Single-Center Experience with Ifosfamide Monotherapy as Second-Line Treatment of Recurrent/Metastatic Osteosarcoma.

BACKGROUND: The effectiveness of second-line palliative chemotherapy in patients with recurrent/metastatic osteosarcoma is not well defined. Several small studies (6-19 patients) have reported on ifosfamide as second-line treatment. In this study we report our single-center experience with second-line ifosfamide monotherapy in patients treated for recurrent/metastatic osteosarcoma. METHODS: A chart review was conducted of all patients with osteosarcoma treated with ifosfamide from 1978 until 2017. Until 1997 a 5 g/m2 regimen was used, and from 1997 onwards a 9 g/m2 regimen was used. Overall survival (OS) from start of ifosfamide was the primary endpoint. Progression-free survival (PFS) from start of treatment was also studied. To assess difference in survival between groups the log rank test was applied. To investigate the effect of ifosfamide dose and World Health Organization performance status (PS) a Cox proportional hazard regression model was estimated. RESULTS: Sixty-two patients were selected with recurrent/metastatic osteosarcoma treated with second-line ifosfamide monotherapy (dose of 5 g/m2 , n = 26; 9 g/m2 , n = 36). OS was significantly better in univariate analysis for 9 g/m2 compared with 5 g/m2 (10.9 months [95% confidence interval (CI), 9.3-12.6] vs. 6.7 months [95% CI, 5.9-7.6], respectively) and for PS (median OS PS 0, 13.0 months [95% CI, 2.3-23.8]; PS 1, 8.2 months [95% CI, 5.4-11.1]; PS ≥2, 6.2 months [95% CI, 2.2-10.3]; and unknown PS, 5.4 months [95% CI, 2.2-8.5]). In multivariate analysis only PS showed a significant difference. No difference in PFS was found between 5 and 9 g/m2 ifosfamide treatment or PS. CONCLUSION: This study suggests that ifosfamide is an effective second-line treatment for patients with recurrent/metastatic osteosarcoma. IMPLICATIONS FOR PRACTICE: Ifosfamide monotherapy is commonly used as second-line treatment in osteosarcoma, although large series to support this are lacking. This retrospective study reports overall and progression-free survival for regimens with 5 g/m2 and with 9 g/m2 . This study was unable to show a significant difference in survival between 5 and 9 g/m2 but showed an important impact of World Health Organization performance status on overall survival. This study sets a standard and reference for comparison with the multiple phase II studies under development.

Which Factors Are Associated with Local Control and Survival of Patients with Localized Pelvic Ewing's Sarcoma? A Retrospective Analysis of Data from the Euro-EWING99 Trial.

BACKGROUND: Local treatment of pelvic Ewing's sarcoma may be challenging, and intergroup studies have focused on improving systemic treatments rather than prospectively evaluating aspects of local tumor control. The Euro-EWING99 trial provided a substantial number of patients with localized pelvic tumors treated with the same chemotherapy protocol. Because local control included surgical resection, radiation therapy, or a combination of both, we wanted to investigate local control and survival with respect to the local modality in this study cohort. QUESTIONS/PURPOSES: (1) Do patients with localized sacral tumors have a lower risk of local recurrence and higher survival compared with patients with localized tumors of the innominate bones? (2) Is the local treatment modality associated with local control and survival in patients with sacral and nonsacral tumors? (3) Which local tumor- and treatment-related factors, such as response to neoadjuvant chemotherapy, institution where the biopsy was performed, and surgical complications, are associated with local recurrence and patient survival in nonsacral tumors? (4) Which factors, such as persistent extraosseous tumor growth after chemotherapy or extent of bony resection, are independently associated with overall survival in patients with bone tumors undergoing surgical treatment? METHODS: Between 1998 and 2009, 1411 patients with previously untreated, histologically confirmed Ewing's sarcoma were registered in the German Society for Pediatric Oncology and Hematology Ewing's sarcoma database and treated in the Euro-EWING99 trial. In all, 24% (339 of 1411) of these patients presented with a pelvic primary sarcoma, 47% (159 of 339) of which had macroscopic metastases at diagnosis and were excluded from this analysis. The data from the remaining 180 patients were reviewed retrospectively, based on follow-up data as of July 2016. The median (range) follow-up was 54 months (5 to 191) for all patients and 84 months (11 to 191) for surviving patients. The study endpoints were overall survival, local recurrence and event-free survival probability, which were calculated with the Kaplan-Meier method and compared using the log-rank test. Hazard ratios (HRs) with their respective 95% CIs were estimated in a multivariate Cox regression model. RESULTS: Sacral tumors were associated with a reduced probability of local recurrence (12% [95% CI 1 to 22] versus 28% [95% CI 20 to 36] at 5 years, p = 0.032), a higher event-free survival probability (66% [95% CI 51 to 81] versus 50% [95% CI 41 to 58] at 5 years, p = 0.026) and a higher overall survival probability (72% [95% CI 57 to 87] versus 56% [95% CI 47 to 64] at 5 years, p = 0.025) compared with nonsacral tumors. With the numbers available, we found no differences between patients with sacral tumors who underwent definitive radiotherapy and those who underwent combined surgery and radiotherapy in terms of local recurrence (17% [95% CI 0 to 34] versus 0% [95% CI 0 to 20] at 5 years, p = 0.125) and overall survival probability (73% [95% CI 52 to 94] versus 78% [95% CI 56 to 99] at 5 years, p = 0.764). In nonsacral tumors, combined local treatment was associated with a lower local recurrence probability (14% [95% CI 5 to 23] versus 33% [95% CI 19 to 47] at 5 years, p = 0.015) and a higher overall survival probability (72% [95% CI 61 to 83] versus 47% [95% CI 33 to 62] at 5 years, p = 0.024) compared with surgery alone. Even in a subgroup of patients with wide surgical margins and a good histologic response to induction treatment, the combined local treatment was associated with a higher overall survival probability (87% [95% CI 74 to 100] versus 51% [95% CI 33 to 69] at 5 years, p = 0.009), compared with surgery alone.A poor histologic response to induction chemotherapy in nonsacral tumors (39% [95% CI 19 to 59] versus 64% [95% CI 52 to 76] at 5 years, p = 0.014) and the development of surgical complications after tumor resection (35% [95% CI 11 to 59] versus 68% [95% CI 58 to 78] at 5 years, p = 0.004) were associated with a lower overall survival probability in nonsacral tumors, while a tumor biopsy performed at the same institution where the tumor resection was performed was associated with lower local recurrence probability (14% [95% CI 4 to 24] versus 32% [95% CI 16 to 48] at 5 years, p = 0.035), respectively.In patients with bone tumors who underwent surgical treatment, we found that after controlling for tumor localization in the pelvis, tumor volume, and surgical margin status, patients who did not undergo complete (defined as a Type I/II resection for iliac bone tumors, a Type II/III resection for pubic bone and ischium tumors and a Type I/II/III resection for tumors involving the acetabulum, according to the Enneking classification) removal of the affected bone (HR 5.04 [95% CI 2.07 to 12.24]; p < 0.001), patients with a poor histologic response to induction chemotherapy (HR 3.72 [95% CI 1.51 to 9.21]; p = 0.004), and patients who did not receive additional radiotherapy (HR 4.34 [95% CI 1.71 to 11.05]; p = 0.002) had a higher risk of death. The analysis suggested that the same might be the case in patients with a persistent extraosseous tumor extension after induction chemotherapy (HR 4.61 [95% CI 1.03 to 20.67]; p = 0.046), although the wide CIs pointing at a possible sparse-data bias precluded any definitive conclusions. CONCLUSION: Patients with sacral Ewing's sarcoma appear to have a lower probability for local recurrence and a higher overall survival probability compared with patients with tumors of the innominate bones. Our results seem to support a recent recommendation of the Scandinavian Sarcoma Group to locally treat most sacral Ewing's sarcomas with definitive radiotherapy. Combined surgical resection and radiotherapy appear to be associated with a higher overall survival probability in nonsacral tumors compared with surgery alone, even in patients with a wide resection and a good histologic response to neoadjuvant chemotherapy. Complete removal of the involved bone, as defined above, in patients with nonsacral tumors may be associated with a decreased likelihood of local recurrence and improved overall survival. Persistent extraosseous tumor growth after induction treatment in patients with nonsacral bone tumors undergoing surgical treatment might be an important indicator of poorer overall survival probability, but the possibility of sparse-data bias in our cohort means that this factor should first be validated in future studies. LEVEL OF EVIDENCE: Level III, therapeutic study.

Quantifying skeletal burden in fibrous dysplasia using sodium fluoride PET/CT.

PURPOSE: To quantify Na18F-PET/CT uptake in relation to clinical and biochemical parameters of fibrous dysplasia (FD) severity and healthy bone (HB) metabolism. Secondary aims: comparing normalization for volume of distribution and determining reproducibility of Na18F-PET/CT uptake parameters in HB and FD. Relating Na18F uptake to skeletal burden score (SBS), bisphosphonate therapy and pain measured by Brief Pain Inventory (BPI). METHODS: In a prospective cohort study (n = 20), Na18F-PET/CT parameters of HB and FD were assessed by two independent readers to determine the cutoff defining increased bone uptake, optimized normalization, and interobserver agreement (ICC) and were related to SBS, serum biomarkers, medication, and clinical parameters. RESULTS: Physiological bone standardized uptake value (SUV) was best normalized but displayed large interpatient variation (total range 4.1-13.7 g/mL), with very high interobserver agreement (ICC = 0.964). FD burden defined by patient-specific SUV cutoffs reached near-perfect agreement for SUVpeak (ICC = 0.994) and total lesion fluorination (TLF) (ICC = 0.999). TLF correlated weakly with SBS (R2 = 0.384, p = 0.047). TLF correlated positively with serum alkaline phosphatase (R2 = 0.571, p = 0.004) and procollagen type 1 N-terminal propeptide (R2 = 0.621, p = 0.002), SBS did not (p > 0.06). SBS and TLF both correlated with increased fibroblast growth factor-23 (R2 = 0.596, p = 0.007 and R2 = 0.541, p = 0.015, respectively). TLF was higher in use of bisphosphonates (p = 0.023), SBS was not. Average BPI scores correlated to increased FGF-23 (R2 = 0.535, p = 0.045), work-related BPI scores to higher SBS (R2 = 0.518, p = 0.024), higher TLF (R2 = 0.478, p = 0.036), and higher levels of FGF-23 (R2 = 0.567, p = 0.034). CONCLUSIONS: Individualized Na18F-PET/CT SUV cutoffs reproducibly discriminated HB from FD and were well-normalized. The strong relations of bone formation serum markers with Na18F-PET/CT FD burden measurements suggest clinical relevance over SBS as an adjunct instrument in FD patients. The correlation of both imaging modalities with increased work-related BPI scores also indicates clinical applicability. Moreover, SBS is known to remain stationary irrespective of use of medication, whereas TLF on Na18F-PET/CT was higher in baseline patients using bisphosphonates. This makes Na18F-PET/CT a promising tool to quantitatively measure treatment efficacy in FD.

Denosumab in Patients With Fibrous Dysplasia Previously Treated With Bisphosphonates.

CONTEXT: Fibrous dysplasia/McCune-Albright syndrome (FD/MAS) is a rare bone disorder commonly treated with bisphosphonates, but clinical and biochemical responses may be incomplete. OBJECTIVE: To evaluate the efficacy and tolerability of the receptor activator of nuclear factor-κB ligand inhibitor denosumab in the treatment of patients with FD/MAS refractory to bisphosphonate therapy. DESIGN: Case series. SETTING: Academic center of expertise for rare bone diseases. PATIENTS: Data were collected from 12 consecutive patients with FD/MAS with persistent pain and increased biochemical markers of bone turnover (BTMs) after long-term treatment with bisphosphonates (median, 8.8 years) and were treated with subcutaneous denosumab 60 mg at 3- or 6-month intervals with a follow-up for at least 12 months. MAIN OUTCOME(S): Sustained reduction of BTMs and bone pain. RESULTS: A 60 mg dose of denosumab once every 3 months, but not once every 6 months, induced a sustained reduction of BTMs. After a median treatment period of 15.5 months (range, 12 to 19) serum alkaline phosphatase activity and propeptide of type 1 procollagen levels were respectively reduced from 212 ± 39.4 IU/L to 79 ± 6.0 IU/L (P = 0.004) and from 346.2 ± 111.1 ng/mL to 55.7 ± 16.6 ng/mL (P = 0.023) and normalized in 70% and 75% of patients, respectively. Although not quantitavely measured, 10 patients reported a reduction in bone pain of whom 6 reported complete elimination of pain. Treatment with denosumab was well tolerated. CONCLUSION: Our results indicate that 60 mg of denosumab every 3 months is a promising, well-tolerated treatment of most patients with FD/MAS refractory to bisphosphonate therapy. These results together with those of previously published case reports provide the necessary background for the design of a larger, controlled study.

Can Navigation Improve the Ability to Achieve Tumor-free Margins in Pelvic and Sacral Primary Bone Sarcoma Resections? A Historically Controlled Study.

BACKGROUND: Anatomic and surgical complexity make pelvic and sacral bone sarcoma resections challenging. Positive surgical margins are more likely to occur in patients with pelvic and sacral bone sarcomas than in those with extremity sarcomas and are associated with an increased likelihood of local recurrence. Intraoperative navigation techniques have been proposed to improve surgical accuracy in achieving negative margins, but available evidence is limited to experimental (laboratory) studies and small patient series. Only one small historically controlled study is available. Because we have experience with both approaches, we wanted to assess whether navigation improves our ability to achieve negative resection margins. QUESTIONS/PURPOSES: Are navigated resections for pelvic and sacral primary bone sarcomas better able to achieve adequate surgical margins than nonnavigated resections? METHODS: Thirty-six patients with pelvic or sacral sarcomas treated with intraoperative navigation were retrospectively compared with 34 patients undergoing resections without navigation. All patients underwent resections between 2000 and 2017 with the intention to achieve a wide margin. Patients in the navigation group underwent surgery between 2008 and 2017; during this period, all resections of pelvic and sacral primary bone sarcomas with the intention to achieve a wide margin were navigation-assisted by either CT fluoroscopy or intraoperative CT. Patients in the control group underwent surgery before 2008 (when navigation was unavailable at our institution), to avoid selection bias. We did not attempt to match patients to controls. Nonnavigated resections were performed by two senior orthopaedic surgeons (with 10 years and > 25 years of experience). Navigated resections were performed by a senior orthopaedic surgeon with much experience in surgical navigation. The primary outcome was the bone and soft-tissue surgical margin achieved, classified by a modified Enneking system. Wide margins (≥ 2 mm) and wide-contaminated margins, in which the tumor or its pseudocapsule was exposed intraoperatively but further tissue was removed to achieve wide margins, were considered adequate; marginal (0-2 mm) and intralesional margins were considered inadequate. RESULTS: Adequate bone margins were achieved in more patients in the navigated group than in the nonnavigation group (29 of 36 patients [81%] versus 17 of 34 [50%]; odds ratio, 4.14 [95% CI, 1.43-12.01]; p = 0.007). With the numbers available, we found no difference in our ability to achieve adequate soft-tissue margins between the navigation and nonnavigation group (18 of 36 patients [50%] versus 18 of 34 [54%]; odds ratio, 0.89 [95% CI, 0.35-2.27]; p = 0.995). CONCLUSIONS: Intraoperative guidance techniques improved our ability to achieve negative bony margins when performing surgical resections in patients with pelvic and sacral primary bone sarcomas. Achieving adequate soft-tissue margins remains a challenge, and these margins do not appear to be influenced by navigation. Larger studies are needed to confirm our results, and longer followup of these patients is needed to determine if the use of navigation will improve survival or the risk of local recurrence. LEVEL OF EVIDENCE: Level III, therapeutic study.

What Factors Are Associated With Implant Breakage and Revision After Intramedullary Nailing for Femoral Metastases?

BACKGROUND: Actual and impending pathologic fractures of the femur are commonly treated with intramedullary nails because they provide immediate stabilization with a minimally invasive procedure and enable direct weightbearing. However, complications and revision surgery are prevalent, and despite common use, there is limited evidence identifying those factors that are associated with complications. QUESTIONS/PURPOSES: Among patients treated with intramedullary nailing for femoral metastases, we asked the following questions: (1) What is the cumulative incidence of local complications? (2) What is the cumulative incidence of implant breakage and what factors are associated with implant breakage? (3) What is the cumulative incidence of revision surgery and what factors are associated with revision surgery? METHODS: Between January 2000 and December 2015, 245 patients in five centers were treated with intramedullary nails for actual and impending pathologic fractures of the femur caused by bone metastases. During that period, the general indications for intramedullary nailing of femoral metastases were impending fractures of the trochanter region and shaft and actual fractures of the trochanter region if sufficient bone stock remained; nails were used for lesions of the femoral shaft if they were large or if multiple lesions were present. Of those treated with intramedullary nails, 51% (117) were actual fractures and 49% (111) were impending fractures. A total of 60% (128) of this group were women; the mean age was 65 years (range, 29-93 years). After radiologic followup (at 4-8 weeks) with the orthopaedic surgeon, because of the palliative nature of these treatments, subsequent in-person followup was performed by the primary care provider on an as-needed basis (that is, as desired by the patient, without any scheduled visits with the orthopaedic surgeon) throughout each patient's remaining lifetime. However, there was close collaboration between the primary care providers and the orthopaedic team such that orthopaedic complications would be reported. A total of 67% (142 of 212) of the patients died before 1 year, and followup ranged from 0.1 to 175 months (mean, 14.4 months). Competing risk models were used to estimate the cumulative incidence of local complications (including persisting pain, tumor progression, and implant breakage), implant breakage separately, and revision surgery (defined as any reoperation involving the implant other than débridement with implant retention for infection). A cause-specific multivariate Cox regression model was used to estimate the association of factors (fracture type/preoperative radiotherapy and fracture type/use of cement) with implant breakage and revision, respectively. RESULTS: Local complications occurred in 12% (28 of 228) of the patients and 6-month cumulative incidence was 8% (95% confidence interval [CI], 4.7-11.9). Implant breakage occurred in 8% (18 of 228) of the patients and 6-month cumulative incidence was 4% (95% CI, 1.4-6.5). Independent factors associated with increased risk of implant breakage were an actual (as opposed to impending) fracture (cause-specific hazard ratio [HR_cs], 3.61; 95% CI, 1.23-10.53, p = 0.019) and previous radiotherapy (HR_cs, 2.97; 95% CI, 1.13-7.82, p = 0.027). Revisions occurred in 5% (12 of 228) of the patients and 6-month cumulative incidence was 2.2% (95% CI, 0.3-4.1). The presence of an actual fracture was independently associated with a higher risk of revision (HR_cs, 4.17; 95% CI, 0.08-0.82, p = 0.022), and use of cement was independently associated with a lower risk of revision (HR_cs, 0.25; 95% CI, 1.20-14.53, p = 0.025). CONCLUSIONS: The cumulative incidence of local complications, implant breakage, and revisions is low, mostly as a result of the short survival of patients. Based on these results, surgeons should consider use of cement in patients with intramedullary nails with actual fractures and closer followup of patients after actual fractures and preoperative radiotherapy. Future, prospective studies should further analyze the effects of adjuvant therapies and surgery-related factors on the risk of implant breakage and revisions. LEVEL OF EVIDENCE: Level III, therapeutic study.

Pathologic fractures of the distal femur: Current concepts and treatment options.

Pathologic fractures of the distal femur caused by bone metastases are not as common as those in the proximal femur but provide great difficulty to adequately treat. This systematic review shows that insufficient literature exists to draw clinically relevant conclusions for essential questions, such as "what factors indicate an endoprosthetic reconstruction for distal femur pathologic fractures?" Due to paucity of literature in the systematic review, a current concepts review (including treatment flowchart), based on instructional reviews and experience, was also performed.

Individualized approach to the surgical management of fibrous dysplasia of the proximal femur.

BACKGROUND: Fibrous dysplasia of the proximal femur presents with heterogeneous clinical manifestations dictating different surgical approaches. However, to date there are no clear recommendations to guide the choice of surgical approach and no general guidelines for the optimal orthopedic management of these lesions. The objective of this study was to evaluate treatment outcomes of angled blade plates and intramedullary nails, using as outcome indicators revision-free survival, pain, function and femoral neck-shaft-angle. Based on a review of published literature and our study findings, we propose a treatment algorithm, taking into account different factors, which may play a role in the selection of one surgical approach over another. METHODS: Data were evaluated in thirty-two patients (18 male) from a combined cohort from the Netherlands and Austria, who had a surgical intervention using an angled blade plate (n = 27) or an intramedullary nail (n = 5) between 1985 and 2015, and who had a minimal follow-up of one year. The primary outcome was success of the procedure according to the revised Henderson classification. Secondary outcomes, which were assessed at one year and at the end of follow-up included: function (as measured by walking ability), pain and change in femoral neck-shaft angle over time. RESULTS: Analysis of data showed that revision-free survival was 72% after a median follow-up of 4.1 years. Revision was necessary in two patients for structural failure due to a fracture distal to an angled blade plate and in 7 patients due to angled blade plate-induced iliotibial tract pain. At the end of follow-up 91% of all patients had good walking ability and 91% were pain free. There was no significant postoperative change in femoral neck shaft angle. CONCLUSION: Our data show that fibrous dysplasia of the proximal femur can be adequately and safely treated with angled blade plates or intramedullary nails, providing these are used according to specific characteristics of the individual patient. Based on published literature and our own experience, we propose an individualized, patient-tailored approach for the surgical management of fibrous dysplasia of the proximal femur.

Conventional Primary Central Chondrosarcoma of the Pelvis: Prognostic Factors and Outcome of Surgical Treatment in 162 Patients.

BACKGROUND: Studies focusing on the oncological outcome after treatment of conventional primary central chondrosarcoma of pelvic bone are lacking. We conducted this retrospective study at 5 referral centers to gain insight in the outcome of treatment for this tumor type and to identify risk factors for impaired oncological outcome. METHODS: One hundred and sixty-two consecutive patients (118 male patients [73%]) who underwent resection of a conventional primary central chondrosarcoma of pelvic bone from 1985 to 2013 were evaluated. The median age was 51 years (range, 15 to 78 years). The median follow-up was 12.6 years (95% confidence interval [CI], 8.4 to 16.9 years). There were 30 grade-I lesions (19%), 93 grade-II lesions (57%), and 39 grade-III lesions (24%). RESULTS: Sixty-two patients (38%) experienced local recurrence: 9 grade-I lesions (30%), 31 grade-II lesions (33%), and 22 grade-III lesions (56%). Forty-eight patients (30%) developed metastases. The risk of disease-related death was 3% for grade-I tumors (1 of 30; this patient had a grade-II recurrence and died of metastases), 33% (31 of 93) for grade-II tumors, and 54% (21 of 39) for grade-III tumors. Identified risk factors for impaired disease-specific survival were tumor grade (grade II: hazard ratio [HR], 20.18; p = 0.003; and grade III: HR, 58.94; p < 0.001), resection margins (marginal: HR, 3.21; p = 0.001; and intralesional: HR, 3.56; p < 0.001), and maximal tumor size (HR, 1.08 per cm; p = 0.026). Deep infection (19% [n = 31]) was the predominant complication. CONCLUSIONS: This study offers a standard for survival rates for conventional primary central chondrosarcoma of the pelvis. The survival for grade-I tumors was excellent. Wide resection margins were associated with a significant survival advantage for higher-grade tumors. Because of the inability to reliably distinguish low-grade and high-grade tumors preoperatively, we conclude that any central pelvic chondrosarcoma should be treated with aggressive primary resection with the aim of obtaining wide resection margins. There may be aggressive biologic features in some tumors for which a surgical procedure alone may not be adequate to improve outcomes. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

A prediction model for treatment decisions in high-grade extremity soft-tissue sarcomas: Personalised sarcoma care (PERSARC).

BACKGROUND: To support shared decision-making, we developed the first prediction model for patients with primary soft-tissue sarcomas of the extremities (ESTS) which takes into account treatment modalities, including applied radiotherapy (RT) and achieved surgical margins. The PERsonalised SARcoma Care (PERSARC) model, predicts overall survival (OS) and the probability of local recurrence (LR) at 3, 5 and 10 years. AIM: Development and validation, by internal validation, of the PERSARC prediction model. METHODS: The cohort used to develop the model consists of 766 ESTS patients who underwent surgery, between 2000 and 2014, at five specialised international sarcoma centres. To assess the effect of prognostic factors on OS and on the cumulative incidence of LR (CILR), a multivariate Cox proportional hazard regression and the Fine and Gray model were estimated. Predictive performance was investigated by using internal cross validation (CV) and calibration. The discriminative ability of the model was determined with the C-index. RESULTS: Multivariate Cox regression revealed that age and tumour size had a significant effect on OS. More importantly, patients who received RT showed better outcomes, in terms of OS and CILR, than those treated with surgery alone. Internal validation of the model showed good calibration and discrimination, with a C-index of 0.677 and 0.696 for OS and CILR, respectively. CONCLUSIONS: The PERSARC model is the first to incorporate known clinical risk factors with the use of different treatments and surgical outcome measures. The developed model is internally validated to provide a reliable prediction of post-operative OS and CILR for patients with primary high-grade ESTS. LEVEL OF SIGNIFICANCE: level III.

Higher incidence rates than previously known in tenosynovial giant cell tumors.

Background and purpose - Tenosynovial giant cell tumors (TGCT) are rare, benign tumors, arising in synovial lining of joints, tendon sheaths, or bursae. 2 types are distinguished: localized, either digits or extremity, and diffuse lesions. Current TGCT incidence is based on 1 single US-county study in 1980, with an incidence of 9 and 2 per million person-years in localized (including digits) and diffuse TGCT, respectively. We aim to determine nationwide and worldwide incidence rates (IR) in TGCT affecting digits, localized-extremity TGCT and diffuse-type TGCT. Material and methods - Over a 5-year period, the Dutch Pathology Registry (PALGA) identified 4,503 pathology reports on TGCT. Reports affecting digits were solely used for IR calculations. Reports affecting extremities were clinically evaluated. Dutch IRs were converted to world population IRs. Results - 2,815 (68%) digits, 933 (23%) localized-extremity and 390 (9%) diffuse-type TGCT were identified. Dutch IR in digits, localized-extremity, and diffuse-type TGCT was 34, 11 and 5 per million person-years, respectively. All 3 groups showed a female predilection and highest number of new cases in age category 40-59 years. The knee joint was most often affected: localized-extremity (46%) and diffuse-type (64%) TGCT, mostly treated with open resection: localized (65%) and diffuse (49%). Reoperation rate due to local recurrence for localized-extremity was 9%, and diffuse TGCT 23%. Interpretation - This first nationwide study and detailed analyses of IRs in TGCT estimated a worldwide IR in digits, localized-extremity and diffuse TGCT of 29, 10, and 4 per million person-years, respectively. Recurrence rate in diffuse type is 2.6 times higher, compared with localized extremity. TGCT is still considered a rare disease; however, it is more common than previously understood.

Functional outcome after surgery in patients with bone sarcoma around the knee; results from a long-term prospective study.

BACKGROUND AND OBJECTIVES: In a previous conducted study functional outcome of young patients with bone sarcoma located around the knee was longitudinally evaluated during the first 2 years postoperatively. Functional outcome improved significantly over the first 2 years. The purpose of this descriptive study was to evaluate the functional outcome of these patients at long-term follow-up of 7 years. METHODS: Functional outcome was assessed with the TESS, MSTS, Baecke questionnaire, and three functional performance tests: time up and down stairs (TUDS), various walking activities (VWA), and the 6-min walking test (6MWT). Linear Mixed Model has been employed for the repeated measurements. RESULTS: Twenty patients of the original study (n = 44) participated in the current study. Fifteen limb-salvage and five ablative surgery patients, median follow-up 7.4 years (6.8-8.0) (CI 95%), mean age 22.3 years (18.2-31.6). Between 2 and 7 years after surgery, 8 limb-salvage patients (53%) encountered surgery related complications. Questionnaires and functional performance tests showed no significant difference in functional outcome between 2 years and 7 years after surgery (P < 0.05). CONCLUSIONS: Between 2 years and follow-up at average 7 years after surgery no further improvements were noticed at young patients with a bone sarcoma located around the knee.

Determinants of impaired quality of life in patients with fibrous dysplasia.

BACKGROUND: Fibrous dysplasia is a rare bone disorder, commonly associated with pain, deformity and fractures, which may significantly impact on quality of life. In this study we evaluate quality of life in patients with fibrous dysplasia using the Short Form-36 and the Brief Pain Inventory questionnaires. Data were compared with those of the general Dutch population. RESULTS: Out of 138 patients from a cohort of 255 patients with fibrous dysplasia that were sent questionnaires assessing quality of life and pain, the response rate was 70.3%, with 97 patients, predominantly female (65%), completing the questionnaires. Monostotic fibrous dysplasia was predominant (n = 62, 64%). Fibrous dysplasia patients had significantly lower quality of life outcome scores than the general Dutch population for all tested domains of the Short Form-36 except for the "Mental health" and the "Role emotional" domains. More severe forms of fibrous dysplasia, had the more severe Short-Form-36 quality of life outcomes, but there was no significant difference in Brief Pain Inventory domains between different subtypes of fibrous dysplasia. Quality of life was lower in patients with higher disease burden, as reflected by high skeletal burden scores (p = 0.003) and high levels of P1NP (p = 0.002). CONCLUSION: We demonstrate impairments in all domains of quality of life, except for 'Mental health' and 'Role emotional' domains, across the wide spectrum of fibrous dysplasia including its milder forms. We identified high skeletal burden scores, reflecting disease severity, as the most consistent predictor of impaired quality of life. Our findings hold significant clinical implications as they draw attention to the clinically unmet need to address quality of life issues in the management of patients with all subtypes of fibrous dysplasia, including its milder forms.

Giant cell tumour of bone in the denosumab era.

Giant cell tumour of bone (GCTB) is an intermediate locally aggressive primary bone tumour, occurring mostly at the meta-epiphysis of long bones. Overexpression of receptor activator of nuclear factor kappa-B ligand (RANKL) by mononuclear neoplastic stromal cells promotes recruitment of numerous reactive multinucleated osteoclast-like giant cells, causing lacunar bone resorption. Preferential treatment is curettage with local adjuvants such as phenol, alcohol or liquid nitrogen. The remaining cavity may be filled with bone graft or polymethylmethacrylate (PMMA) bone cement; benefits of the latter are a lower risk of recurrence, possibility of direct weight bearing and early radiographic detection of recurrences. Reported recurrence rates are comparable for the different local adjuvants (27-31%). Factors increasing the local recurrence risk include soft tissue extension and anatomically difficult localisations such as the sacrum. When joint salvage is impossible, en-bloc resection and endoprosthetic joint replacement may be performed. Local tumour control on the one hand and maintenance of a functional native joint and quality of life on the other hand are the main pillars of surgical treatment for this disease. Current knowledge and development in the fields of imaging, functional biology and systemic therapy are forcing us into a paradigm shift from a purely surgical approach towards a multidisciplinary approach. Systemic therapy with denosumab (RANKL inhibitor) or zoledronic acid (bisphosphonates) blocks, respectively inhibits, bone resorption by osteoclast-like giant cells. After use of zoledronic acid, stabilisation of local and metastatic disease has been reported, although the level of evidence is low. Denosumab is more extensively studied in two prospective trials, and appears effective for the optimisation of surgical treatment. Denosumab should be considered in the standard multidisciplinary treatment of advanced GCTB (e.g. cortical destruction, soft tissue extension, joint involvement or sacral localisation) to facilitate surgery at a later stage, and thereby aiming at immediate local control. Even though several questions concerning optimal treatment dose, duration and interval and drug safety remain unanswered, denosumab is among the most effective drug therapies in oncology.

Individualised risk assessment for local recurrence and distant metastases in a retrospective transatlantic cohort of 687 patients with high-grade soft tissue sarcomas of the extremities: a multistate model.

OBJECTIVES: This study investigates the effect of surgical margins and radiotherapy, in the presence of individual baseline characteristics, on survival in a large population of high-grade soft tissue sarcoma of the extremities using a multistate model. DESIGN: A retrospective multicentre cohort study. SETTING: 4 tertiary referral centres for orthopaedic oncology. PARTICIPANTS: 687 patients with primary, non-disseminated, high-grade sarcoma only, receiving surgical treatment with curative intent between 2000 and 2010 were included. MAIN OUTCOME MEASURES: The risk to progress from 'alive without disease' (ANED) after surgery to 'local recurrence' (LR) or 'distant metastasis (DM)/death'. The effect of surgical margins and (neo)adjuvant radiotherapy on LR and overall survival was evaluated taking patients' and tumour characteristics into account. RESULTS: The multistate model underlined that wide surgical margins and the use of neoadjuvant radiotherapy decreased the risk of LR but have little effect on survival. The main prognostic risk factors for transition ANED to LR are tumour size (HR 1.06; 95% CI 1.01 to 1.11 (size in cm)) and (neo)adjuvant radiotherapy. The HRs for patients treated with adjuvant or no radiotherapy compared with neoadjuvant radiotherapy are equal to 4.36 (95% CI 1.34 to 14.24) and 14.20 (95% CI 4.14 to 48.75), respectively. Surgical resection margins had a protective effect for the occurrence of LR with HRs equal to 0.61 (95% CI 0.33 to 1.12), and 0.16 (95% CI 0.07 to 0.41) for margins between 0 and 2 mm and wider than 2 mm, respectively. For transition ANED to distant metastases/Death, age (HR 1.64 (95% CI 0.95 to 2.85) and 1.90 (95% CI 1.09 to 3.29) for 25-50 years and >50 years, respectively) and tumour size (1.06 (95% CI 1.04 to 1.08)) were prognostic factors. CONCLUSIONS: This paper underlined the alternating effect of surgical margins and the use of neoadjuvant radiotherapy on oncological outcomes between patients with different baseline characteristics. The multistate model incorporates this essential information of a specific patient's history, tumour characteristics and adjuvant treatment modalities and allows a more comprehensive prediction of future events.

What Are the Long-term Results of MUTARS® Modular Endoprostheses for Reconstruction of Tumor Resection of the Distal Femur and Proximal Tibia?

BACKGROUND: Modular endoprostheses are commonly used to reconstruct defects of the distal femur and proximal tibia after bone tumor resection. Because limb salvage surgery for bone sarcomas is relatively new, becoming more frequently used since the 1980s, studies focusing on the long-term results of such prostheses in treatment of primary tumors are scarce. QUESTIONS/PURPOSES: (1) What proportion of patients experience a mechanical complication with the MUTARS® modular endoprosthesis when used for tumor reconstruction around the knee, and what factors may be associated with mechanical failure? (2) What are the nonmechanical complications? (3) What are the implant failure rates at 5, 10, and 15 years? (4) How often is limb salvage achieved using this prosthesis? METHODS: Between 1995 and 2010, endoprostheses were the preferred method of reconstruction after resection of the knee in adolescents and adults in our centers. During that period, we performed 114 MUTARS® knee replacements in 105 patients; no other endoprosthetic systems were used. Four patients (four of 105 [4%]) were lost to followup, leaving 110 reconstructions in 101 patients for review. The reverse Kaplan-Meier method was used to calculate median followup, which was equal to 8.9 years (95% confidence interval [CI], 8.0-9.7). Mean age at surgery was 36 years (range, 13-82 years). Predominant diagnoses were osteosarcoma (n = 56 [55%]), leiomyosarcoma of bone (n = 10 [10%]), and chondrosarcoma (n = 9 [9%]). In the early period of our study, we routinely used uncemented uncoated implants for primary reconstructions. Later, hydroxyapatite (HA)-coated implants were the standard. Eighty-nine reconstructions (89 of 110 [81%]) were distal femoral replacements (78 uncemented [78 of 89 {88%}, 42 of which were HA-coated [42 of 78 {54%}]) and 21 (21 of 110 [19%]) were proximal tibial replacements. In 26 reconstructions (26 of 110 [24%]), the reconstruction was performed for a failed previous reconstruction. We used a competing risk model to estimate the cumulative incidence of implant failure. RESULTS: Complications of soft tissue or instability occurred in seven reconstructions (seven of 110 [6%]). With the numbers we had, for uncemented distal femoral replacements, we could not detect a difference in loosening between revision (five of 17 [29%]) and primary reconstructions (eight of 61 [13%]) (hazard ratio [HR], 1.72; 95% CI, 0.55-5.38; p = 0.354). Hydroxyapatite-coated uncemented implants had a lower risk of loosening (two of 42 [5%]) than uncoated uncemented implants (11 of 36 [31%]) (HR, 0.23; 95% CI, 0.05-1.06; p = 0.060). Structural complications occurred in 15 reconstructions (15 of 110 [14%]). Infections occurred in 14 reconstructions (14 of 110 [13%]). Ten patients had a local recurrence (10 of 101 [10%]). With failure for mechanical reasons as the endpoint, the cumulative incidences of implant failure at 5, 10, and 15 years were 16.9% (95% CI, 9.6-24.2), 20.7% (95% CI, 12.5-28.8%), and 37.9% (95% CI, 16.1-59.7), respectively. We were able to salvage some of the failures so that at followup, 90 patients (90 of 101 [89%]) had a MUTARS® in situ. CONCLUSIONS: Although no system has yet proved ideal to restore normal function and demonstrate long-term retention of the implant, MUTARS® modular endoprostheses represent a reliable long-term option for knee replacement after tumor resection, which seems to be comparable to other modular implants available to surgeons. Although the number of patients is relatively small, we could demonstrate that with this prosthesis, an uncemented HA-coated implant is useful in achieving durable fixation. LEVEL OF EVIDENCE: Level IV, therapeutic study.

LUMiC® Endoprosthetic Reconstruction After Periacetabular Tumor Resection: Short-term Results.

BACKGROUND: Reconstruction of periacetabular defects after pelvic tumor resection ranks among the most challenging procedures in orthopaedic oncology, and reconstructive techniques are generally associated with dissatisfying mechanical and nonmechanical complication rates. In an attempt to reduce the risk of dislocation, aseptic loosening, and infection, we introduced the LUMiC® prosthesis (implantcast, Buxtehude, Germany) in 2008. The LUMiC® prosthesis is a modular device, built of a separate stem (hydroxyapatite-coated uncemented or cemented) and acetabular cup. The stem and cup are available in different sizes (the latter of which is also available with silver coating for infection prevention) and are equipped with sawteeth at the junction to allow for rotational adjustment of cup position after implantation of the stem. Whether this implant indeed is durable at short-term followup has not been evaluated. QUESTIONS/PURPOSES: (1) What proportion of patients experience mechanical complications and what are the associated risk factors of periacetabular reconstruction with the LUMiC® after pelvic tumor resection? (2) What proportion of patients experience nonmechanical complications and what are the associated risk factors of periacetabular reconstruction with the LUMiC® after pelvic tumor resection? (3) What is the cumulative incidence of implant failure at 2 and 5 years and what are the mechanisms of reconstruction failure? (4) What is the functional outcome as assessed by Musculoskeletal Tumor Society (MSTS) score at final followup? METHODS: We performed a retrospective chart review of every patient in whom a LUMiC® prosthesis was used to reconstruct a periacetabular defect after internal hemipelvectomy for a pelvic tumor from July 2008 to June 2014 in eight centers of orthopaedic oncology with a minimum followup of 24 months. Forty-seven patients (26 men [55%]) with a mean age of 50 years (range, 12-78 years) were included. At review, 32 patients (68%) were alive. The reverse Kaplan-Meier method was used to calculate median followup, which was equal to 3.9 years (95% confidence interval [CI], 3.4-4.3). During the period under study, our general indications for using this implant were reconstruction of periacetabular defects after pelvic tumor resections in which the medial ilium adjacent to the sacroiliac joint was preserved; alternative treatments included hip transposition and saddle or custom-made prostheses in some of the contributing centers; these were generally used when the medial ilium was involved in the tumorous process or if the LUMiC® was not yet available in the specific country at that time. Conventional chondrosarcoma was the predominant diagnosis (n = 22 [47%]); five patients (11%) had osseous metastases of a distant carcinoma and three (6%) had multiple myeloma. Uncemented fixation (n = 43 [91%]) was preferred. Dual-mobility cups (n = 24 [51%]) were mainly used in case of a higher presumed risk of dislocation in the early period of our study; later, dual-mobility cups became the standard for the majority of the reconstructions. Silver-coated acetabular cups were used in 29 reconstructions (62%); because only the largest cup size was available with silver coating, its use depended on the cup size that was chosen. We used a competing risk model to estimate the cumulative incidence of implant failure. RESULTS: Six patients (13%) had a single dislocation; four (9%) had recurrent dislocations. The risk of dislocation was lower in reconstructions with a dual-mobility cup (one of 24 [4%]) than in those without (nine of 23 [39%]) (hazard ratio, 0.11; 95% CI, 0.01-0.89; p = 0.038). Three patients (6%; one with a preceding structural allograft reconstruction, one with poor initial fixation as a result of an intraoperative fracture, and one with a cemented stem) had loosening and underwent revision. Infections occurred in 13 reconstructions (28%). Median duration of surgery was 6.5 hours (range, 4.0-13.6 hours) for patients with an infection and 5.3 hours (range, 2.8-9.9 hours) for those without (p = 0.060); blood loss was 2.3 L (range, 0.8-8.2 L) for patients with an infection and 1.5 L (range, 0.4-3.8 L) for those without (p = 0.039). The cumulative incidences of implant failure at 2 and 5 years were 2.1% (95% CI, 0-6.3) and 17.3% (95% CI, 0.7-33.9) for mechanical reasons and 6.4% (95% CI, 0-13.4) and 9.2% (95% CI, 0.5-17.9) for infection, respectively. Reasons for reconstruction failure were instability (n = 1 [2%]), loosening (n = 3 [6%]), and infection (n = 4 [9%]). Mean MSTS functional outcome score at followup was 70% (range, 33%-93%). CONCLUSIONS: At short-term followup, the LUMiC® prosthesis demonstrated a low frequency of mechanical complications and failure when used to reconstruct the acetabulum in patients who underwent major pelvic tumor resections, and we believe this is a useful reconstruction for periacetabular resections for tumor or failed prior reconstructions. Still, infection and dislocation are relatively common after these complex reconstructions. Dual-mobility articulation in our experience is associated with a lower risk of dislocation. Future, larger studies will need to further control for factors such as dual-mobility articulation and silver coating. We will continue to follow our patients over the longer term to ascertain the role of this implant in this setting. LEVEL OF EVIDENCE: Level IV, therapeutic study.

Lack of clinical evidence for postoperative radiotherapy after surgical fixation of impending or actual pathologic fractures in the long bones in patients with cancer; a systematic review.

Patients with disseminated cancer and bone metastases have a limited life expectancy and therefore any treatment should have a clear beneficial effect, outweighing all possible downsides. This systematic review aims to identify and evaluate available evidence regarding function, pain, quality of life, survival and complications of postoperative radiotherapy (RT) after surgical stabilization of impending or actual pathologic fractures of the long bones due to bone metastases. A literature search resulted in two articles reporting on 64 and 110 patients of whom 55% and 28% received postoperative RT, respectively. Both studies were retrospective cohort studies and postoperative RT had been administered depending on the surgeons' choice. The first study reported better outcomes regarding function, re-interventions and survival in patients receiving postoperative RT. The second study reported no significant difference regarding complications between the two groups. The quality of the evidence was very low due to the observational character of both studies, risk of indication bias, small study sizes, use of non-standardized outcome measures, and limited statistical analyses. The current available literature is insufficient to conclude whether postoperative RT after surgical stabilization should be standard care. It is important to realize this lack of clear evidence when calling upon RT as adjuvant palliative treatment.