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Background: Adolescents and young adults (AYAs) with Ewing sarcoma have a worse prognosis than children. Population-based survival evaluations stratifying findings by important clinical factors are, however, limited. This Dutch population study comprehensively compared survival of children and AYAs with Ewing sarcoma over three decades considering diagnostic period, tissue of origin, tumor site, and disease stage., Methods: Data on all children (0-17 years, N = 463) and AYAs (18-39 years, N = 379) diagnosed with Ewing sarcoma in the Netherlands between 1990-2018 were collected from the Netherlands Cancer Registry with follow-up until February 2023. Five-year relative survival was calculated using the cohort method. Multivariable analyses were conducted through Poisson regression., Results: Children with Ewing sarcoma had a significantly higher 5-year relative survival than AYAs (65 % vs. 44 %). An increasing trend in survival was noted reaching 70 % in children and 53 % in AYAs in 2010-2018. Results were similar for Ewing bone sarcoma and extraosseous Ewing sarcoma. AYAs had a poorer prognosis than children for most tumor sites and regardless of disease stage. Survival probabilities were 60 % vs. 78 % for localized disease and 20 % vs. 33 % for metastatic disease. Multivariable-regression analysis, adjusted for follow-up time, diagnostic period, sex, disease stage, and tumor site, confirmed increased excess mortality among AYAs compared with children (excess HR: 1.7, 95 % CI: 1.3-2.1)., Conclusions: Despite survival improvements since the 1990s, AYAs with Ewing sarcoma in the Netherlands continue to fare considerably worse than children. This survival disparity was present irrespective of tissue of origin, tumor site, and disease stage., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Osteosarcoma and Ewing sarcoma are bone tumors mostly diagnosed in children, adolescents, and young adults. Despite multimodal therapy, morbidity is high and survival rates remain low, especially in the metastatic disease setting. Trials investigating targeted therapies and immunotherapies have not been groundbreaking. Better understanding of biological subgroups, the role of the tumor immune microenvironment, factors that promote metastasis, and clinical biomarkers of prognosis and drug response are required to make progress. A prerequisite to achieve desired success is a thorough, systematic, and clinically linked biological analysis of patient samples, but disease rarity and tissue processing challenges such as logistics and infrastructure have contributed to a lack of relevant samples for clinical care and research. There is a need for a Europe-wide framework to be implemented for the adequate and minimal sampling, processing, storage, and analysis of patient samples. Two international panels of scientists, clinicians, and patient and parent advocates have formed the Fight Osteosarcoma Through European Research consortium and the Euro Ewing Consortium. The consortia shared their expertise and institutional practices to formulate new guidelines. We report new reference standards for adequate and minimally required sampling (time points, diagnostic samples, and liquid biopsy tubes), handling, and biobanking to enable advanced biological studies in bone sarcoma. We describe standards for analysis and annotation to drive collaboration and data harmonization with practical, legal, and ethical considerations. This position paper provides comprehensive guidelines that should become the new standards of care that will accelerate scientific progress, promote collaboration, and improve outcomes., (©2024 The Authors; Published by the American Association for Cancer Research.)

Osteosarcoma is a primary bone tumor that exhibits a complex genomic landscape characterized by gross chromosomal abnormalities. Osteosarcoma patients often develop metastatic disease, resulting in limited therapeutic options and poor survival rates. To gain knowledge on the mechanisms underlying osteosarcoma heterogeneity and metastatic process, it is important to obtain a detailed profile of the genomic alterations that accompany osteosarcoma progression. We performed WGS on multiple tissue samples from six patients with osteosarcoma, including the treatment naïve biopsy of the primary tumor, resection of the primary tumor after neoadjuvant chemotherapy, local recurrence, and distant metastases. A comprehensive analysis of single-nucleotide variants (SNVs), structural variants, copy number alterations (CNAs), and chromothripsis events revealed the genomic heterogeneity during osteosarcoma progression. SNVs and structural variants were found to accumulate over time, contributing to an increased complexity of the genome of osteosarcoma during disease progression. Phylogenetic trees based on SNVs and structural variants reveal distinct evolutionary patterns between patients, including linear, neutral, and branched patterns. The majority of osteosarcomas showed variable copy number profiles or gained whole-genome doubling in later occurrences. Large proportions of the genome were affected by loss of heterozygosity (LOH), although these regions remain stable during progression. Additionally, chromothripsis is not confined to a single early event, as multiple other chromothripsis events may appear in later occurrences. Together, we provide a detailed analysis of the complex genome of osteosarcomas and show that five of six osteosarcoma genomes are highly dynamic and variable during progression., (© 2024 The Author(s). Genes, Chromosomes and Cancer published by Wiley Periodicals LLC.)

Current prediction models for patients with ostosarcoma are restricted to predictions from a single, static point in time, such as diagnosis or surgery. These approaches discard information which becomes available during follow-up and may have an impact on patient's prognosis. This study aims at developing a dynamic prediction model providing 5-year overall survival (OS) predictions from different time points during follow-up. The developed model considers relevant baseline prognostic factors, accounting for where appropriate time-varying effects and time-varying intermediate events such as local recurrence (LR) and new metastatic disease (NM). A landmarking approach is applied to 1965 patients with high-grade resectable osteosarcoma from the EURAMOS-1 trial (NCT00143030). Results show that LR and NM negatively affected 5-year OS (HRs: 2.634, 95% CI 1.845-3.761; 8.558, 95% CI 7.367-9.942, respectively). Baseline factors with strong prognostic value (HRs > 2) included poor histological response (≥10% viable tumor), axial tumor location, and the presence of lung metastases. The effect of poor versus good histological response changed over time, becoming non-significant from 3.25 years post-surgery onwards. This time-varying effect, as well as the strong impact of disease-related time-varying variables, show the importance of including updated information collected during follow-up in the model to provide more accurate survival predictions.

Introduction: Chordomas are rare malignant bone tumors arising in the axial skeleton, with an incidence of 0.3-0.88 per million inhabitants. We studied the annual incidence rate and centralization of treatment for chordoma in the Netherlands., Methods: We retrieved pathology excerpts from the PALGA nationwide Dutch Pathology Registry between 1991 and 2019 for patients with a chordoma to calculate incidence rates. From pathology reports we extracted patient age at diagnosis, sex, year of diagnosis, localization of primary tumor, histologic chordoma subtype (conventional including chondroid, poorly differentiated or dedifferentiated), center of diagnosis (bone tumor referral center (BTC) or other hospital), and partial identification of the BTCs., Results: A total of 420 individual chordoma patients were identified in the given time period. The incidence of chordoma increased from 0.593 per million inhabitants between 1991-1995 to 1.111 from 2015-2019 (P = 0.001). Median age at diagnosis was 63 years (range 1-95), 252 patients (60%) were male. The proportion of samples analyzed in a BTC either primarily or secondary, as a consultation, revision or referral, increased significantly from 29.3% to 84.4% (P < 0.001). Most primary and secondary samples were analyzed at the Leiden University Medical Center (LUMC, 54.4% and 57% respectively)., Conclusions: This study shows an increase in the standardized incidence of pathology proven chordoma in the Netherlands. We observed an increase in samples being analysed in the specialized BTCs as well, which is in line with current guidelines and will hopefully lead to more accurate diagnoses and optimal treatment plans for chordoma patients in specialized treatment centers., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: To identify which dynamic contrast-enhanced (DCE-)MRI features best predict histological response to neoadjuvant chemotherapy in patients with an osteosarcoma., Methods: Patients with osteosarcoma who underwent DCE-MRI before and after neoadjuvant chemotherapy prior to resection were retrospectively included at two different centers. Data from the center with the larger cohort (training cohort) was used to identify which method for region-of-interest selection (whole slab or focal area method) and which change in DCE-MRI features (time to enhancement, wash-in rate, maximum relative enhancement and area under the curve) gave the most accurate prediction of histological response. Models were created using logistic regression and cross-validated. The most accurate model was then externally validated using data from the other center (test cohort)., Results: Fifty-five (27 poor response) and 30 (19 poor response) patients were included in training and test cohorts, respectively. Intraclass correlation coefficient of relative DCE-MRI features ranged 0.81-0.97 with the whole slab and 0.57-0.85 with the focal area segmentation method. Poor histological response was best predicted with the whole slab segmentation method using a single feature threshold, relative wash-in rate <2.3. Mean accuracy was 0.85 (95%CI: 0.75-0.95), and area under the receiver operating characteristic curve (AUC-index) was 0.93 (95%CI: 0.86-1.00). In external validation, accuracy and AUC-index were 0.80 and 0.80., Conclusion: In this study, a relative wash-in rate of <2.3 determined with the whole slab segmentation method predicted histological response to neoadjuvant chemotherapy in osteosarcoma. Consistent performance was observed in an external test cohort., (© 2023. The Author(s).)

Purpose: The phase III, open-label, prospective, multicenter, randomized Ewing 2008R1 trial (EudraCT2008-003658-13) was conducted in 12 countries to evaluate the effect of zoledronic acid (ZOL) maintenance therapy compared with no add-on regarding event-free survival (EFS, primary endpoint) and overall survival (OS) in standard-risk Ewing sarcoma (EWS)., Patients and Methods: Eligible patients had localized EWS with either good histologic response to induction chemotherapy and/or small tumors (<200 mL). Patients received six cycles of VIDE induction and eight cycles of VAI (male) or eight cycles of VAC (female) consolidation. ZOL treatment started parallel to the sixth consolidation cycle. Randomization was stratified by tumor site (pelvis/other). The two-sided adaptive inverse-normal four-stage design (planned sample size 448 patients, significance level 5%, power 80%) was changed after the first interim analysis using the Müller-Schäfer method., Results: Between April 2010 and November 2018, 284 patients were randomized (142 ZOL/142 no add-on). With a median follow-up of 3.9 years, EFS was not significantly different between ZOL and no add-on group in the adaptive design (HR, 0.74; 95% CI, 0.43-1.28, P = 0.27, intention-to-treat). Three-year EFS rates were 84.0% (95% CI, 77.7%-90.8%) for ZOL vs. 81.7% (95% CI, 75.2%-88.8%) for no add-on. Results were similar in the per-protocol collective. OS was not different between groups. The 3-year OS was 92.8% (95% CI, 88.4%-97.5%) for ZOL and 94.6% (95% CI, 90.9%-98.6%) for no add-on. Noticeable more renal, neurologic, and gastrointestinal toxicities were observed for ZOL (P < 0.05). Severe renal toxicities occurred more often in the ZOL arm (P = 0.003)., Conclusions: In patients with standard-risk localized EWS, there is no additional benefit from maintenance treatment with ZOL., (©2023 American Association for Cancer Research.)

Background: Since giant cell tumors of bone (GCTB) and other giant cell rich tumors of bone (GCRTB) share the histological presence of osteoclastic giant cells and expression of RANK/RANKL, we hypothesized that GCRTB will respond similarly to denosumab as GCTB. The primary objective of this study was to determine the efficacy of denosumab in patients with GCRTB that have recurred or require morbid surgery., Methods: In this open-label, multicenter, phase II trial, patients with GCRTB were included (June 2018-March 2020). Recruitment was stopped because of low accrual. Patients received denosumab (120 mg) subcutaneously (SC) on day 1 of every 4-week cycle with a loading dose of 120 mg SC on days 8 and 15., Results: Three patients were enrolled. One withdrew consent before start of study. The remaining patients had central giant cell granuloma of the jawbone (CGCG). Median treatment duration was 15 cycles (range 12-18). In both subjects, improvement in ossification of lesions was seen. Median follow-up was 28.5 months (range 20-37). One patient developed a recurrence for which surgery was performed., Conclusion: Due to critical emerging real-world data of denosumab in GCRTBs, the study was prematurely stopped and not supportive of use of denosumab for this indication. (ClinicalTrials.gov Identifier: NCT03605199)., (© The Author(s) 2023. Published by Oxford University Press.)

Background: Patients with osteosarcoma (OS) and Ewing sarcoma (ES) are considered to have a high venous thromboembolism (VTE) risk, although the exact incidence and prognostic impact are under-researched in general as well as in relevant age groups., Aims: To study the impact of VTE and major bleeding (MB) in OS and ES patients, subdivided in children, Adolescents Young Adults (AYAs; aged 18-39) and older adults., Methods: Retrospective single-center chart review in 519 OS and 165 ES patients treated between 1980 and 2018. Patients were followed from sarcoma diagnosis until an outcome of interest (VTE, MB) or death occurred. Cumulative incidences were estimated with death as competing risk. Cox models were used to determine prognostic impact., Results: Five-year cumulative incidences of VTE were 12 % (95%CI 9.1-15) for OS and 6.7 % (95%CI 3.5-11) for ES patients, mostly happening in patients ≥18 years; the most frequent VTE presentation was catheter-related upper-extremity thrombosis (OS: 18/65, ES: 7/11). Five-year cumulative incidences for MB were 5.8 % (95%CI 4.0-8.1) in OS and 5.4 % (95%CI 2.5-9.8) in ES patients. 192 OS and 77 ES AYAs were included, who faced similar VTE and MB incidences as older adults. In OS, VTE and MB were both associated with mortality (adjusted HRs 2.0 [95%CI 1.4-2.9] and 2.4 [95%CI 1.4-4.0], respectively), whereas in ES this association was only present for MB (aHR 3.4 [95%CI 1.2-9.6])., Conclusions: VTE is a frequent complication in adult OS and to a lesser extent in ES patients, while the rate of MB was comparably high in both sarcoma types., Competing Interests: Declaration of competing interest F.A.K. has received research support from Bayer, BMS, BSCI, MSD, Leo Pharma, Actelion, The Netherlands Organisation for Health Research and Development, The Dutch Thrombosis Association, The Dutch Heart Foundation and the Horizon Europe Program, all paid to his institution and independent of the current work. M.V.H. reports unrestricted grant support from The Netherlands Organisation for Health Research and Development (ZonMW), and unrestricted grant support and fees for presentations from Boehringer-Ingelheim, Pfizer-BMS, Bayer Health Care, Aspen, Daiichi-Sankyo, all outside the submitted work. The other authors have no conflicts of interest to declare., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: In all giant-cell-rich lesions (GCRL) occurring in bone, a common underlying excessive RANKL expression is held responsible for the osteolytic activity. Apart from giant cell tumour of bone (GCTB), systematic outcome analysis of RANKL inhibition in other GCRL is unavailable. The aim of this study is to assess the efficacy and safety of a 1-year denosumab protocol in giant cell lesions of the jaw (GCLJ)., Methods: A retrospective cohort study was conducted compromising patients treated with a 1-year protocol of monthly subcutaneously administered 120 mg denosumab. Objective tumour response based on histology and imaging was used to calculate objective tumour response rate, progression-free survival (PFS) and time to progression. Type, severity and frequency of adverse events were recorded in a standardised way to assess safety., Results: Twenty patients, predominantly female (90%), were included. Fifty-five per cent of lesions were located in the mandible; most classified as aggressive lesions (90%). Thirty-five per cent (7/20) of cases were either recurrent after prior treatment or progressive, while on other drug treatment. Objective tumour response rate was 100% after 12 months of treatment. Median PFS was 50.4 months (95% CI 38.0-62.8) with a cumulative PFS rate of 22.6% (95% CI 1.8-43.4) at 5 years follow-up. Median time to progression was 38.4 months (95% CI 26.0-50.8). Treatment was well tolerated, and none of the patients had to interrupt therapy for toxicity., Conclusion: High-dose denosumab is effective and safe in achieving a complete response in GCLJ within 12 months. The high long-term relapse rate after treatment cessation is the main obstacle for denosumab to become standard treatment for GCLJ., Competing Interests: Conflict of interest statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Internationally, a single standard chemotherapy treatment for Ewing sarcoma is not defined. Because different chemotherapy regimens were standard in Europe and the USA for newly diagnosed Ewing sarcoma, and in the absence of novel agents to investigate, we aimed to compare these two strategies., Methods: EURO EWING 2012 was a European investigator-initiated, open-label, randomised, controlled phase 3 trial done in 10 countries. We included patients aged 2-49 years, with any histologically and genetically confirmed Ewing sarcoma of bone or soft tissue, or Ewing-like sarcomas. The eligibility criteria originally excluded patients with extrapulmonary metastatic disease, but this was amended in the protocol (version 3.0) in September, 2016. Patients were randomly assigned (1:1) to either the European regimen of vincristine, ifosfamide, doxorubicin, and etoposide induction, and consolidation using vincristine, actinomycin D, with ifosfamide or cyclophosphamide, or busulfan and melphalan (group 1); or the US regimen of vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide induction, plus ifosfamide and etoposide, and consolidation using vincristine and cyclophosphamide, or vincristine, actinomycin D, and ifosfamide, with busulfan and melphalan (group 2). All drugs were administered intravenously. The primary outcome measure was event-free survival. We used a Bayesian approach for the design, analysis, and interpretation of the results. Patients who received at least one dose of study treatment were considered in the safety analysis. The trial was registered with EudraCT, 2012-002107-17, and ISRCTN, 54540667., Findings: Between March 21, 2014, and May 1, 2019, 640 patients were entered into EE2012, 320 (50%) randomly allocated to each group. Median follow-up of surviving patients was 47 months (range 0-84). Event-free survival at 3 years was 61% with group 1 and 67% with group 2 (adjusted hazard ratio [HR] 0·71 [95% credible interval 0·55-0·92 in favour of group 1). The probability that the true HR was less than 1·0 was greater than 0·99. Febrile neutropenia as a grade 3-5 treatment toxicity occurred in 234 (74%) patients in group 1 and in 183 (58%) patients in group 2. More patients in group 1 (n=205 [64%]) required at least one platelet transfusion compared with those in group 2 (n=138 [43%]). Conversely, more patients required blood transfusions in group 2 (n=286 [89%]) than in group 1 (n=277 [87%])., Interpretation: Dose-intensive chemotherapy with vincristine, doxorubicin, cyclophosphamide, ifosfamide, and etoposide is more effective, less toxic, and shorter in duration for all stages of newly diagnosed Ewing sarcoma than vincristine, ifosfamide, doxorubicin, and etoposide induction and should now be the standard of care for Ewing sarcoma., Funding: The European Union's Seventh Framework Programme for Research, Technological Development, and Demonstration; The National Coordinating Centre in France, Centre Léon Bérard; SFCE; Ligue contre le cancer; Cancer Research UK., Competing Interests: Declaration of interests SS has received honoraria and consulting fees from GSK, Lilly, and Ceridwen Oncology. JM-B reports institutional grants from Adaptimmune, Amgen, AROG, Bayer, Blueprint, Bristol Myers Squibb, Celgene, Daichii-Sankyo, Deciphera, Eisai, FORMA, GSK, IMMIX Biopharma, Karyopharm, Lilly, Nektar, Novartis, Pfizer, and PharmaMar; honoraria from PharmaMar and Tecnofarma; payment for expert testimony from Bayer, Eisai, Lilly, and PharmaMar; support for attending meetings and travel from PharmaMar and Asofarma; and participation on a data safety monitoring board or advisory board for Asofarma, PharmaMar, Boheringer, Tecnofarma, Roche, and Bayer. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Recently, we performed a meta-analysis based on a literature review for STS trials (published 2003-2018, ≥10 adult patients) to update long-standing reference values for leiomyosarcomas. This work is extended for liposarcomas (LPS) and synovial sarcomas (SS)., Materials and Methods: Study endpoints were progression-free survival rates (PFSRs) at 3 and 6 months. Trial-specific estimates were pooled per treatment line (first-line or pre-treated) with random effects meta-analyses. The choice of the therapeutic benefit to target in future trials was guided by the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS)., Results: Information was acquired for 1030 LPS patients (25 trials; 7 first-line, 17 pre-treated, 1 both) and 348 SS patients (13 trials; 3 first-line, 10 pre-treated). For LPS, the overall pooled first-line PFSRs were 69% (95%-CI 60-77%) and 56% (95%-CI 45-67%) at 3 and 6 months, respectively. These rates were 49% (95%-CI 40-57%)/28% (95%-CI 22-34%) for &gt;1 lines. For SS, first-line PFSRs were 74% (95%-CI 58-86%)/56% (95%-CI 31-78%) at 3 and 6 months, and pre-treated rates were 45% (95%-CI 34-57%)/25% (95%-CI 16-36%). Following ESMO-MCBS guidelines, the minimum values to target are 79% and 69% for first-line LPS (82% and 69% for SS) at 3 and 6 months. For pre-treated LPS, recommended PFSRs at 3 and 6 months suggesting drug activity are 63% and 44% (60% and 41% for SS)., Conclusions: New benchmarks are proposed for advanced/metastatic LPS or SS to design future histology-specific phase II trials. More data are needed to provide definitive thresholds for the different LPS subtypes., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: J.-Y.B. has reported research support and honoraria from GSK Adaptimmune, Pharmamar, and Novartis; all outside the scope of this article. S.S. has reported personal financial interests (honoraria, consultancy, or advisory role) for Aadi, Bavarian Nordic, Bayer, Boeringher, Daiichi Sankyo, Deciphera, Epizyme, Glaxo, Ikena, Maxivax, Novartis, Pharmamar, Rainthera, and Servier; institutional financial interests with Advenchen, Amgen Dompè, Bayer, Daiichi Sankyo, Deciphera, Epizyme, Eli Lilly, Glaxo, Inhibrix, Hutchinson, Karyopharm, Novartis, Pfizer, Pharmamar, RainThera, and Springworks; all outside the scope of the submitted work. L.D'.A. has reported advisory board for PSI CRO Italy, GSK, AstraZenca, and Eisai; received travel support for meeting participation from Pharmamar, Eli Lilly, Celgene, and AstraZeneca; all outside the submitted article. W.G. has reported advisory role for Bayer, GSK, Springworks and PTC Therapeutics; received research grant support to the Institute from Eli Lilly; all outside the submitted work. All remaining authors have declared no conflicts of interest., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: No prospective trial with anthracycline-based chemotherapy has individually assessed response in a well-differentiated (WD)/dedifferentiated (DD) liposarcoma patient cohort. We conducted a retrospective analysis of first-line chemotherapy in liposarcoma of intra-abdominal origin (IA-LPS) in patients who had entered the European Organisation for Research and Treatment of Cancer (EORTC)/Soft Tissue and Bone Sarcoma Group (STBSG) trials., Methods: We searched for all adult patients treated with first-line chemotherapy for advanced IA-LPS in the EORTC STBSG phase 2 and 3 trials from 1978. Treatment was aggregated into 5 groups: anthracycline alone, ifosfamide alone, doxorubicin plus ifosfamide (D+IFO), doxorubicin/cyclophosphamide/vincristine/dacarbazine, and "other" (brostallicin, trabectedin). Response was assessed prospectively by Response Evaluation Criteria in Solid Tumors or World Health Organization criteria. Progression-free survival (PFS) and overall survival (OS) were computed by Kaplan-Meier method., Results: A total of 109 patients with IA-LPS from 13 trials were identified (104 evaluable for response). Overall, there were 10/109 (9.2%) responders: 3/48 (6.3%) in the anthracycline alone group, 2/15 (13%) in the ifosfamide alone group, and 4/18 (22%) in the D+IFO group. At the 10-month median follow-up (interquartile range, 6-24), the median OS was 19 months (95% CI, 15-21) and median PFS 4 months (95% CI, 3-6). D+IFO achieved a not statistically significant longer median PFS (12 months) and median OS (31 months) than observed with other regimens. Univariate/multivariate analysis did not identify prognostic factors., Conclusions: Cytotoxic chemotherapy, in particular anthracycline alone, had marginal activity in advanced IA-LPS. Ifosfamide-containing regimens showed higher activity, although it was not statistically significant and in a small number of cases, with the combination of doxorubicin and ifosfamide appearing to be the more active regimen available in fit patients. This series provides a benchmark for future trials on new drugs in WD/DD liposarcoma., (© 2022 American Cancer Society.)

Purpose of Review: Giant cell tumors of bone (GCTB) are intermediate, locally aggressive primary bone tumors. For conventional GCTB, surgery remains treatment of choice. For advanced GCTB, a more important role came into play for systemic therapy including denosumab and bisphosphonates over the last decade., Recent Findings: In diagnostics, focus has been on H3F3A (G34) driver mutations present in GCTB. The most frequent mutation (G34W) can be detected using immunohistochemistry and is highly specific in differentiating GCTB from other giant cell containing tumors. PD-L1 expression can be used as biological marker to predict higher recurrence risks in GCTB patients.The use of bisphosphonate-loaded bone cement is under investigation in a randomized controlled trial. A new technique consisting of percutaneous microwave ablation and bisphosphonate-loaded polymethylmethacrylate cementoplasty was proposed for unresectable (pelvic) GCTB.Increased experience with use of denosumab raised concern on elevated recurrence rates. However, conclusions of meta-analyses should be interpreted with risk of indication bias in mind. Several small studies are published with short-course denosumab (varying from 3 to 6 doses). One small trial directly compared denosumab and zoledronic acid, with no statistical differences in radiological and clinical outcome, and nonsignificantly higher recurrence rate after denosumab. As bisphosphonates directly target neoplastic stromal cells in GCTB, larger directly comparative trials are still warranted., Summary: Neoadjuvant denosumab is highly effective for advanced GCTB, and a short-course is advised to facilitate surgery, whereas increased recurrence rates remain of concern. Randomized controlled trials are conducted on bisphosphonate-loaded bone cement and on optimal dose and duration of neoadjuvant denosumab. PD-L1 could be a potential new therapy target in GCTB., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

The phase III clinical study of adjuvant liposomal muramyl tripeptide (MTP-PE) in resected high-grade osteosarcoma (OS) documented positive results that have been translated into regulatory approval, supporting initial promise for innate immune therapies in OS. There remains, however, no new approved treatment such as MTP-PE for either metastatic or recurrent OS. Whilst the addition of different agents, including liposomal MTP-PE, to surgery for metastatic or recurrent high-grade osteosarcoma has tried to improve response rates, a mechanistic hiatus exists in terms of a detailed understanding the therapeutic strategies required in advanced disease. Here we report a Bayesian designed multi-arm, multi-centre, open-label phase II study with randomisation in patients with metastatic and/or recurrent OS, designed to investigate how patients with OS might respond to liposomal MTP-PE, either given alone or in combination with ifosfamide. Despite the trial closing because of poor recruitment within the allocated funding period, with no objective responses in eight patients, we report the design and feasibility outcomes for patients registered into the trial. We demonstrate the feasibility of the Bayesian design, European collaboration, tissue collection with genomic analysis and serum cytokine characterisation. Further mechanistic investigation of liposomal MTP-PE alone and in combination with other agents remains warranted in metastatic OS., (© 2022. The Author(s).)

Objectives: Cure rate models accounting for cured and uncured patients, provide additional insights into long and short-term survival. We aim to evaluate the prognostic value of histological response and chemotherapy intensification on the cure fraction and progression-free survival (PFS) for the uncured patients., Design: Retrospective analysis of a randomised controlled trial, MRC BO06 (EORTC 80931)., Setting: Population-based study but proposed methodology can be applied to other trial designs., Participants: A total of 497 patients with resectable highgrade osteosarcoma, of which 118 were excluded because chemotherapy was not started, histological response was not reported, abnormal dose was reported or had disease progression during treatment., Interventions: Two regimens with the same anticipated cumulative dose (doxorubicin 6×75 mg/m 2 /week; cisplatin 6×100 mg/m 2 /week) over different time schedules: every 3 weeks in regimen-C and every 2 weeks in regimen-DI., Primary and Secondary Outcome Measures: The primary outcome is PFS computed from end of treatment because cure, if it occurs, may happen at any time during treatment. A mixture cure model is used to study the effect of histological response and intensified chemotherapy on the cure status and PFS for the uncured patients., Results: Histological response is a strong prognostic factor for the cure status (OR 3.00, 95% CI 1.75 to 5.17), but it has no clear effect on PFS for the uncured patients (HR 0.78, -95% CI 0.53 to 1.16). The cure fractions are 55% (46%-63%) and 29% (22%-35%), respectively, among patients with good and poor histological response (GR, PR). The intensified regimen was associated with a higher cure fraction among PR (OR 1.90, 95% CI 0.93 to 3.89), with no evidence of effect for GR (OR 0.78, 95% CI 0.38 to 1.59)., Conclusions: Accounting for cured patients is valuable in distinguishing the covariate effects on cure and PFS. Estimating cure chances based on these prognostic factors is relevant for counselling patients and can have an impact on treatment decisions., Trial Registration Number: ISRCTN86294690., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Investigating the effect of prognostic factors in a multistate framework on survival in a large population of patients with osteosarcoma. Of interest is how prognostic factors affect different disease stages after surgery, with stages of local recurrence (LR), new metastatic disease (NM), LR+NM, secondary malignancy, a second NM, and death., Design: An open-label, international, phase 3 randomised controlled trial., Setting: 325 sites in 17 countries., Participants: The subset of 1631 metastases-free patients from 1965 patients with high-grade resectable osteosarcoma, from the European and American Osteosarcoma Study., Main Outcome Measures: The effect of prognostic factors on different disease stages, expressed as HRs; predictions of disease progression on an individual patient basis, according to patient-specific characteristics and history of intermediate events., Results: Of 1631 patients, 526 experienced an intermediate event, and 305 died by the end of follow-up. An axial tumour site substantially increased the risk of LR after surgery (HR=10.84, 95% CI 8.46 to 13.86) and death after LR (HR=11.54, 95% CI 6.11 to 21.8). A poor histological increased the risk of NM (HR=5.81, 95% CI 5.31 to 6.36), which sharply declined after 3 years since surgery. Young patients (<12 years) had a lower intermediate event risk (eg, for LR: HR=0.66, 95% CI 0.51 to 0.86), when compared with adolescents (12-18 years), but had an increased risk of subsequent death, while patients aged >18 had a decreased risk of death after event (eg, for death after LR: HR=2.40, 95% CI 1.52 to 3.90; HR=0.35, 95% CI 0.21 to 0.56, respectively)., Conclusions: Our findings suggest that patients with axial tumours should be monitored for LR and patients with poor histological response for NM, and that for young patients (<12) with an LR additional treatment options should be investigated., Trial Registration Number: NCT00134030., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Objectives: This study aims at exploring and quantifying multiple types of adverse events (AEs) experienced by patients during cancer treatment. A novel longitudinal score to evaluate the Multiple Overall Toxicity (MOTox) burden is proposed. The MOTox approach investigates the personalised evolution of high overall toxicity (high-MOTox) during the treatment., Design: Retrospective analysis of the MRC-BO06/EORTC-80931 randomised controlled trial for osteosarcoma., Setting: International multicentre population-based study., Participants: A total of 377 patients with resectable high-grade osteosarcoma, who completed treatment within 180 days after randomisation without abnormal dosages (+25% higher than planned)., Interventions: Patients were randomised to six cycles of conventional versus dose-intense regimens of doxorubicin and cisplatin. Non-haematological toxicity data were collected prospectively and graded according to the Common Terminology Criteria for Adverse Events (CTCAE)., Main Outcome Measures: The MOTox score described the overall toxicity burden in terms of multiple toxic AEs, maximum-severity episode and cycle time-dimension. Evolution of high-MOTox was assessed through multivariable models, that investigated the impact of personalised characteristics (eg, achieved chemotherapy dose, previous AEs or biochemical factors) cycle-by-cycle., Results: A cycle-by-cycle analysis identifies different evolutions of MOTox levels during treatment, detecting differences in patients' health. Mean MOTox values and percentages of patients with high-MOTox decreased cycle-by-cycle from 2.626 to 1.953 and from 57.8% to 36.6%, respectively. High - MOTox conditions during previous cycles were prognostic risk factors for a new occurrence (ORs range from 1.522 to 4.439), showing that patient's history of toxicities played an important role in the evolution of overall toxicity burden during therapy. Conventional regimen may be preferred to dose-intense in terms of AEs at cycles 2-3 (p<0.05)., Conclusions: The novel longitudinal method developed can be applied to any cancer studies with CTCAE-graded toxicity data. After validation in other studies, the MOTox approach may lead to improvements in healthcare assessment and treatment planning., Trial Registration Number: ISRCTN86294690; Post-results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Competing Interests: Disclosure SJS has received honoraria for participation in advisory board for GlaxoSmithKline (GSK); NA non-remunerated leadership and advisory roles for Sociedade Portuguesa de Cirurgia; JB has no personal financial disclosure, received research grants (institutional) from Eli Lilly, Novartis, Roche, Samsung Bioepis, Paxman Coolers Ltd, Sun Pharma and non-remunerated advisory role for Novartis, non-remunerated leadership activities for Immuno-oncology society of India, Indian Society of Medical and Paediatric Oncology, Teenage and Young Adult Cancer Foundation and Indian cooperative oncology network; SB has received honoraria for participation in advisory boards for Deciphera, Blueprint Medicines, Lilly, Novartis, Daiichi-Sankyo, Plexxikon, Roche, GSK, invited speaker fees from Pfizer and PharmaMar, institutional research grant from Novartis, institutional research as principal investigator (PI) for Daiichi-Sankyo, Roche, Deciphera, Lilly, Novartis, Blueprint Medicines, Bristol Myers Squibb (BMS), Incyte, non-remunerated activities for Federal Institute for Drugs and Medical Devices (BfArm) and founding member of German Sarcoma Foundation; RB reports non-remunerated activities as PI for IRCSS Galeazzi Orthopedic Institute and IRE-ISG Regina Elena Institute, participation at the Clinical Experience Exchange Meeting, III IDBN National Congress 2019, Italian Association of Medical Oncology (AIOM), IRE-ISG Regina Elena Institute and Lazio Association of Orthopaedic Hospital Traumatologists (ALOTO); SBi has received honoraria for participation in advisory boards from Bayer Healthcare, Boehringer Ingelheim, ClinGen, Hofmann La Roche, Ipsen, Eli Lilly and Sensorion, non-remunerated activities for Bayer and membership of the German Pediatric Oncology Society and European Musculoskeletal Oncology Society; JYB received research support from Merck Sharp & Dohme (MSD), Roche, GSK, Novartis, Bayer, PharmaMar outside the present work; SBon has received honoraria for advisory board from Nanobiotix and as invited speaker for PharmaMar, trial research grant from the Institut National du Cancer (INCa); IB has received honoraria for participation in advisory boards for Roche, Lilly, Sanofi, Pierre Fabre, Ipsen, and as invited speaker for Amgen, BMS, Novartis, Leo Pharma, AstraZeneca and Genesis, member of Board of Directors for Hellenic Society of Medical Oncology, Hellenic Society of Sarcomas and Rare Tumors, Hellenic Oncology Research Group (HORG), PI trial research support from Novartis, BMS, Regeneron, MSD, Lilly and Roche; JVMGB receives royalties from UpToDate and Wolters Kluwer, and direct research funding from TRACON pharmaceuticals; KB has received honoraria for expert testimony and advisory boards for Bayer, invited speaker fees and research grant from Eli Lilly, PI for Deciphera and Novartis; TB has received honoraria for participation in advisory boards for Bayer and Eli Lilly, invited speaker fees from PharmaMar and Novartis; EDÁ has received honoraria for participation in advisory board for Bayer, invited speaker for Lilly, PharmaMar and Roche, institutional research support from Pfizer, Roche and AstraZeneca; APDT has received honoraria for participation in advisory boards for Bayer and Roche, invited speaker for PharmaMar and Novartis; XGDM has received honoraria for participation in advisory boards for Ipsen, EUSA Pharma, BMS, Pfizer, Roche and PharmaMar, invited speaker for Lilly, Astellas Pharma, Eisai and Pfizer and institutional research grant from AstraZeneca; ME has received honoraria for participation in advisory boards for Clinigen and Bayer, consulting fees from Blueprint Medicines, institutional research funding from Novartis; AF has received honoraria for participation in advisory board for Novartis and invited speaker fees for MSD and Amgen; VF has received honoraria for participation in advisory boards and speaker fees for BMS, Novartis and MSD and speaker fees from Pierre Fabre; NG has received honoraria as invited speaker for Eisai and reports membership of the European Society for Paediatric Oncology (SIOPE), ACCELERATE, Societe Francaise de lutte contre les cancers et leucemies de l'enfant et de l'adolescent (SFCE) and Groupe Onco- hématologie Adolescents et Jeunes Adultes (GO-AJA); SG has reported institutional research for Blueprint Medicines and member of American Society of Clinical Oncology (ASCO) and AIOM; HG has reported PI research for Daiichi, Deciphera and Novartis, co-ordinating PI for Boehringer Ingelheim and AmMax Bio; FG has received honoraria for participation in advisory board for Amgen and expert testimony for Deciphera, stock ownership for Atlanthera, licensing fees from Zimmer, non-remunerated activities for 3D-Side and INCa DGOS funding and member of the board of NetSarc the French clinical reference network for soft tissue and visceral sarcomas; GG has received honoraria for participation in advisory boards for Lilly, Eisai, Merck, Bayer and GSK, invited speaker fees from PharmaMar and Novartis, institutional grants from PharmaMar, Bayer and Novartis; AG has received honoraria for participation in advisory boards for Novartis, Pfizer, Bayer, Lilly, PharmaMar, SpringWorks and Nanobiotix, invited speaker for Lilly, PharmaMar and research grant from PharmaMar; RH has received honoraria from GSK; ABH is a member of Board of Directors for EIT health UK and Ireland, received or currently receives direct research funding as a PI from Roche, performs work in clinical trials or contracted research for the Institution and Clinical Director of the Oncology and Haematology Directorate, Oxford Cancer Centre; SHN reports institutional research role as deputy PI for Eisai, non-remunerated activity for Harmonization International Bones Sarcoma Consortium (HIBISCus), membership of SIOPE, German, Swiss, Austrian Society of Paediatric Oncology and Hematology (GPOH) and German Society of Pediatrics and Adolescent Medicine (DGKJ); NH has received honoraria as expert testimony and invited speaker from PharmaMar, performs work in clinical trials or contracted research for which his/her institution received financial support from PharmaMar, Lilly, Adaptimmune Therapeutics, AROG Pharmaceuticals, Bayer, Eisai, Lixte, Karyopharm, Deciphera, GSK, Novartis, Blueprint Medicines, Nektar Therapeutics, Forma, Amgen and Daiichi-Sankyo, non-remunerated leadership roles for Grupo Español de Investigación en Sarcomas (GEIS) and SELNET, and has non-remunerated membership or affiliation with ESMO, Sociedad Española de Oncología Médica (SEOM), ASCO, Connective Tissue Oncology Society (CTOS) and European Organisation for Research and Treatment of Cancer (EORTC); PH has received honoraria for participation in advisory boards for Pfizer, Roche and GSK, invited speaker fees from PharmaMar and Lilly, clinical expert fees from Boehringer Ingelheim, institutional research funding for clinical trials from Siemens, Novartis, Blueprint Medicines and meeting sponsorship from PEKKIP Oncology, non-remunerated activities for the German Sarcoma Foundation (DSS), German Interdisciplinary Sarcoma Group (GISG) and Interdisciplinary Working Party on Sarcomas (IAWS) of the German Cancer Society (DKG), advisory role for the German Cancer Aid (DKH) Committee on Health Technology Assessment and Sarcoma Patients EuroNet (SPAEN); HJ has received honoraria for participation in advisory boards for Orion Pharma, Neutron Therapeutics and Maud Kuistila Memorial Foundation, had full time or part time employment at Orion Pharma, until 31 August 2020, stocks in Orion Pharma and Sartar Therapeutics; RLJ has received honoraria for expert testimony consultancy for Adaptimmune, Bayer, Boehringer Ingelheim, Blueprint Medicines, Clinigen, Eisai, Epizyme, Daiichi, Deciphera, Immune Design, Lilly, SpringWorks, Tracon, UpToDate, PharmaMar, advisory board for Athenex, institutional research grant from MSD; CJ has received travel grants from Ipsen and PharmaMar; LK has received honoraria for participation in advisory boards for Bayer, Novartis and Agios; BK has received honoraria for participation in advisory boards for Bayer, Blueprint Medicines, Boehringer Ingelheim, SpringWorks, GSK and PharmaMar, institutional research support from PharmaMar and SpringWorks, member of EORTC and Chair of the EORTC soft tissue and bone sarcoma group (STBSG); AK has received honoraria for participation in advisory boards for Daiichi-Sankyo and Otsuka and invited speaker fees from Novartis, Taiho and Eisai; KK has received honoraria for participation in advisory board for Bayer and expert testimony for Eli Lilly and Roche; ALC has received honoraria for participation in advisory boards for Deciphera and Lilly, invited speaker fees from PharmaMar and Bayer; EL received honoraria from SpringWorks Therapeutics for scientific advisory board participation and member of the European Reference Network GENTURIS; AL has received institutional research grants from Johnson & Johnson, Alphamed, Medacta and ImplanTec, non-remunerated activities for European Musculoskeletal Society (EMSOS), Austrian Society of Orthopaedic Surgeons (OGO) and membership of CTOS; ALP has received honoraria as invited speaker for PharmaMar, institutional research funding from the Spanish Health Ministry, reported non-remunerated activities as PI for PharmaMar, Cebiotex, Deciphera, Lilly, GSK, Daiichi, Epizyme, Advenchen Laboratories, Novartis, Karyopharm, Blueprint medicines, GEIS and other activity for EORTC; JMB has received honoraria for expert testimony for Lilly, PharmaMar, Eisai, Bayer, invited speaker fee from PharmaMar, institutional research for PharmaMar, Eisai, Novartis, Immix Biopharma, Lixte, Karyopharm, Bayer, Celgene, Pfizer, BMS, Blueprint Medicines, Deciphera, Nektar Therapeutics, Forma, Amgen, Daiichi-Sankyo, Lilly, AROG Pharmaceutcials, Adaptimmune and GSK; OM has received honoraria for participation in advisory boards for MSD, Megapharm, AstraZeneca, Takeda and Progenetics, invited speaker fees from MSD and Roche; CM has performed non-remunerated activities for International Cancer Imaging Society and EORTC STBSG; OMi has received honoraria for participation in advisory boards for Bayer, Blueprint Medicines, MSD, Pfizer, invited speaker fees from BMS, Eli Lilly, Ipsen, Roche and Servier, institutional research for Blueprint Medicines, Bayer, Epizyme and Eli-Lilly; BM has received honoraria from Clinigen as invited speaker; EP has received honoraria for participation in advisory boards for SynOx, Daiichi-Sankyo and Deciphera Pharmaceuticals and invited speaker fees from Peer View Educational; MAP has received honoraria for participation in advisory boards for Roche, invited speaker fees from Eli Lilly, Pfizer, and Novartis, expert testimony from Blueprints Medicine and institutional research grant from Novartis; SPN has received honoraria for participation in advisory board for Immunocore; PR has received honoraria for participation in advisory boards for Bayer, Clinigen, Roche, MSD, Deciphera, Mundibiopharma, PharmaMar, Blueprint Medicines, invited speaker fees from Lilly, PharmaMar, institutional research for PharmaMar, Karyopharm, SpringWorks, AROG Pharmaceuticals, Blueprint, Deciphera, Amgen, Astellas, Epizyme, Lilly, MSD, Pfizer, Novartis and Philogen, membership of German Sarcoma Foundation; PRu has received honoraria for participation in advisory boards for MSD, BMS, Pierre Fabre, Merck, Sanofi, Blueprint Medicines, invited speaker fees from MSD, BMS, Pierre Fabre, Merck, Sanofi, Novartis, institutional research funding from Pfizer, BMS and non-remunerated activities for the Polish Society of Surgical Oncology and ASCO; MS has received honoraria for travel grant from PharmaMar and writing engagement for Lilly; SS has reported a research grant from Johnson & Johnson and research funding from Roche Austria; PS has received honoraria for participation in advisory boards for Deciphera, Blueprint Medicines, Boehringer Ingelheim, Ellipses Pharma, Transgene, Exelixis, Medscape, Guided Clarity, Ysios, Modus Outcomes, Studiecentrum voor Kernenergie, Curio Science, institutional honoraria for advisory boards for Blueprint Medicines, Ellipses Pharma, Intellisphere, expert testimony for Advanced Medical/Teladoc Health, institutional research funding from CoBioRes NV, Eisai, G1 Therapeutics, Novartis and PharmaMar; SSl Chair of Centre for Personalised Cancer Treatment and Route Personalised Medicine, Dutch Science Agenda, member of supervisory board for SkylineDX and Scientific advisory committee Pan-Cancer T BV; KSH reports non-remunerated activity for CTOS as President 2020 and membership of the Scandinavian Sarcoma Group; MAJvdS has performed work in clinical trials or contracted research for which the institution received financial support from Daiichi-Sankyo, Implantcast and Carbofix; WTAvdG has received institutional honoraria for participation in advisory boards for Bayer and GSK, institutional research grants from Novartis and Lilly and consultancy work for SpringWorks; WJvH has received institutional honoraria for participation in advisory board for Belpharma, invited speaker fees from Amgen, expert testimony for Sanofi and MSD, personal travel grant from Novartis and institutional research grant from BMS; TF reported institutional research funding from the Foundation ARC and Ligue Régionale contre le Cancer, leadership role for ERN GENTURIS; PGC has received honoraria for participation in advisory board for Bayer, institutional research funding from Amgen Dompé, Advenchen, Bayer, Blueprint, Deciphera, Eli Lilly, Epizyme, Daiichi, GSK, Karyopharm, Novartis, Pfizer, PharmaMar, SpringWorks, AROG Pharmaceuticals and Eisai, non-remunerated activities for the Italian Sarcoma Group, European School of Oncology, Federation of Italian Cooperative Groups and Rare Cancers Europe; SSta has received honoraria for participation in advisory boards for Bayer, Deciphera, Eli Lilly, Daiichi, Maxivax, Novartis, invited speaker fees from GSK and PharmaMar, expert testimony fee from Bavarian Nordic and Epizyme, institutional research funding from Amgen Dompé, Advenchen, Bayer, Blueprint Medicines, Deciphera, Eli Lilly, Epizyme, Daiichi, GSK, Karyopharm, Novartis, Pfizer, PharmaMar, SpringWorks and Hutchinson MediPharma International Inc., non-remunerated activities for CTOS, Chordoma Foundation, Epithelioid Haemangioendothelioma Foundation, Desmoid Foundation, EORTC STBSG and Italian Sarcoma Group Onlus. AMF, AB, SBo, BB, AD, FF, AFer, PJ, DAK, FLG, ABM, MM, CMo, RP, AAS, CS, DS, AT, MU and RL have declared no conflicts of interests.

Purpose of Review: Giant cell tumour of bone (GCTB) is an intermediate, locally aggressive primary bone tumour. In addition to local therapy, new drugs became available for this disease. Denosumab, a receptor activator of nuclear factor κ-B-ligand inhibitor, was introduced as systemic targeted therapy for advanced or inoperable and metastatic GCTB. Also, the bisphosphonate zoledronic acid has activity in GCTB by directly targeting the neoplastic stromal cells., Recent Findings: In a small RCT, bisphosphonates were successful in controlling tumour growth and a higher apoptotic index of tumour cells was seen after zoledronic acid versus controls. Although bisphosphonate-loaded bone cement has not been studied to a large extent, it does not seem harmful and may constitute a logical local adjuvant. From the largest clinical trial to date, the risk-to-benefit ratio for denosumab in patients with advanced GCTB remains favourable, also in facilitating less morbid surgery. Concerns have arisen that recurrence rates would be higher than after conventional treatment, ranging from 20 to 100% in a systematic review, although this may be because of bias. H3F3A (G34W) driver mutations are helpful in the differentiation between GCTB and other giant cell-containing malignancies. H3.3-G34W proved sufficient to drive tumourigenesis. The cumulative incidence of malignancy in GCTB is estimated at 4%, of which primary malignancy 1.6% and secondary malignancy 2.4%, the latter mainly after radiation. To date, a potential causal relationship between denosumab and pulmonary metastases has not been confirmed; if they do not behave indolently, it would be advised to reassess diagnosis and consider malignancy., Summary: Denosumab remains a highly effective treatment option for patients with advanced GCTB. A short duration of 2-4 months neoadjuvant denosumab is advised to facilitate less morbid surgery and prevent incomplete curettage by macroscopic tumour alterations. Reduced dose intensity is being studied to reduce long term side-effects. Further research on bisphosphonates and other targets including H3.3-G34W remains warranted.

Background: The optimal treatment for advanced leiomyosarcoma is still debated. Given histotype-specific prospective controlled data lacking, this study retrospectively evaluated doxorubicin plus dacarbazine, doxorubicin plus ifosfamide, and doxorubicin alone as first-line treatments for advanced/metastatic leiomyosarcoma treated at European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group (EORTC-STBSG) sites., Methods: The inclusion criteria were a confirmed histological diagnosis, treatment between January 2010 and December 2015, measurable disease (Response Evaluation Criteria in Solid Tumors 1.1), an Eastern Cooperative Oncology Group performance status ≤2, and an age ≥ 18 years. The endpoints were progression-free survival (PFS), overall survival (OS), and overall response rate (ORR). PFS was analyzed with methods for interval-censored data. Patients were matched according to their propensity scores, which were estimated with a logistic regression model accounting for histology, grade, age, sex, performance status, tumor site, and tumor extent., Results: Three hundred three patients from 18 EORTC-STBSG sites were identified. One hundred seventeen (39%) received doxorubicin plus dacarbazine, 71 (23%) received doxorubicin plus ifosfamide, and 115 (38%) received doxorubicin. In the 2:1:2 propensity score-matched population (205 patients), the estimated median PFS was 9.2 months (95% confidence interval [CI], 5.2-9.7 months), 8.2 months (95% CI, 5.2-10.1 months), and 4.8 months (95% CI, 2.3-6.0 months) with ORRs of 30.9%, 19.5%, and 25.6% for doxorubicin plus dacarbazine, doxorubicin plus ifosfamide, and doxorubicin alone, respectively. PFS was significantly longer with doxorubicin plus dacarbazine versus doxorubicin (hazard ratio [HR], 0.72; 95% CI, 0.52-0.99). Doxorubicin plus dacarbazine was associated with longer OS (median, 36.8 months; 95% CI, 27.9-47.2 months) in comparison with both doxorubicin plus ifosfamide (median, 21.9 months; 95% CI, 16.7-33.4 months; HR, 0.65; 95% CI, 0.40-1.06) and doxorubicin (median, 30.3 months; 95% CI, 21.0-36.3 months; HR, 0.66; 95% CI, 0.43-0.99). Adjusted analyses retained an effect for PFS but not for OS. None of the factors selected for multivariate analysis had a significant interaction with the received treatment for both PFS and OS., Conclusions: This is the largest retrospective study of first-line treatment for advanced leiomyosarcoma. In the propensity score-matched population, doxorubicin and dacarbazine showed favorable activity in terms of both ORR and PFS and warrants further evaluation in prospective trials., (© 2020 American Cancer Society.)

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/m 2 regimen was used, and from 1997 onwards a 9 g/m 2 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/m 2 , n = 26; 9 g/m 2 , n = 36). OS was significantly better in univariate analysis for 9 g/m 2 compared with 5 g/m 2 (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/m 2 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/m 2 and with 9 g/m 2 . This study was unable to show a significant difference in survival between 5 and 9 g/m 2 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., (© 2019 The Authors. The Oncologist published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.)

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.

Background: Although there have been multiple randomised trials in newly diagnosed Ewing sarcoma family of tumours (ESFT) and these have been conducted over many years and involved many international cooperative groups, the outcomes for all stages of disease have plateaued. Internationally, the standard treatment of ESFT is not defined, and there is a need to add new agents other than conventional chemotherapy to improve outcomes. This trial will compare two different induction/consolidation chemotherapy regimens: (1) vincristine, ifosfamide, doxorubicin and etoposide (VIDE) induction and vincristine, actinomycin D, ifosfamide or cyclophosphamide, or busulfan and mephalan (VAI/VAC/BuMel) consolidation and (2) vincristine, doxorubicin, cyclophosphamide, ifosfamide and etoposide (VDC/IE) induction and ifosfamide and etoposide, vincristine and cyclophosphamide, vincristine, actinomycin D and ifosfamide, or busulfan and mephalan (IE/VC/VAI/BuMel) consolidation (randomisation 1, or R1). A second randomisation (R2) will determine whether the addition of zoledronic acid to consolidation chemotherapy, as assigned at R1, is associated with improved clinical outcome., Methods: EURO EWING 2012 is an international, multicentre, phase III, open-label randomised controlled trial. There are two randomisations: R1 and R2. Patients are randomly assigned at two different time points: at entry to the trial (R1) and following local control therapy (R2). The primary outcome measure is event-free survival. The secondary outcome measures include overall survival, adverse events and toxicity, histological response of the primary tumour, response of the primary tumour, regional lymph nodes or metastases (or both), and achievement of local control at the end of treatment., Discussion: This study will establish which is the "standard regimen" of chemotherapy, taking into account both clinical outcomes and toxicity. This will form the chemotherapy backbone for future interventional studies where we may want to add new targeted agents. It will also determine the role of zoledronic acid in conjunction with the separate EE2008 trial. Any trial in ESFT needs to take into account the rarity of the tumour and consider that international cooperation is needed to provide answers in a timely manner., Trial Registration: Registered with EudraCT number 2012-002107-17 on 26 February 2012. Registered with ISRCTN number 54540667 on 4 November 2013.

Purpose: The R2Pulm trial was conducted to evaluate the effect of busulfan-melphalan high-dose chemotherapy with autologous stem-cell rescue (BuMel) without whole-lung irradiation (WLI) on event-free survival (main end point) and overall survival, compared with standard chemotherapy with WLI in Ewing sarcoma (ES) presenting with pulmonary and/or pleural metastases., Methods: From 2000 to 2015, we enrolled patients younger than 50 years of age with newly diagnosed ES and with only pulmonary or pleural metastases. Patients received chemotherapy with six courses of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) and one course of vincristine, dactinomycin, and ifosfamide (VAI) before either BuMel or seven courses of VAI and WLI (VAI plus WLI) by randomized assignment. The analysis was conducted as intention to treat. The estimates of the hazard ratio (HR), 95% CI, and P value were corrected for the three previous interim analyses by the inverse normal method., Results: Of 543 potentially eligible patients, 287 were randomly assigned to VAI plus WLI (n = 143) or BuMel (n = 144). Selected patients requiring radiotherapy to an axial primary site were excluded from randomization to avoid excess organ toxicity from interaction between radiotherapy and busulfan. Median follow-up was 8.1 years. We did not observe any significant difference in survival outcomes between treatment groups. Event-free survival was 50.6% versus 56.6% at 3 years and 43.1% versus 52.9% at 8 years, for VAI plus WLI and BuMel patients, respectively, resulting in an HR of 0.79 (95% CI, 0.56 to 1.10; P = .16). For overall survival, the HR was 1.00 (95% CI, 0.70 to 1.44; P = .99). Four patients died as a result of BuMel-related toxicity, and none died after VAI plus WLI. Significantly more patients in the BuMel arm experienced severe acute toxicities than in the VAI plus WLI arm., Conclusion: In ES with pulmonary or pleural metastases, there is no clear benefit from BuMel compared with conventional VAI plus WLI.

Background: Giant-cell tumour of bone (GCTB) is a rare, locally aggressive osteoclastogenic stromal tumour of the bone. This phase 2 study aimed to assess the safety and activity of denosumab in patients with surgically salvageable or unsalvageable GCTB., Methods: In this multicentre, open-label, phase 2 study done at 30 sites in 12 countries we enrolled adults and skeletally mature adolescents (aged ≥12 years) weighing at least 45 kg with histologically confirmed and radiographically measurable GCTB, Karnofsky performance status 50% or higher (Eastern Cooperative Oncology Group status 0, 1, or 2), and measurable active disease within 1 year of study enrolment. Patients had surgically unsalvageable GCTB (cohort 1), had surgically salvageable GCTB with planned surgery expected to result in severe morbidity (cohort 2), or were enrolled from a previous study of denosumab for GCTB (cohort 3). Patients received 120 mg subcutaneous denosumab once every 4 weeks during the treatment phase, with loading doses (120 mg subcutaneously) administered on study days 8 and 15 to patients in cohorts 1 and 2 (patients in cohort 3 did not receive loading doses). The primary endpoint was safety in terms of the type, frequency, and severity of adverse events; secondary endpoints included time to disease progression from cohort 1 and the proportion of patients without surgery at month 6 for cohort 2. The safety analysis set included all enrolled patients who received at least one dose of denosumab. This study is registered with ClinicalTrials.gov, number NCT00680992, and has been completed., Findings: Between Sept 9, 2008, and Feb 25, 2016, 532 patients were enrolled: 267 in cohort 1, 253 in cohort 2, and 12 in cohort 3. At data cutoff on Feb 24, 2017, median follow-up was 58·1 months (IQR 34·0-74·4) in the overall patient population, and 65·8 months (40·9-82·4) in cohort 1, 53·4 months (28·2-64·1) in cohort 2, and 76·4 months (61·2-76·5) in cohort 3. During the treatment phase, the most common grade 3 or worse adverse events were hypophosphataemia (24 [5%] of 526 patients), osteonecrosis of the jaw (17 [3%], pain in extremity (12 [2%]), and anaemia (11 [2%]). Serious adverse events were reported in 138 (26%) of 526 patients; the most common were osteonecrosis of the jaw (17 [3%]), anaemia (6 [1%]), bone giant cell tumour (6 [1%]), and back pain (5 [1%]). 28 (5%) patients had positively adjudicated osteonecrosis of the jaw, four (1%) had atypical femur fracture, and four (1%) had hypercalcaemia occurring 30 days after denosumab discontinuation. There were four cases (1%) of sarcomatous transformation, consistent with historical data. Ten (2%) treatment-emergent deaths occurred (two of which were considered treatment-related; bone sarcoma in cohort 2 and sarcoma in cohort 1). Median time to progression or recurrence for patients in cohort 1 during the first treatment phase was not reached (28 [11%] of 262 patients had progression or recurrence). 227 (92%; 95% CI 87-95) of 248 patients who received at least one dose of denosumab in cohort 2 had no surgery in the first 6 months of the study., Interpretation: The types and frequencies of adverse events were consistent with the known safety profile of denosumab, which showed long-term disease control for patients with GCTB with unresectable and resectable tumours. Our results suggest that the overall risk to benefit ratio for denosumab treatment in patients with GCTB remains favourable., Funding: Amgen., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objective: To determine the level of discrepancy between magnetic resonance imaging (MRI) and 18 F-FDG PET-CT in detecting osseous metastases in patients with Ewing sarcoma., Methods: Twenty patients with histopathologically confirmed Ewing sarcoma between 2000 and 2017 who underwent 18 F-FDG PET-CT and MRI within a 4-week range were included. Each imaging modality was evaluated by a separate observer. Reference diagnosis of each lesion was based on histopathology or consensus of an expert panel using all available data, including at least 6 months' follow-up. Sensitivity, specificity, and predictive values were determined. Osseous lesions were analyzed on a patient and a lesion basis. Factors possibly related to false-negative findings were evaluated using Pearson's Chi-squared or Fisher's exact test., Results: A total of 112 osseous lesions were diagnosed in 13 patients, 107 malignant and 5 benign. Seven patients showed no metastases on either 18 F-FDG PET-CT or MRI. Forty-one skeletal metastases (39%) detected with MRI did not show increased 18 F-FDG uptake on 18 F-FDG PET-CT (false-negative). Lesion-based sensitivities and specificities were 62% (95%CI 52-71%) and 100% (48-100%) for 18 F-FDG PET-CT; and 99% (97-100%) and 100% (48-100%) for MRI respectively. Bone lesions were more likely to be false-negative on 18 F-FDG PET-CT if hematopoietic bone marrow extension was widespread and active (p = 0.001), during or after (neo)-adjuvant treatment (p = 0.001) or when the lesion was smaller than 10 mm (p < 0.001)., Conclusion: Although no definite conclusions can be drawn from this small retrospective study, it shows that caution is needed when using 18 F-FDG PET-CT for diagnosing skeletal metastases in Ewing sarcoma. Poor contrast between metastases and active hematopoietic bone marrow, chemotherapeutic treatment, and/or small size significantly decrease the diagnostic yield of 18 F-FDG PET-CT, but not of MRI.

Background: We investigated the effects of surgical margins, histological response, and radiotherapy on local recurrence (LR), distant metastasis (DM), and survival in Ewing sarcoma., Procedure: Disease evolution was retrospectively studied in 982 patients with Ewing sarcoma undergoing surgery after chemotherapy using a multistate model with initial state surgery, intermediate states LR, pulmonary metastasis (DMpulm), other DM ± LR (DMother), and final state death. Effect of risk factors was estimated using Cox proportional hazard models., Results: The median follow-up was 7.6 years (95% CI, 7.2-8.0). Risk factors for LR are pelvic location, HR 2.04 (1.10-3.80), marginal/intralesional resection, HR 2.28 (1.25-4.16), and radiotherapy, HR 0.52 (0.28-0.95); for DMpulm the risk factors are <90% necrosis, HR 2.13 (1.13-4.00), and previous pulmonary metastasis, HR 4.90 (2.28-8.52); for DMother are 90% to 99% necrosis, HR 1.56 (1.09-2.23), <90% necrosis, HR 2.66 (1.87-3.79), previous bone/other metastasis, HR 3.08 (2.03-4.70); and risk factors for death without LR/DM are pulmonary metastasis, HR 8.08 (4.01-16.29), bone/other metastasis, HR 10.23 (4.90-21.36), and <90% necrosis, HR 6.35 (3.18-12.69). Early LR (0-24 months) negatively influences survival, HR 3.79 (1.34-10.76). Once DMpulm/DMother arise only previous bone/other metastasis remain prognostic for death, HR 1.74 (1.10-2.75)., Conclusion: Disease extent and histological response are risk factors for progression to DM or death. Tumor site and surgical margins are risk factors for LR. If disease progression occurs, previous risk factors lose their relevance. In case of isolated LR, time to recurrence is important for decision-making. Radiotherapy seems protective for LR especially in pelvic/axial. Low percentages of LR in extremity tumors and associated toxicity question the need for radiotherapy in extremity Ewing sarcoma., (© 2019 The Authors. Pediatric Blood & Cancer Published byWiley Periodicals, Inc.)

Accurate survival estimations in Ewing sarcoma are necessary to develop risk- and response adaptive treatment strategies allowing for early decision-making. We aim to develop an easy-to-use survival estimation tool from diagnosis and surgery. A retrospective study of 1314 Ewing sarcoma patients was performed. Associations between prognostic variables at diagnosis/surgery and overall survival (OS), were investigated using Kaplan-Meier and multivariate Cox models. Predictive accuracy was evaluated by cross-validation and Harrell C-statistics. Median follow-up was 7.9 years (95%CI 7.6-8.3). Independent prognostic factors at diagnosis were age, volume, primary tumor localization and disease extent. 5 risk categories (A-E) were identified with 5-year OS of 88% (86-94), 69% (64-74), 57% (50-64), 51% (42-60) and 28% (22-34) respectively. Harrell C-statistic was 0.70. Independent prognostic factors from surgery were age, volume, disease extent and histological response. In categories A-B, 5y OS increased to 92% (87-97) and 79% (71-87) respectively for 100% necrosis and decreased to 76% (67-85) and 62% (55-69) respectively for <100% necrosis. In categories C-E, 5y OS increased to 65% (55-75), 65% (52-78) and 52% (38-66) respectively for ≥90% necrosis and decreased to 38% (22-54), 11% (0-26) and 7% (0-19) respectively for <90% necrosis. We present an easy-to-use survival estimation tool from diagnosis in Ewing sarcoma based on age, volume, primary tumor localization and disease extent. Histological response is a strong additional prognostic factor for OS.

Lessons Learned: Adjuvant treatment with zoledronic acid did not decrease the recurrence rate of giant cell tumor of bone (GCTB) in this study. The efficacy could not be determined because of the small sample size.GCTB recurrences, even in the denosumab era, are still an issue; therefore, a randomized study exploring the efficacy of zoledronic acid in the adjuvant setting in GCTB is still valid., Background: Bisphosphonates are assumed to inhibit giant cell tumor of bone (GCTB)-associated osteoclast activity and have an apoptotic effect on the neoplastic mononuclear cell population. The primary objective of this study was to determine the 2-year recurrence rate of high-risk GCTB after adjuvant zoledronic acid versus standard care., Methods: In this multicenter randomized open-label phase II trial, patients with high-risk GCTB were included (December 2008 to October 2013). Recruitment was stopped because of low accrual after the introduction of denosumab. In the intervention group, patients received adjuvant zoledronic acid (4 mg) intravenously at 1, 2, 3, 6, 9, and 12 months after surgery., Results: Fourteen patients were included (intervention n = 8, controls n = 6). Median follow-up was long: 93.5 months (range, 48-111). Overall 2-year recurrence rate was 38% (3/8) in the intervention versus 17% (1/6) in the control group ( p = .58). All recurrences were seen within the first 15 months after surgery., Conclusion: Adjuvant treatment with zoledronic acid did not decrease the recurrence rate of GCTB in this study. The efficacy could not be determined because of the small sample size. Because recurrences, even in the denosumab era, are still an issue, a randomized study exploring the efficacy of zoledronic acid in the adjuvant setting in GCTB is still valid., (© AlphaMed Press; the data published online to support this summary are the property of the authors.)

Purpose of Review: Giant cell tumor of bone (GCTB) is an uncommon benign primary bone tumor, consisting of receptor activator of nuclear factor kappa-B (RANK) expressing reactive osteoclast-like giant cells and neoplastic spindle-shaped cells. Denosumab was approved by FDA in 2013 and by EMA in 2014 to treat adults and skeletally mature adolescents with unresectable GCTB or when resection is likely to result in severe morbidity. However, there is much discussion regarding the optimal applied treatment strategy., Recent Findings: Neoadjuvant treatment of GCTB with denosumab can effectively downstage tumors to facilitate less morbid surgery or completely avoid the need for resection, but there is concern about local recurrence postsurgery. Definitive treatment of unresectable GTCB improves symptoms and halts tumor progression. The optimal treatment duration is unclear and long-term treatment is associated with adverse events like osteonecrosis of the jaw (ONJ) and atypical femoral fractures. Denosumab maintenance dose interval is currently being investigated., Summary: For the related but heterogenous group of giant cell rich tumors of bone, like aneurysmal bone cysts (ABC) and central giant cell granuloma (CGCG), denosumab is a new treatment modality under investigation. Given the effectiveness in GCTB, this could be a promising treatment option for selected patients with advanced disease.

Objectives: In cancer studies, the target received dose intensity (tRDI) for any regimen, the intended dose and time for the regimen, is commonly taken as a proxy for achieved RDI (aRDI), the actual individual dose and time for the regimen. Evaluating tRDI/aRDI mismatches is crucial to assess study results whenever patients are stratified on allocated regimen. The manuscript develops a novel methodology to highlight and evaluate tRDI/aRDI mismatches., Design: Retrospective analysis of a randomised controlled trial, MRC BO06 (EORTC 80931)., Setting: Population-based study but proposed methodology can be applied to other trial designs., Participants: A total of 497 patients with resectable high-grade osteosarcoma, of which 19 were excluded because chemotherapy was not started or the estimated dose was abnormally high (>1.25 × prescribed dose)., Interventions: Two regimens with the same anticipated cumulative dose (doxorubicin 6×75 mg/m 2 /week; cisplatin 6×100 mg/m 2 /week) over different time schedules: every 3 weeks in regimen-C and every 2 weeks in regimen-DI. PRIMARY AND SECONDARY OUTCOME MEASURES: tRDI distribution was measured across groups of patients derived from k-means clustering of treatment data. K-means creates groups of patients who are aRDI-homogeneous. The main outcome is the proportion of tRDI values in groups of homogeneous aRDI., Results: For nearly half of the patients, there is a mismatch between tRDI and aRDI; for 21%, aRDI was closer to the tRDI of the other regimen., Conclusions: For MRC BO06, tRDI did not predict well aRDI. The manuscript offers an original procedure to highlight the presence of and quantify tRDI/aRDI mismatches. Caution is required to interpret the effect of chemotherapy-regimen intensification on survival outcome at an individual level where such a mismatch is present.The study relevance lies in the use of individual realisation of the intended treatment, which depends on individual delays and/or dose reductions reported throughout the treatment., Trial Registration Number: ISRCTN86294690., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: There is lack of consensus on the prognostic value of received high dose intensity in osteosarcoma survivorship. Many studies have not shown a clear survival benefit when dose intensity is increased. The aim of this study is to go beyond chemotherapy intensification by arm-wide escalation of intended dose and/or compression of treatment schedule, while conversely addressing the relationship between treatment intensity and survival at the patient level. The study focusses on the difference in outcome results, based on a novel, progressively more individualised approach to dose intensity., Methods: A retrospective analysis of data from MRC BO06/EORTC 80931 randomised controlled trial for treatment of osteosarcoma was conducted. Three types of post hoc patient groups are formed using the intended regimen: the individually achieved cumulative dose and time on treatment, and the increase of individual cumulative dose over time. Event-free survival is investigated and compared in these three stratifications., Results: The strata of intended regimen and achieved treatment yields equivalent results. Received cumulative dose over time produces groups with evident different survivorship characteristics. In particular, it highlights a group of patients with an estimated 3-year event-free survival much larger (more than 10%) than other patient groups. This group mostly contains patients randomised to an intensified regimen. In addition, adverse events reported by that group show the presence of increased preoperative myelotoxicity., Conclusions: The manuscript shows the benefits of analyzing studies by using longitudinal data, e.g. recorded per cycle. This has impact on the drafting of future trials by showing why such a level of detail is needed for both treatment and adverse event data. The novel method proposed, based on cumulative dose received over time, shows that longitudinal treatment data might be used to link survival outcome with drug metabolism. This is particularly valuable when pharmacogenetics data for metabolism of cytotoxic agents are not collected., Trial Registration: ISRCTN86294690.

Background: High-grade osteosarcoma is a primary malignant bone tumour mainly affecting children and young adults. The European and American Osteosarcoma Study (EURAMOS)-1 is a collaboration of four study groups aiming to improve outcomes of this rare disease by facilitating randomised controlled trials., Methods: Patients eligible for EURAMOS-1 were aged ≤40 years with M0 or M1 skeletal high-grade osteosarcoma in which case complete surgical resection at all sites was deemed to be possible. A three-drug combination with methotrexate, doxorubicin and cisplatin was defined as standard chemotherapy, and between April 2005 and June 2011, 2260 patients were registered. We report survival outcomes and prognostic factors in the full cohort of registered patients., Results: For all registered patients at a median follow-up of 54 months (interquartile range: 38-73) from biopsy, 3-year and 5-year event-free survival were 59% (95% confidence interval [CI]: 57-61%) and 54% (95% CI: 52-56%), respectively. Multivariate analyses showed that the most adverse factors at diagnosis were pulmonary metastases (hazard ratio [HR] = 2.34, 95% CI: 1.95-2.81), non-pulmonary metastases (HR = 1.94, 95% CI: 1.38-2.73) or an axial skeleton tumour site (HR = 1.53, 95% CI: 1.10-2.13). The histological subtypes telangiectatic (HR = 0.52, 95% CI: 0.33-0.80) and unspecified conventional (HR = 0.67, 95% CI: 0.52-0.88) were associated with a favourable prognosis compared with chondroblastic subtype. The 3-year and 5-year overall survival from biopsy were 79% (95% CI: 77-81%) and 71% (95% CI: 68-73%), respectively. For patients with localised disease at presentation and in complete remission after surgery, having a poor histological response was associated with worse outcome after surgery (HR = 2.13, 95% CI: 1.76-2.58). In radically operated patients, there was no good evidence that axial tumour site was associated with worse outcome., Conclusions: In conclusion, data from >2000 patients registered to EURAMOS-1 demonstrated survival rates in concordance with institution- or group-level osteosarcoma trials. Further efforts are required to drive improvements for patients who can be identified to be at higher risk of adverse outcome. This trial reaffirms known prognostic factors, and owing to the large numbers of patients registered, it sheds light on some additional factors to consider., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background and purpose - Giant cell tumors of bone (GCT-B) are rare, locally aggressive tumors characterized by an abundance of giant cells. Incidence studies for GCT-B are rare. This is the first study using a fully automated 100% covering pathology database, the nationwide Dutch Pathology Registry (17 million inhabitants), PALGA, to calculate incidence rates for GCT-B. Patients and methods - From PALGA, all pathology excerpts were retrieved for patients diagnosed with GCT-B, giant cell tumors of tenosynovium, and giant cell tumors of soft tissue between January 1, 2009 and December 31, 2013. The incidence of GCT-B was calculated. Results - In total, 8,156 excerpts of 5,922 patients were retrieved; these included 138 first GCT-B diagnosis. For GCT-B the incidence was 1.7 per million inhabitants per year with a male to female ratio of 1:1.38 and a median age of 35 years (9-77). Most common localization was the femur (35%), followed by the tibia (18%). No differences in localization according to age and sex were found. The incidence rate of local recurrence was 0.40 per million inhabitants per year. Interpretation - This is the first nationwide study reporting the incidence of GCT-B, based on a nationwide pathology database with 100% coverage of pathology departments. Current incidence calculations are based only on doctor-driven registries. We confirmed that GCT-B is a rare disease with an incidence that is slightly higher than previously published. The relatively young median age of patients and the high incidence of recurrence stresses the importance of developing more effective treatments for this disease.

Background: Denosumab has been shown to reduce tumor size and progression, reform mineralized bone, and increase intralesional bone density in patients with giant cell tumor of bone (GCTB); however, radiologic assessment of tumors in bone is challenging. The study objective was to assess tumor response to denosumab using three different imaging parameters in a prespecified analysis in patients with GCTB from two phase 2 studies., Methods: The studies enrolled adults and adolescents (skeletally mature and at least 12 years of age) with radiographically measurable GCTB that were given denosumab 120 mg every 4 weeks, with additional doses on days 8 and 15 of cycle 1. The proportion of patients with an objective tumor response was assessed using either Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST), European Organisation for Research and Treatment of Cancer response criteria (positron emission tomography [PET] scan criteria), or inverse Choi density/size (ICDS) criteria. Target lesions were measured by computed tomography or magnetic resonance imaging (both studies), PET (study 2 only), or plain film radiograph (study 2 only)., Results: Most patients (71.6%) had an objective tumor response by at least one response criteria. Per RECIST, 25.1% of patients had a response; per PET scan criteria, 96.2% had a response; per ICDS, 76.1% had a response. 68.5% had an objective tumor response ≥ 24 weeks. Using any criteria, crude incidence of response ranged from 56% (vertebrae/skull) to 91% (lung/soft tissue), and 98.2% had tumor control ≥ 24 weeks. Reduced PET avidity appeared to be an early sign of response to denosumab treatment., Conclusion: Modified PET scan criteria and ICDS criteria indicate that most patients show responses and higher benefit rates than modified RECIST, and therefore may be useful for early assessment of response to denosumab., Trial Registration: ClinicalTrials.gov Clinical Trials Registry NCT00396279 (retrospectively registered November 6, 2006) and NCT00680992 (retrospectively registered May 20, 2008).

Background: Giant cell tumor of bone (GCTB) is an osteolytic, locally aggressive, rarely metastazing bone tumor. This is a retrospective study evaluating a large series of GCTB patients treated with denosumab in routine practice in 6 European reference centers., Methods: Patients with locally advanced, unresectable or metastatic GCTB, treated with denosumab outside clinical trials were eligible. Primary end-point was progression-free survival (PFS) for all patients; secondary end-points were: type of surgery, relapse rate and event-free survival for patients after preoperative denosumab + surgery., Results: We identified 138 patients treated in the period 2011-2016. In 40/43 cases the diagnosis was confirmed by H3F3A gene mutation. Median follow-up time was 23 months (range 6-48). Primary tumor was located in lower limb (38%) - mostly in femur and tibia, in upper limb (34%), and in pelvis/axial skeleton/ribs (28%). 110 (80%) patients had primary tumors, 28 (22%) recurrent tumors after previous surgical procedures (+/- radiotherapy). 89/138 patients had locally advanced GCTB and underwent neoadjuvant denosumab. The median denosumab treatment duration was 8 months (median number of cycles 11), 98% had clinical benefit from therapy. 39 (44%) had wide en-bloc resection - WE (+implantation of the prosthesis in 17 cases), the other 50 (56%) cases had intralesional curettage - C. Progression after surgical treatment was observed in 19 patients, 16 of them after C (32%); 13 patients underwent denosumab re-challenge, and all responded. Two-year progression-free survival (PFS; from denosumab start) rate was 81%; 2-year EventFS (from surgery) was significantly better in WE group (93%) vs 55% in C group (p = 0.006). Treatment was well tolerated with only 2 cases of grade 3 toxicity and one osteonecrosis of the jaw., Conclusion: Our retrospective study confirms that denosumab is extremely efficient in unresectable/metastatic disease as well as in a neoadjuvant setting. Our data confirm excellent efficacy and short-term tolerability of this drug. Our data suggest that neoadjuvant therapy with denosumab is the option for treatment of initially locally advanced tumors to facilitate complete surgical resection or avoid mutilating surgery. The risk of recurrences after curettage of GCTB following denosumab raises questions about the optimal management of such cases., (Copyright © 2018 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Introduction: As both anti-tumour effects and toxicity are thought to be dose-dependent, patients with the greatest toxicity may also have the best outcome. We assessed whether severity of doxorubicin-induced hematological toxicity is associated with outcome in advanced soft tissue sarcoma (STS) patients. In addition, risk factors for hematological toxicity were explored., Methods: Worst haematological toxicities (anaemia, leukopenia, neutropenia and thrombocytopenia) seen during treatment were scored according to CTCAE toxicity score. Differences in overall survival (OS), progression free survival (PFS) and response rate (RR) between patients with or without high haematological toxicity (grades 0-2 vs. 3-4) were assessed using conventional statistical tests. Associations between baseline characteristics and hematological toxicity were established using logistic multivariate regression., Results: In 557 patients eligible for this analysis, 47.2% of the patients received at least six cycles of treatment; 45% stopped treatment early due to progression, 3% because of toxicity. Relative dose intensity (RDI) was constant over the cycles. OS, PFS, and RR did not differ between patients with grade 3/4 toxicity during treatment versus those with grade 1/2. Risk factors for grade 3/4 haematological toxicity, in particular neutropenia, were age above 60 years, low BMI, and female gender., Conclusion: In this large series, risk factors for haematological toxicity in STS patients receiving doxorubicin monotherapy were revealed. The finding that there was no association between outcome and haematological toxicity during doxorubicin treatment may be useful to reassure advanced STS patients that failure to experience haematological toxicity during treatment does not equate to under-treatment.

Background: The Cooperative Ewing Sarcoma Study and the Late Effects Surveillance System of the Society for Paediatric Oncology and Haematology recommend a structured follow-up imaging protocol (FUIP) for patients with Ewing sarcoma (EwS) with decreasing frequency of imaging over the first 5 years. The present study aims to assess the effectiveness of the FUIP for EwS patients regarding survival after relapse., Patients and Methods: A retrospective multicenter analysis on 160 eligible patients with EwS recurrence was performed. Potential survival differences following recurrence diagnosis between patients with protocol-detected and symptomatic relapse were investigated using the Kaplan-Meier method. Additional subgroup analyses were performed on the relapse type. Overall survival (OS) was calculated from diagnosis of relapse to last follow-up or death., Results: In the multicenter analysis, recurrence was detected by FUIP in 77 of 160 patients (48%) and due to symptoms in 83 patients (52%). Regarding the entire study population, OS was significantly superior in patients with protocol-detected relapse compared to patients with symptomatic relapse (median, 2.4 vs. 1.2 years; P < 0.001). In the subgroup analyses, patients whose lung recurrences were detected by the FUIP experienced longer survival after recurrence than those whose recurrences were detected symptomatically (P = 0.023). In the 83 symptomatic patients, pain was the most prevalent symptom of relapse (72%)., Conclusion: FUIP may benefit survival in EwS relapse, especially in lung recurrence. Pain was the leading symptom of relapse., (© 2018 Wiley Periodicals, Inc.)

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., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: We designed the EURAMOS-1 trial to investigate whether intensified postoperative chemotherapy for patients whose tumour showed a poor response to preoperative chemotherapy (≥10% viable tumour) improved event-free survival in patients with high-grade osteosarcoma., Methods: EURAMOS-1 was an open-label, international, phase 3 randomised, controlled trial. Consenting patients with newly diagnosed, resectable, high-grade osteosarcoma aged 40 years or younger were eligible for randomisation. Patients were randomly assigned (1:1) to receive either postoperative cisplatin, doxorubicin, and methotrexate (MAP) or MAP plus ifosfamide and etoposide (MAPIE) using concealed permuted blocks with three stratification factors: trial group; location of tumour (proximal femur or proximal humerus vs other limb vs axial skeleton); and presence of metastases (no vs yes or possible). The MAP regimen consisted of cisplatin 120 mg/m 2 , doxorubicin 37·5 mg/m 2 per day on days 1 and 2 (on weeks 1 and 6) followed 3 weeks later by high-dose methotrexate 12 g/m 2 over 4 h. The MAPIE regimen consisted of MAP as a base regimen, with the addition of high-dose ifosfamide (14 g/m 2 ) at 2·8 g/m 2 per day with equidose mesna uroprotection, followed by etoposide 100 mg/m 2 per day over 1 h on days 1-5. The primary outcome measure was event-free survival measured in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00134030., Findings: Between April 14, 2005, and June 30, 2011, 2260 patients were registered from 325 sites in 17 countries. 618 patients with poor response were randomly assigned; 310 to receive MAP and 308 to receive MAPIE. Median follow-up was 62·1 months (IQR 46·6-76·6); 62·3 months (IQR 46·9-77·1) for the MAP group and 61·1 months (IQR 46·5-75·3) for the MAPIE group. 307 event-free survival events were reported (153 in the MAP group vs 154 in the MAPIE group). 193 deaths were reported (101 in the MAP group vs 92 in the MAPIE group). Event-free survival did not differ between treatment groups (hazard ratio [HR] 0·98 [95% CI 0·78-1·23]); hazards were non-proportional (p=0·0003). The most common grade 3-4 adverse events were neutropenia (268 [89%] patients in MAP vs 268 [90%] in MAPIE), thrombocytopenia (231 [78% in MAP vs 248 [83%] in MAPIE), and febrile neutropenia without documented infection (149 [50%] in MAP vs 217 [73%] in MAPIE). MAPIE was associated with more frequent grade 4 non-haematological toxicity than MAP (35 [12%] of 301 in the MAP group vs 71 [24%] of 298 in the MAPIE group). Two patients died during postoperative therapy, one from infection (although their absolute neutrophil count was normal), which was definitely related to their MAP treatment (specifically doxorubicin and cisplatin), and one from left ventricular systolic dysfunction, which was probably related to MAPIE treatment (specifically doxorubicin). One suspected unexpected serious adverse reaction was reported in the MAP group: bone marrow infarction due to methotrexate., Interpretation: EURAMOS-1 results do not support the addition of ifosfamide and etoposide to postoperative chemotherapy in patients with poorly responding osteosarcoma because its administration was associated with increased toxicity without improving event-free survival. The results define standard of care for this population. New strategies are required to improve outcomes in this setting., Funding: UK Medical Research Council, National Cancer Institute, European Science Foundation, St Anna Kinderkrebsforschung, Fonds National de la Recherche Scientifique, Fonds voor Wetenschappelijk Onderzoek-Vlaanderen, Parents Organization, Danish Medical Research Council, Academy of Finland, Deutsche Forschungsgemeinschaft, Deutsche Krebshilfe, Federal Ministry of Education and Research, Semmelweis Foundation, ZonMw (Council for Medical Research), Research Council of Norway, Scandinavian Sarcoma Group, Swiss Paediatric Oncology Group, Cancer Research UK, National Institute for Health Research, University College London Hospitals, and Biomedical Research Centre., (Copyright © 2016 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY license. Published by Elsevier Ltd.. All rights reserved.)

Ewing sarcoma (ES) is a form of primary bone cancer, with few treatment options for patients who develop relapse with an overall 5-year survival of 13%. New treatment options are needed and histone deacetylase (HDAC) inhibitors show encouraging results in preclinical studies. Our patient developed inoperable progressive lung metastases and was treated with the HDAC inhibitor panobinostat. During 18 months of treatment, no new lesions appeared; the treatment was stopped due to progression. This clinical observation warrants further evaluation of HDAC inhibitors in ES. Combination with chemotherapy and biomarker studies could improve the therapeutic index of these classes of compounds., (© 2016 Wiley Periodicals, Inc.)

Purpose of Review: The prognosis of patients with unresectable or metastatic chondrosarcoma of the bone is poor. Chondrosarcomas are in general resistant to chemotherapy and radiotherapy. This review discusses recent developments in the characterization of molecular pathways involved in the oncogenesis of chondrosarcoma that should be explored to improve prognosis of patients with advanced chondrosarcoma., Recent Findings: The different oncogenic pathways for chondrosarcoma have become better defined. These include alterations in pathways such as isocitrate dehydrogenase mutation, hedgehog signalling, the retinoblastoma protein and p53 pathways, apoptosis and survival mechanisms, and several tyrosine kinases. These specific alterations can be employed for use in clinical interventions in advanced chondrosarcoma., Summary: As many different genetic alterations in chondrosarcoma have been identified, it is of the utmost importance to classify druggable targets that may improve the prognosis of chondrosarcoma patients. In recent years an increased number of trials evaluating targeted therapies are being conducted. As chondrosarcoma is an orphan disease consequently all studies are performed with small numbers of patients. The results of clinical studies so far have been largely disappointing. Therapeutic intervention studies of these new targets emerging from preclinical studies are of highest importance to improve prognosis of chondrosarcoma patients with advanced disease.

Osteosarcoma is the most common primary malignant bone tumour. Patients often develop lung metastasis and have a poor prognosis despite extensive chemotherapy and surgical resections. Tissue Factor is associated with poor clinical outcome in a wide range of cancer types, and promotes angiogenesis and metastasis. The role of Tissue Factor in OS tumourigenesis is unknown. Fifty-three osteosarcoma pre-treatment biopsies and four osteosarcoma cell lines were evaluated for Tissue Factor expression, and a possible association with clinical parameters was investigated. Tissue Factor function was inhibited in an osteosarcoma cell line (143B) by shRNA knockdown or specific antibodies, and pro-tumourigenic gene expression, proliferation, matrigel invasion and transwell migration was examined. 143B cells were implanted in mice in the presence of Tissue Factor-blocking antibodies, and tumour volume, micro-vessel density and metastases in the lung were evaluated. Tissue Factor was highly expressed in 73.6 % of osteosarcoma biopsies, and expression associated significantly with disease-free survival. Tissue Factor was expressed in all four investigated cell lines. Tissue Factor was knocked down in 143B cells, which led to reduced expression of IL-8, CXCL-1, SNAIL and MMP2, but not MMP9. Tissue Factor knockdown or inhibition with antibodies reduced matrigel invasion. Tissue Factor antibodies limited 143B tumour growth in vivo, and resulted in decreased intra-tumoural micro-vessel density. Furthermore, lung metastasis from the primary tumour was significantly reduced. Thus, Tissue Factor expression in osteosarcoma reduces metastasis-free survival in patients, and increases pro-tumourigenic behaviour both in vitro and in vivo.

Objective: Irreversible hearing loss is a frequent side effect of the chemotherapeutic agent cisplatin and shows considerable interpatient variability. The variant rs1872328 in the ACYP2 gene was recently identified as a risk factor for the development of cisplatin-induced ototoxicity in children with brain tumors. We aimed to replicate this finding in patients with osteosarcoma., Methods: An independent cohort of 156 patients was genotyped for the rs1872328 variant and evaluated for the presence of cisplatin-induced ototoxicity., Results: A significant association was observed between carriership of the A allele and cisplatin-induced ototoxicity after the end of treatment (P=0.027)., Conclusion: This is the first study replicating the association of ACYP2 variant rs1872328 with cisplatin-induced ototoxicity in patients with osteosarcoma who did not receive potentially ototoxic cranial irradiation. Hence, the ACYP2 variant should be considered a predictive pharmacogenetic marker for hearing loss, which may be used to guide therapies for patients treated with cisplatin.

Objective: To evaluate the efficacy of enzalutamide (Enz) as fourth- or fifth-line treatment in men with metastasized castration-resistant prostate cancer (mCRPC), by analyzing a retrospective cohort of heavily pretreated patients., Methods: We evaluated toxicity, overall survival (OS), progression-free survival (PFS) and time to prostate-specific antigen (PSA) progression data from 47 CRPC patients treated with fourth- or fifth-line Enz., Results: All patients were treated with docetaxel and abiraterone acetate and 42 patients (89%) with cabazitaxel. The median age of the patients was 69 years (IQR, 63-73.5), 79% had bone metastases, 55% had lymph node metastases, and 17% had visceral metastases. The median duration of Enz treatment was 12.0 weeks (IQR, 8.3-20.4), and 11 patients (23%) responded to Enz (maximum PSA decline ≥50%). In general, Enz was well tolerated, with the most frequently reported adverse events being fatigue and nausea. The median OS was 40.1 weeks (95% CI, 25.4-61.4), the median PFS was 12.1 weeks (95% CI, 9.9-14.0) and the median time to PSA progression was 15.7 weeks (95% CI, 14.0-28.7)., Conclusions: Analysis of this retrospective cohort suggests that Enz is well tolerated and that there is a 23% response rate in heavily pretreated CRPC patients, which is comparable with third-line treatment outcomes., (© 2016 S. Karger AG, Basel.)

Background: In the last three decades the outcome for patients with localised Ewing sarcoma (ES) has improved significantly since the introduction of multimodality primary treatment. However, for patients with (extra-) pulmonary metastatic and/or non-resectable relapsed disease the outcome remains poor and new treatment options are urgently needed. Currently the insulin-like growth factor 1 receptor (IGF-1R) pathway and the poly-ADP(adenosinediphosphate)-ribose-polymerase (PARP) pathway are being investigated for potential targeted therapies. IGF-1R: The IGF-1R pathway is known to be deregulated by the EWSR1-FLI1 translocation which makes it a potential target for therapy. Clinical trials have been reported in which only ES patients were treated with an IGF-1R inhibitor, either as single agent or in combination. In total 291 ES patients were included in these trials, in which two (0.7%) complete responses, 32 (11%) partial responses of which some durable, and 61 (21%) stable diseases were observed. PARP: In the presence of a PARP inhibitor DNA strand breaks cannot be efficiently repaired, leading to cell death. The first phase II trial with ES patients was recently published and showed no clinical responses, which may have been due to the drug being non-effective as a single agent., Discussion: The IGF-1R pathway is an interesting target for ES and should be explored further, as biomarkers to select patients that might benefit from treatment are lacking. PARP inhibitors as single agent have so far failed to show improvement in outcome. Future directions include dual insulin receptor/IGF-1R blockade with linsitinib as well as chemotherapy-PARP combinations. Both therapeutic strategies are currently being explored., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Based on the randomised Euro-EWING99-R1 trial, vincristine, adriamycin, cyclophosphamide (VAC) may be able to replace vincristine, adriamycin, ifosfamide (VAI) in the treatment of standard-risk Ewing sarcoma. However some heterogeneity of treatment effect by gender was observed. The current exploratory study aimed at investigating the influence of gender on treatment efficacy and acute toxicity., Patients and Methods: Impact of gender on event-free survival (EFS), acute toxicity by course, switches between treatment arms and cumulative dose of alkylating agents was evaluated in multivariable models adjusted for age including terms to test for heterogeneity of treatment effect by gender. The analysis of the EFS was performed on the intention-to-treat population., Results: EFS did not significantly differ between the 509 males and 347 females (p=0.33), but an interaction in terms of efficacy was suspected between treatment and gender (p=0.058): VAC was associated with poorer EFS than VAI in males, hazard ratio (HR) (VAC/VAI)=1.37 [95% confidence interval (CI), 0.98-1.90], contrasting with HR=0.81 [95%CI, 0.53-1.24] in females. Severe toxicity was more frequent in females, whatever the toxicity type. Thirty patients switched from VAI to VAC (9/251 males, 4%, and 21/174 females, 12%) mostly due to renal toxicity, and three from VAC to VAI (2/258 males, 0.8%, and 1/173 females, 0.6%). A reduction of alkylating agent cumulative dose >20% was more frequent in females (15% versus 9%, p=0.005), with no major difference between VAC and VAI (10% versus 13%, p=0.15)., Conclusion: Differences of acute toxicity rate and cumulative doses of alkylating agents could not explain the marginal interaction observed in the Euro-EWING99-R1 trial data. Effects of gender-dependent polymorphism/activity of metabolic enzymes (e.g. known for CYP2B6) of ifosfamide versus cyclophosphamide should be explored. External data are required to further evaluate whether there is heterogeneity of alkylating agent effect by gender., Trial Numbers: NCT00987636 and EudraCT 2008-003658-13., (Copyright © 2015 Elsevier Ltd. All rights reserved.)