Y.M. van der Linden

The assessment of the risk of fracture in femora with metastatic lesions: Comparing case-specific finite element analyses with predictions by clinical experts

Previously, we showed that case-specific non-linear finite element (FE) models are better at predicting the load to failure of metastatic femora than experienced clinicians. In this study we improved our FE modelling and increased the number of femora and characteristics of the lesions. We retested the robustness of the FE predictions and assessed why clinicians have difficulty in estimating the load to failure of metastatic femora. A total of 20 femora with and without artificial metastases were mechanically loaded until failure. These experiments were simulated using case-specific FE models. Six clinicians ranked the femora on load to failure and reported their ranking strategies. The experimental load to failure for intact and metastatic femora was well predicted by the FE models (R(2) = 0.90 and R(2) = 0.93, respectively). Ranking metastatic femora on load to failure was well performed by the FE models (τ = 0.87), but not by the clinicians (0.11 < τ < 0.42). Both the FE models and the clinicians allowed for the characteristics of the lesions, but only the FE models incorporated the initial bone strength, which is essential for accurately predicting the risk of fracture. Accurate prediction of the risk of fracture should be made possible for clinicians by further developing FE models.

Poor Outcomes after Whole Brain Radiotherapy in Patients with Brain Metastases: Results from an International Multicentre Cohort Study

AIMS To describe the characteristics and outcomes of cancer patients receiving Whole Brain Radiotherapy (WBRT) and delineate poor outcome groups after WBRT. MATERIALS AND METHODS From 1991 to 2007, 3459 patients receiving WBRT for brain metastases at three centres (in Australia and the Netherlands) were retrospectively reviewed. The effect of clinicodemographic factors, including age, gender, primary cancer, time to WBRT from primary cancer diagnosis and WBRT timing relative to other radiotherapy courses on overall survival, survival from WBRT commencement (WBRT-SV) and death within 6 weeks were analysed. RESULTS WBRT was the first radiotherapy course in 2161/3459 (63%) and the last in 2932/3459 (85%). The most common primary cancer sites with brain metastases were lung (n = 1800; 52%), breast (n = 568; 16%), melanoma (n = 350; 10%) and colorectal (n = 209; 6%). The median time to WBRT from primary cancer diagnosis was 34 weeks, overall survival 1.42 years (0.04-28.70) and WBRT-SV 0.33 years (0-8.60). Older age, male gender and a shorter time from the primary cancer diagnosis to WBRT predicted worse overall survival and WBRT-SV. Seventeen per cent survived less than 6 weeks. Older patients with a shorter time from the primary cancer diagnosis to WBRT and a lower WBRT episode number were more likely to die less than 6 weeks after WBRT. CONCLUSIONS Cancer patients with brain metastases have poor overall outcomes. High mortality within 6 weeks of starting WBRT suggests patient selection remains challenging.

The Treatment of Bone Metastasis with Highly Conformal Radiation Therapy: A Brave New World or a Costly Mistake?

*Department of Radiation Oncology, Arthur G. James Cancer Hospital, The Ohio State University, Columbus, OH, USA; yDepartment of Radiation Oncology, Sunnybrook Health Sciences Centre and Princess Margaret Hospital, University of Toronto, Toronto, ON, Canada; zDepartment of Radiation Oncology, Advocate Good Samaritan Cancer Center, Downers Grove, IL, USA; xDepartment of Radiation Oncology, Blanchard Valley Regional Cancer Center, Findlay, OH, USA; {Department of Radiology and Radiotherapy, University of Patras School of Medicine, Greece; jjRadiotherapeutic Institution Friesland, Leeuwarden, The Netherlands; **Mount Vernon Cancer Centre, Northwood, Middlesex, UK

The effect of radiotherapy, and radiotherapy combined with bisphosphonates or RANK ligand inhibitors on bone quality in bone metastases. A systematic review

PURPOSE The role of radiotherapy in stabilizing metastatic bones is unclear. This systematic review assessed the effects of (1) radiotherapy, (2) radiotherapy combined with bisphosphonates, and (3) radiotherapy combined with RANK ligand (RANKL) inhibitors on bone quality and bone strength in bone metastases originating from solid tumors. METHODS Pubmed, EMBASE and the Cochrane Library were searched. Any type of study design and type and dose of radiotherapy, bisphosphonates and RANKL inhibitors were allowed. RESULTS 39 articles were identified. Animal studies showed that radiotherapy had similar effects on bone quality and strength as receiving no treatment, whereas adding bisphosphonates to radiotherapy restored bone quality and strength. In patient studies, bone density increased after radiotherapy and radiotherapy combined with bisphosphonates. However, due to the often non-optimal study design and study quality, it was unclear whether this increase could be attributed to these treatments. There was insufficient evidence to assess the additional effect of bisphosphonates or RANKL inhibitors. CONCLUSION Despite the clinical experience that radiotherapy is an effective treatment for bone metastases, there was no sufficient evidence for a positive effect on bone quality and fracture risk. Animal studies showed that adding bisphosphonates to radiotherapy restored bone quality and strength, whereas this was not proven in patients. There were no studies addressing the adjunct effect of RANKL inhibitors to radiotherapy. Although associated with several methodological, practical and ethical challenges, randomized controlled trials are needed.

An Easy-to-Use Prognostic Model for Survival Estimation for Patients with Symptomatic Long Bone Metastases

Background: A survival estimation for patients with symptomatic long bone metastases (LBM) is crucial to prevent overtreatment and undertreatment. This study analyzed prognostic factors for overall survival and developed a simple, easy-to-use prognostic model. Methods: A multicenter retrospective study of 1,520 patients treated for symptomatic LBM between 2000 and 2013 at the radiation therapy and/or orthopaedic departments was performed. Primary tumors were categorized into 3 clinical profiles (favorable, moderate, or unfavorable) according to an existing classification system. Associations between prognostic variables and overall survival were investigated using the Kaplan-Meier method and multivariate Cox regression models. The discriminatory ability of the developed model was assessed with the Harrell C-statistic. The observed and expected survival for each survival category were compared on the basis of an external cohort. Results: Median overall survival was 7.4 months (95% confidence interval [CI], 6.7 to 8.1 months). On the basis of the independent prognostic factors, namely the clinical profile, Karnofsky Performance Score, and presence of visceral and/or brain metastases, 12 prognostic categories were created. The Harrell C-statistic was 0.70. A flowchart was developed to easily stratify patients. Using cutoff points for clinical decision-making, the 12 categories were narrowed down to 4 categories with clinical consequences. Median survival was 21.9 months (95% CI, 18.7 to 25.1 months), 10.5 months (95% CI, 7.9 to 13.1 months), 4.6 months (95% CI, 3.9 to 5.3 months), and 2.2 months (95% CI, 1.8 to 2.6 months) for the 4 categories. Conclusions: This study presents a model to easily stratify patients with symptomatic LBM according to their expected survival. The simplicity and clarity of the model facilitate and encourage its use in the routine care of patients with LBM, to provide the most appropriate treatment for each individual patient. Level of Evidence: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Effectiveness of Repeat Radiotherapy for Painful Bone Metastases in Clinical Practice: A 10 Year Historical Cohort Study

AIMS Repeat radiotherapy for palliation of painful bone metastases is often prescribed to non-responders or those with recurrent pain, although studies on retreatment remain scarce. We assessed the effectiveness of retreatment for painful bone metastases in terms of pain relief in everyday clinical practice and identified factors associated with response. MATERIALS AND METHODS We carried out a single-institution 10 year retrospective cohort study among 247 patients retreated for painful bone metastases. Response was defined as a decrease in pain between 2 and 12 weeks after retreatment. The overall pain response rate was calculated in an evaluable-patients-only analysis and a worst-case analysis. Multivariate logistic regression analyses were used to identify factors associated with pain response. RESULTS A follow-up of ≥2 weeks was available in 162 of 247 patients (65%). The overall pain response was 66% (95% confidence interval 58-73%) in an evaluable-patients-only analysis and 43% (95% confidence interval 37-50%) in a worst-case analysis. Response to first irradiation (odds ratio 2.16, P = 0.049) and use of systemic therapy (odds ratio 0.39, P = 0.037) were independently associated with the response to retreatment. The median overall survival was 7.1 months. CONCLUSION In everyday clinical practice, retreatment for painful bone metastases leads to pain reduction in 66% of evaluable patients and 43% of patients in a worst-case analysis. Patients who responded to initial radiotherapy were more likely to respond again and those on systemic therapy were less likely to respond. Overall, repeat radiotherapy should be considered in patients with persisting bone pain.

Effect of different CT scanners and settings on femoral failure loads calculated by finite element models: CT SCANNERS AND FAILURE LOADS

In a multi‐center patient study, using different CT scanners, CT‐based finite element (FE) models are utilized to calculate failure loads of femora with metastases. Previous studies showed that using different CT scanners can result in different outcomes. This study aims to quantify the effects of (i) different CT scanners; (ii) different CT protocols with variations in slice thickness, field of view (FOV), and reconstruction kernel; and (iii) air between calibration phantom and patient, on Hounsfield Units (HU), bone mineral density (BMD), and FE failure load. Six cadaveric femora were scanned on four CT scanners. Scans were made with multiple CT protocols and with or without an air gap between the body model and calibration phantom. HU and calibrated BMD were determined in cortical and trabecular regions of interest. Non‐linear isotropic FE models were constructed to calculate failure load. Mean differences between CT scanners varied up to 7% in cortical HU, 6% in trabecular HU, 6% in cortical BMD, 12% in trabecular BMD, and 17% in failure load. Changes in slice thickness and FOV had little effect (≤4%), while reconstruction kernels had a larger effect on HU (16%), BMD (17%), and failure load (9%). Air between the body model and calibration phantom slightly decreased the HU, BMD, and failure loads (≤8%). In conclusion, this study showed that quantitative analysis of CT images acquired with different CT scanners, and particularly reconstruction kernels, can induce relatively large differences in HU, BMD, and failure loads. Additionally, if possible, air artifacts should be avoided.

A systematic review of prognostic factors predicting survival in patients with spinal bone metastases

PurposeFor the selection of treatment in patients with spinal bone metastases (SBM), survival estimation plays a crucial role to avoid over- and under-treatment. To aid clinicians in this difficult task, several prediction models have been developed, consisting of many different risk factors. The aim of this systematic review was to identify prognostic factors that are associated with survival in patients with SBM to support development of predictive models.MethodsA systematic review was performed with focus on prognostic factors associated with survival in patients with SBM. Two reviewers independently selected studies for inclusion and assessed the risk of bias. A level of evidence synthesis was performed for each prognostic factor. Inter-observer agreement for the risk of bias assessment was determined by the kappa-statistic.ResultsAfter screening, 142 full-text articles were obtained, of which 22 met the eligibility criteria. A total of 43 different prognostic factors were investigated in the included studies, of which 17 were relevant to pre-treatment survival estimation. The prognostic factors most frequently associated with survival were the primary tumor and the performance status. The prognostic factors most frequently not associated with survival were age, gender, number and location of the SBM and the presence of a pathologic fracture.ConclusionsPrognostication for patients with SBM should be based on an accurate primary tumor classification, combined with a performance score. The benefit of adding other prognostic factors is doubtful.

Epidermal growth factor receptor mutations should be considered as a prognostic factor for survival of patients with pathological fractures or painful bone metastases from non-small cell lung cancer

Aims This study aims to assess first, whether mutations in the epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma (kRAS) genes are associated with overall survival (OS) in patients who present with symptomatic bone metastases from non‐small cell lung cancer (NSCLC) and secondly, whether mutation status should be incorporated into prognostic models that are used when deciding on the appropriate palliative treatment for symptomatic bone metastases. Patients and Methods We studied 139 patients with NSCLC treated between 2007 and 2014 for symptomatic bone metastases and whose mutation status was known. The association between mutation status and overall survival was analysed and the results applied to a recently published prognostic model to determine whether including the mutation status would improve its discriminatory power. Results The median OS was 3.9 months (95% confidence interval (CI) 2.1 to 5.7). Patients with EGFR (15%) or kRAS mutations (34%) had a median OS of 17.3 months (95% CI 12.7 to 22.0) and 1.8 months (95% CI 1.0 to 2.7), respectively. Compared with EGFR‐positive patients, EGFR‐negative patients had a 2.5 times higher risk of death (95% CI 1.5 to 4.2). Incorporating EGFR mutation status in the prognostic model improved its discriminatory power. Conclusion Survival prediction models for patients with symptomatic bone metastases are used to determine the most appropriate (surgical) treatment for painful or fractured lesions. This study shows that NSCLC should not be regarded as a single entity in such models.