Bone sarcomas: ESMO–EURACAN–GENTURIS–ERN PaedCan Clinical Practice Guideline for diagnosis, treatment and follow-up

•This Clinical Practice Guideline provides key recommendations on the management of bone sarcomas.•Recommendations have been agreed following a consensus meeting of representatives from ESMO, EURACAN, GENTURIS and ERNPaedCan.•Authorship includes a multidisciplinary group of experts from different institutions and countries worldwide. Primary bone sarcomas (BSs) account for <0.2% of malignant neoplasms across all ages.1Gatta G. Capocaccia R. Botta L. et al.Burden and centralised treatment in Europe of rare tumours: results of RARECAREnet-a population-based study.Lancet Oncol. 2017; 18: 1022-1039Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar The overall incidence rate ranges between 0.8 and 0.9 cases per 100 000/year, with single BS types having no more than 0.3 incident cases per 100 000/year. Osteosarcoma and Ewing sarcoma (ES) have a relatively high incidence in the second decade of life, whereas conventional chondrosarcomas are more common in older age.2de Pinieux G. Karanian M. Le Loarer F. et al.Nationwide incidence of sarcomas and connective tissue tumors of intermediate malignancy over four years using an expert pathology review network.PLoS One. 2021; 16 (e0246958)Crossref PubMed Scopus (42) Google Scholar Osteosarcoma is the most common BS (incidence: 0.3/100 000/year). The incidence is higher in adolescents (0.8-1.1/100 000/year at age 15-19 years) but there is a significant second peak in the seventh and eighth decades of life.1Gatta G. Capocaccia R. Botta L. et al.Burden and centralised treatment in Europe of rare tumours: results of RARECAREnet-a population-based study.Lancet Oncol. 2017; 18: 1022-1039Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar,2de Pinieux G. Karanian M. Le Loarer F. et al.Nationwide incidence of sarcomas and connective tissue tumors of intermediate malignancy over four years using an expert pathology review network.PLoS One. 2021; 16 (e0246958)Crossref PubMed Scopus (42) Google Scholar The male to female ratio is 1.4 : 1. In younger patients, most osteosarcomas arise in extremities, whereas the proportion of axial tumour sites increases with age. Risk factors for the occurrence of osteosarcoma include previous radiotherapy (RT), Paget disease of the bone and germline genetic abnormalities associated with Li–Fraumeni syndrome, Werner syndrome, Rothmund–Thomson syndrome, Bloom syndrome and hereditary retinoblastoma.3Fuchs B. Pritchard D.J. Etiology of osteosarcoma.Clin Orthop Relat Res. 2002; 397: 40-52Crossref PubMed Scopus (185) Google Scholar ES is a round cell sarcoma (RCS) marked by a gene fusion involving a member of the FET family and a member of the ETS family of transcription factors. ES is the third most common BS (incidence: ∼0.1/100 000/year) and occurs most frequently in children and adolescents but is also seen in adults. Median age at diagnosis is 15 years and there is a male predominance. The most common ES primary sites are the extremity bones (50%), followed by pelvis, ribs and vertebrae. Any bone can potentially be affected, however, a soft tissue origin is also possible, especially in adults (30% of cases). ES is currently regarded as distinct from rarer and recently identified entities such as RCS with EWSR1 non-ETS fusions, CIC-rearranged sarcomas and sarcomas with BCOR alteration.4WHO Classification of Tumours Editorial BoardSoft Tissue and Bone Tumours.5th ed. IARC Publications, Lyon2020Google Scholar Among RCSs with EWSR1 non-ETS fusions, EWSR1-NFATC2 is the commonest, has a strong male predominance, affects an older population and occurs mainly in bone.5Diaz-Perez J.A. Nielsen G.P. Antonescu C. et al.EWSR1/FUS-NFATc2 rearranged round cell sarcoma: clinicopathological series of 4 cases and literature review.Hum Pathol. 2019; 90: 45-53Crossref PubMed Scopus (36) Google Scholar CIC-rearranged sarcomas mostly arise from soft tissues and are rare in bone.6Antonescu C.R. Owosho A.A. Zhang L. et al.Sarcomas with CIC-rearrangements are a distinct pathologic entity with aggressive outcome: a clinicopathologic and molecular study of 115 cases.Am J Surg Pathol. 2017; 41: 941-949Crossref PubMed Scopus (189) Google Scholar Among RCSs with BCOR alterations, the BCOR-CCNB3 variant occurs mainly in the bones and predominantly affects paediatric patients, whereas BCOR with internal tandem duplication has been described in soft tissue tumours of infancy.7Kao Y.C. Owosho A.A. Sung Y.S. et al.BCOR-CCNB3 fusion positive sarcomas: a clinicopathologic and molecular analysis of 36 cases with comparison to morphologic spectrum and clinical behavior of other round cell sarcomas.Am J Surg Pathol. 2018; 42: 604-615Crossref PubMed Scopus (139) Google Scholar,8Kao Y.C. Sung Y.S. Zhang L. et al.Recurrent BCOR internal tandem duplication and YWHAE-NUTM2B fusions in soft tissue undifferentiated round cell sarcoma of infancy: overlapping genetic features with clear cell sarcoma of kidney.Am J Surg Pathol. 2016; 40: 1009-1020Crossref PubMed Scopus (122) Google Scholar Conventional chondrosarcoma is the most frequent BS of adulthood (incidence: ∼0.2/100 000/year), with a median age at diagnosis between 30 and 60 years and no gender predominance.1Gatta G. Capocaccia R. Botta L. et al.Burden and centralised treatment in Europe of rare tumours: results of RARECAREnet-a population-based study.Lancet Oncol. 2017; 18: 1022-1039Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar Dedifferentiated chondrosarcoma (DCS), mesenchymal chondrosarcoma (MCS) and clear-cell chondrosarcoma are ultra-rare chondrosarcoma subtypes, with an incidence of <0.1/100 000/year. Extraskeletal myxoid chondrosarcoma, although originally thought to be a cartilaginous neoplasm, does not show cartilage differentiation and is classified as a mesenchymal tumour of uncertain differentiation. This is covered by the European Society for Medical Oncology-European Reference Network for Rare Adult Solid Cancers-European Reference Network for Genetic Tumour Risk Syndromes (ESMO-EURACAN-GENTURIS) Clinical Practice Guideline (CPG) on soft tissue sarcomas (STSs).9Gronchi A. Miah A.B. Dei Tos A.P. et al.Soft tissue and visceral sarcomas: ESMO-EURACAN-GENTURIS Clinical Practice Guidelines for diagnosis, treatment and follow-up.Ann Oncol. 2021; 32: 1348-1365Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar Conventional chordomas are even rarer than other types of BS, with an incidence of approximately 0.08/100 000/year and a median age at diagnosis of 60 years. There is a slight male predominance. Dedifferentiated and poorly differentiated chordomas are ultra-rare subtypes.1Gatta G. Capocaccia R. Botta L. et al.Burden and centralised treatment in Europe of rare tumours: results of RARECAREnet-a population-based study.Lancet Oncol. 2017; 18: 1022-1039Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar,10Frezza A.M. Botta L. Trama A. et al.Chordoma: update on disease, epidemiology, biology and medical therapies.Curr Opin Oncol. 2019; 31: 114-120Crossref PubMed Scopus (36) Google Scholar Giant cell tumour of bone (GCTB) is locally aggressive, rarely metastasising and represents 5% of primary bone tumours, with an incidence of ∼1/1 000 000/year.1Gatta G. Capocaccia R. Botta L. et al.Burden and centralised treatment in Europe of rare tumours: results of RARECAREnet-a population-based study.Lancet Oncol. 2017; 18: 1022-1039Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar High-grade spindle/pleomorphic sarcomas of bone are a heterogeneous group of primary malignant bone tumours that do not fulfil the histological criteria for a diagnosis of osteosarcoma, chondrosarcoma or ES.11Sbaraglia M. Righi A. Gambarotti M. et al.Soft tissue tumors rarely presenting primary in bone; diagnostic pitfalls.Surg Pathol Clin. 2017; 10: 705-730Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar A general diagnostic strategy for BS is shown in Figure 1. The presence of persistent and often progressive non-mechanical bone pain, predominantly at night, should prompt a radiological assessment. Swelling and functional impairment can be present if the tumour has progressed through the cortex and distended the periosteum, but these are often later signs. The differential diagnoses of a BS include osteomyelitis, benign tumours and bone metastases, all of which outnumber primary BS. The diagnosis can be strongly oriented by patient age. For patients <5 years old, a destructive bone lesion could be interpreted predominantly as either metastatic neuroblastoma or Langerhans cell histiocytosis. For patients aged ≥5 years, the likelihood of a primary BS is higher. After 40 years of age, bone metastases and myeloma will be the most common diagnoses. Conventional radiography in two planes is the first radiological investigation. When the diagnosis of malignancy cannot be definitely excluded on radiographs, magnetic resonance imaging (MRI) of the whole compartment with adjacent joints should be carried out. MRI is currently regarded as the best modality for local staging for tumours of the extremities, spine and pelvis. Computed tomography (CT) may provide additional information on bone involvement (presence of calcification, periosteal bone formation and cortical destruction) and can be chosen as the preferred imaging modality for other primary sites. All patients with a bone lesion which is suspected to be a primary BS on a radiological basis should be referred to a BS reference centre or to an institution belonging to a sarcoma network.12Blay J.Y. Soibinet P. Penel N. et al.Improved survival using specialized multidisciplinary board in sarcoma patients.Ann Oncol. 2017; 28: 2852-2859Abstract Full Text Full Text PDF PubMed Scopus (146) Google Scholar Children and adolescents should be referred to centres that, in addition, provide age-specific expertise. The biopsy of a suspected primary BS should be carried out by either the surgical team who will carry out the definitive tumour resection or by a dedicated interventional radiologist after discussing with the surgeon.12Blay J.Y. Soibinet P. Penel N. et al.Improved survival using specialized multidisciplinary board in sarcoma patients.Ann Oncol. 2017; 28: 2852-2859Abstract Full Text Full Text PDF PubMed Scopus (146) Google Scholar For those patients whose pathological diagnosis was obtained outside a reference network, an expert pathological review in a sarcoma reference centre is mandatory. In most patients, a core-needle biopsy, taken under imaging guidance, represents an appropriate alternative to open biopsy. Contamination of surrounding tissue should be minimised, and adequate multiple sampling of representative areas must always be provided. If required, an open biopsy should be carried out using a longitudinal incision. In aggressive and malignant bone tumours, the biopsy tract and the channels through which drains have been placed must be considered potentially contaminated and must later be removed, together with the resection specimen, in an effort to minimise the risk of a local recurrence (LR). Therefore, biopsy tracts should be clearly marked to ensure that the location is recognised at the time of the definitive procedure. In case of spinal column involvement, laminectomy or decompression should be avoided unless necessary to relieve spinal cord compression, and tissue sampling must be carried out whenever a BS is suspected. Histology specimens must be interpreted by an experienced bone tumour pathologist, in collaboration with the radiologist, and discussed in a multidisciplinary team (MDT). With the increasing capability for accurate molecular diagnosis, samples should be quickly submitted for pathological assessment.13Bovee J.A.F. Baumhoer D. Bloem J.L. et al.Primary tumour in bone histopathology reporting guide biopsy specimens. International Collaboration on Cancer Reporting; Sydney, Australia.http://www.iccr-cancer.org/datasets/published-datasets/soft-tissue-boneDate: 2021Google Scholar The collection of fresh snap-frozen tissue is encouraged to overcome damage to nucleic acids resulting from decalcification, and to allow subsequent molecular assessment. The nature of the bone specimen received for pathology reporting should be recorded (i.e. needle biopsy, curettage or excision). It is usually necessary to decalcify the bone tumour biopsy. EDTA is preferred over acid-based methods; in case of the latter, sampling frozen tissue is essential to allow molecular diagnostics. Tumour type must be diagnosed according to the most recent version of the World Health Organization (WHO) classification for tumours of soft tissue and bone (2020).4WHO Classification of Tumours Editorial BoardSoft Tissue and Bone Tumours.5th ed. IARC Publications, Lyon2020Google Scholar It is important to note that for BS, the histotype determines the histological grade, with few exceptions.4WHO Classification of Tumours Editorial BoardSoft Tissue and Bone Tumours.5th ed. IARC Publications, Lyon2020Google Scholar The results of ancillary investigations (e.g. immunohistochemistry or molecular assessments) should be accurately recorded whenever relevant. Examples include translocation detection in RCS and MCS, isocitrate dehydrogenase (IDH1 and IDH2) mutations in conventional chondrosarcoma and MDM2 amplification in parosteal and intramedullary low-grade osteosarcoma. At the time of the resection of the primary tumour, for surgical specimens, the size of the tumour in the resected bone should be recorded (at least the maximal diameter, but preferably three-dimensional measurement, in mm). The pathology report should describe the extent of local tumour spread, including involvement of specific anatomical soft tissue and bone compartments. It should be recorded whether the resection margins are either clear (R0) or microscopically (R1) or macroscopically (R2) involved. In case of negative margins, the distance (in mm) of tumour from the nearest resection margin as well as the distance to the closest osteotomy margin should be measured. A complete, representative slab of the tumour, usually through its largest dimension in the longitudinal axis as guided by the radiological images, should be embedded for microscopy in a grid manner. This is especially relevant after neoadjuvant chemotherapy (ChT) to assess response. The percentage of viable tumour/percentage of histological response (including necrosis, fibrosis and calcification) should be documented, as this has prognostic value, especially in ES and osteosarcoma. In osteosarcoma, a cut-off value of 10% viable tumour cells or ≥90% response is used to indicate a good response.14Picci P. Bacci G. Campanacci M. et al.Histologic evaluation of necrosis in osteosarcoma induced by chemotherapy. Regional mapping of viable and nonviable tumor.Cancer. 1985; 56: 1515-1521Crossref PubMed Scopus (205) Google Scholar For ES, the cut-off is less well defined. Recent studies suggest that 100% response is most optimal to define a good tumour response in ES.15Albergo J.I. Gaston C.L. Laitinen M. et al.Ewing's sarcoma: only patients with 100% of necrosis after chemotherapy should be classified as having a good response.Bone Joint J. 2016; 98-B: 1138-1144Crossref PubMed Google Scholar Earlier reports, however, define good response between 90% and 100% necrosis, fibrosis and calcification.16Akerman M. Tumour necrosis and prognosis in Ewing's sarcoma.Acta Orthop Scand Suppl. 1997; 273: 130-132Crossref PubMed Google Scholar,17Righi A. Pacheco M. Palmerini E. et al.Histological response to neoadjuvant chemotherapy in localized Ewing sarcoma of the bone: a retrospective analysis of available scoring tools.Eur J Surg Oncol. 2021; 47: 1778-1783Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar •The initial work-up of a suspected primary BS tumour should be carried out at a sarcoma reference centre, and should include medical history, physical examination, radiological assessment and biopsy [IV, B].•Pathological diagnosis should be made by a bone tumour expert dedicated pathologist according to the 2020 WHO classification and should be supported by ancillary investigations whenever relevant [IV, A].•For surgical specimens, tumour size and local extent of spread, site, status of surgical margins and percentage of pathological response to preoperative ChT should be described [V, B]. Several staging systems for BS are in use, with no unifying system accepted as standard.18Enneking W.F. Spanier S.S. Goodman M.A. A system for the surgical staging of musculoskeletal sarcoma.Clin Orthop Relat Res. 1980; 153: 106-120Crossref PubMed Scopus (1780) Google Scholar, 19American Joint Committee on CancerAJCC Cancer Staging Manual.8th ed. American Joint Committee on Cancer, New York2017Google Scholar, 20Brierley J.D. Gospodarowicz M.K. Wittekind C. TNM Classification of Malignant Tumours. 8th ed. John Wiley & Sons, Oxford2016Google Scholar Tumour burden and the presence of detectable metastases are the two main factors taken into consideration in the clinical staging of these diseases. General staging should be carried out to assess the extent of distant disease, including bone scintigraphy and dedicated chest CT. Whole-body (WB)-MRI and [18F]2-fluoro-2-deoxy-d-glucose (FDG)–positron emission tomography (PET)-CT or PET-MRI are increasingly utilised for staging of bone and bone marrow metastases (including skip bone lesions). Additional appropriate imaging studies and biopsies can be taken from suspicious sites. No specific laboratory tests for the diagnosis of BS are routinely available. Baseline serum analysis in ES and osteosarcoma should include alkaline phosphatase (AP) and lactate dehydrogenase (LDH) given their proven prognostic value and their use as response monitoring during treatment. Prognostic features also include clinical presentation; a pathological fracture may lead to the dissemination of tumour cells into surrounding tissues and increase the risk of recurrence, especially in osteosarcoma. ChT for BS can result in renal, cardiac and auditory dysfunction. Before starting therapy, baseline renal function testing, assessment of cardiac function and an audiogram (in the case of platinum derivatives) should be carried out. Sperm storage is recommended for male patients of reproductive age. For female patients, consultation with a fertility physician about potential ovarian sampling, cryopreservation, use of gonadotrophin-releasing hormone agonists and other means of ovarian suppression for fertility preservation should be considered, where available. There is still, however, limited scientific knowledge on gonadotoxic effects of the different ChT used and variability of health care policies across nations. Additional guidance on germline TP53 testing in osteosarcoma is provided in the Supplementary Material and in Supplementary Table S1, available at https://doi.org/10.1016/j.annonc.2021.08.1995. •General staging should be carried out to assess the extent of distant disease, including chest CT, bone scintigraphy and/or WB-MRI and and/or FDG–PET-CT/MRI as clinically indicated. Baseline serum analysis in ES and osteosarcoma should include AP and LDH levels [III, B]. Given their rarity and the complexity of management, the accepted standard for BS is treatment at reference centres and/or within reference networks able to provide access to the full spectrum of care and age-specific expertise [III, A]. In these centres/networks, therapy is usually given within either the framework of prospective, often collaborative, clinical studies or established treatment protocols. Supplementary Table S2, available at https://doi.org/10.1016/j.annonc.2021.08.1995 lists systemic agents that have been associated with preliminary or partial evidence of activity in BSs; however, they have not entered standard practice and/or they are not approved/reimbursed in all European countries. Thus, if available, their use may be considered depending on the clinical context with individualised patient–physician shared decisions. The principles for the treatment of osteosarcoma and ES are summarised in Figure 2. Osteosarcoma usually arises in the metaphysis of a long bone, most commonly around the knee, in children and adolescents.2de Pinieux G. Karanian M. Le Loarer F. et al.Nationwide incidence of sarcomas and connective tissue tumors of intermediate malignancy over four years using an expert pathology review network.PLoS One. 2021; 16 (e0246958)Crossref PubMed Scopus (42) Google Scholar Involvement of the axial skeleton and craniofacial bones is primarily observed in adult patients. High-grade osteosarcoma patients frequently develop metastases with the lung being the most frequent metastatic site followed by distant bones. The diagnosis of osteosarcoma is based on morphological findings, and no specific diagnostic molecular tests are available. Conventional osteosarcoma is always high-grade. Periosteal osteosarcoma is intermediate-grade and often chondroblastic. Low-grade central osteosarcoma and parosteal osteosarcoma are low-grade malignancies, arising intramedullary and from the bone surface, respectively. These malignancies can sometimes show high-grade components.21Ruengwanichayakun P. Gambarotti M. Frisoni T. et al.Parosteal osteosarcoma: a monocentric retrospective analysis of 195 patients.Hum Pathol. 2019; 91: 11-18Crossref PubMed Scopus (13) Google Scholar In the case of parosteal osteosarcoma with limited low-grade component, the differential diagnosis with conventional osteosarcoma can be helped by the detection of MDM2 amplification, which is present in >85% of cases.22Duhamel L.A. Ye H. Halai D. et al.Frequency of Mouse Double Minute 2 (MDM2) and Mouse Double Minute 4 (MDM4) amplification in parosteal and conventional osteosarcoma subtypes.Histopathology. 2012; 60: 357-359Crossref PubMed Scopus (51) Google Scholar Adverse prognostic factors for conventional osteosarcoma include primary metastases, axial or proximal extremity tumour site, large tumour volume, elevated serum AP or LDH levels and older age [III, B].23Smeland S. Bielack S.S. Whelan J. et al.Survival and prognosis with osteosarcoma: outcomes in more than 2000 patients in the EURAMOS-1 (European and American Osteosarcoma Study) cohort.Eur J Cancer. 2019; 109: 36-50Abstract Full Text Full Text PDF PubMed Scopus (198) Google Scholar Curative treatment of high-grade osteosarcoma consists of ChT and surgery [II, A]. Compared with surgery alone, multimodality management with ChT and surgery for high-grade, localised osteosarcoma increases disease-free survival (DFS) probability from <20% to >60%. In general, ChT is administered before and after surgery, although there is no evidence that giving preoperative ChT improves survival, as long as ChT is administered. It allows the assessment of histological response to preoperative ChT, however, which predicts survival.23Smeland S. Bielack S.S. Whelan J. et al.Survival and prognosis with osteosarcoma: outcomes in more than 2000 patients in the EURAMOS-1 (European and American Osteosarcoma Study) cohort.Eur J Cancer. 2019; 109: 36-50Abstract Full Text Full Text PDF PubMed Scopus (198) Google Scholar Surgery should be carried out by a surgical team familiar with the wide range of surgical reconstructions. Paediatric and adolescent patients need to be treated by surgeons with experience in the field of paediatric bone tumours, including age-specific reconstruction challenges, such as the reconstruction of growing bones. Most patients should be considered candidates for limb salvage. R1 and R2 margins both increase the LR rate, which is associated with reduced overall survival (OS). Thus, clear margins are the first goal of surgery [III, B]. Areas where there is suspicion of close margins should be marked on the surgical specimen sent to pathology. In cases of fracture, internal fixation is contraindicated as it disseminates the tumour further into both bone and soft tissues and increases the risk of LR. External splintage is recommended. Pathological fracture does not necessarily require an amputation. Primary neoadjuvant ChT can be used with the expectation that it will allow the fracture haematoma to contract and allow subsequent resection of the tumour and the involved soft tissues. Doxorubicin, cisplatin, high-dose methotrexate (HD-MTX) and ifosfamide have antitumour activity in osteosarcoma [I, A].24Marina N.M. Smeland S. Bielack S.S. et al.Comparison of MAPIE versus MAP in patients with a poor response to preoperative chemotherapy for newly diagnosed high-grade osteosarcoma (EURAMOS-1): an open-label, international, randomised controlled trial.Lancet Oncol. 2016; 17: 1396-1408Abstract Full Text Full Text PDF PubMed Scopus (252) Google Scholar, 25Whelan J.S. Bielack S.S. Marina N. et al.EURAMOS-1, an international randomised study for osteosarcoma: results from pre-randomisation treatment.Ann Oncol. 2015; 26: 407-414Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar, 26Ferrari S. Smeland S. Mercuri M. et al.Neoadjuvant chemotherapy with high-dose Ifosfamide, high-dose methotrexate, cisplatin, and doxorubicin for patients with localized osteosarcoma of the extremity: a joint study by the Italian and Scandinavian Sarcoma Groups.J Clin Oncol. 2005; 23: 8845-8852Crossref PubMed Scopus (359) Google Scholar, 27Bajpai J. Chandrasekharan A. Talreja V. et al.Outcomes in non-metastatic treatment naive extremity osteosarcoma patients treated with a novel non-high dosemethotrexate-based, dose-dense combination chemotherapy regimen ‘OGS-12’.Eur J Cancer. 2017; 85: 49-58Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar The doxorubicin/cisplatin/HD-MTX (MAP) regimen is most frequently used as front-line ChT in children and young adult patients;24Marina N.M. Smeland S. Bielack S.S. et al.Comparison of MAPIE versus MAP in patients with a poor response to preoperative chemotherapy for newly diagnosed high-grade osteosarcoma (EURAMOS-1): an open-label, international, randomised controlled trial.Lancet Oncol. 2016; 17: 1396-1408Abstract Full Text Full Text PDF PubMed Scopus (252) Google Scholar, 25Whelan J.S. Bielack S.S. Marina N. et al.EURAMOS-1, an international randomised study for osteosarcoma: results from pre-randomisation treatment.Ann Oncol. 2015; 26: 407-414Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar, 26Ferrari S. Smeland S. Mercuri M. et al.Neoadjuvant chemotherapy with high-dose Ifosfamide, high-dose methotrexate, cisplatin, and doxorubicin for patients with localized osteosarcoma of the extremity: a joint study by the Italian and Scandinavian Sarcoma Groups.J Clin Oncol. 2005; 23: 8845-8852Crossref PubMed Scopus (359) Google Scholar however, HD-MTX can be challenging to administer in adults.27Bajpai J. Chandrasekharan A. Talreja V. et al.Outcomes in non-metastatic treatment naive extremity osteosarcoma patients treated with a novel non-high dosemethotrexate-based, dose-dense combination chemotherapy regimen ‘OGS-12’.Eur J Cancer. 2017; 85: 49-58Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar,28Piperno-Neumann S. Ray-Coquard I. Occean B.V. et al.Results of API-AI based regimen in osteosarcoma adult patients included in the French OS2006/Sarcome-09 study.Int J Cancer. 2020; 146: 413-423Crossref PubMed Scopus (10) Google Scholar In patients aged >40 years, the use of MTX (8 g/m2) after a poor response to non-MTX induction ChT was proved to be feasible, and regimens combining doxorubicin, cisplatin and potentially ifosfamide are an alternative.24Marina N.M. Smeland S. Bielack S.S. et al.Comparison of MAPIE versus MAP in patients with a poor response to preoperative chemotherapy for newly diagnosed high-grade osteosarcoma (EURAMOS-1): an open-label, international, randomised controlled trial.Lancet Oncol. 2016; 17: 1396-1408Abstract Full Text Full Text PDF PubMed Scopus (252) Google Scholar, 25Whelan J.S. Bielack S.S. Marina N. et al.EURAMOS-1, an international randomised study for osteosarcoma: results from pre-randomisation treatment.Ann Oncol. 2015; 26: 407-414Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar, 26Ferrari S. Smeland S. Mercuri M. et al.Neoadjuvant chemotherapy with high-dose Ifosfamide, high-dose methotrexate, cisplatin, and doxorubicin for patients with localized osteosarcoma of the extremity: a joint study by the Italian and Scandinavian Sarcoma Groups.J Clin Oncol. 2005; 23: 8845-8852Crossref PubMed Scopus (359) Google Scholar,29Ferrari S. Bielack S.S. Smeland S. et al.EURO-B.O.S.S.: a European study on chemotherapy in bone-sarcoma patients aged over 40: outcome in primary high-grade osteosarcoma.Tumori. 2018; 104: 30-36Crossref PubMed Scopus (51) Google Scholar Most current protocols for localised disease include a period of preoperative ChT, to facilitate local surgical treatment and to allow the assessment of histological response, although there is no evidence to support a change in ChT based on this alone.24Marina N.M. Smeland S. Bielack S.S. et al.Comparison of MAPIE versus MAP in patients with a poor response to preoperative chemotherapy for newly diagnosed high-grade osteosarcoma (EURAMOS-1): an open-label, international, randomised controlled trial.Lancet Oncol. 2016; 17: 1396-1408Abstract Full Text Full Text PDF PubMed Scopus (252) Google Scholar, 25Whelan J.S. Bielack S.S. Marina N. et al.EURAMOS-1, an international randomised study for osteosarcoma: results from pre-randomisation treatment.Ann Oncol. 2015; 26: 407-414Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar, 26Ferrari S. Smeland S. Mercuri M. et al.Neoadjuvant chemotherapy with high-dose Ifosfamide, high-dose methotrexate, cisplatin, and doxorubicin for patients with localized osteosarcoma of the extremity: a joint study by the Italian and Scandinavian Sarcoma