Individualizing Follow-Up Strategies in High-Grade Soft Tissue Sarcoma with Flexible Parametric Competing Risk Regression Models.

Currently, patients with extremity soft tissue sarcoma (eSTS) who have undergone curative resection are followed up by a heuristic approach, not covering individual patient risks. The aim of this study was to develop two flexible parametric competing risk regression models (FPCRRMs) for local recurrence (LR) and distant metastasis (DM), aiming at providing guidance on how to individually follow-up patients. Three thousand sixteen patients (1931 test, 1085 validation cohort) with high-grade eSTS were included in this retrospective, multicenter study. Histology (9 categories), grading (time-varying covariate), gender, age, tumor size, margins, (neo)adjuvant radiotherapy (RTX), and neoadjuvant chemotherapy (CTX) were used in the FPCRRMs and performance tested with Harrell-C-index. Median follow-up was 50 months (interquartile range: 23.3-95 months). Two hundred forty-two (12.5%) and 603 (31.2%) of test cohort patients developed LR and DM. Factors significantly associated with LR were gender, size, histology, neo- and adjuvant RTX, and margins. Parameters associated with DM were margins, grading, gender, size, histology, and neoadjuvant RTX. C-statistics was computed for internal (C-index for LR: 0.705, for DM: 0.723) and external cohort (C-index for LR: 0.683, for DM: 0.772). Depending on clinical, pathological, and patient-related parameters, LR- and DM-risks vary. With the present model, implemented in the updated Personalised Sarcoma Care (PERSARC)-app, more individualized prediction of LR/DM-risks is made possible.

Prevalence and Clinical Features of Mazabraud Syndrome: A Multicenter European Study.

BACKGROUND: Mazabraud syndrome is a rare disorder, characterized by the presence of fibrous dysplasia (FD) with associated intramuscular myxomas. Data are scarce on the prevalence, clinical features, and natural history of this disorder and outcomes. In this multicenter study, we evaluated a series of patients from 6 European centers. METHODS: All centers affiliated with the European Musculo-Skeletal Oncology Society (EMSOS) were invited to include data on all patients with Mazabraud syndrome who were seen between 1980 and 2015. The study investigated the prevalence of Mazabraud syndrome, the type, severity, and localization of FD lesions in relation to myxomas, the histopathology of myxomas, and results of GNAS-mutation analysis, when available. RESULTS: Thirty-two patients (22 female) from 6 centers were included. The prevalence of Mazabraud syndrome was 2.2% in the combined cohort of 1,446 patients with FD, and the syndrome was diagnosed at a mean of 10.1 years after diagnosis of FD. The myxomas were predominantly localized in the upper leg. Excision was performed in 20 patients, recurrence occurred in 6 of these patients (30%) at a median of 8.5 years (range, 1.9 to 16.0 years), and revision surgery was necessary in 5 (25%). High cellularity of myxomas was associated with recurrence (p < 0.05). A GNAS mutation was identified in the myxoma tissue of 5 (83%) of 6 patients with GNAS-mutation analysis. CONCLUSIONS: This study is the first, to our knowledge, to provide data on the prevalence of Mazabraud syndrome in a relatively large cohort. Although the outcomes of surgical resection were good, a quarter of the patients required revision surgery despite clear resection margins. High cellularity of myxomas was associated with recurrence. GNAS mutations were identified in 83% (5 of 6), emphasizing the shared origin of FD and myxomas. Our data show that patients with FD who have disproportionate complaints, irrespective of FD type, extent, or severity, should be investigated for the possible presence of myxomas. LEVEL OF EVIDENCE: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Clinical management of spinal metastases-The Dutch national guideline.

This article is a summary of the revised Dutch multidisciplinary evidence-based guideline 'Spinal metastases' (English translation available at: https://www.oncoline.nl/spinal-metastases) that was published at the end of 2015. This summary provides an easy-to-use overview for physicians to use in their daily practice.

The Dutch national guideline on metastases and hematological malignancies localized within the spine; a multidisciplinary collaboration towards timely and proactive management.

Here, we describe the development of a Dutch national guideline on metastases and hematological malignancies localized within the spine. The aim was to create a comprehensive guideline focusing on proactive management of these diseases, enabling healthcare professionals to weigh patient perspectives, life expectancy, and expected outcomes to make informed treatment recommendations. A national multidisciplinary panel consisting of clinicians, a nurse, a patient advocate, an epidemiologist, and a methodologist drafted the guideline. The important role of patients in the realization of the guideline enabled us to identify and address perceived shortcomings in patient care. The guideline covers not only metastatic epidural spinal cord compression, but also the treatment of uncomplicated metastases and hematological malignancies localized within the spine. The guideline is applicable in daily practice and provides an up-to-date and concise overview of the diagnostic and treatment possibilities for patients suffering from a disease that can have a serious impact on their quality of life. Suggestions for the practical implementation of patient care in hospitals are also provided, including approaches for pursuing proactive management. The crucial role of the patient in decision making is emphasized in this guideline.

Clinical Evaluation of the Spinal Instability Neoplastic Score in Patients Treated With Radiotherapy for Symptomatic Spinal Bone Metastases.

STUDY DESIGN: Retrospective cohort study. OBJECTIVE: To determine the predictive value of the Spinal Instability Neoplastic Score (SINS) in a cohort of patients treated with radiotherapy for spinal bone metastases. SUMMARY OF BACKGROUND DATA: Assessment of spinal stability in metastatic disease is challenging and is mostly done by relying on clinical experience, in the absence of validated guidelines or an established predetermined set of risk factors. The SINS provides clinicians with a tool to assess tumor-related spinal instability. METHODS: A total of 110 patients were included in this retrospective study. Time to event was calculated as the difference between start of radiotherapy and date of occurrence of an adverse event or last follow-up, with death being considered a competing event. A competing risk analysis was performed to estimate the effect of the SINS on the cumulative incidence of the occurrence of an adverse event. RESULTS: Sixteen patients (15%) experienced an adverse event during follow-up. The cumulative incidence for the occurrence of an adverse event at 6 and 12 months was 11.8% (95% confidence interval 5.1%-24.0%) and 14.5% (95% confidence interval 6.9%-22.2%), respectively. Competing risk analysis showed that the final SINS classification was not significantly associated with the cumulative incidence of an adverse event within the studied population. CONCLUSION: The clinical applicability of the SINS as a tool to assess spinal instability seems limited. LEVEL OF EVIDENCE: 3.

Current status and unanswered questions on the use of Denosumab in giant cell tumor of bone.

Denosumab is a monoclonal antibody to RANK ligand approved for use in giant cell tumour (GCT) of bone. Due to its efficacy, Denosumab is recommended as the first option in inoperable or metastatic GCT. Denosumab has also been used pre-operatively to downstage tumours with large soft tissue extension to allow for less morbid surgery. The role of Denosumab for conventional limb GCT of bone is yet to be defined. Further studies are required to determine whether local recurrence rates will be decreased with the adjuvant use of Denosumab along with surgery. The long term use and toxicity of this agent is unknown as is the proportion of patients with primary or secondary resistance. It is advised that complicated cases of GCT requiring Denosumab treatment should be referred and followed up at expert centres. Collaborative studies involving further clinical trials and rigorous data collection are strongly recommended to identify the optimum use of this drug.

Predictive Value of Six Prognostic Scoring Systems for Spinal Bone Metastases: An Analysis Based on 1379 Patients.

STUDY DESIGN: A retrospective cohort study. OBJECTIVE: The aim of this study was to assess and compare the predictive accuracy of six models designed to estimate survival of patients suffering from spinal bone metastases Just (SBMs). SUMMARY OF BACKGROUND DATA: On the basis of the estimated survival of patients with SBM, extent of treatment can be adjusted. To aid clinicians in the difficult task of assessing probability of survival, prognostic scoring systems have been developed by Tomita, Tokuhashi, Van der Linden, Bauer, Rades, and Bollen. METHODS: All patients who were treated for SBM between 2000 and 2010 were included in this international, multicenter, retrospective study (n = 1379). Medical records were reviewed for all items needed to use the scoring systems. Survival time was calculated as the difference between start of treatment for SBM and date of death. Survival curves were estimated using the Kaplan-Meier method and accuracy was assessed with the c-statistic. Survival rates of the worst prognostic groups were evaluated at 4 months. RESULTS: Median follow-up was 6.7 years [95% confidence interval (95% CI) 5.6-7.7] with a minimum of 2.3 years and a maximum of 12.3 years. The overall median survival was 5.1 months (95% CI 4.6-5.6). The most common primary tumors were breast (n = 388, 28%), lung (n = 318, 23%), and prostate cancer (n = 259, 19%). The Tokuhashi, Bauer, Tomita, and Van der Linden models performed similar with a c-statistic of 0.64 to 0.66 and a 4-month accuracy of 62% to 65%. The Rades model (c-statistic 0.44) and Bollen model (c-statistic 0.70) had a 4-month accuracy of 69% and 75%, respectively. CONCLUSION: The Bollen model performs better than the other models. However, improvements are still warranted to increase the accuracy. LEVEL OF EVIDENCE: 3.

Surgical downstaging in an open-label phase II trial of denosumab in patients with giant cell tumor of bone.

BACKGROUND: Surgical resection with curative intent for giant cell tumor of bone (GCTB) may be associated with severe morbidity. This interim analysis evaluated reduction in surgical invasiveness after denosumab treatment in patients with resectable GCTB. METHODS: Patients with primary or recurrent GCTB, for whom the initially planned surgery was associated with functional compromise or morbidity, received denosumab 120 mg subcutaneously every 4 weeks (additional doses on days 8 and 15 of the first cycle). Planned and actual GCTB-related surgical procedures before and after denosumab treatment were reported. Patients were followed for surgical outcome, adverse events, and recurrence following resection. RESULTS: Overall, 222 patients were evaluable for surgical downstaging (54 % were women; median age 34 years). Lesions (67 % primary and 33 % recurrent) were located in the axial (15 %) and appendicular skeleton (85 %). At the data cutoff date, most patients had not yet undergone surgery (n = 106; 48 %) or had a less morbid procedure (n = 84; 38 %) than originally planned. Median (interquartile range) time on denosumab was 19.5 (12.4-28.6) months for the 106 patients who had not undergone surgery and were continuing on monthly denosumab. Native joint preservation was 96 % (n = 24/25) for patients with planned joint/prosthesis replacement and 86 % (n = 30/35) for patients with planned joint resection/fusion. Of the 116 patients who had surgery (median postsurgical follow-up 13.0 [8.5-17.9] months), local recurrence occurred in 17 (15 %) patients. CONCLUSION: For patients with resectable GCTB, neoadjuvant denosumab therapy resulted in beneficial surgical downstaging, including either no surgery or a less morbid surgical procedure.

Hyperplasia of rib and vertebra, associated with infiltrating lipoma: a rare case of focal overgrowth.

PURPOSE: Syndromes with focal overgrowth are rare and diagnosis is difficult because manifestations are highly variable and symptoms overlap between syndromes. Diagnosis depends on clinical history, physical examination, and radiologic and histologic findings. This report describes a case of focal overgrowth of the left seventh rib and half of the adjacent thoracic vertebra, with overlying infiltrating lipoma. METHODS: A 13-year-old boy presented with an asymptomatic chest wall mass caused by enlargement of the seventh rib and an overlying soft-tissue mass accompanied by enlargement of half of the seventh thoracic vertebra. MRI showed infiltration of lipomatous tissue in the muscles, but no interfascicular accumulation of adipose tissue in the thoracic spinal nerve. RESULTS: A similar case was presented in 1985 but without MR imaging. CONCLUSION: We report on a second case of focal overgrowth of a rib and half of the adjacent vertebra, and overlying lipoma. In addition to the first case, we present MR images demonstrating infiltration of the adipose tissue.

An easy tool to predict survival in patients receiving radiation therapy for painful bone metastases.

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.

The intravertebral cleft in painful long-standing osteoporotic vertebral compression fractures treated with percutaneous vertebroplasty: diagnostic assessment and clinical significance.

STUDY DESIGN: Prospective follow-up study. OBJECTIVE: Evaluation of the diagnostic assessment and clinical significance of the intravertebral cleft in painful, long-standing osteoporotic vertebral compression fractures (OVCFs) treated with percutaneous vertebroplasty (PVP). SUMMARY OF BACKGROUND DATA: Patients with painful OVCFs with intravertebral clefts provide a unique and possibly superior indication for PVP. However, comparative studies are scarce, and the results are conflicting. The extent of the difference attributable to interobserver variation in the identification of an intravertebral cleft is currently unknown. METHODS: A total of 102 patients received PVP for 197 painful long-standing OVCFs and were prospectively observed, using a pain-intensity numerical-rating scale for back pain, the 36-Item Short Form Health Survey quality-of-life questionnaire, and routine spinal radiographs. Three experienced examiners retrospectively examined all preoperative radiographs and magnetic resonance imaging (MRI) T1-weighted and short-tau-inversion-recovery (STIR) sequences and the direct postoperative computed tomographic scans for the presence of an intravertebral cleft. Disagreements were re-examined and discussed for consensus. RESULTS: Interobserver agreement for the detection of an intravertebral cleft was moderate on preoperative radiography (κ, 0.55-0.59) and substantial on preoperative MRI (κ, 0.71-0.79) and postoperative computed tomography (κ, 0.67-0.85). On the basis of consensus, 42 (21.3%) clefts were detected. The associated sensitivity of preoperative radiography was low (31.7%-48.8%), but the specificity was high (94.7%-99.3%). The diagnostic performance of preoperative MRI T1-weighted and STIR sequences was excellent, with both high sensitivity (85.7%-88.1%) and high specificity (89.7%-98.1%). Pain decrease and increase in quality of life obtained from PVP were ultimately comparable with patients without intravertebral clefts but was obtained more gradually during the first postoperative year. An intravertebral cleft was a strong risk factor for the occurrence of cortical cement leakage (odds ratio, 4.29; 95% confidence interval, 1.51-12.2; P = 0.006). CONCLUSION: There is variation between observers in the identification of an intravertebral cleft, and the identification of an intravertebral cleft is not always straightforward. For preoperative assessment, we recommend MRI with T1-weighted and STIR sequences. Regarding patient-reported outcome, patients with long-standing OVCFs with intravertebral clefts benefit from PVP, but, compared with patients with OVCFs without intravertebral clefts, the benefit obtained was not superior and may be delayed.

Long-term results: adjuvant radiotherapy in en bloc resection of sacrococcygeal chordoma is advisable.

STUDY DESIGN: A cross-sectional study. OBJECTIVE: The purpose of this report is to define the role of postoperative radiotherapy in the prevention of local recurrence (LR). SUMMARY OF BACKGROUND DATA: Sacrococcygeal chordoma is a slow growing, malignant tumor with a clinical poor outcome due to a high LR rate. Several studies emphasize that margin-free tumor resection is the most important predictor of LR. However, even after extralesional resection a high LR up to 80% remains. METHODS: A retrospective series of 15 patients who underwent surgical treatment for sacrococcygeal chordoma in one center between 1981 and 2003 was reviewed. Overall survival and continuous disease-free survival rates were compared between patients with intralesional resection with standard radiotherapy and patients with extralesional resection and no standard radiotherapy. RESULTS: The median age at surgery was 53 years. The mean follow-up was 7 years or until death. Mean duration of preoperative complaints was 3 years. In 10 patients, an en bloc resection was (histologic resection margins were free) performed and in 5 patients, an intralesional resection was achieved. All but one patients with intralesional resection received radiotherapy (>50 Gy) and patients with extralesional resection only received radiotherapy in case of LR (6 of 10 patients). After extralesional resection (no initial radiotherapy), all 10 patients had LR of the tumor with a mean time to recurrence of 2 years. Six of these ten patients received radiotherapy after LR and had mean survival duration of 7 years. Only one (of five patients) in the group with intralesional resection and postoperative radiotherapy had LR after 11 years. The time to recurrence was significantly longer and we found a trend toward a longer overall survival in the group that received immediate radiotherapy after surgery. CONCLUSION: The results support the strategy to add radiotherapy as standard adjuvant therapy to sacrococcygeal chordoma tumor resection.

No haploinsufficiency but loss of heterozygosity for EXT in multiple osteochondromas.

Multiple osteochondromas (MO) is an autosomal dominant disorder caused by germline mutations in EXT1 and/or EXT2. In contrast, solitary osteochondroma (SO) is nonhereditary. Products of the EXT gene are involved in heparan sulfate (HS) biosynthesis. In this study, we investigated whether osteochondromas arise via either loss of heterozygosity (2 hits) or haploinsufficiency. An in vitro three-dimensional chondrogenic pellet model was used to compare heterozygous bone marrow-derived mesenchymal stem cells (MSCs EXT(wt/-)) of MO patients with normal MSCs and the corresponding tumor specimens (presumed EXT(-/-)). We demonstrated a second hit in EXT in five of eight osteochondromas. HS chain length and structure, in vitro chondrogenesis, and EXT expression levels were identical in both EXT(wt/-) and normal MSCs. Immunohistochemistry for HS, HS proteoglycans, and HS-dependent signaling pathways (eg, TGF-ß/BMP, Wnt, and PTHLH) also showed no differences. The cartilaginous cap of osteochondroma contained a mixture of HS-positive and HS-negative cells. Because a heterozygous EXT mutation does not affect chondrogenesis, EXT, HS, or downstream signaling pathways in MSCs, our results refute the haploinsufficiency theory. We found a second hit in 63% of analyzed osteochondromas, supporting the hypothesis that osteochondromas arise via loss of heterozygosity. The detection of the second hit may depend on the ratio of HS-positive (normal) versus HS-negative (mutated) cells in the cartilaginous cap of the osteochondroma.

A clinical comparative study on low versus medium viscosity polymethylmetacrylate bone cement in percutaneous vertebroplasty: viscosity associated with cement leakage.

STUDY DESIGN: Comparative, prospective follow-up study. OBJECTIVE: Comparison of outcome between patients treated with Percutaneous VertebroPlasty (PVP) using low and medium viscosity PolyMethylMetAcrylate (PMMA) bone cement. SUMMARY OF BACKGROUND DATA: Viscosity is the characterizing parameter of PMMA bone cement, currently the standard augmentation material in PVP, and influences interdigitation, cement distribution inside the vertebral body, injected volume and extravasation, thereby affecting the clinical outcome of PVP. Currently, low, medium, and high viscosity PMMA bone cements are used interchangeably. However, effect of viscosity on clinical outcome in patients with Osteoporotic Vertebral Compression Fractures (OVCFs) has not yet been explicit subject of investigation. METHODS: Follow-up was conducted using a 0 to 10 Pain Intensity Numerical Rating Scale (PI-NRS) and the Short Form 36 (SF-36) Quality of Life questionnaire before PVP and at 7 days (PI-NRS only), 1, 3, and 12 months after PVP. Injected cement volume, degree of interdigitation, and cement leakage were analyzed on direct postoperative computed tomography scanning. At 6 and 52 weeks and at suspicion, patients were analyzed for new fractures. RESULTS: A total of 30 consecutive patients received PVP using low viscosity PMMA bone cement (OsteoPal-V) for 62 OVCFs, followed by 34 patients who received PVP using medium viscosity PMMA bone cement (Disc-O-Tech) for 67 OVCFs. Results regarding PI-NRS and SF-36 were comparable between both groups. Postoperative comparison of injected cement volume, degree of interdigitation, proportion of bipedicular procedures, incidence of new vertebral fractures and complications revealed no differences between both groups. Viscosity was identified as a risk factor for the occurrence of cement leakage (yes/no, OR: 2.925, 95% confidence interval: [1.072-7.984], P = 0.036). CONCLUSION: No major differences in clinical outcome after PVP in OVCFs using low and medium viscosity PMMA bone cement were found. Viscosity of PMMA bone cement was identified as an independent predictor of cement leakage.

Radiofrequency ablation of spinal osteoid osteoma: clinical outcome.

STUDY DESIGN: A prospective study on 24 patients with spinal osteoid osteoma treated with radiofrequency ablation (RFA). OBJECTIVE: To determine if and when computed tomography (CT)-guided RFA is a safe and effective treatment for spinal osteoid osteomas. SUMMARY OF BACKGROUND DATA: Surgery has been considered the standard treatment for spinal osteoid osteomas. Surgery may cause spinal instability, infection, and nervous injury. We evaluated CT-guided RFA as an alternative treatment. METHODS: A total of 28 RFA procedures in 24 patients with spinal osteoid osteoma were performed, using a 5-mm noncooled electrode. Clinical symptoms and spinal deformity were evaluated before and after the procedure. Unsuccessful treatment was defined as the presence of residual or recurrent symptoms. The mean follow-up was 72 months (range: 9-142 months). RESULTS: Nineteen (79%) patients were successfully treated after 1 RFA, and all except one after repeat RFA. One patient with nerve root compression needed further surgery. No complications were observed. Spinal deformity persisted in 3 of 7 patients after successful RFA. CONCLUSION: CT-guided RFA is a safe and effective treatment for spinal osteoid osteoma. Surgery should be reserved for lesions causing nerve root compression.

Prediction of survival in patients with metastases in the spinal column: results based on a randomized trial of radiotherapy.

BACKGROUND: Adequate prediction of survival is important in deciding on treatment for patients with symptomatic spinal metastases. The authors reviewed 342 patients with painful spinal metastases without neurologic impairment who were treated conservatively within a large, prospectively randomized radiotherapy trial. Response to radiotherapy and prognostic factors for survival were studied. METHODS: The data base of the Dutch Bone Metastasis Study was used. Response to treatment and prognostic factors for overall survival (OS) were studied using a Cox regression model. A scoring system was developed to predict OS. RESULTS: Responses were noted in 73% of patients. In 3% of patients, spinal cord compression was reported a mean of 3.5 months after randomization. The median OS was 7 months, and significant predictors for survival were Karnofsky performance score, primary tumor (multivariate analysis; both P < 0.001), and the absence of visceral metastases (multivariate analysis; P = 0.02). A scoring system based on these predictors was developed, and 34% of patients were in Group A (median OS = 3.0 months), 48% of patients were in Group B (median OS = 9.0 months), and 18% of patients were in Group C (median OS = 18.7 months). Group C was comprised of patients with breast carcinoma, a good performance, and no visceral metastases. CONCLUSIONS: Most patients with spinal metastases have a limited life expectancy and should be treated with caution regarding surgical procedures. Radiotherapy is a safe and effective, noninvasive treatment modality for pain. The new scoring system will enable physicians to select patients who may survive long enough to benefit from more radical treatment.

Simple radiographic parameter predicts fracturing in metastatic femoral bone lesions: results from a randomised trial.

BACKGROUND AND PURPOSE: In the randomised Dutch Bone Metastasis Study on the palliative effect of a single fraction (SF) of 8 Gy versus six fractions of 4 Gy on painful bone metastases, 14 fractures occurred in 102 patients with femoral metastases. Purpose of the present study was to identify lesional risk factors for fracturing and to evaluate the influence of the treatment schedule. MATERIAL AND METHODS: Pretreatment radiographs of femoral metastases were collected. Three observers separately measured the lesions and scored radiographic characteristics. RESULTS: Ten fractures occurred after median 7 weeks in 44 SF patients (23%) and four after median 20 weeks in 58 multiple fraction patients (7%) (UV, P=0.02). In 110 femoral metastases, an axial cortical involvement >30 mm significantly predicted fracturing (MV, P=0.02). Twelve out of 14 fractured lesions and 40 out of 96 non-fractured metastases had an axial cortical involvement >30 mm (negative predictive value, 97%). When correcting for the axial cortical involvement, the treatment schedule was not predictive anymore (MV, P=0.07). CONCLUSIONS: Fracturing of the femur mostly depended on the amount of axial cortical involvement of the metastasis. We recommend to treat femoral metastases with an axial cortical involvement < or =30 mm with an SF of 8 Gy for relief of pain. If the axial cortical involvement is >30 mm, prophylactic surgery should be performed to minimize the risk of pathological fracturing or, if the patient's condition is limited, irradiation to a higher total dose.