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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PubMed Central search for free-access publications about Bone Cancer (secondary) MeSH term: Bone Neoplasms US National Library of Medicine PubMed has over 22 million citations for biomedical literature from MEDLINE, life science journals, and online books. Constantly updated.
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Kotecha R, Angelov L, Barnett GH, et al. Calvarial and skull base metastases: expanding the clinical utility of Gamma Knife surgery. J Neurosurg. 2014; 121 Suppl:91-101 [PubMed] Related Publications
OBJECT: Traditionally, the treatment of choice for patients with metastases to the calvaria or skull base has been conventional radiation therapy. Because patients with systemic malignancies are also at risk for intracranial metastases, the utility of Gamma Knife surgery (GKS) for these patients has been explored to reduce excess radiation exposure to the perilesional brain parenchyma. The purpose of this study was to report the efficacy of GKS for the treatment of calvarial metastases and skull base lesions. METHODS: The authors performed a retrospective chart review of 21 patients with at least 1 calvarial or skull base metastatic lesion treated with GKS during 2001-2013. For 7 calvarial lesions, a novel technique, in which a bolus was placed over the treatment site, was used. For determination of local control or disease progression, radiation therapy data were examined and posttreatment MR images and oncology records were reviewed. Survival times from the date of procedure were estimated by using Kaplan-Meier analyses. RESULTS: The median patient age at treatment was 57 years (range 29-84 years). A total of 19 (90%) patients received treatment for single lesions, 1 patient received treatment for 3 lesions, and 1 patient received treatment for 4 lesions. The most common primary tumor was breast cancer (24% of patients). Per lesion, the median clinical and radiographic follow-up times were 10.3 months (range 0-71.9 months) and 7.1 months (range 0-61.3 months), respectively. Of the 26 lesions analyzed, 14 (54%) were located in calvarial bones and 12 (46%) were located in the skull base. The median lesion volume was 5.3 cm(3) (range 0.3-55.6 cm(3)), and the median prescription margin dose was 15 Gy (range 13-24 Gy). The median overall survival time for all patients was 35.9 months, and the 1-year local control rate was 88.9% (95% CI 74.4%-100%). Local control rates did not differ between lesions treated with the bolus technique and those treated with traditional methods or between calvarial lesions and skull base lesions (p > 0.05). Of the 3 patients for whom local treatment failed, 1 patient received no further treatment and 2 patients responded to salvage chemotherapy. Subsequent brain parenchymal metastases developed in 2 patients, who then underwent GKS. CONCLUSIONS: GKS is an effective treatment modality for patients with metastases to the calvarial bones or skull base. For patients with superficial calvarial lesions, a novel approach with bolus application resulted in excellent rates of local control. GKS provides an effective therapeutic alternative to conventional radiation therapy and should be considered for patients at risk for calvarial metastases and brain parenchymal metastases.
Xin G, Du J, Xu Y Isolated sacral metastases as the initial presentation from an endometroid ovarian carcinoma: a case report. Eur J Gynaecol Oncol. 2014; 35(5):589-91 [PubMed] Related Publications
Bone metastases are rarely in ovarian carcainoma. It usually occurrs only when the cancer is advanced or recurrent. A case of endometrioid carcinoma in right ovary with intact capsule is reported. The isolated sacral metastasis was found as the initial presentation, and no distant metastases were reported.
Morii T, Ohtsuka K, Ohnishi H, et al. BH3 mimetics inhibit growth of chondrosarcoma--a novel targeted-therapy for candidate models. Anticancer Res. 2014; 34(11):6423-30 [PubMed] Related Publications
BACKGROUND: Chondrosarcoma is refractory to conventional chemotherapy. BH-3 mimetics ABT-737 and ABT-263 are synthetic small-molecule inhibitors of anti-apoptotic proteins B-cell lymphoma-2 (Bcl2) and Bcl-xL, which play a critical role in survival of chondrosarcoma cells. MATERIALS AND METHODS: Chondrosarcoma cell lines SW-1353 and CS-1 were used as the disease model. We used immunoblotting to assess the expression of target molecules Bcl2 and Bcl-xL, and the apoptotic inducers Bcl2-associated X (Bax) and Bcl2-antagonist/killer (Bak). In vitro growth inhibition by BH-3 mimetics was confirmed by photomicroscopic cell counting and 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt (MTS) assay. Apoptotic induction was confirmed by Enzyme-Linked ImmunoSorbent Assay (ELISA). In vivo growth inhibition was assessed in a non-obese diabetic/severe combined immunodeficient (NOD/SCID) mouse model. RESULTS: Expression of the target and effector molecules was confirmed in chondrosarcoma cell lines. BH3 mimetics significantly inhibited cell growth and induced apoptosis in vitro. Administration of ABT-263 inhibited chondrosarcoma growth and improved survival in a mouse model. CONCLUSION: BH3 mimetics represent a novel treatment modality for chondrosarcoma.
Chu G, Lo P, Ramakrishna B, et al. Bone tumor segmentation on bone scans using context information and random forests. Med Image Comput Comput Assist Interv. 2014; 17(Pt 1):601-8 [PubMed] Related Publications
Bone tumor segmentation on bone scans has recently been adopted as a basis for objective tumor assessment in several phase II and III clinical drug trials. Interpretation can be difficult due to the highly sensitive but non-specific nature of bone tumor appearance on bone scans. In this paper we present a machine learning approach to segmenting tumors on bone scans, using intensity and context features aimed at addressing areas prone to false positives. We computed the context features using landmark points, identified by a modified active shape model. We trained a random forest classifier on 100 and evaluated on 73 prostate cancer subjects from a multi-center clinical trial. A reference segmentation was provided by a board certified radiologist. We evaluated our learning based method using the Jaccard index and compared against the state of the art, rule based method. Results showed an improvement from 0.50 +/- 0.31 to 0.57 +/- 0.27. We found that the context features played a significant role in the random forest classifier, helping to correctly classify regions prone to false positives.
Papp Z, Marosfői M, Szikora I, Banczerowski P Treatment of C-2 metastatic tumors with intraoperative transoral or transpedicular vertebroplasty and occipitocervical posterior fixation. J Neurosurg Spine. 2014; 21(6):886-91 [PubMed] Related Publications
OBJECT: Metastatic spinal tumors of the atlantoaxial region are quite uncommon, and surgery is challenging. The aim in this study was to evaluate the safety and efficacy of transoral or transpedicular vertebroplasty combined with posterior fixation in C-2 metastatic disease. METHODS: The authors collected from a hospital database all cases of C-2 metastatic tumor treated in the period from January 2009 to December 2012. Cases with histologically confirmed metastatic disease were included, but those with epidural tumorous propagation and signs of spinal cord compression were excluded. RESULTS: Five patients (3 females, 2 males) with osteolytic C-2 metastasis were eligible for this study. In 3 cases a purely posterior approach was taken to perform a dorsal open C-2 biopsy and transpedicular vertebroplasty followed by posterior occipitocervical fixation. In the other 2 cases a transoral C-2 biopsy and vertebroplasty were performed in combination with dorsal occipitocervical fixation during the same operative session. Patients were followed up with regular fluoroscopy, MRI, and CT studies as well as neurological examinations. During an average follow-up of 13 months (range 8-19 months), no surgical or neurological complications were associated with this combined approach. In all cases spinal stability and pain reduction were detected. The average pain score according to the visual analog scale was 3.5 after surgery (range 2-5); before surgery, the average score was 7 (range 6-8). The average volume of polymethylmethacrylate injected was 4 ml. The body and dens of the C-2 vertebra was filled more than 60% for each patient. CONCLUSIONS: In this small series, simultaneous intraoperative transoral or transpedicular vertebroplasty and dorsal occipitocervical fixation proved to be a safe and effective treatment for patients with osteolytic C-2 metastatic tumors. These techniques may provide excellent pain relief and improvements in quality of life. The true value of these combined techniques should be evaluated in larger series.
Leblanc R, Lee SC, David M, et al. Interaction of platelet-derived autotaxin with tumor integrin αVβ3 controls metastasis of breast cancer cells to bone. Blood. 2014; 124(20):3141-50 [PubMed] Article available free on PMC after 13/11/2015 Related Publications
Autotaxin (ATX), through its lysophospholipase D activity controls physiological levels of lysophosphatidic acid (LPA) in blood. ATX is overexpressed in multiple types of cancers, and together with LPA generated during platelet activation promotes skeletal metastasis of breast cancer. However, the pathophysiological sequelae of regulated interactions between circulating LPA, ATX, and platelets remain undefined in cancer. In this study, we show that ATX is stored in α-granules of resting human platelets and released upon tumor cell-induced platelet aggregation, leading to the production of LPA. Our in vitro and in vivo experiments using human breast cancer cells that do not express ATX (MDA-MB-231 and MDA-B02) demonstrate that nontumoral ATX controls the early stage of bone colonization by tumor cells. Moreover, expression of a dominant negative integrin αvβ3-Δ744 or treatment with the anti-human αvβ3 monoclonal antibody LM609, completely abolished binding of ATX to tumor cells, demonstrating the requirement of a fully active integrin αvβ3 in this process. The present results establish a new mechanism for platelet contribution to LPA-dependent metastasis of breast cancer cells, and demonstrate the therapeutic potential of disrupting the binding of nontumor-derived ATX with the tumor cells for the prevention of metastasis.
Miwa S, Takeuchi A, Shirai T, et al. Outcomes and complications of reconstruction using tumor-bearing frozen autografts in patients with metastatic bone tumors. Anticancer Res. 2014; 34(10):5569-77 [PubMed] Related Publications
BACKGROUND: Tumor-bearing frozen autografts have been used for reconstruction of bone defects after resection of bone tumors. In the present study, outcomes and complications of reconstruction using frozen autografts were assessed to determine indications for this procedure in patients with metastatic bone lesions. PATIENTS AND METHODS: Twenty-two patients were treated with reconstruction using frozen autografts. The surgical technique involved excision of the bone lesion, curettage, freezing in liquid nitrogen, thawing and reconstruction. RESULTS: Limb function was evaluated in 11 patients; wa found excellent in 10 patients and good in 1 patient. Five-year overall survival and disease-free survival rates were 46.7% and 26.3%, respectively. Five-year fracture-free survival and recurrence-free survival rates were 79.9% and 100%, respectively. Complications were observed in 6 patients and included fractures (4), deep infection (1) and osteoarthritis (1). CONCLUSION: Reconstruction using frozen autografts is a beneficial treatment option in patients with long expected survival or complete cure of the primary cancer.
Tolia M, Fotineas A, Nikolaou K, et al. Radiotherapy combined with daily escitalopram in patients with painful bone metastasis: clinical evaluation and quality of life measurements. J BUON. 2014 Jul-Sep; 19(3):819-25 [PubMed] Related Publications
PURPOSE: To prospectively assess the efficacy of the selective serotonin inhibitor escitalopram on painful bone metastases, in combination with external beam irradiation. METHODS: Forty-three patients with cancer metastatic to bone and suffering from depression were treated with 3 Dimensional Conformal Radiotherapy (3DCRT) (30 Gy; 3 Gy/fraction, 5 days/week) combined with escitalopram (20 mg/day). Pain relief was evaluated with Wong/Baker Faces Pain Scale. The patients reported outcome using a RTOG-EORTC quality-of-life self-questionnaire (QLQ-C30 v3.0) and the status of depression according to Hamilton Scale (HAM-17). The assessment was performed at baseline and 6-8 weeks after radiotherapy. RESULTS: Patients treated with radiotherapy and escitalopram tended to show a good response to pain and improvement of their quality of life. CONCLUSIONS: Though our data concerned a rather small number of patients, addition of escitalopram to 3DCRT accomplished a high clinical benefit rate on neuropathic pain from bone metastasis.
Westhoff PG, de Graeff A, Monninkhof EM, et al. An easy tool to predict survival in patients receiving radiation therapy for painful bone metastases. Int J Radiat Oncol Biol Phys. 2014; 90(4):739-47 [PubMed] Related Publications
PURPOSE: Patients with bone metastases have a widely varying survival. A reliable estimation of survival is needed for appropriate treatment strategies. Our goal was to assess the value of simple prognostic factors, namely, patient and tumor characteristics, Karnofsky performance status (KPS), and patient-reported scores of pain and quality of life, to predict survival in patients with painful bone metastases. METHODS AND MATERIALS: In the Dutch Bone Metastasis Study, 1157 patients were treated with radiation therapy for painful bone metastases. At randomization, physicians determined the KPS; patients rated general health on a visual analogue scale (VAS-gh), valuation of life on a verbal rating scale (VRS-vl) and pain intensity. To assess the predictive value of the variables, we used multivariate Cox proportional hazard analyses and C-statistics for discriminative value. Of the final model, calibration was assessed. External validation was performed on a dataset of 934 patients who were treated with radiation therapy for vertebral metastases. RESULTS: Patients had mainly breast (39%), prostate (23%), or lung cancer (25%). After a maximum of 142 weeks' follow-up, 74% of patients had died. The best predictive model included sex, primary tumor, visceral metastases, KPS, VAS-gh, and VRS-vl (C-statistic = 0.72, 95% CI = 0.70-0.74). A reduced model, with only KPS and primary tumor, showed comparable discriminative capacity (C-statistic = 0.71, 95% CI = 0.69-0.72). External validation showed a C-statistic of 0.72 (95% CI = 0.70-0.73). Calibration of the derivation and the validation dataset showed underestimation of survival. CONCLUSION: In predicting survival in patients with painful bone metastases, KPS combined with primary tumor was comparable to a more complex model. Considering the amount of variables in complex models and the additional burden on patients, the simple model is preferred for daily use. In addition, a risk table for survival is provided.
Fisher CG, Versteeg AL, Schouten R, et al. Reliability of the spinal instability neoplastic scale among radiologists: an assessment of instability secondary to spinal metastases. AJR Am J Roentgenol. 2014; 203(4):869-74 [PubMed] Related Publications
OBJECTIVE: The spinal instability neoplastic scale (SINS) is a new classification system for tumor-related spinal instability. The SINS may prove to be a valuable tool for radiologists to communicate with oncologists and surgeons in a standardized evidence-based manner. The objective of this study was to determine the inter- and intraobserver reliability and validity of the SINS among radiologists. MATERIALS AND METHODS: Thirty-seven radiologists from 10 international sites used the SINS to categorize the degree of spinal instability in 30 patients with spinal tumors. To assess validity, we compared the SINS scores assigned by the radiologists with the SINS scores of 11 spine oncology surgeons (reference standard). Each total SINS score (range, 0-18 points) was converted into one of the following three clinical categories: 0-6 points, stable; 7-12 points, potentially unstable; and 13-18 points, unstable. In addition, each total SINS score was converted into a binary scale: 0-6 points was defined as stable, and 7-18 points was considered a current or possible instability for which surgical consultation is recommended. RESULTS: Radiologists using the SINS binary scale showed excellent (κ = 0.88) validity, substantial (κ = 0.76) interobserver agreement, and excellent (κ = 0.82) intraobserver reproducibility. Radiologists rated all unstable cases and 621 of 629 (98.7%) potentially unstable cases with a SINS score of 7 or more points, thus appropriately initiating a referral for surgical assessment. CONCLUSION: SINS is a reliable tool for radiologists rating tumor-related spinal instability. It accurately discriminates between stable and potentially unstable or unstable lesions and, therefore, can guide the need for surgical consultation.
Evans S, Ramasamy A, Jeys L, Grimer R Delayed diagnosis in metastatic lesions of the foot. Ann R Coll Surg Engl. 2014; 96(7):536-8 [PubMed] Related Publications
INTRODUCTION: Pedal acrometastases are a rare complication of disseminated malignancy. To date, there is little in the literature documenting their clinical course. METHODS: Our large orthopaedic oncology database was used to review the clinical course of symptomatic pedal acrometastases. RESULTS: A total of 15 cases of pedal acrometastases were identified from 2,595 patients with metastases. The median age at presentation was 64.5 years (range: 14-83 years) and the median length of foot symptoms (predominantly pain and swelling) prior to diagnosis of metastasis was 16 weeks (range: 6-104 weeks). The median survival following diagnosis was 4.6 months (range: 2.3-104.5 months). CONCLUSIONS: This study suggests that 0.58% of all osseous metastases involve the foot, and that symptoms of foot pain and swelling are often misdiagnosed, leading to delays in treatment. A high index of suspicion is required to diagnose pedal acrometastases early, thereby allowing early treatment so that the patient's quality of life can be maintained prior to death.
Kapur RA, McCann PA, Sarangi PP Reverse geometry shoulder replacement for proximal humeral metastases. Ann R Coll Surg Engl. 2014; 96(7):e32-5 [PubMed] Related Publications
The management of skeletal metastases can be challenging for the orthopaedic surgeon. They represent a significant source of pain and disability for cancer patients, adding to the morbidity of their condition. Treatment is directed at the alleviation of symptoms and the restoration of function. Metastatic involvement of the proximal humerus can be especially debilitating, having the potential to cause severe pain and loss of function. We present a report of three such cases where reverse geometry proximal shoulder replacement was used to provide a pain free functional range of movement in patients with concomitant rotator cuff disease. In all cases, significant symptomatic relief was achieved postoperatively with preservation of upper limb function. No surgical complications were noted. It is our belief that this novel surgical strategy provides a valuable and effective option for the management of proximal humeral metastatic disease in the rotator cuff deficient patient.
Kim YJ, Kim SH, Kim JW, et al. Gastric cancer with initial bone metastasis: a distinct group of diseases with poor prognosis. Eur J Cancer. 2014; 50(16):2810-21 [PubMed] Related Publications
BACKGROUND: Bone metastasis (BM) is reported as a poor prognostic factor in gastric cancer. However, the clinicopathologic characteristics and clinical outcomes of patients with BM compared with patients without BM have not been well described. PATIENTS AND METHODS: The medical records of all metastatic or recurrent gastric cancer (MRGC) patients who visited our institution were reviewed. A total of 137 evaluable patients with BM were analysed together with historical control without BM (N=111). RESULTS: Of 1342 MRGC patients, 141 (10.5%) had BM. Patients with BM could be divided into initial BM (BM present at initial diagnosis of MRGC; N=90) and late BM (N=47) groups. The median survival after the diagnosis of BM in all patients was 4.4 months (95% confidence interval [CI] 3.69-5.11). However, overall survival after the diagnosis of MRGC was significantly shorter in the initial BM group (5.0 versus 12.2 months, p<0.001). Compared with historical controls, patients with initial BM showed distinct clinicopathologic characteristics. Independent predictors of initial BM were a younger age, signet ring cell histology, primary tumour involving ⩾two-thirds of the stomach, pleural metastasis, thrombocytopenia and elevated alkaline phosphatase. According to a Cox proportional hazard model including both patients with BM and historical controls, initial BM, poor performance status, peritoneal metastasis, hypercalcemia and high carcinoembryonic antigen (CEA) were identified as poor prognostic factors, whereas chemotherapy was identified as a favourable factor (hazard ratio [HR] 0.33, 95% CI 0.22-0.49). CONCLUSION: MRGC with initial BM is a distinct group of diseases with specific clinicopathologic characteristics and poor prognosis. Chemotherapy may improve survival in these patients.
Thibault I, Al-Omair A, Masucci GL, et al. Spine stereotactic body radiotherapy for renal cell cancer spinal metastases: analysis of outcomes and risk of vertebral compression fracture. J Neurosurg Spine. 2014; 21(5):711-8 [PubMed] Related Publications
OBJECT: The aim of this study was to evaluate local control (LC) and the risk of vertebral compression fracture (VCF) after stereotactic body radiotherapy (SBRT) in patients with renal cell cancer spinal metastases. METHODS: Prospectively collected data on 71 spinal segments treated with SBRT in 37 patients were reviewed. The median follow-up was 12.3 months (range 1.2-55.4 months). The LC rate was assessed based on each spinal segment treated and overall survival (OS) according to each patient treated. Sixty of 71 segments (85%) were radiation naive, 11 of 71 (15%) were previously irradiated, and 10 of 71 (14%) were treated with postoperative SBRT. The median SBRT total dose and number of fractions were 24 Gy and 2, respectively. The VCF analysis also included evaluation of the Spinal Instability Neoplastic Score criteria. RESULTS: The 1-year OS and LC rates were 64% and 83%, respectively. Multivariate analysis identified oligometastatic disease (13 of 37 patients) as a positive prognostic factor (p = 0.018) for OS. Of 61 non-postoperative spinal segments treated, 10 (16%) developed VCFs; 3 of 10 were de novo VCFs and 7 of 10 occurred as progression of an existing VCF. The 1-year VCF-free probability rate was 82%. Multivariate analysis identified single-fraction SBRT and baseline VCF as significant predictors of SBRT-induced VCF (p = 0.028 and p = 0.012, respectively). CONCLUSIONS: Spine SBRT yields high rates of local tumor control in patients with renal cell cancer. Baseline VCF and 18-24 Gy delivered in a single fraction were predictive of further collapse. Patients with oligometastatic disease may benefit most from such aggressive local therapy, given the prolonged survival observed.
Hayashi S, Tanaka H, Hoshi H External beam radiotherapy for painful bone metastases from hepatocellular carcinoma: multiple fractions compared with an 8-Gy single fraction. Nagoya J Med Sci. 2014; 76(1-2):91-9 [PubMed] Related Publications
External beam radiotherapy (EBRT) for hepatocellular carcinoma (HCC) bone metastases has not been popular in palliative therapy, and optimum dose schedules have not been decided because of limited published reports. We here evaluated the palliative effect of EBRT for HCC bone metastases and compared the dose-response relationship between multiple fractions (MFs) and an 8-Gy single fraction (SF). Twenty-eight patients (42 sites) with painful bone metastases who received EBRT and were analyzed retrospectively. Eight patients (12 sites) received SF. Of the remaining 20 patients (30 sites), 10 received MFs at moderate doses (20-30 Gy; 17 sites) and 10 received MFs at high doses (36-52 Gy; 13 sites). Overall response was achieved at 83% (35) of all sites; 75% (9) and 87% (26) for the SF and MF patients (88%, moderate dose; 85%, high dose), respectively. No significant differences in overall response were observed between each fraction schedule. Response duration was significantly longer for the high-dose MF patients than for the SF patients and moderate-dose MF patients (P < 0.05). SF was as effective as MF radiotherapy in terms of pain relief, but high-dose MF delivery relieved pain for a significantly longer duration.
Nakayama R, Horiuchi K, Susa M, et al. Clinical outcome after bone metastasis (BM) surgery in patients with differentiated thyroid carcinoma (DTC): a retrospective study of 40 cases. Jpn J Clin Oncol. 2014; 44(10):918-25 [PubMed] Related Publications
OBJECTIVE: The purpose of this study is to identify factors that affect survival of patients with differentiated thyroid carcinoma with bone metastases and to optimize surgical treatment modality for bone metastatic lesion by comparing duration of patient survival and local control. METHODS: We examined 52 bone metastatic lesions from 40 patients with differentiated thyroid carcinoma who were treated surgically between 1994 and 2008 at Keio University Hospital. Median follow-up time was 46 months (range: 4-233 months). Patients' disease-specific survival, local control duration and factors that potentially affected disease-specific survival after bone metastasis surgery were statistically analyzed. RESULTS: The 2-, 5- and 10-year disease-specific survival rates were 77.2, 64.3 and 45.7%, respectively. Factors that were significantly associated with poor survival rates in multivariate analyses included age at bone metastasis surgery ≥65 years (P = 0.0068), time from diagnosis of primary cancer to bone metastasis surgery ≥5 years (P = 0.0018) and presence of visceral metastases (P = 0.0092). The 2-, 5- and 10-year local control rates in our series were 91.4, 72.7 and 63.6%, respectively. The 5-year local control rates for radical and palliative surgery were 84.4 and 55.3%, respectively, and differed significantly (P = 0.019). CONCLUSIONS: Because disease-specific survival of patients with differentiated thyroid carcinoma is fairly good, inadequate treatment of bone metastatic lesions can result in severe disabilities. Therefore, radical surgery for bone metastatic lesions should be considered, especially for those with favorable prognostic factors.
Fizazi K, Scher HI, Miller K, et al. Effect of enzalutamide on time to first skeletal-related event, pain, and quality of life in men with castration-resistant prostate cancer: results from the randomised, phase 3 AFFIRM trial. Lancet Oncol. 2014; 15(10):1147-56 [PubMed] Related Publications
BACKGROUND: In the AFFIRM trial of patients with metastatic castration-resistant prostate cancer after progression with docetaxel treatment, enzalutamide significantly increased overall survival compared with placebo. Here we present the prospectively defined analyses of some secondary endpoints, including occurrence of skeletal-related events, measures of pain control, and patient-reported health-related quality of life (HRQoL). METHODS: In this phase 3, double-blind trial, patients were randomly assigned (2:1) to receive enzalutamide 160 mg/day or placebo orally, stratified by ECOG baseline performance status (0 or 1 vs 2) and mean pain score (Brief Pain Inventory-Short Form [BPI-SF] question 3 worst pain, score ≤3 vs ≥4). Secondary endpoints were time to first skeletal-related event (defined as radiation therapy or surgery to bone); change from baseline to week 13 in pain severity and interference; pain palliation and progression at week 13; time to pain progression; overall improvement in HRQoL; improvements in HRQoL domains; and time to HRQoL deterioration. Analysis was done on the intention-to-treat population for each endpoint. AFFIRM is registered with ClinicalTrials.gov, number NCT00974311. FINDINGS: Median time to first skeletal-related event in the enzalutamide (n=800) and placebo (n=399) groups was 16·7 months (95% CI 14·6 to 19·1) and 13·3 months (95% CI 9·9 to not yet reached), respectively (hazard ratio [HR] 0·69 [95% CI 0·57-0·84]; p=0·0001). Pain progression at week 13 occurred in 174 (28%) of 625 evaluable patients in the enzalutamide group versus 101 (39%) of 259 patients in the placebo group (difference -11·2%, 95% CI -18·1 to -4·3; p=0·0018). Median time to pain progression was not yet reached in the enzalutamide group (95% CI not yet reached to not yet reached) versus 13·8 (13·8 to not yet reached) months in the placebo group (HR 0·56 [95% CI 0·41 to 0·78]; p=0·0004). Mean treatment effects for pain severity (mean change from baseline in the enzalutamide group -0·15, 95% CI -0·28 to -0·02, vs placebo 0·50, 0·29 to 0·70; difference -0·65, 95% CI -0·89 to -0·41; p<0·0001) and interference (-0·01, -0·18 to 0·16, vs 0·74, 0·47 to 1·00; respectively, difference -0·74, 95% -1·06 to -0·43; p<0·0001) were significantly better with enzalutamide than with placebo. 22 (45%) of 49 evaluable patients in the enzalutamide group reported pain palliation at week 13 versus one (7%) of 15 in the placebo group (difference 38·2%, 95% CI 19·4-57·0; p=0·0079). Overall improvement in HRQoL was reported in more patients receiving enzalutamide (275 [42%] of 652) than in those receiving placebo (36 [15%] of 248; p<0·0001). Patients in the enzalutamide group had longer median time to HRQoL deterioration than did those in the placebo group (9·0 months, 95% CI 8·3-11·1, vs 3·7 months, 95% CI 3·0-4·2; HR 0·45, 95% CI 0·37-0·55; p<0·0001) in risk of deterioration. INTERPRETATION: Our results show that, in addition to improving overall survival, enzalutamide improves wellbeing and everyday functioning of patients with metastatic castration-resistant prostate cancer. FUNDING: Astellas Pharma and Medivation.
Merdan S, Womble PR, Miller DC, et al. Toward better use of bone scans among men with early-stage prostate cancer. Urology. 2014; 84(4):793-8 [PubMed] Related Publications
OBJECTIVE: To evaluate the performance of published guidelines compared with that of current practice for radiographic staging of men with newly diagnosed prostate cancer. MATERIALS AND METHODS: Using data from the Michigan Urological Surgery Improvement Collaborative clinical registry, we identified 1509 men diagnosed with prostate cancer from March 2012 through June 2013. Clinical data included age, prostate-specific antigen (PSA) level, Gleason score (GS), clinical trial stage, number of biopsy cores, and bone scan (BS) results. We then fit a multivariate logistic regression model to examine the association between clinical variables and the occurrence of bone metastases. Because some patients did not undergo BS, we used established methods to correct for verification bias and estimate the diagnostic accuracy of published guidelines. RESULTS: Among 416 men who received a BS, 48 (11.5%) had evidence of bone metastases. Patients with bone metastases were older, with higher PSA levels and GS (all P <.05). In multivariate analyses, PSA (P <.001) and GS (P = .004) were the only independent predictors of positive BS. Guidelines from the American Urological Association and the National Comprehensive Cancer Network demonstrated similar performance in detecting bone metastases in our population, with fewer negative study results than those of the European Association of Urology guideline. Applying the American Urological Association recommendations (ie, image when PSA level >20 ng/mL or GS ≥ 8) to current clinical practice, we estimate that <1% of positive study results would be missed, whereas the number of negative study results would be reduced by 38%. CONCLUSION: Based on current practice patterns, more uniform application of existing guidelines would ensure that BS is performed for almost all men with bone metastases, while avoiding many negative imaging studies.
Okegawa T, Higaki M, Matsumoto T, et al. Zoledronic acid improves clinical outcomes in patients with bone metastatic hormone-naïve prostate cancer in a multicenter clinical trial. Anticancer Res. 2014; 34(8):4415-20 [PubMed] Related Publications
AIM: To assess whether zoledronic acid (ZOL) adds to the effect of combined androgen blockade (CAB) in patients with hormone-naive bone metastatic prostate cancer. PATIENTS AND METHODS: Patients were treated with either a combination of CAB (luteinizing hormone-releasing hormone agonist and bicalutamide) and ZOL (CAB-Z group) or CAB-alone (historical control patients, CAB-C group). ZOL was injected intravenously at 4 mg every 4 weeks. One hundred and five and 100 patients among 205 enrolled patients were assigned to the CAB-Z group and CAB-C group, respectively. The time to prostate-specific antigen (PSA) failure in patients in the CAB-Z group was compared to that in the CAB-C group. The primary end-point of the study was the time-to-PSA failure. RESULTS: PSA and serum N-telopeptide of type I collagen (NTx) levels were examined before treatment and every 3 months after treatment. PSA failure occurred in 42 (40.0%) patients in the CAB-Z group and 48 (48.0%) patients in the CAB-C group. The biochemical recurrence-free rate was significantly lower in patients in the CAB-C group (p=0.004, by log-rank test). The categorical biopsy Gleason score pre-treatment serum NTx and treatment with ZOL were shown to be independent predictors of PSA failure-free survival time (p=0.040, p=0.005 and p=0.026, respectively). CONCLUSION: ZOL given with CAB as initial treatment delays the time-to-PSA failure in patients with hormone-naive bone metastatic prostate cancer.
Krzeszinski JY, Wei W, Huynh H, et al. miR-34a blocks osteoporosis and bone metastasis by inhibiting osteoclastogenesis and Tgif2. Nature. 2014; 512(7515):431-5 [PubMed] Article available free on PMC after 28/02/2015 Related Publications
Bone-resorbing osteoclasts significantly contribute to osteoporosis and bone metastases of cancer. MicroRNAs play important roles in physiology and disease, and present tremendous therapeutic potential. Nonetheless, how microRNAs regulate skeletal biology is underexplored. Here we identify miR-34a as a novel and critical suppressor of osteoclastogenesis, bone resorption and the bone metastatic niche. miR-34a is downregulated during osteoclast differentiation. Osteoclastic miR-34a-overexpressing transgenic mice exhibit lower bone resorption and higher bone mass. Conversely, miR-34a knockout and heterozygous mice exhibit elevated bone resorption and reduced bone mass. Consequently, ovariectomy-induced osteoporosis, as well as bone metastasis of breast and skin cancers, are diminished in osteoclastic miR-34a transgenic mice, and can be effectively attenuated by miR-34a nanoparticle treatment. Mechanistically, we identify transforming growth factor-β-induced factor 2 (Tgif2) as an essential direct miR-34a target that is pro-osteoclastogenic. Tgif2 deletion reduces bone resorption and abolishes miR-34a regulation. Together, using mouse genetic, pharmacological and disease models, we reveal miR-34a as a key osteoclast suppressor and a potential therapeutic strategy to confer skeletal protection and ameliorate bone metastasis of cancers.
Ellsworth SG, Alcorn SR, Hales RK, et al. Patterns of care among patients receiving radiation therapy for bone metastases at a large academic institution. Int J Radiat Oncol Biol Phys. 2014; 89(5):1100-5 [PubMed] Related Publications
PURPOSE: This study evaluates outcomes and patterns of care among patients receiving radiation therapy (RT) for bone metastases at a high-volume academic institution. METHODS AND MATERIALS: Records of all patients whose final RT course was for bone metastases from April 2007 to July 2012 were identified from electronic medical records. Chart review yielded demographic and clinical data. Rates of complicated versus uncomplicated bone metastases were not analyzed. RESULTS: We identified 339 patients whose final RT course was for bone metastases. Of these, 52.2% were male; median age was 65 years old. The most common primary was non-small-cell lung cancer (29%). Most patients (83%) were prescribed ≤10 fractions; 8% received single-fraction RT. Most patients (52%) had a documented goals of care (GOC) discussion with their radiation oncologist; hospice referral rates were higher when patients had such discussions (66% with vs 50% without GOC discussion, P=.004). Median life expectancy after RT was 96 days. Median survival after RT was shorter based on inpatient as opposed to outpatient status at the time of consultation (35 vs 136 days, respectively, P<.001). Hospice referrals occurred for 56% of patients, with a median interval between completion of RT and hospice referral of 29 days and a median hospice stay of 22 days. CONCLUSIONS: These data document excellent adherence to American Society for Radiation Oncolology Choosing Wisely recommendation to avoid routinely using >10 fractions of palliative RT for bone metastasis. Nonetheless, single-fraction RT remains relatively uncommon. Participating in GOC discussions with a radiation oncologist is associated with higher rates of hospice referral. Inpatient status at consultation is associated with short survival.
Olson RA, Tiwana MS, Barnes M, et al. Use of single- versus multiple-fraction palliative radiation therapy for bone metastases: population-based analysis of 16,898 courses in a Canadian province. Int J Radiat Oncol Biol Phys. 2014; 89(5):1092-9 [PubMed] Related Publications
PURPOSE: There is abundant evidence that a single fraction (SF) of palliative radiation therapy (RT) for bone metastases is equivalent to more protracted and costly multiple fraction courses. Despite this, there is low utilization of SFRT internationally. We sought to determine the utilization of SFRT in a population-based, publicly funded health care system. METHODS AND MATERIALS: All consecutive patients with bone metastases treated with RT during 2007 to 2011 in British Columbia (BC) were identified. Associations between utilization of SFRT and patient and provider characteristics were investigated. RESULTS: A total of 16,898 courses of RT were delivered to 8601 patients. SFRT was prescribed 49% of the time. There were positive relationships among SFRT utilization and primary tumor group (P<.001; most commonly in prostate cancer), worse prognosis (P<.001), increasing physician experience (P<.001), site of metastases (P<.001; least for spine metastases), and area of training (P<.001; most commonly for oncologists trained in the United Kingdom). There was wide variation in the prescription of SFRT across 5 regional cancer centers, ranging from 25.5% to 73.4%, which persisted after controlling for other, potentially confounding factors (P<.001). CONCLUSIONS: The large variability in SFRT utilization across BC Cancer Agency (BCCA) cancer centers suggests there is a strong cultural effect, where physicians' use of SFRT is influenced by their colleagues' practice. SFRT use in BC was similar to that in other Canadian and western European reports but strikingly higher than in the United States. Further work is needed to standardize SFRT prescribing practices internationally for this common indication for RT, with the potential for huge health system cost savings and substantial improvements in patients' quality of life.
Lach B, Joshi SS, Murty N, Huq N Transformation of Merkel cell carcinoma to ganglioneuroblastoma in intracranial metastasis. Hum Pathol. 2014; 45(9):1978-81 [PubMed] Related Publications
Merkel cell carcinoma is an aggressive neuroendocrine tumor occasionally demonstrating aberrant differentiation to other epithelial and nonepithelial cell lines. We describe a case of Merkel cell carcinoma displaying unique patterns of differentiation in the primary focus and brain metastasis. The skin primary was almost uniformly small cell carcinoma positive for epithelial and neuroendocrine markers, with a few glial fibrillary acidic protein- and cytokeratin 20-positive cells. The neoplasm contained giant cells immunoreactive for neurofilament and negative for epithelial markers. The neck lymph node metastasis was a typical neuroendocrine Merkel cell carcinoma positive for cytokeratin 20. A solitary dural intracranial metastasis displayed features of aggressive ganglioneuroblastoma, expressing many neuronal antigens with no evidence of glial or epithelial differentiation. After total gross resection, the tumor recurred within 3 months, and the patient developed skeletal metastases and died 6 months after craniotomy.
Krygier JE, Lewis VO, Cannon CP, et al. Operative management of metastatic melanoma in bone may require en bloc resection of disease. Clin Orthop Relat Res. 2014; 472(10):3196-203 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
BACKGROUND: Bone metastasis is a poor prognostic indicator in melanoma. Some authors have advocated only palliative treatment for patients with osseous disease. QUESTIONS/PURPOSES: We determined (1) overall survival after surgery for bone metastasis in patients with malignant melanoma, (2) the rate of local relapse after surgery for bone metastasis, (3) whether certain patients might benefit from more extensive surgery to reduce the risk of local recurrence, and (4) whether there is an effect of prior radiation on survival and local progression. METHODS: We identified 37 patients who underwent 41 orthopaedic procedures for metastatic melanoma to bone in the pelvis or appendicular skeleton, including 20 for pathologic fracture, from our institutional orthopaedic database and performed a retrospective review of their charts and radiographs. The femur (n = 19) and humerus (n = 11) were the most common operative sites. Kaplan-Meier survivorship was used to determine overall survival and local progression-free survival. RESULTS: The median survival from surgery was 9 months (range, 1-135 months). Kaplan-Meier analysis showed overall survival of 30% at 12 months and 17% at 24 months. Local recurrence developed in seven of 41 lesions (17%). The local progression-free survival was 87% at 12 months and 67% at 24 months. Patients for whom prior radiation failed and patients who did not have excision of osseous metastases had higher rates of local recurrence. Two patients underwent amputation for uncontrolled local progression of disease. CONCLUSIONS: Osseous metastasis from melanoma behaves aggressively. The rate of local progression is substantial, and two of 37 patients in this series required amputation for progressive disease. Despite the poor overall prognosis, local control of bone disease is an important issue, and patients may benefit from resection of osseous metastases, particularly if prior radiation has failed.
Miwa S, Matsumoto Y, Hiroshima Y, et al. Fluorescence-guided surgery of prostate cancer bone metastasis. J Surg Res. 2014; 192(1):124-33 [PubMed] Related Publications
BACKGROUND: The aim of this study is to investigate the effectiveness of fluorescence-guided surgery (FGS) of prostate cancer experimental skeletal metastasis. MATERIALS AND METHODS: Green fluorescent protein-expressing PC-3 human prostate cancer cells (PC-3-green fluorescent protein) were injected into the intramedullary cavity of the tibia in 32 nude mice. After 2 wk, 16 of the mice underwent FGS; the other 16 mice underwent bright-light surgery (BLS). Half of BLS and FGS mice (8 mice in each group) received zoledronic acid (ZOL). Weekly fluorescence imaging of the mice was performed. Six weeks after surgery, metastases to lung and inguinal lymph node were evaluated by fluorescence imaging. RESULTS: The percentage of residual tumor after BLS and FGS was 9.9 ± 2.2% and 0.9 ± 0.3%, respectively (P < 0.001). FGS reduced recurrent cancer growth compared with BLS (P < 0.005). Although FGS alone had no significant effect on inguinal lymph node metastases, lung metastasis or disease-free survival (DFS), ZOL in combination with FGS significantly increased DFS (P = 0.01) in comparison with the combination of BLS and ZOL. ZOL reduced lymph node metastases (P = 0.033) but not lung metastasis. CONCLUSIONS: FGS significantly reduced recurrence of experimental prostate cancer bone metastasis compared with BLS. The combination of FGS and ZOL increased DFS over BLS and ZOL. ZOL inhibited lymph node metastasis but not lung metastasis.
Yin J, Liu YN, Tillman H, et al. AR-regulated TWEAK-FN14 pathway promotes prostate cancer bone metastasis. Cancer Res. 2014; 74(16):4306-17 [PubMed] Related Publications
The recurrence of prostate cancer metastases to bone after androgen deprivation therapy is a major clinical challenge. We identified FN14 (TNFRSF12A), a TNF receptor family member, as a factor that promotes prostate cancer bone metastasis. In experimental models, depletion of FN14 inhibited bone metastasis, and FN14 could be functionally reconstituted with IKKβ-dependent, NFκB signaling activation. In human prostate cancer, upregulated FN14 expression was observed in more than half of metastatic samples. In addition, FN14 expression was correlated inversely with androgen receptor (AR) signaling output in clinical samples. Consistent with this, AR binding to the FN14 enhancer decreased expression. We show here that FN14 may be a survival factor in low AR output prostate cancer cells. Our results define one upstream mechanism, via FN14 signaling, through which the NFκB pathway contributes to prostate cancer metastasis and suggest FN14 as a candidate therapeutic and imaging target for castrate-resistant prostate cancers.
Mantel F, Glatz S, Toussaint A, et al. Long-term safety and efficacy of fractionated stereotactic body radiation therapy for spinal metastases. Strahlenther Onkol. 2014; 190(12):1141-8 [PubMed] Related Publications
PURPOSE: Patients with long life expectancy despite metastatic status might benefit from long-term local control of spinal metastases. Dose-intensified radiotherapy (RT) is believed to control tumor growth better and thus offers longer pain relief. This single-institution study reports on fractionated stereotactic body radiation therapy (SBRT) for spinal metastases in patients with good life expectancy based on performance status, extent of metastases, histology, and time to metastasis. METHODS: Between 2004 and 2010, 36 treatment sites in 32 patients (median age 55 years; male 61%; median Karnofsky performance score 85) were treated with fractionated SBRT. The median treatment dose was 60 Gy (range, 48.5-65 Gy) given in a median of 20 fractions (range, 17-33); the median maximum dose to the planning risk volume for the spinal cord (PRV-SC) was 46.6 Gy. RESULTS: All patients suffering from pain prior to RT reported pain relief after treatment; after a median follow-up of 20.3 months, 61% of treatment sites were pain-free, another 25% associated with mild pain. In 86% of treatments, patients were free from neurological symptoms at the time of the last clinical follow-up. Acute grade 1 toxicities (CTCAE 3.0) were observed in 11 patients. Myelopathy did not occur in any patient. Radiologically controlled freedom from local progression was 92 and 84% after 12 and 24 months, respectively. Median overall survival (OS) was 19.6 months. CONCLUSION: Patient selection resulted in long OS despite metastatic disease, and dose-intensified fractionated SBRT for spinal metastases was safe and achieved long-term local tumor control and palliation of pain.
Sharan AD, Szulc A, Krystal J, et al. The integration of radiosurgery for the treatment of patients with metastatic spine diseases. J Am Acad Orthop Surg. 2014; 22(7):447-54 [PubMed] Related Publications
Significant evidence emerging in the spinal oncology literature recommends radiosurgery as a primary modality of treatment of spinal metastasis. Improvements in the methods of delivering radiation have increased the ability to provide a higher and more exacting dose of radiation to a tumor bed than previously. Using treatment-planning software, radiation is contoured around a specific lesion with the intent of administering a tumoricidal dose. Combined with a minimally invasive, tumor-load reducing surgery, this advanced form of radiation therapy can provide better local control of the tumor compared with conventional external beam radiation.
Merten R, Hecht M, Haderlein M, et al. Increased skin and mucosal toxicity in the combination of vemurafenib with radiation therapy. Strahlenther Onkol. 2014; 190(12):1169-72 [PubMed] Related Publications
BACKGROUND: Palliative radiotherapy is often required for patients with metastatic malignant melanoma in the case of bone or brain metastases. Since BRAF inhibitor therapy is highly efficient in V600-mutated melanomas, there is hesitation to stop it during radiotherapy. Consequently, radiotherapy under simultaneous vemurafenib treatment is frequently needed. CASE REPORT: We report the case of a patient receiving palliative radiotherapy of spinal bone metastases before and during vemurafenib therapy. The skin reactions were quantitatively scored using computer-assisted digital image evaluation. RESULTS: Radiotherapy without vemurafenib was tolerated very well, whereas radiotherapy under simultaneous vemurafenib treatment resulted in accentuated skin reactions. Furthermore, the patient developed dysphagia and had to be hospitalized for parenteral nutrition. In the quantitative analysis, there was a twofold increase in pigmentation and erythema of the irradiated skin area of the thoracic spine when vemurafenib was combined with radiotherapy compared with radiotherapy treatment alone. This is the first reported case of a patient showing no complications during radiotherapy without vemurafenib but remarkable skin and mucosal toxicity under concurrent vemurafenib therapy. Thus, a genetically conditioned individually elevated radiosensitivity can definitely be excluded. Compared with other reported cases, radiosensitization was not limited to the skin, but also affected the esophageal mucosa. CONCLUSION: Vemurafenib is a strong radiosensitizer. Patients receiving radiotherapy under simultaneous vemurafenib treatment should be monitored very closely.
Pazionis TJ, Papanastassiou ID, Maybody M, Healey JH Embolization of hypervascular bone metastases reduces intraoperative blood loss: a case-control study. Clin Orthop Relat Res. 2014; 472(10):3179-87 [PubMed] Article available free on PMC after 01/10/2015 Related Publications
BACKGROUND: Small case series suggest that preoperative transcatheter arterial embolization minimizes bleeding and facilitates surgery for hypervascular metastatic bone tumors. However, control groups would make our confidence in clinical recommendations stronger, but small patient numbers make prospective trials difficult to conduct on this topic. QUESTIONS/PURPOSES: In this case-control study, we asked whether (1) patients who undergo embolization have less estimated blood loss and/or shorter operative time than patients who do not have embolization; (2) larger tumor size, greater initial tumor vascularity, and longer interval from embolization to surgery are associated with greater estimated blood loss and packed red blood cell transfusion volume; and (3) embolization does not affect renal function in patients with normal preoperative renal function. METHODS: We retrospectively reviewed records of patients with hypervascular bone metastases treated at our institution between 1998 and 2008. Twenty-seven patients with renal cell carcinoma and 12 with thyroid carcinoma who underwent embolization before 41 surgical procedures were matched to 41 patients who did not have embolization with respect to age, diagnosis, tumor size and potential vascularity, and procedure type; matching was performed without knowledge of outcomes. In univariate and multivariate analyses, age, tumor size, use of embolization, surgery type and risk, embolization-to-surgery interval, and degree of devascularization were evaluated for correlations with estimated blood loss, packed red blood cell transfusion volume, operative time, and postembolization renal function. RESULTS: Overall, patients who had embolization had less mean estimated blood loss (0.90 versus 1.77 L; p = 0.002), packed red blood cell transfusion volume (2.15 versus 3.56 U; p = 0.020), and operative time (3.13 versus 3.91 hours; p < 0.001). Larger tumor size correlated with greater estimated blood loss (r = 0.451; p = 0.003), packed red blood cell transfusion volume (r = 0.50; p = 0.002), and operative time (r = 0.595; p < 0.001). Neither the interval for embolization to surgery nor the degree of devascularization correlated with estimated blood loss or transfusion volume. In open rodding with intralesional curettage, transcatheter arterial embolization was associated with reduced estimated blood loss, transfusion volume, and operative time. Packed red blood cell transfusion volume was not reduced by embolization in intramedullary nailing procedures with the patient numbers available. Among patients with normal preoperative renal function who had embolization, creatinine levels remained normal. Mild transient, reversible renal function change occurred in one patient with preoperatively abnormal renal function. CONCLUSIONS: This study suggests that preoperative embolization probably reduces estimated blood loss, particularly for large tumors and during open femoral procedures.