrospectively reviewed the charts of 5 patients with metastatic spinal pheochromocytoma who had undergone surgical treatment over the past 10 years at their medical center. They reviewed patient age, history of pheochromocytoma resection, extent and location of metastases, history of alpha blockage, surgical level, surgical procedure, postoperative complications, tumor recurrence, and survival. Metastases involved the cervical (1 patient), thoracic (3 patients), and lumbar (2 patients) levels. Preoperative treatment included primary pheochromocytoma resection, chemotherapy, alpha blockade, embolization, and radiation. Three patients had tumor recurrence, and 2 underwent 2-stage reoperations for tumor extension. Hemodynamic complications were common: 2 patients developed pulseless electrical activity arrest within 4 months after surgery, 1 patient had profound postoperative tachycardia with fever and an elevated creatine kinase level, and 1 patient experienced transient postoperative hypotension and paraplegia. One patient died of complications related to disseminated cerebral and spinal disease. With careful preoperative and surgical management, patients with symptomatic metastatic spinal pheochromocytoma can benefit from aggressive surgical treatment. Postoperative cardiovascular complications are common even months after surgery, and patients should be closely monitored long term.

Kasliwal MK, Tan LA, O'Toole JE
Intradural tumor recurrence after resection of extradural metastasis: a rare but potential complication of intraoperative durotomy.
J Neurosurg Spine. 2014; 20(6):734-9 [PubMed] Related Publications
Spinal metastases are the most common of spinal neoplasms and occur predominantly in an extradural location. Their appearance in an intradural location is uncommon and is associated with a poor prognosis. Cerebrospinal fluid dissemination accounts for a significant number of intradural spinal metastases mostly manifesting as leptomeningeal carcinomatoses or drop metastases from intracranial tumors. The occurrence of local tumor dissemination intradurally following surgery for an extradural spinal metastasis has not been reported previously. The authors describe 2 cases in which local intradural and intramedullary tumor recurrences occurred following resection of extradural metastases that were complicated by unintended durotomy. To heighten clinical awareness of this unusual form of local tumor recurrence, the authors discuss the possible etiology and clinical consequences of this entity.

Related: Colorectal (Bowel) Cancer Fluorouracil Leucovorin

Valta MP, Zhao H, Ingels A, et al.
Development of a realistic in vivo bone metastasis model of human renal cell carcinoma.
Clin Exp Metastasis. 2014; 31(5):573-84 [PubMed] Related Publications
About one-third of patients with advanced renal cell carcinoma (RCC) have bone metastases. The incidence of RCC is increasing and bone metastatic RCC merits greater focus. Realistic preclinical bone metastasis models of RCC are lacking, hampering the development of effective therapies. We developed a realistic in vivo bone metastasis model of human RCC by implanting precision-cut tissue slices under the renal capsule of immunodeficient mice. The presence of disseminated cells in bone marrow of tissue slice graft (TSG)-bearing mice was screened by human-specific polymerase chain reaction and confirmed by immunohistology using human-specific antibody. Disseminated tumor cells in bone marrow of TSG-bearing mice derived from three of seven RCC patients were detected as early as 1 month after tissue implantation at a high frequency with close resemblance to parent tumors (e.g., CAIX expression and high vascularity). The metastatic patterns of TSGs correlated with disease progression in patients. In addition, TSGs retained capacity to metastasize to bone at high frequency after serial passaging and cryopreservation. Moreover, bone metastases in mice responded to Temsirolimus treatment. Intratibial injections of single cells generated from TSGs showed 100 % engraftment and produced X-ray-visible tumors as early as 3 weeks after cancer cell inoculation. Micro-computed tomography (μCT) and histological analysis revealed osteolytic characteristics of these lesions. Our results demonstrated that orthotopic RCC TSGs have potential to develop bone metastases that respond to standard therapy. This first reported primary RCC bone metastasis model provides a realistic setting to test therapeutics to prevent or treat bone metastases in RCC.

Related: Kidney Cancer

Hadji P, Kyvernitakis J, Albert U, et al.
Gender differences in persistency to bisphosphonates in patients with metastatic breast and prostate cancer.
Int J Clin Pharmacol Ther. 2014; 52(5):352-9 [PubMed] Related Publications
BACKGROUND: Bisphosphonates (BIS) treatment is a standard of care in metastatic bone disease (MBD) and regular intake is of upmost importance to ensure the effectiveness. The aim of this study was to investigate gender specific differences in persistence with BIS in MBD for the first time in this regard.
PATIENTS AND METHODS: Out of the original database of 16 million patients, we extracted first-time metastatic cancer related BIS prescriptions from January 2001 to December 2011 in patients diagnosed with MBD following breast cancer (BC) or prostate cancer (PC). Patients were matched (1 : 1) in accordance to age. For persistence analyses, 1,007 patients with metastatic BC and PC were available.
RESULTS: After 1 year of follow-up, 35.3% of BC and 26.6% of PC patients treated with BIS discontinued their treatment (p < 0.001). The differences were irrespective of increased refill gaps and route of BIS administration. The multivariate hazard ratios of the Cox regression models for 1-year risk of BIS discontinuation (adjusting for multiple variables) showed no increased risk for treatment discontinuation for BC vs. PC patients (HR: 0.87; 95% CI: 0.65 - 1.17). The use of co-medications decreased, regional and insurance aspects increased the risk of treatment discontinuation (HR of 0.88, 1.50, and 1.42).
CONCLUSIONS: Although apparent in the primary analysis, we found no significant difference in the gender specific persistency after 12 months of first BIS treatment in MBD. Only co-medication, geographical and insurance aspects were associated with differences in discontinuation rates. Further studies are needed to investigate this clinically important relationship.

Related: Breast Cancer Bisphosphonates Prostate Cancer

Wick MR
Metastases to bones.
Semin Diagn Pathol. 2014; 31(1):53-65 [PubMed] Related Publications
Metastatic tumors involving the bones may derive from a number of visceral primary sites, and they can assume several histological appearances. In selected instances, diagnostic confusion with some primary bone tumors may eventuate, necessitating the use of adjunctive pathologic studies to reach a final interpretation. This review considers metastatic osseous neoplasms in the small-cell, large-polygonal-cell, and spindle-cell-pleomorphic microscopic categories. The use of immunohistology and molecular analysis to study such tumors is discussed.

Related: Signal Transduction

Cante D, Franco P, Sciacero P, et al.
Penile metastasis from prostate cancer: a case report.
Tumori. 2014 Jan-Feb; 100(1):e14-6 [PubMed] Related Publications
Metastatic involvement of the penis is rare. About 80% of secondary lesions originate from pelvic primary tumors, mainly bladder and prostate. We present a case of prostatic mucinous adenocarcinoma with penile metastasis symptomatic for pain, which was treated with external-beam radiation (35 Gy/14 fractions; 2.5 Gy daily) combined with androgen deprivation, resulting in complete pain relief and objective response after treatment.

Related: Prostate Cancer

Folkert MR, Bilsky MH, Tom AK, et al.
Outcomes and toxicity for hypofractionated and single-fraction image-guided stereotactic radiosurgery for sarcomas metastasizing to the spine.
Int J Radiat Oncol Biol Phys. 2014; 88(5):1085-91 [PubMed] Related Publications
PURPOSE: Conventional radiation treatment (20-40 Gy in 5-20 fractions, 2-5 Gy per fraction) for sarcoma metastatic to the spine provides subtherapeutic doses, resulting in poor durable local control (LC) (50%-77% at 1 year). Hypofractionated (HF) and/or single-fraction (SF) image-guided stereotactic radiosurgery (IG-SRS) may provide a more effective means of managing these lesions.
METHODS AND MATERIALS: Patients with pathologically proven high-grade sarcoma metastatic to the spine treated with HF and SF IG-SRS were included. LC and overall survival (OS) were analyzed by the use of Kaplan-Meier statistics. Univariate and multivariate analyses were performed by the use of Cox regression with competing-risks analysis; all confidence intervals are 95%. Toxicities were assessed according to Common Terminology Criteria for Adverse Events, version 4.0.
RESULTS: From May 2005 to November 11, 2012, 88 patients with 120 discrete metastases received HF (3-6 fractions; median dose, 28.5 Gy; n=52, 43.3%) or SF IG-SRS (median dose, 24 Gy; n=68, 56.7%). The median follow-up time was 12.3 months. At 12 months, LC was 87.9% (confidence interval [CI], 81.3%-94.5%), OS was 60.6% (CI, 49.6%-71.6%), and median survival was 16.9 months. SF IG-SRS demonstrated superior LC to HF IG-SRS (12-month LC of 90.8% [CI, 83%-98.6%] vs 84.1% [CI, 72.9%-95.3%] P=.007) and retained significance on multivariate analysis (P=.030, hazard ratio 0.345; CI, 0.132-0.901]. Treatment was well tolerated, with 1% acute grade 3 toxicity, 4.5% chronic grade 3 toxicity, and no grade >3 toxicities.
CONCLUSIONS: In the largest series of metastatic sarcoma to the spine to date, IG-SRS provides excellent LC in the setting of an aggressive disease with low radiation sensitivity and poor prognosis. Single-fraction IG-SRS is associated with the highest rates of LC with minimal toxicity.

Related: Soft Tissue Sarcomas

Jin X, Zhu Z, Shi Y
Metastasis mechanism and gene/protein expression in gastric cancer with distant organs metastasis.
Bull Cancer. 2014; 101(1):E1-12 [PubMed] Related Publications
Metastasis is the most fatal characteristics of malignancy tumor, which accounted for more than 90% of tumor-related mortality. Distant organ or tissue metastasis is a sign of poor prognosis in patients with gastric cancer. Tumor cells metastasis is a very complex process including tumor cell transformation, growth, angiogenesis, invasion, dissemination and survival in the circulation, and subsequent adhesion and colonization the secondary organ or tissue. The origin of tumor cell, genetic variation, the circulatory mode and the physiological structure of the metastatic organ determines the specific sites of distant metastasis. In theory, the metastatic lesion is originated from their primary tumor, so they should have the same molecular profile with the primary tumor. But this view has been confirmed to be wrong in various tumors, including gastric cancer. The gene expression of primary gastric cancer and its metastasis have differences, which may contribute to the early diagnosis and individualized treatment of metastasis. However, the heterogeneity of tumor cells is still unclear in different metastasis lesion of gastric cancer, which will be a major focus of future research. In this review, we discuss the basic principles of cancer metastasis, the unique physiological characteristics of the various metastasis organs and the expression of different functions of gene/protein in primary and metastasis of gastric cancer. In addition, we also discuss the diagnosis, prognosis and treatment in various organ metastasis of gastric cancer.

Related: Angiogenesis and Cancer Stomach Cancer Gastric Cancer

Mori Y, Hashizume C, Shibamoto Y, et al.
Stereotactic radiotherapy for spinal intradural metastases developing within or adjacent to the previous irradiation field--report of three cases.
Nagoya J Med Sci. 2013; 75(3-4):263-71 [PubMed] Related Publications
Results of stereotactic radiotherapy (SRT) for spinal intradural metastases developing inside or adjacent to the previous external-beam radiation therapy (EBRT) field are shown in 3 cases. One case of spinal intramedullary metastasis and two cases of intradural extramedullary metastases were treated using a Novalis shaped-beam SRT. Case 1 developed an intramedullary metastatic tumor in the C1 spinal medulla inside the previous whole brain EBRT field and another lesion adjacent to the field in the C2 spinal medulla. Case 2 developed intradural extramedullary metastasis around C6-8 inside the previous EBRT field for the primary lung adenocarcinoma. Case 3 developed multiple spinal intradural extramedullary metastatic deposits after surgical resection and following whole brain EBRT for brain metastasis. We delivered 24 to 36 Gy in 5 to 12 fractions. The treated tumors were stable or decreased in size until the patients' death from the primary cancer (10, 22, and 5 months). Neurological symptoms were stable or improved in all 3 patients. Palliative SRT using Novalis is expected to be safe and effective even if the patient develops spinal intradural metastases within or adjacent to the previous irradiation field.

Related: Lung Cancer

Graham TJ, Box G, Tunariu N, et al.
Preclinical evaluation of imaging biomarkers for prostate cancer bone metastasis and response to cabozantinib.
J Natl Cancer Inst. 2014; 106(4):dju033 [PubMed] Related Publications
BACKGROUND: Prostate cancer is incurable once it has metastasized to the bone. Appropriate preclinical models are lacking. The therapeutic efficacy of the multikinase inhibitor cabozantinib was assessed in an orthotopic xenograft model of castration-resistant prostate cancer (CRPC) bone metastasis using noninvasive, multimodality functional imaging.
METHODS: NOD/SCID mice were injected intratibially with luciferase-expressing ERG (v-ets avian erythroblastosis virus E26 oncogene homolog) rearranged VCaP human prostate carcinoma cells. The response of VCaP xenografts (n = 7 per group) to cabozantinib was investigated using bioluminescence imaging and anatomical and diffusion weighted magnetic resonance imaging. This enabled quantitation of tumor volume and apparent diffusion coefficient (ADC). Bone uptake of technetium-methylene diphosphonate ((99m)Tc-MDP) was assessed by single-photon emission computed tomography. Ex vivo micro computed tomography was used to quantify bone volume and correlated with appropriate histopathology. Statistical significance was determined using the two-sided Mann-Whitney test or Wilcoxon signed rank test.
RESULTS: VCaP xenografts were predominantly osteosclerotic with some osteolytic activity. Fluorescent in situ hybridization analysis confirmed retention of ERG oncogene rearrangements. Cabozantinib induced a statistically significant 52% reduction in tumor luminance (P = .02) and stasis in tumor volume after 15 days of treatment. Tumor ADC statistically significantly increased with cabozantinib and was associated with extensive necrosis (after 10 days, mean tumor ADC ± SD = 556±43×10(-6) mm(2)/s vs pretreatment ADC = 485±43×10(-6) mm(2)/s; P = .02 ). Tumor-associated uptake of (99m)Tc-MDP was statistically significantly reduced after 3 days of treatment (P = .02), sustained over 15 days treatment, and associated with a statistically significant (P = .048) reduction in bone growth on the tibial cortex, yet a highly statistically significant (P = .001) increase in trabecular bone volume.
CONCLUSIONS: The intratibial VCaP model faithfully emulates clinical disease. Cabozantinib exerts potent effects on both tumor and tumor-induced bone matrix remodeling, and quantitation of ADC provides a clinically translatable imaging biomarker for early, sensitive assessment of treatment response in CRPC bone metastasis.

Duncker-Rohr V, Freund U, Momm F
Radiation recall dermatitis after docetaxel chemotherapy. Treatment by antioxidant ointment.
Strahlenther Onkol. 2014; 190(5):491-3 [PubMed] Related Publications
Radiation recall dermatitis (RRD) is an acute skin toxicity caused by different anticancer or antibiotic drugs within a former completely healed irradiation field. Predictive factors for RRD are not known and its mechanisms are not completely understood. A case of RRD induced by docetaxel and successfully treated by an antioxidant ointment (Mapisal(®)) is presented here. Such an ointment might be useful not only in RRD therapy, but also in the treatment of high-grade dermatitis induced by radiotherapy and thus may contribute to the improvement of patients' quality of life and to the scheduled completion of cancer therapies.

Related: Prostate Cancer Docetaxel

Jeffery JJ, Lux K, Vogel JS, et al.
Autocrine inhibition of the c-fms proto-oncogene reduces breast cancer bone metastasis assessed with in vivo dual-modality imaging.
Exp Biol Med (Maywood). 2014; 239(4):404-13 [PubMed] Related Publications
Breast cancer cells preferentially home to the bone microenvironment, which provides a unique niche with a network of multiple bidirectional communications between host and tumor, promoting survival and growth of bone metastases. In the bone microenvironment, the c-fms proto-oncogene that encodes for the CSF-1 receptor, along with CSF-1, serves as one critical cytokine/receptor pair, functioning in paracrine and autocrine fashion. Previous studies concentrated on the effect of inhibition of host (mouse) c-fms on bone metastasis, with resulting decrease in osteolysis and bone metastases as a paracrine effect. In this report, we assessed the role of c-fms inhibition within the tumor cells (autocrine effect) in the early establishment of breast cancer cells in bone and the effects of this early c-fms inhibition on subsequent bone metastases and destruction. This study exploited a multidisciplinary approach by employing two non-invasive, in vivo imaging methods to assess the progression of bone metastases and bone destruction, in addition to ex vivo analyses using RT-PCR and histopathology. Using a mouse model of bone homing human breast cancer cells, we showed that an early one-time application of anti-human c-fms antibody delayed growth of bone metastases and bone destruction for at least 31 days as quantitatively measured by bioluminescence imaging and computed tomography, compared to controls. Thus, neutralizing human c-fms in the breast cancer cell alone decreases extent of subsequent bone metastasis formation and osteolysis. Furthermore, we are the first to show that anti-c-fms antibodies can impact early establishment of breast cancer cells in bone.

Related: Breast Cancer CSF1R

Olechnowicz SW, Edwards CM
Contributions of the host microenvironment to cancer-induced bone disease.
Cancer Res. 2014; 74(6):1625-31 [PubMed] Article available free on PMC after 15/03/2015 Related Publications
The bone marrow provides a specialized and highly supportive microenvironment for tumor growth and development of the associated bone disease. It is a preferred site for breast and prostate cancer bone metastasis and the hematologic malignancy, multiple myeloma. For many years, researchers have focused upon the interactions between tumor cells and the cells directly responsible for bone remodeling, namely osteoclasts and osteoblasts. However, there is ever-increasing evidence for a multitude of ways in which the bone marrow microenvironment can promote disease pathogenesis, including via cancer-associated fibroblasts, the hematopoietic stem cell niche, myeloid-derived suppressor cells, and the sympathetic nervous system. This review discusses the recent advances in our understanding of the contribution of the host microenvironment to the development of cancer-induced bone disease.

Related: Angiogenesis and Cancer

Higano CS
To treat or not to treat, that is the question: the role of bone-targeted therapy in metastatic prostate cancer.
J Clin Oncol. 2014; 32(11):1107-11 [PubMed] Related Publications
The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice. A 62-year-old construction site manager experienced 6 weeks of back pain that was not responsive to over-the-counter nonsteroidal anti-inflammatory medications. He visited his wife's primary care physician for evaluation. He denied neurologic symptoms or worsening of pain while lying down. He smoked (30 pack-years, quit 4 years ago), and drinks 3 beers each evening and more on weekends (up to a six-pack). He has had two lower extremity fractures from falls at construction sites. At the time of the physical examination, he was 5 feet 11 inches tall and weighed 194 pounds. He was alert, oriented, and in mild distress. He had no percussion tenderness of his spine, and a neurologic examination was negative. A digital rectal examination revealed an enlarged prostate with an area of induration of the left, normal rectal tone, and guaiac-negative stool. Laboratory studies included normal blood counts, electrolytes, and renal and liver function tests (including lactic acid dehydrogenase and total protein). The prostate-specific antigen (PSA) was 114 ng/mL; he had no prior PSA test. A bone scan showed diffuse bony involvement including the T7 vertebral body and left pedicle, ribs, pelvis, and calvarium. Magnetic resonance imaging of his spine confirmed bone metastases but showed no evidence of extension into the epidural space or spinal cord compromise. A prostate biopsy revealed Gleason 4+4 adenocarcinoma of the prostate. Androgen deprivation therapy with leuprolide acetate was initiated, and the addition of a bone-targeted agent was considered.

Related: Bisphosphonates Prostate Cancer

Smith MR, Halabi S, Ryan CJ, et al.
Randomized controlled trial of early zoledronic acid in men with castration-sensitive prostate cancer and bone metastases: results of CALGB 90202 (alliance).
J Clin Oncol. 2014; 32(11):1143-50 [PubMed] Article available free on PMC after 10/04/2015 Related Publications
PURPOSE: Zoledronic acid decreases the risk for skeletal-related events (SREs) in men with castration-resistant prostate cancer and bone metastases but its role earlier in the natural history of the disease is unknown. This phase III study evaluated the efficacy and safety of earlier treatment with zoledronic acid in men with castration-sensitive metastatic prostate cancer.
PATIENTS AND METHODS: Men with castration-sensitive prostate cancer and bone metastases whose androgen-deprivation therapy was initiated within 6 months of study entry were randomly assigned in a blinded 1:1 ratio to receive zoledronic acid (4 mg intravenously every 4 weeks) or a placebo. After their disease progressed to castration-resistant status, all patients received open-label treatment with zoledronic acid. The primary end point was time to first SRE, defined as radiation to bone, clinical fracture, spinal cord compression, surgery to bone, or death as a result of prostate cancer. Target accrual was 680 patients. Primary analysis was planned after 470 SREs. The study was discontinued prematurely (645 patients; 299 SREs) after the corporate supporter withdrew study drug supply.
RESULTS: Early zoledronic acid was not associated with increased time to first SRE. The median time to first SRE was 31.9 months in the zoledronic acid group (95% CI, 24.2 to 40.3) and 29.8 months in the placebo group (95% CI, 25.3 to 37.2; hazard ratio, 0.97; 95% CI, 0 to 1.17; one-sided stratified log-rank P = .39). Overall survival was similar between the groups (hazard ratio, 0.88; 95% CI, 0.70 to 1.12; P = .29). Rates of adverse events were similar between the groups.
CONCLUSION: In men with castration-sensitive prostate cancer and bone metastases, early treatment with zoledronic acid was not associated with lower risk for SREs.

Related: Bisphosphonates Prostate Cancer Zoledronic acid (Zometa)

Wang Y, Lei R, Zhuang X, et al.
DLC1-dependent parathyroid hormone-like hormone inhibition suppresses breast cancer bone metastasis.
J Clin Invest. 2014; 124(4):1646-59 [PubMed] Article available free on PMC after 10/04/2015 Related Publications
Bone metastasis is a frequent complication of breast cancer that is often accelerated by TGF-β signaling; however, little is known about how the TGF-β pathway is regulated during bone metastasis. Here we report that deleted in liver cancer 1 (DLC1) is an important regulator of TGF-β responses and osteolytic metastasis of breast cancer cells. In murine models, breast cancer cells lacking DLC1 expression exhibited enhanced capabilities of bone metastasis. Knockdown of DLC1 in cancer cells promoted bone metastasis, leading to manifested osteolysis and accelerated death in mice, while DLC1 overexpression suppressed bone metastasis. Activation of Rho-ROCK signaling in the absence of DLC1 mediated SMAD3 linker region phosphorylation and TGF-β-induced expression of parathyroid hormone-like hormone (PTHLH), leading to osteoclast maturation for osteolytic colonization. Furthermore, pharmacological inhibition of Rho-ROCK effectively reduced PTHLH production and breast cancer bone metastasis in vitro and in vivo. Evaluation of clinical breast tumor samples revealed that reduced DLC1 expression was linked to elevated PTHLH expression and organ-specific metastasis to bone. Overall, our findings define a stroma-dependent paradigm of Rho signaling in cancer and implicate Rho-TGF-β crosstalk in osteolytic bone metastasis.

Related: Breast Cancer Signal Transduction

Habib MJ, Merali T, Mills A, Uon V
Canadian health care institution resource utilization resulting from skeletal-related events.
Hosp Pract (1995). 2014; 42(1):15-22 [PubMed] Related Publications
PURPOSE: We describe the types of major institution health care resources consumed as a result of skeletal-related events (SREs) [ie, pathological fracture, bone surgery, radiation to bone, spinal cord compression].
METHODS: A retrospective multicenter chart review of cancer patients with bone metastases who experienced SREs was conducted. Patients with multiple SREs occurring during the same hospitalization within 21 days of each other were grouped into SRE clusters.
RESULTS: We reviewed 156 patient charts from 4 Canadian institutions, accounting for 358 SREs and 259 SRE clusters. Of the total patients, 63% experienced 1 SRE; 19%, 2 SREs; 10%, 3 SREs; and 8%, ≥ 4 events. Health care resource utilization was captured for ≥ 90 days following each SRE: 54% of all SRE events resulted in an inpatient stay; 34% in an emergency visit; 85% of SREs required the use of diagnostic procedures (including radiography, magnetic resonance imaging, Computerized Axial Tomography scans, and radio scans); 57% required radiation treatment; 34% required a surgical procedure; 35% received outpatient treatment visits (ie, physiotherapy or occupational therapy). Bone surgery and spinal cord compression were more often associated with hospitalization than were other SRE types. Spinal cord compression was associated with the greatest number of inpatients stays (1.09 per SRE), longest duration of hospital stay (mean 26.18 days per SRE), and more outpatient visits, relative to other SRE types.
CONCLUSION: Results of our Canadian retrospective study clearly demonstrate that SREs occur in cancer patients and each SRE is associated with considerable institutional consumption of health care resources.

Gu YF, Li YD, Wu CG, et al.
Safety and efficacy of percutaneous vertebroplasty and interventional tumor removal for metastatic spinal tumors and malignant vertebral compression fractures.
AJR Am J Roentgenol. 2014; 202(3):W298-305 [PubMed] Related Publications
OBJECTIVE: The purpose of this study was to determine the safety and efficacy of percutaneous vertebroplasty and interventional tumor removal in the management of metastatic spinal tumors and malignant vertebral compression fractures.
SUBJECTS AND METHODS: Thirty-one patients with metastatic spinal tumors and malignant vertebral compression fractures were treated with percutaneous vertebroplasty and interventional tumor removal. Insertion of a 14-gauge needle and guidewire into the vertebral body was followed by sequential dilation of the track with working cannulae until the last cannula reached the anterior portions of the pedicle. Interventional tumor removal was performed with marrow nucleus rongeurs, and 5-10 mL of cement was injected into the treated vertebra. Outcome data (visual analog scale score, Oswestry disability index score, and Karnofsky performance scale score) were collected preoperatively; 1 week and 1, 3, and 6 months after the procedure; and every 6 months thereafter until death.
RESULTS: The overall clinical assessment at the last follow-up evaluation showed that pain was completely resolved in 23 patients, decreased in six patients, and unimproved in two patients, yielding a pain relief rate of 94%. The average preoperative visual analog scale score was 7.2, which decreased to 2.4 at 1 month, 1.9 at 6 months, and 1.6 at 1 year and was maintained at 1.3 at the follow-up evaluations performed after more than 1 year. Statistically significant improvement in Oswestry disability index and Karnofsky performance scale scores was also seen between the preoperative evaluation and every follow-up assessment postoperatively (p<0.001).
CONCLUSION: Percutaneous vertebroplasty and interventional tumor removal are safe, effective, and minimally invasive palliative therapies for reducing pain and improving function in patients with metastatic spinal tumors and malignant vertebral compression fractures.

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